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Aim: The aim of this study was to understand the provision and need, quality of and trust in COVID-19 vaccines information from the perspectives of people who have had COVID-19 infection.Method: People who have had a COVID-19 infection were approached via their general practice and invited to participate in the Nivel Corona Cohort. They completed questionnaires at baseline (Q1), and at three months (Q2). Outcome measures were based on health information-seeking behaviour, as used in the Comprehensive Model of Information Seeking. Antecedents (i.e., gender, age, education level, health literacy) were used from Q1, and one's beliefs and experiences (i.e., trust in the information and healthcare system, how applicable the information is), information carrier factors (i.e., information quality perceptions and via which sources), health-information seeking actions (i.e., decision to vaccinate and information sufficiency) and vaccination status from Q2. Data were analysed using descriptive analyses, analysis of variance tests (F-tests) and χ2 tests with the statistical software STATA.Results: Of the respondents (N = 314), 96% were vaccinated at least once, mostly after having had the virus. Most retrieved information about COVID-19 vaccines on the website of the National Institute for Public Health and the Environment (79%), broader via the internet (56%), or from family and friends (35%). Almost all had trust in the information (89%) and healthcare system (94%). Most found the information applicable to their situation (67%). Moreover, most perceived the information as correct (71%) and did not perceive the information to be misleading (85%), while fewer people found the information reliable (59%) and clear (58%). Overall, the majority indicated that the information met their expectations to make a well-informed decision to vaccinate (89%).Conclusion: Different characteristics of people who had COVID-19 and sought information were identified, which is important to offer tailored information. People who had COVID-19 in this study, mainly middle-aged, vaccinated and highly educated, were generally positive about the vaccines information, but overall the reliability and clarity could be improved. This is important for a high vaccination uptake, booster programs and coming pandemics.Patient or public contribution: The questionnaire was reviewed by patients who had COVID-19, one of whom is a health services researcher.

Introduction: The use of benzodiazepines and/or z-drugs in women of childbearing age has increased. Objective: The aim of the study was to evaluate whether gestational benzodiazepine and/or z-drug exposure is associated with adverse birth and neurodevelopmental outcomes. Methods: A population-based cohort including mother-child pairs from 2001 to 2018 in Hong Kong was analysed to compare gestationally exposed and nonexposed children on the risk of preterm birth, small for gestational age, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) through logistic/Cox proportional hazards regression with a 95% confidence interval (CI). Sibling-matched analyses and negative control analyses were applied. Results: When comparing gestationally exposed with gestationally nonexposed children, the weighted odds ratio (wOR) was 1.10 (95% CI = 0.97–1.25) for preterm birth and 1.03 (95% CI = 0.76–1.39) for small for gestational age, while the weighted hazard ratio (wHR) was 1.40 (95% CI = 1.13–1.73) for ASD and 1.15 (95% CI = 0.94–1.40) for ADHD. Sibling-matched analyses showed no association between gestationally exposed children and their gestationally nonexposed siblings for all outcomes (preterm birth: wOR = 0.84, 95% CI = 0.66–1.06; small for gestational age: wOR = 1.02, 95% CI = 0.50–2.09; ASD: wHR = 1.10, 95% CI = 0.70–1.72; ADHD: wHR = 1.04, 95% CI = 0.57–1.90). Similarly, no significant differences were observed when comparing children whose mothers took benzodiazepines and/or z-drugs during pregnancy to children whose mothers took benzodiazepines and/or z-drugs before but not during pregnancy for all outcomes. Conclusions: The findings do not support a causal relationship between gestational benzodiazepines and/or z-drugs exposure and preterm birth, small for gestational age, ASD, or ADHD. Clinicians and pregnant women should carefully balance the known risks of benzodiazepines and/or z-drugs use against those of untreated anxiety and sleep problems.

Trends in prescribing psychotropic drugs before and during pregnancy may have changed over the years, but actual information is lacking. We therefore compared and assessed the exposure and acceptance rates of classes of antipsychotic (+ lithium), anxiolytic, sedative/hypnotic, antidepressant, and psychostimulant before and during pregnancy in the past two decades. All singleton pregnancies with ≥1 prescription of psychotropic drug from six months before pregnancy until child’s birthdate were identified in the pregnancy subset of the IADB.nl prescription database. The prescription patterns of psychotropics were distinguished as continuation rate (CR), initiation rate (IR), discontinuation rate (DR), total exposure rate (TER), and acceptance rate. Singleton pregnancies exposed to psychotropic drugs before and during pregnancy increased from 118.4 to 136.5 (per 1000 singleton pregnancies) between decades. Changing trends were observed in decade 2, including a high increase in the TER of antipsychotic class (3.3 to 6.8) and antidepressant class (23.0 to 40.6). A marked increase for individual drugs was seen for sertraline (TER: 0.6 to 6.6 and PAT: 35.3% to 82.5%), citalopram (TER: 2.3 to 10.0 and PAT: 51.1% to 74.6%), and quetiapine (TER: 0.4 to 3.1 and PAT: 57.1% to 66.0%). Although the total exposure rates of five classes of psychotropics in singleton pregnancies increased in decade 2, only antidepressant class had a higher acceptance rate during pregnancy. Certain SSRI antidepressants and atypical antipsychotics were more frequently prescribed in decade 2 than in decade 1, reflecting that treatment options were preferred for safer treatment choices.

OBJECTIVE: To investigate and describe the protocolized treatment of DOAC-related bleeds in all Dutch hospitals.METHODS: From August to December 2020 a nationwide survey among all 70 hospitals in the Netherlands was conducted on their protocols for management of bleeding in patients treated with direct oral anticoagulants (DOACs, i.e. apixaban, edoxaban, rivaroxaban and dabigatran). The protocols were assessed the following characteristics: bleeding definitions (mild, moderate and severe bleed), diagnostic parameters (hemoglobin [Hb], loss of blood, surgical procedure needed, etc), first and second choice of treatment, effectiveness criteria and the level of evidence/references upon which protocols were based.RESULTS: All 70 hospitals responded (100%). We received 69 protocols in total, 6 of which were identical because hospitals worked together. In 35 (50%) of the protocols a definition of minor, moderate or severe bleeds was described. Diagnostic parameters for bleeds were present in 2%, 41% and 47% of protocols for a mild, moderate and severe bleed. While the first choice treatment for severe bleeding under dabigatran was idarucizumab in 96% of protocols, considerably more therapeutic options (mostly different prothrombin complex concentrate (PCC) doses) are described for Xa inhibitors. When considering criteria for effectiveness more than 90% of protocols did not have a clear description.CONCLUSION: This study provides an overview of the current state of protocols for management of DOAC-related bleeding in The Netherlands. Protocols vary in the content of information provided and often do not include information, especially for diagnostic criteria and criteria for establishing the effectiveness of the intervention. The results of this study can assist in improving and harmonizing the protocols.

OBJECTIVES: In patients with myelodysplastic syndromes (MDS) with >20 transfusions and ferritin levels >1000 μg/L, international guidelines recommend iron chelation therapy (ICT). The study's objective was to determine guideline adherence and the intensity of ferritin monitoring in clinical practice.METHODS: We performed an observational population-based study using the HemoBase Registry, which contains data of all MDS patients diagnosed since 2005 in Friesland, the Netherlands. Clinical information on transfusions, ferritin measurements, ICT, and clinical performance as defined by age ≤80 years, Charlson Comorbidity Index RESULTS: 237 of 292 patients (81.1%) received ≥1 transfusion, and 121 (41.4%) received >20 transfusions. In 57 of these 121 patients (47.1%), ferritin measurements were performed at least once. Clinical performance was significantly associated with monitoring ferritin around the 20th transfusion (RR: 2.49, p=0.016). Clinical performance was also associated with initiating ICT (RR: 5.99, pCONCLUSIONS: In this population-based study, ferritin levels were measured in 20 transfusions, and clinical performance was significantly associated with measuring ferritin. Our study suggests that in heavily transfused MDS patients, ferritin monitoring is primarily based on patients' clinical performance rather than guideline recommendations.

Objectives: To investigate and describe the protocolized perioperative management in patient using Direct oral anticoagulants (DOACs) in Dutch hospitals.Methods: Between August and December 2020, a nationwide survey in 70 hospitals in the Netherlands was conducted. We asked hospital pharmacists to submit their protocols for perioperative management of DOAC (apixaban, dabigatran, edoxaban and rivaroxaban) users. The protocols were assessed for a number of parameters divided into categories: interruption and restart timetables DOACs for elective procedures, criteria for the start of an urgent procedure without antidotes, criteria for the use of antidotes and advised antidotes for urgent procedures.Results: A total of 49 hospitals (70%) sent a protocol for perioperative management of DOACs. Two pairs of protocols were identical because hospitals cooperated closely, leaving 47 individual protocols for analysis. Thirty-five of these protocols contained a policy for both elective and urgent procedure; five protocols contained only a policy for elective and seven only for urgent procedures. In protocols for elective procedure, we found great variation in interruption and restart timetables intended for patients with renal impairment (Estimated Glomerular Filtration Ratio < 80 ml/min). In case of urgent procedures, there is variation in choice of antidote, criteria for administration of an antidote and antidote dosing.Conclusion: This study provides an overview of the current state of the perioperative protocols in the Netherlands in patients treated with direct oral anticoagulants. Protocols are often not complete and show important and unwanted variation. We have found that national guidelines do not provide unambiguous advice on all points (urgent procedures) and are therefore often elaborated at a local level. The results of this research can help in improving and harmonizing the perioperative protocols on a national level.

Objective We aimed to assess the cost-effectiveness of screening smokers and ex-smokers for lung cancer in the Netherlands. Methods A Markov model was used to evaluate the health effects and costs of lung cancer screening from the healthcare perspective. The effects and costs of ten screening scenarios with different start and stop ages of screening were examined across a lifetime horizon in a cohort of 100,000 smokers and ex- smokers 50 years and older. Results The incremental cost-effectiveness ratios (ICERs) of screening smokers and ex-smokers aged 50–60 years, 50–70 years, and 50 years and older are below the cost-effectiveness threshold of € 20,000 per quality adjusted life year (QALY) gained. Screening 50–60-year-old smokers and ex-smokers was the most cost-effective scenario with an ICER of € 14,094 per QALY gained. However, screening smokers and ex-smokers 50 years and older yielded the highest QALYs and resulted in an ICER of € 16,594 per QALY, which is below the threshold of € 20,000 per QALY. All screening scenarios compared to no screening resulted in CERs between the € 14,000 and € 16,000 per QALY gained. The efficiency frontier showed that screening smokers and ex-smokers in the age groups 70 years and older, 60–70 years, 60 years and older are excluded by extended dominance by no screening, screening smokers and ex-smokers aged 50–60 years and 50–70 years. Conclusion This study showed that lung cancer screening is cost-effective in the Netherlands.

The a priori risk for infections in patients with myelodysplastic syndromes (MDS) is unknown. This study examines prescription rates of anti-infective agents in MDS patients before and after diagnosis, in both in- and outpatient settings, to provide information on infection management in clinical practice. We performed a population-based study using the HemoBase registry, containing data of all MDS patients diagnosed since 2005 in Friesland, the Netherlands. Community and hospital pharmacies provided prescription data from 1995 to 2020. Data were obtained for 203 of 292 patients (70%). Patients received significantly more anti-infective agents, predominantly antibacterials (70%), after diagnosis compared to before: 148.7 defined daily dose/1000 days (DID) (95% CI: 146.9-150.5) and 55.1 DID (95% CI: 54.5-55.8, p < 0.01), respectively, corresponding to median 23.5 and 7.6 treatment days/year. Higher-risk (449.9 DID) and lower-risk patients (129.1 DID) both received significantly more anti-infective agents after diagnosis; comorbidities, neutropenia, and age did not show significant differences relative to prescription rates. Before diagnosis, 10% of patients had infection-related hospital admissions versus 38% after diagnosis. In conclusion, MDS patients received significantly more anti-infective agents compared to before diagnosis. This is the first study that has quantified the prescription rate of anti-infective agents within and beyond the clinical setting in MDS.

Because alcohol use disorder (AUD) is often accompanied by mood disorder (MD) and both alcoholism and depression result in activation of the immune system, this study compares serum cytokine levels in the presence of co-morbidity with those in either AUD or MD alone. In this naturalistic prospective study the levels of 15 different cytokines were measured in serum samples of patients with MD (n = 43), participants with combined AUD-MD (n = 44) and AUD without MD (n = 42). The levels were compared cross-sectionally among themselves and with those in 50 healthy volunteers. Pro-inflammatory IFN-2α levels were consistently significantly higher and anti-inflammatory IL-1RA significantly lower in all study groups in comparison to healthy volunteers. In the MD only group we found increased IL-6 (p = 0.001), IL-7 (p = 0.001) and IL-13 (p = 0.006) levels, and decreased TNFα (p = 0.0001), IL-1RA (p = 0.012), IL-10 (p = 0.002) compared with group MD + AUD. Patients with AUD only showed elevated levels of IL-1β (p = 0.046), IL-2 (p = 0.004), IL-7 (p = 0.0001), IL-4 (p = 0.049) and IL-13 (p = 0.015) in contrast with MD + AUD group. Because the interactions of alcohol with peripheral and cerebral immune systems are multifaceted, the pertinent connection to the mechanism how alcohol consumption contributes to the development of mood disorders cannot be properly explored.

BACKGROUND AND OBJECTIVE: Several cases of venous thromboembolism in patients treated with direct oral anticoagulants (DOACs) have been reported in the literature, but a quantative analysis of postmarketing reports is lacking. The objective of this study was to determine the post-marketing odds ratio (OR) and reporting odds ratio (ROR) of venous thromboembolism in patients receiving DOACs compared among each other and to vitamin K antagonists (VKAs).METHODS: The OR and ROR were used to determine the ratio of reports for deep vein thrombosis and pulmonary embolism between 1 January, 2012 and 15 November, 2020 using the World Health Organization VigiLyze database. This was performed using all venous thromboembolism events in which a DOAC or a VKA was the suspected medication. The OR and ROR including 95% confidence intervals were calculated for each DOAC drug in comparison to all VKAs as a group.RESULTS: The OR of deep vein thrombosis was highest for rivaroxaban compared with dabigatran and apixaban [2.63 (2.41-2.89); 1.84 (1.72-1.97)]. The OR of deep vein thrombosis was lowest for edoxaban compared with dabigatran, apixaban and rivaroxaban [0.44 (0.32-0.61); 0.31 (0.22-0.42); 0.17 (0.12-0.23)]. The OR of pulmonary embolism was also highest for rivaroxaban compared with dabigatran and apixaban [2.59 (2.37-2.83); 1.79 (1.68-1.92)]. The OR of pulmonary embolism was also lowest for edoxaban compared with dabigatran, apixaban and rivaroxaban [0.77 (0.60-0.97); 0.59 (0.41-0.67); 0.30 (0.23-0.37)]. Comparing RORs of various DOACs with VKAs, rivaroxaban had the highest RORs for deep vein thrombosis/pulmonary embolism, in comparison to apixaban, dabigatran and edoxaban.CONCLUSIONS: Our findings may indicate a higher association between rivaroxaban therapy and venous thromboembolism as compared with apixaban, dabigatran and edoxaban. These findings are uncertain owing to the reliability of a post-marketing registration system that is negatively influenced by a high level of under-reporting. However, based on pharmacodynamics, we cannot exclude the possibility that there is a real effect that may be driven by non-adherence.

BACKGROUND: Potential overtreatment with cardiometabolic medication (i.e., glucose lowering medication, antihypertensives and statins) has been observed in 10-40% of older people with type 2 diabetes (T2D).OBJECTIVE: The potential effects of a pharmacist-led clinical medication review targeted at T2D patients who were at high risk of hypoglycaemia will be investigated.METHODS: A quasi-experimental study was conducted in 14 Dutch community pharmacies. Patients with a high risk of hypoglycaemia were identified using a previously developed algorithm. Pharmacists confirmed eligibility and selected patients for the intervention. Remaining eligible patients were included as controls receiving usual care. The primary outcome was the proportion of intervention patients for whom an action on deprescribing or appropriate use of cardiometabolic medication was implemented. After three months, changes in cardiometabolic medication were compared between the intervention and control group using a Fischer exact test.RESULTS: In total 90 intervention patients and 107 control patients were included. Intervention patients had an average age of 70, used on average 10 medications, five of which were cardiometabolic medication. For half of the intervention patients an action on deprescribing cardiometabolic medication was implemented (n = 25) and/or an advice about appropriate use of cardiometabolic medication was given (n = 22). In 48% of intervention patients at least one cardiometabolic medication (e.g. insulin, sulfonylurea, diuretic, beta-blocker, statin) was either stopped or reduced in dose compared to 31% of control patients (p = 0.018).CONCLUSIONS: A pharmacist-led tailored clinical medication review has the potential to increase deprescribing and improve appropriate use of cardiometabolic medication in half of T2D patients at high risk of hypoglycaemia.

Background: Non-medical medication switches, a change to another medicine or medication label not motivated by medical reasons, occur frequently. Switches often lead to negative patient emotions, such as confusion and anger. Pharmacy staff's communication, i.e. delivering the message and addressing patients' emotions is crucial, but experienced as difficult.Objective: To develop and test a communication training for the pharmacy team to facilitate medication switch conversations.Methods: A communication training was developed based on the 'breaking bad news model' and 'positive message framing' strategies, and incorporating needs and preferences from practice. The training consisted of an e-learning with theory and reflective exercises, a half-day live training session, and an online reflection session. The Kirkpatrick training evaluation model (levels one 'reaction' and two 'learning') was used to evaluate the training. Quantitative data were analyzed using descriptive statistics and interview data was transcribed verbatim and analyzed thematically.Results: Twelve pharmacists and 27 pharmacy technicians from 15 Dutch pharmacies participated in the training. According to Kirkpatrick's model level one, the major learning outcome was to give space to patients to express their emotions and/or concerns (e.g. more silences in the conversations). For level two, most participants valued practicing the conversations, role-playing, and receiving feedback. The majority of the participants indicated that they had sufficient tools and practice during the live training to apply the strategies in daily practice. A few participants still needed time and practice, or missed examples to apply the strategies.Conclusion: The communication training based on the two strategies was well-received and participants felt well-equipped post-training. The take-away for participants was to give space to patients to express their emotions. Using these strategies and skills, pharmacy teams can tailor their medication counseling to patients' emotions and concerns during non-medical medication switches to better support patients in proper medication use.

The ileocolonic-targeted delivery of vitamins can establish beneficial alterations in gut microbial composition. Here, we describe the development of capsules containing riboflavin, nicotinic acid, and ascorbic acid covered with a pH-sensitive coating (ColoVit) to establish site-specific release in the ileocolon. Ingredient properties (particle size distribution, morphology) relevant for formulation and product quality were determined. Capsule content and the in vitro release behaviour were determined using a HPLC-method. Uncoated and coated validation batches were produced. Release characteristics were evaluated using a gastro-intestinal simulation system. All capsules met the required specifications. The contents of the ingredients were in the 90.0–120.0% range, and uniformity requirements were met. In the dissolution test a lag-time in drug release of 277–283 min was found, which meets requirements for ileocolonic release. The release itself is immediate as shown by dissolution of the vitamins of more than 75% in 1 h. The production process of the ColoVit formulation was validated and reproducible, it was shown that the vitamin blend was stable during the production process and in the finished coated product. The ColoVit is intended as an innovative treatment approach for beneficial microbiome modulation and optimization of gut health.

Photosensitizing properties of hydrochlorothiazide may increase skin cancer risk. To date, study findings on the association between hydrochlorothiazide use and skin cancer risk are inconsistent, notably regarding confounding and dose-response. The aim of this study was to investigate the association between hydrochlorothiazide use and incidence of skin cancer in a cohort of unselected Caucasian adults, taking dosing into account. As part of the PharmLines Initiative, which links data from the Lifelines Cohort Study and prescription database IADB.nl, patients aged ≥ 40 years were included from Lifelines, a prospective population-based cohort study in the north of the Netherlands. Skin cancer incidence was compared between subjects starting hydrochlorothiazide treatment (n = 608), subjects starting treatment with other antihypertensives (n = 508), and non-antihypertensive long-term medication users (n = 1,710). Cox regression analyses were performed to obtain hazard ratios, adjusted for potential confounders. The risk of any skin cancer, keratinocyte carcinoma, basal cell carcinoma and squamous cell carcinoma was not significantly increased in general hydrochlorothiazide users. A clear association was observed between high cumulative hydrochlorothiazide use (≥ 5,000 defined daily dose; ≥ 125,000 mg) and the risk of any skin cancer (adjusted hazard ratio 5.32, 95% confidence interval (95% CI) 2.40–11.81), keratinocyte carcinoma (adjusted hazard ratio 7.31, 95% CI 3.12–17.13), basal cell carcinoma (adjusted hazard ratio 7.72, 95% CI 3.11–19.16) and squamous cell carcinoma (adjusted hazard ratio 19.63, 95% CI 3.12–123.56). These findings should lead to awareness with high use of hydrochlorothiazide in Caucasian adults.

BACKGROUND: Post-transplant anaemia and reduced muscle mass and strength are highly prevalent in kidney transplant recipients (KTRs). Decreased haemoglobin levels, a marker of anaemia, could adversely affect muscle mass and strength through multiple mechanisms, among others, through diminished tissue oxygenation. We aimed to investigate the association between haemoglobin levels with muscle mass and strength in KTRs.METHODS: We included stable KTRs from the TransplantLines Biobank and Cohort study with a functional graft ≥1 year post-transplantation. Muscle mass was assessed using 24 h urinary creatinine excretion rate (CER) and bioelectrical impedance analysis (BIA). Muscle strength was assessed with a handgrip strength test using a dynamometer and, in a subgroup (n = 290), with the five-times sit-to-stand (FTSTS) test. We used multivariable linear and logistic regression analyses to investigate the associations of haemoglobin levels with muscle mass and strength.RESULTS: In 871 included KTRs [median age 58 (interquartile range (IQR), 48-66)] years; 60% men; eGFR 51 ± 18 mL/min/1.73 m2 ) who were 3.5 (1.0-10.2) years post-transplantation, the mean serum haemoglobin level was 13.9 ± 1.8 g/dL in men and 12.8 ± 1.5 g/dL in women. Lower haemoglobin levels were independently associated with a lower CER (std. β = 0.07, P = 0.01), BIA-derived skeletal muscle mass (std. β = 0.22, P < 0.001), handgrip strength (std. β = 0.15, P < 0.001), and worse FTSTS test scores (std. β = -0.17, P = 0.02). KTRs in the lowest age-specific and sex-specific quartile of haemoglobin levels had an increased risk of being in the worst age-specific and sex-specific quartile of CER (fully adjusted OR, 2.09; 95% CI 1.15-3.77; P = 0.02), handgrip strength (fully adjusted OR, 3.30; 95% CI 1.95-5.59; P < 0.001), and FTSTS test score (fully adjusted OR, 7.21; 95% CI 2.59-20.05; P < 0.001).CONCLUSIONS: Low haemoglobin levels are strongly associated with decreased muscle mass and strength in KTRs. Future investigation will need to investigate whether maintaining higher haemoglobin levels may improve muscle mass and strength in KTRs.

Key summary pointsAim To investigate the performance of an adverse drug reaction (ADR) trigger tool in patients with polypharmacy acutely admitted to our geriatric ward. Findings The ADR trigger tool had a positive predictive value (PPV) of 41.8%. Usual care recognised 83.5% of ADRs considered as possible, probable or certain, increasing to 97.1% when restricted to probable and certain ADRs. Message It is unlikely that implementation of the ADR trigger tool will improve detection of unrecognised ADRs in older patients acutely admitted to our geriatric ward.Purpose Adverse drug reactions (ADRs) account for 10% of acute hospital admissions in older people, often under-recognised by physicians. The Dutch geriatric guideline recommends screening all acutely admitted older patients with polypharmacy with an ADR trigger tool comprising ten triggers and associated drugs frequently causing ADRs. This study investigated the performance of this tool and the recognition by usual care of ADRs detected with the tool. Methods A cross-sectional study was performed in patients >= 70 years with polypharmacy acutely admitted to the geriatric ward of the University Medical Centre Utrecht. Electronic health records (EHRs) were screened for trigger-drug combinations listed in the ADR trigger tool. Two independent appraisers assessed causal probability with the WHO-UMC algorithm and screened EHRs for recognition of ADRs by attending physicians. Performance of the tool was defined as the positive predictive value (PPV) for ADRs with a possible, probable or certain causal relation. Results In total, 941 trigger-drug combinations were present in 73% (n = 253/345) of the patients. The triggers fall, delirium, renal insufficiency and hyponatraemia covered 86% (n = 810/941) of all trigger-drug combinations. The overall PPV was 41.8% (n = 393/941), but the PPV for individual triggers was highly variable ranging from 0 to 100%. Usual care recognised the majority of ADRs (83.5%), increasing to 97.1% when restricted to possible and certain ADRs. Conclusion The ADR trigger tool has predictive value; however, its implementation is unlikely to improve the detection of unrecognised ADRs in older patients acutely admitted to our geriatric ward. Future research is needed to investigate the tool's clinical value when applied to older patients acutely admitted to non-geriatric wards.

Background: To improve efficacy, therapeutic drug monitoring is often used in clozapine therapy. Trough level monitoring is regular, but trough levels provide limited information about the pharmacokinetics of clozapine and exposure in time. The area under the concentration time curve (AUC) is generally valued as better marker of drug exposure in time but calculating AUC needs multiple sampling. An alternative approach is a limited sampling scheme in combination with a population pharmacokinetic model meant for Bayesian forecasting. Furthermore, multiple venepunctions can be a burden for the patient, whereas collecting samples by means of dried blood spot (DBS) sampling can facilitate AUC-monitoring, making it more patient friendly. Objective: Development of a population pharmacokinetic model and limited sampling strategy for estimating AUC0-12h (a twice-daily dosage regimen) and AUC0-24h (a once-daily dosage regimen) of clozapine, using a combination of results from venepunctions and DBS sampling. Method: From 15 schizophrenia patients, plasma and DBS samples were obtained before administration and 2, 4, 6, and 8 h after clozapine intake. MwPharm® pharmacokinetic software was used to parameterize a population pharmacokinetic model and calculate limited sampling schemes. Results: A three-point sampling strategy with samples at 2, 6, and 8 h after clozapine intake gave the best estimation of the clozapine AUC0-12h and at 4, 10, and 11 h for the AUC0-24h. For clinical practice, however, a two-point sampling strategy with sampling points at 2 and 6 h was sufficient to estimate AUC0-12h and at 4 and 11 h for AUC0-24h. Conclusion: A pharmacokinetic model with a two–time point limited sampling strategy meant for Bayesian forecasting using DBS sampling gives a better prediction of the clozapine exposure in time, expressed as AUC, compared to trough level monitoring. This limited sampling strategy might therefore provide a more accurate prediction of effectiveness and occurrence of side effects compared to trough level monitoring. The use of DBS samples also makes the collection of clozapine samples easier and wider applicable.

Purpose: Polystyrene sulfonate is used for binding potassium in patients with chronic kidney disease (CKD). Because of its binding properties, it can potentially bind other medications and thereby decrease their bioavailability and effectiveness. Amitriptyline, often used by CKD patients for neuropathic pain, shows significant binding to polystyrene sulfonate in vitro. The purpose of this study was to determine the effect of polystyrene sulfonate on the exposure of amitriptyline in vivo when taken concomitantly in healthy volunteers. Methods: We performed a prospective cross-over study in nine healthy volunteers. Participants were 18 years of age or older, did not use any medication, and had no known allergy to amitriptyline or polystyrene sulfonate. Participants visited Deventer Teaching Hospital twice. Once they received a single dose of amitriptyline 50 mg and once they received a single dose of both polystyrene sulfonate 15 g and amitriptyline 50 mg taken concomitantly, with a wash out period of at least 1 week. After intake of the medication, six blood samples were collected, at 2, 3, 4, 5, 6, and 8 h. Blood samples were analysed to determine maximum concentration (Cmax) and area under the curve 0–8 h after intake (AUC0–8 h). Difference in Cmax and AUC0–8 h was analysed with a paired T-test or Wilcoxon signed rank test, depending on normality of the data. A p-value < 0.05 was considered statistically significant. Results: Of the nine participants included, eight participants completed both visits to the hospital. Mean maximum concentration (Cmax) of amitriptyline was 35.61 µg l−1 (95% CI 27.90–43.33 µg l−1) when taken alone, compared to 9.25 µg l−1 (95% CI 6.59–11.92 µg l−1) when taken with polystyrene sulfonate (p < 0.001). Mean AUC0–8 h of amitriptyline was 168.20 µg × h l−1 (95% CI 139.95–196.45 µg × h l−1) when taken alone and 45.78 µg × h l−1 (95% CI 30.20–61.36 µg × h l−1) when taken with polystyrene sulfonate (p < 0.0001). Conclusion: These results show a significant decrease in exposure of amitriptyline of approximately 75% when taken concomitantly with polystyrene sulfonate, thereby probably compromising therapy efficacy. Patients using both amitriptyline and polystyrene sulfonate should be informed to separate intake of these medications. Trial registration: NL8539 (17 April 2020).

Adherence is a particular concern in treating hypertension, and non-adherence to antihypertensive drugs might cause uncontrolled hypertension. This study aimed to measure retrospectively the medication adherence of hypertensive patients with monotherapy treatment in a community health center (Puskesmas) in Bandung city, Indonesia. The retrospective patient data from 2011 to 2015 were obtained from an electronic prescription database. The patient data of those diagnosed with hypertension, >18 years old, and who received mono-antihypertensive therapy within a 12-month period were included in this study. To assess medication adherence, the medication possession ratio (MPR) was applied. Out of 780 patients, 93.6% of patients showed poor adherence, about 5.8% showed intermediate adherence, and 0.6% of patients had high adherence. Males and females showed different levels of adherence (p

Background Sevelamer and polystyrene sulfonate are used for treating hyperphosphatemia and hyperkalaemia in chronic kidney disease patients. Because of their binding properties, these resins potentially bind other drugs in the gastrointestinal tract, thereby decreasing their bioavailability and clinical effectiveness. Aim The aim of this study was to explore co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions. Method In this in silico study, the 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate in the period 2000-2018 were extracted from the University Groningen IADB.nl database. Drugs dispensed to 2.0 were identified as potential interacting drug. For polystyrene sulfonate, drugs with a pKa (base) > 1.5 were identified as potential interacting drug. Results Of the top 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate, 22 and 27 potentially clinically relevant new interacting drugs were identified for sevelamer and polystyrene sulfonate respectively. Conclusion Several potentially relevant novel binding interactions for sevelamer and polystyrene sulfonate were identified based on dispensing data and assessment of chemical properties for which further interaction research is warranted.

INTRODUCTION: Benefits and risks of preventive medication change over time for ageing patients and deprescribing of medication may be needed. Deprescribing of cardiovascular and antidiabetic drugs can be challenging and is not widely implemented in daily practice.OBJECTIVE: The aim of this study was to identify barriers and enablers of deprescribing cardiometabolic medication as seen by healthcare providers (HCPs) of different disciplines, and to explore their views on their specific roles in the process of deprescribing.METHODS: Three focus groups with five general practitioners, eight pharmacists, three nurse practitioners, two geriatricians, and two elder care physicians were conducted in three cities in The Netherlands. Interviews were recorded and transcribed verbatim. Directed content analysis was performed on the basis of the Theoretical Domains Framework. Two researchers independently coded the data.RESULTS: Most HCPs agreed that deprescribing of cardiometabolic medication is relevant but that barriers include lack of evidence and expertise, negative beliefs and fears, poor communication and collaboration between HCPs, and lack of resources. Having a guideline was considered an enabler for the process of deprescribing of cardiometabolic medication. Some HCPs feared the consequences of discontinuing cardiovascular or antidiabetic medication, while others were not motivated to deprescribe when the patients experienced no problems with their medication. HCPs of all disciplines stated that adequate patient communication and involving the patients and relatives in the decision making enables deprescribing. Barriers to deprescribing included the use of medication initiated by specialists, the poor exchange of information, and the amount of time it takes to deprescribe cardiometabolic medication. The HCPs were uncertain about each other's roles and responsibilities. A multidisciplinary approach including the pharmacist and nurse practitioner was seen as the best way to support the process of deprescribing and address barriers related to resources.CONCLUSION: HCPs recognized the importance of deprescribing cardiometabolic medication as a medical decision that can only be made in close cooperation with the patient. To successfully accomplish the process of deprescribing they strongly recommended a multidisciplinary approach.

BACKGROUND: The aim of this study was to evaluate the effect of bariatric surgery on the defined daily dose of levothyroxine (DDD LT4), thyroid-stimulating hormone (TSH), and free thyroxine (fT4) in female patients with hypothyroidism until 48 months after surgery.METHODS: A retrospective observational study of hypothyroid patients who underwent bariatric surgery. Changes in DDD LT4, TSH, and fT4 over a 48 month period after surgery were analyzed.RESULTS: Thirty-seven patients were included: 27 Roux-en-Y gastric bypass (RYGB), 6 sleeve gastrectomy (SG), 3 adjustable gastric band, and 1 one anastomosis gastric bypass. The median DDD LT4 decreased from 125 µg at baseline to 100 µg 12 months after surgery. From 24 to 48 months after surgery, the median DDD LT4 was stable at 125 µg. Most dose adjustments occurred during the first 24 months after surgery. In the time period of 24-48 months after surgery, the dose remained stable in 73.1% of the RYGB patients and in 60.0% of the SG patients. After 48 months in the RYGB group, no significant change in TSH and fT4 levels was observed.CONCLUSIONS: Bariatric surgery led to frequent dose adjustments during the first 2 years after surgery. However, 24-48 months after surgery in the majority of patients, the dosage remained stable. No significant change in TSH and fT4 was observed 48 months after RYGB. In the first 2 years after surgery, clinicians should frequently monitor TSH and fT4 for individual dose adjustment of levothyroxine. Thereafter, the frequency of monitoring may be decreased.

Purpose Varenicline is an effective treatment for smoking cessation. While clinical trials did not confirm a causal role, case reports suggested a possible link of varenicline with neuropsychiatric adverse drug events (NPAEs). This study aims to investigate the risk of NPAEs associated with varenicline initiation among the general population in a real-world setting. Methods We conducted a sequence symmetry analysis (SSA) based on the University of Groningen IADB.nl prescription database. We selected incident users of both varenicline and marker drugs for NPAEs, including depression, anxiety and sleep disorder within different time-intervals. Adjusted sequence ratios (aSR) were calculated for each time-interval. Results Within 365-days' time-interval 1,066 patients were incident users of both varenicline and NPAE marker drugs. In total, 505 patients were prescribed varenicline before NPAE marker drugs and 561 vice versa (crude sequence ratio (cSR) 0.90, 95% CI: 0.80-1.02). After adjustments for trends in prescriptions, overall a null association was found (aSR 1.00, 95% CI: 0.89-1.13). Regarding specific NPAEs, no increased risks were found for depression nor anxiety within any time-interval. A small transient increased risk was found for sleep disorders, particularly in earlier time-intervals 3 and 6 months (aSRs 1.52, 95% CI: 1.10-2.11 and 1.45, 95% CI: 1.15-1.83, respectively). Subgroup and sensitivity analyses showed similar findings. Conclusions Varenicline initiation was unlikely to be associated with an increased risk of taking anti-depressants nor anti-anxiety drugs. Yet a small, but statistically significant, transient association with drugs for sleep disorders was noticed, possibly associated with withdrawal symptoms caused by smoking cessation. This article is protected by copyright. All rights reserved.

Contains fulltext : 249093.pdf (Publisher’s version ) (Open Access) Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C(min) at steady-state. The geometric mean (GM) C(min) at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C(min) at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P

OBJECTIVES: Infections are a major cause of morbidity and mortality in patients with myelodysplastic syndromes (MDS). The objective of the MINDSET study was to evaluate haematologists' management of infection prevention in MDS patients using a case vignette study and to assess the availability of guidelines.METHODS: We conducted a web-based, nationwide survey amongst haematologists in the Netherlands between September and December 2021. The survey included a set of case vignettes. Additionally, the availability of protocols was evaluated.RESULTS: Sixty responses were obtained (23.6%). These responses were well distributed across hospital types as well as level of experience. No protocols regarding infection prophylaxis specifically for MDS patients were received. In the case vignette of a 75-year-old MDS patient, respondents would primarily prescribe infection prophylaxis in case of recurrent infections (96.7%) and neutropenia (75.0% for absolute neutrophil count [ANC]CONCLUSIONS: This study showed diverse reasons and considerations of haematologists regarding whether to prescribe infection prophylaxis in MDS patients. Given the seriousness of infections in MDS patients, patient-tailored recommendations might be valuable in clinical decision-making. This article is protected by copyright. All rights reserved.

This study aimed to assess the level of HIV treatment knowledge, empathy, and HIV stigma of pharmacy students and pharmacists working with patients as well as potential factors associated with stigma. This survey included 250 hospital pharmacists within 33 provinces and 1013 final-year pharmacy students from Java, the most populated island in Indonesia. The data were collected via Qualtrics® and distributed by WhatsApp. The mean age of the participants was (Mean ± SD) 24.68 ± 5.30 years, and 80.0% were female. The mean knowledge score of students and pharmacists were 14.14 ± 2.01 and 15.39 ± 1.87, respectively, out of the maximum score of 21. The mean empathy score of students and pharmacists was 72.06 ± 5.39 and 77.40 ± 1.35, respectively out of the maximum score of 105. The mean stigma score of students and pharmacists was 21.02 ± 4.65 and 20.66 ± 4.41, respectively, out of a maximum score of 48. Regression analysis showed that knowledge, empathy, and willingness to counsel patients were negatively associated with stigma. Working with patients was positively associated with stigma. A multi-level intervention including education may reduce stigma and strengthen the role of pharmacists in caring for patients.

Nonadherence to antihypertensive drugs is an important reason for not reaching blood pressure goals. A possible method to improve nonadherence involves three essential steps: Identification of nonadherent patients (step 1), determination of underlying causes (step 2) and a personalized solution (step 3). We present three unique cases to show the importance and difficulties of this threestep approach. Patients participated in a randomized controlled trial to improve nonadherence to antihypertensive drugs (RHYMERCT, Dutch Trial Register NL6736). Drug level measurements were used to identify nonadherence to antihypertensive drugs and communication on drug levels was supported by a tailored feedback tool in these patients. These cases showed that a three-step approach of identifying nonadherence and determination of the underlying cause, can lead to a personalized solution to improve therapy even when nonadherence was excluded. Open communication with patients remains an essential part when improving nonadherence.

Background The Screening Tool of Older Persons’ Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) instrument is used to evaluate the appropriateness of medication in older people. STOPP/START criteria have been converted into software algorithms and implemented in a clinical decision support system (CDSS) to facilitate their use in clinical practice. Objective Our objective was to determine the frequency of CDSS-generated STOPP/START signals and their subsequent acceptance by a pharmacotherapy team in a hospital setting. Design and Methods Hospitalised older patients with polypharmacy and multimorbidity allocated to the intervention arm of the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial underwent a CDSS-assisted structured medication review in four European hospitals. We evaluated the frequency of CDSS-generated STOPP/START signals and the subsequent acceptance of these signals by a trained pharmacotherapy team consisting of a physician and pharmacist after evaluation of clinical applicability to the individual patient, prior to discussing pharmacotherapy optimisation recommendations with the patient and attending physicians. Multivariate linear regression analysis was used to investigate potential patient-related (e.g. age, number of co-morbidities and medications) and setting-related (e.g. ward type, country of inclusion) determinants for acceptance of STOPP and START signals. Results In 819/826 (99%) of the patients, at least one STOPP/START signal was generated using a set of 110 algorithms based on STOPP/START v2 criteria. Overall, 39% of the 5080 signals were accepted by the pharmacotherapy team. There was a high variability in the frequency and the subsequent acceptance of the individual STOPP/START criteria. The acceptance ranged from 2.5 to 75.8% for the top ten most frequently generated STOPP and START signals. The signal to stop a drug without a clinical indication was most frequently generated (28%), with more than half of the signals accepted (54%). No difference in mean acceptance of STOPP versus START signals was found. In multivariate analysis, most patient-related determinants did not predict acceptance, although the acceptance of START signals increased in patients with one or more hospital admissions (+ 7.9; 95% confidence interval [CI] 1.6–14.1) or one or more falls in the previous year (+ 7.1; 95% CI 0.7–13.4). A higher number of co-morbidities was associated with lower acceptance of STOPP (− 11.8%; 95% CI − 19.2 to − 4.5) and START (− 11.0%; 95% CI − 19.4 to − 2.6) signals for patients with more than nine and between seven and nine co-morbidities, respectively. For setting-related determinants, the acceptance differed significantly between the participating trial sites. Compared with Switzerland, the acceptance was higher in Ireland (STOPP: + 26.8%; 95% CI 16.8–36.7; START: + 31.1%; 95% CI 18.2–44.0) and in the Netherlands (STOPP: + 14.7%; 95% CI 7.8–21.7). Admission to a surgical ward was positively associated with acceptance of STOPP signals (+ 10.3%; 95% CI 3.8–16.8). Conclusion The involvement of an expert team in translating population-based CDSS signals to individual patients is essential, as more than half of the signals for potential overuse, underuse, and misuse were not deemed clinically appropriate in a hospital setting. Patient-related potential determinants were poor predictors of acceptance. Future research investigating factors that affect patients’ and physicians’ agreement with medication changes recommended by expert teams may provide further insight for implementation in clinical practice. Registration ClinicalTrials.gov Identifier: NCT02986425. Supplementary Information The online version contains supplementary material available at 10.1007/s40266-021-00904-z.

Background Information about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors. Methods This retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events. Results Amongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings [Incidence rate ratio (IRR): 1.95 (1.02–3.73)] and approved for long-term use [IRR: 2.76 (1.52–5.00)]. Conclusions and Relevance In this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.

Objectives: There is no existing Vietnamese diabetes knowledge questionnaire. This impedes assessment of patient knowledge that will be helpful in providing effective diabetes intervention. We aimed to validate the Vietnamese Translated Diabetes Knowledge Questionnaire (DKQ).Methodology: Translation and adaptation strictly followed the guidelines of Beaton et al. Internal consistency was assessed by Cronbach's alpha coefficient, test-retest reliability was assessed by Fleiss' Kappa coefficient, and validity value was determined among type 2 diabetes patients in a general hospital.Results: The Vietnamese version of the DKQ had good internal consistency (Cronbach's alpha for all items = 0.898) and stability (Kappa coefficient >0.600). The average score for all equivalence criteria was 1.00, demonstrating good equivalence to the original. The significant difference between knowledge score and education level (p Conclusion: Our study provided a reliable Vietnamese version of the DKQ. Future studies may apply the version in different regions in Vietnam to determine external validity.

AIM: This study examined whether anthropometric and body composition parameters such as body surface area (BSA), lean body mass (LBM), and total body weight (TBW) are correlated with docetaxel clearance and exposure by analyzing area under the curve. In addition, LBM, TBW, and a fixed dose were compared with BSA as dosing parameters for dose individualization of docetaxel. METHODS: Thirty-six patients receiving docetaxel chemotherapy for breast or metastatic castration-resistant prostate carcinoma were included. Before treatment, LBM was measured using a dual-energy X-ray absorptiometry scanner. Blood samples were collected up to 180 minutes after dosing to analyze docetaxel concentrations and determine individual pharmacokinetic parameters. RESULTS: No significant correlations were found between docetaxel clearance and the anthropometric and body composition variables (BSA, LBM, and TBW). The area under the curve was significantly but poorly correlated with BSA [r = 0.452 ( P = 0.016)] and TBW [r = 0.476 ( P = 0.011)]. The mean absolute percentage error and mean error of simulated dosing based on LBM and fixed dosing were not significantly different from those of BSA. For TBW, only mean absolute percentage error was significantly higher compared with dosing based on BSA (24.1 versus 17.1, P = 0.001). CONCLUSIONS: There was no clinically relevant correlation between docetaxel pharmacokinetics and the anthropometric and body composition variables BSA, LBM, and TBW. Therefore, dose individualization of docetaxel based on LBM, TBW, or fixed dosing cannot be recommended over BSA-based dosing.

Objective: To investigate whether statin adherence (defined as proportion days covered, PDC) is associated with LDL-c response in statin initiators on standard and low starting doses of statins, and to detect a possible interaction with sex. Methods: An inception cohort study was conducted using the PharmLines Initiative, a linkage between the Lifelines Cohort Study and the University of Groningen’s IADB.nl (prescription database). First-time statin users were followed from baseline to follow-up measurement. We matched participants (1:1) between the standard-dose and the low-dose group of statin users on the duration of follow-up. Multiple linear regression analysis was used to model the association. Results: In univariate analysis, PDC was significantly associated with LDL-c response similarly (slope = −0.021), in both the standard-dose group (N = 115, p

This article presents an ex-post evaluation of the performance of Dutch Design-Build-Finance-Maintain (DBFM) infrastructure projects compared to Design and Construct (D&C) contracts, which uses quantitative (financial project data and survey) and qualitative (interviews) data. Drawing on institutional theory, notably the economic institutionalism inspired-contractual perspective and the sociological institutionalism-oriented collaborative perspective, the evaluation focuses on four performance indicators—cost, time, quality, and innovation—and five public–private partnership (PPP) performance drivers—private financing, performance-dependent payments, bundling (i.e., the integrated nature of contracts), risk transfer, and collaboration. It was found that the DBFM projects performed similarly to, or better than, the D&C contracts. The impact of bundling on innovation was positive, while its impact on quality was inconclusive. The collaboration proved to be a strong driver for performance and innovation but was not stronger in DBFM projects compared to D&C projects. Over time, collaboration and performance improved suggesting that besides project characteristics, PPP performance is influenced by the way actors deal with contracts and by the gradual process by which they learn to do so. Theoretically, this means that historical institutionalism is part of the explanation of PPP performance.

BackgroundLittle is known about prescription patterns of expensive non-recommended newer long-acting insulins (glargine 300 U/mL and degludec) for patients with type 2 diabetes mellitus (T2DM).AimTo identify practice variation in, and practice- and patient-related characteristics associated with, the prescription of newer long-acting insulins to patients with T2DM in primary care.Design and settingA retrospective cohort study in Dutch general practices (Nivel Primary Care Database).MethodA first prescription for intermediate or long-acting insulins in 2018 was identified in patients aged ≥40 years using other T2DM drugs. Per practice, the median percentage and interquartile range (IQR) of patients with newer insulin prescriptions were calculated. Multilevel logistic regression models were constructed to calculate intraclass correlation coefficients (ICCs) and quantify the association of patient and practice characteristics with prescriptions for newer insulins (odds ratios [ORs] and 95% confidence intervals [CIs]).ResultsIn total, 7757 patients with prescriptions for intermediate or long-acting insulins from 282 general practices were identified. A median percentage of 21.2% (IQR 12.5–36.4%) of all patients prescribed intermediate or long-acting insulins per practice received a prescription for newer insulins. After multilevel modelling, the ICC decreased from 20% to 19%. Female sex (OR 0.77, 95% CI = 0.69 to 0.87), age ≥86 years compared with 40–55 years (OR 0.22, 95% CI = 0.15 to 0.34), prescriptions for metformin (OR 0.66, 95% CI = 0.53 to 0.82), sulfonylurea (OR 0.58, 95% CI = 0.51 to 0.66), or other newer T2DM drugs (OR 3.10, 95% CI = 2.63 to 3.66), and dispensing practices (OR 1.78, 95% CI = 1.03 to 3.10) were associated with the prescription of newer insulins.ConclusionThe inter-practice variation in the prescription of newer insulins is large and could only be partially explained by patient- and practice-related differences. This indicates substantial opportunities for improvement.

INTRODUCTION: Understanding the pharmacokinetics (PK) of antimicrobial drugs in pregnant women is crucial to provide effective and safe treatment. This study is part of a series that systematically reviews literature on the PK and analyzes if, based on the changed PK, evidence-based dosing regimens have been developed for adequate target attainment in pregnant women. This part focusses on antimicrobials other than penicillins and cephalosporins.METHODS: A literature search was conducted in PubMed according to the PRISMA guidelines. Search strategy, study selection, and data extraction were independently performed by two investigators. Studies were labeled as relevant when information on the PK of antimicrobial drugs in pregnant women was available. Extracted parameters included bioavailability for oral drugs, volume of distribution (Vd) and clearance (CL), trough and peak drug concentrations, time of maximum concentration, area under the curve and half-life, probability of target attainment, and minimal inhibitory concentration (MIC). In addition, if developed, evidence-based dosing regimens were also extracted.RESULTS: Of the 62 antimicrobials included in the search strategy, concentrations or PK data during pregnancy of 18 drugs were reported. Twenty-nine studies were included, of which three discussed aminoglycosides, one carbapenem, six quinolones, four glycopeptides, two rifamycines, one sulfonamide, five tuberculostatic drugs, and six others. Eleven out of 29 studies included information on both Vd and CL. For linezolid, gentamicin, tobramycin, and moxifloxacin, altered PK throughout pregnancy, especially in second and third trimester, has been reported. However, no target attainment was studied and no evidence-based dosing developed. On the other hand, the ability to reach adequate targets was assessed for vancomycin, clindamycin, rifampicin, rifapentine, ethambutol, pyrazinamide, and isoniazid. For the first six mentioned drugs, no dosage adaptations during pregnancy seem to be needed. Studies on isoniazid provide contradictory results.CONCLUSION: This systematic literature review shows that a very limited number of studies have been performed on the PK of antimicrobials drugs-other than cephalosporins and penicillins-in pregnant women.

INTRODUCTION: Treatment for myelodysplastic syndromes (MDS) is complex, options are limited, and insight into consecutive treatments is lacking. We performed this study to assess the outcomes in a real-world cohort of patients with MDS.MATERIALS AND METHODS: An observational population-based study was performed using the HemoBase registry. Treatment patterns and overall survival (OS) were analyzed with Kaplan-Meier analyses.RESULTS: In 144 of 280 (51.4%) patients with MDS >50 years, first-line treatment was initiated. The median age was 75.1 years (range: 52.6-92.0); the majority were male (72.2%). Hypomethylating agents (HMA), intensive chemotherapy, lenalidomide, and erythropoiesis-stimulating agents (ESA) were given as first-line treatment to 31.1% (n = 45), 12.5% (n = 18), 2.8% (n = 4), and 53.5% (n = 77) of the population, respectively. The median treatment duration was 5.8 months (95% Confidence Interval [CI]: 1.1-10.4) for HMA, 1.7 months (95%CI: 0.9-2.6) for intensive chemotherapy, 10.8 months (95%CI: 4.7-17.0) for lenalidomide, and 14.8 months (95%CI: 11.4-18.1) for ESA. Consecutive treatments were given to 27.2% of patients. The main reasons for first-line treatment discontinuation were treatment failure (45.8%), toxicity (6.9%), or death (20.1%). Median OS after termination of the initial, second, and third treatment was 5.8 months (95%CI: 3.2-8.5), 9.3 months (95%CI: 0.0-19.6), and 1.0 months (95%CI: 0.0-5.1), respectively.DISCUSSION: This study shows the treatment outcomes in a real-world population of older patients with MDS. Treatment duration and median OS after treatment discontinuation were relatively limited. There is still an urgent need for new treatment options, strategies to further optimize duration of existing treatments, and communication of realistic treatment goals and expectations, especially for older, higher-risk patients with MDS with a poor prognosis.

Purpose Peripheral neuropathy (PN) is common in multiple myeloma (MM) patients. More insight has been gained concerning the role of vitamin D in preventing PN. However, studies evaluating the effects of vitamin D3 supplementation on PN are lacking. The aims of this study are to (1) evaluate the effectiveness of a vitamin D3 regimen on achieving adequate vitamin D levels in deficient MM patients and to (2) exploratively evaluate the effect of vitamin D3 supplementation on PN. Methods Thirty-nine MM patients with inadequate (3 for 6 months according to a dose escalation regimen that consisted of one or two loading doses of 200,000 international units (IU), and maintenance doses of 800, 1600, or 3200 IU/day depending on the 25(OH)D level. A validated questionnaire was used to measure PN. Results Median 25(OH)D increased from 38 (IQR 32–52) nmol/L at baseline to 77 (IQR 72–87) nmol/L after 6 months (P P = 0.007). Conclusion The use of substantially higher vitamin D3 doses than recommended in current guidelines resulted in a significant increase in vitamin D levels in MM patients. Furthermore, evaluation of PN showed a significant decrease in PN grading. However, this exploratory evaluation needs further confirmatory research.

Liquid chromatography (LC) coupled to mass spectrometry (MS) is increasingly used for quantification of proteins in blood. This development is prompted by ongoing improvements in detection sensitivities of LC-MS instruments and corresponding sample preparation workflows. The combination of immunoaffinity enrichment and targeted LC-MS detection is a notable analytical platform in this regard as it allows for the quantification of low abundance proteins in biological matrices like plasma and serum. Here, we describe such hybrid methods which are based on the enrichment of proteins with antibodies or affimers coupled to adsorptive microtiter plates, the proteolytic digestion of enriched proteins to release protein-specific peptides, and the detection of these peptides by microflow LC coupled to selected reaction monitoring MS.

BACKGROUND AND OBJECTIVE: Pharmacokinetics (PK) are severely altered in pregnant women due to changes in volume of distribution (Vd) and/or drug clearance (CL), affecting target attainment of antibiotics in pregnant women. This review is part of a series that reviews literature on the description of PK and target attainment of antibiotics in pregnant women with specific focus on penicillins.METHODS: A systematic literature search was carried out in PubMed. Articles were labelled as relevant when information on PK of penicillins in pregnant women was available.RESULTS: Thirty-two relevant articles were included, 8 of which discussed amoxicillin (with and without clavulanic acid), 15 ampicillin, 4 benzylpenicillin, 1 phenoxymethylpenicillin, and 4 piperacillin (with and without tazobactam). No studies were found on pheneticillin and flucloxacillin in pregnant women. Ten out of 32 articles included information on both Vd and CL. During the second and third trimester of pregnancy, a higher CL and larger Vd was reported than in non-pregnant women and in pregnant women during first trimester. Reduced target attainment was described in second and third trimester pregnant women. Only 7 studies reported dosing advice, 4 of which were for amoxicillin.CONCLUSION: The larger Vd and higher CL in second and third trimester pregnant women might warrant a higher dosage or shortening of the dosing interval of penicillins to increase target attainment. Studies frequently fail to provide dosing advice for pregnant women, even if the necessary PK information was available.

Introduction The first biologic authorized for systemic lupus erythematosus (SLE) up to this date, belimumab, is currently not recommended for use during pregnancy due to lack of data. Provided that the health of the child begins with the health of the mother, pregnant patients face the dilemma of cessation or continuation of belimumab. If belimumab is stopped, there will be a risk of SLE flare and its consequences for the mother and the foetus. Continuation is also not optimal because of the lack of knowledge on safety for use during pregnancy. Aim To compare the reported foetal outcomes in SLE patients who stopped scheduled belimumab within the first trimester (group A) and those who continued scheduled belimumab during the first trimester or thereafter (group B). Material and method All belimumab-exposed pregnancy-related reports were extracted from the EudraVigilance (EV) database until March 11th, 2021. After case review, repeated cases, uninformative reports, non-medical elective abortions and foetal chromosomal abnormalities were excluded. Included pregnancies were divided into two groups (group A and B, as described above). Foetal outcomes were divided into live birth or foetal death (due to miscarriage or stillbirth) and were compared between both groups. Furthermore, neonatal outcomes, such as reporting rates of preterm birth, low birth weight and major congenital malformations were compared. Results No statistical difference in foetal death was observed between group A and B (reported numbers (%) = 32 (46.4) and 11 (52.4), respectively). Odds ratio (OR, [95% Confidence Intervals (CIs)]) of foetal death in group B compared to group A was 1.27 [0.48, 3.32]. Reporting rates of preterm birth and low birth weight were higher – though not statistically different – in group A. Conclusion The positive results of our study are supportive for the continuation of belimumab during pregnancy. Since the analysis is based on spontaneous reports/retrospective data, additional studies are needed to confirm the results.

Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treat-ment is superior to standard treatment for invasive aspergillosis.Methods: A multicentre ( n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged >= 18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treat-ment initiation of voriconazole and repeated during treatment in both groups. The TDM group had mea-sured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups ( P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) ( P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Background: The immediacy of the onset of opioids may be associated with the risk of dependency and accidental overdose. Nasal and oromucosal fentanyl dosage forms are so called immediate release fentanyl (IRF). These IRFs have been approved to treat breakthrough pain in patients with cancer who are on chronic opioid treatment only. There are signals of increased off-label prescribing of IRFs in general practices.Objectives: This study aims to provide insight into the frequency of IRF prescription in Dutch general practices and the extent to which IRF is prescribed off-label.Methods: Routinely collected electronic health records of general practices (GPs) participating in Nivel Primary Care Database were used. Adult patients with IRF prescriptions in 2019 were selected from whom dispensing data on 2018 and 2019 was available. Diagnoses were recorded by GPs using International Classification of Primary Care. Descriptive analyses were performed.Results: This study included 342 GPs with a patient population of 1,297,942 patients, 1,368 patients received at least one IRF prescription in 2019, which is equal to 1.1 patients per 1,000 registered patients. Most patients (74.9%) with an IRF prescription received an off-label prescription. A slight majority had a cancer diagnosis but nearly 65.2% did not have a maintenance therapy and 14% were opioid-naive before receiving their first IRF prescription.Conclusion: IRFs are not prescribed frequently in Dutch general practices. However, when prescribed, a relatively large portion of patients received an off-label prescription.

Background Deprescribing of preventive medication is recommended in older patients with polypharmacy, including people with type 2 diabetes (T2D). It seems that many patients in low-middle-income countries are not willing to have their medicines deprescribed. This study aims to assess attitudes of Indonesian patients with T2D towards deprescribing in general and regarding specific cardiometabolic medicines, and factors influencing their willingness to stop medicines. Methods Primary care patients with T2D of ≥60 years in Indonesia completed the revised Patients’ Attitudes Towards Deprescribing (rPATD) questionnaire. Attitudes in general and for cardiometabolic medicines were reported descriptively. Proportions of patients willing to stop one or more medicines when recommended by different healthcare professionals were compared with Chi-square test. Multiple regression analysis was used to analyse the influence between patient-related factors and the willingness to stop medicines. Results The survey was completed by 196 participants (median age 69 years, 73% female). The percentages willing to stop medicines were 69, 67, and 41%, when the general practitioner (GP), the specialist, or the pharmacist initiates the process (p-value p-value = 0.02). Using complementary or alternative medicines was not associated with the willingness to stop. If proposed by their pharmacist, patients without substantial education were more willing to stop than educated patients. Conclusions Only two-thirds of older people with T2D in Indonesia were willing to stop one or more of their medicines if the GP or specialist recommended this, and even less when the pharmacist proposed this. Attention should be given to concerns about stopping specific medicines, especially among patients using multiple glucose-lowering medicines, who may be more eligible but were less willing to accept deprescribing.

Intranasal administration of corticosteroids: patients, administration techniques and instructionsIntranasal corticosteroids (INCs) are used in allergic rhinitis and suppress allergic inflammation in the nasal mucosa. Adequate administration of INCs has received limited attention in clinical practice and scientific literature, whilst research about correct administration of asthma inhalers is widely available and has become a major focus area. Corine Rollema approaches different aspects related to treatment with INCs in her thesis. This thesis shows that there is sufficient research about the efficacy and safety of INCs. However, efficacy and safety may also depend on nasal particle deposition. According to Rollema's research it remains unclear whether, and to what extent, a set of administration variables affect deposition.In addition, patients apply certain habits for administration of INCs based on different instructional sources. The conducted research shows that various instructional sources including instructions in patient information leaflets, given by healthcare providers and in videos on YouTube® are incomplete, non-uniform or of insufficient quality.This thesis describes what characterizes current INC-users and what side effects may occur in clinical practice. In addition, the administration technique of patients was analyzed and knowledge about the administration of INCs was found to be insufficient. To successfully instruct children about the administration of INCs, this thesis indicates that an instructional video for children is an effective tool to improve administration.Rollema hopes that further research about the administration of INCs will lead to a combination of a well-substantiated administration technique and a patient-tailored instruction and evaluation, which may lead to optimal treatment with INCs.

When medicines cause side effects, we often assume that the original active substance is responsible for this. However, after ingestion, the active substance is processed (metabolized) by enzymes or attached to polar compounds in order to accelerate its excretion from the body. The original active substance undergoes chemical changes and drug metabolites are formed. These drug metabolites have their own characteristics and can also cause side effects. Recognizing, predicting and preventing these side effects requires knowledge of the metabolism of the parent drug, the formation of metabolites and their effects in the body. In this thesis we investigated the knowledge about the role of drug metabolization and metabolites on side effects. Various data sources have been explored and used for this purpose. Phenoconversion has also been investigated as a method to intervene in drug metabolization and prevent the formation of unwanted metabolites. It appears that the role of drug metabolism and the formation of drug metabolites in side effects is well recognized, but the available information is not yet fully exploited. For example, knowledge about certain chemical structures in medicines can be included more often in the recognition and prediction of known and unknown side effects. Once the role of drug metabolism and the formation of the drug metabolites in the development of the side effect is recognized, action can be taken to prevent side effects. Phenoconversion appears to be a suitable method to prevent the formation of unwanted metabolites and could be investigated and possibly be applied more often.

This thesis explores how the pharmacy team can support patients in challenging situations through patient-centred information and communication. Challenging situations, such as unexpected situations like the COVID-19 pandemic or medication changes due to medication shortages or agreements with health insurers, can affect medication use. Patient characteristics that are not easily changeable, such as limited health literacy and low literacy levels, can also influence medication use. Therefore, clear information for patients and effective communication between the pharmacy team and patients are important in these situations to prevent negative consequences such as side effects, reduced drug efficacy, and hospitalizations. Emotions, such as anger over a medication switch or uncertainty about the effectiveness of a new vaccine, often play a role in challenging situations. (Properly) dealing with emotions can lead to improved medication use, increased patient trust in their medication, and a better understanding of the importance of taking medication. Recognizing medication-related concerns of patients can also result in improved medication use. Furthermore, patient-centred information provision and communication in challenging situations can positively impact the job satisfaction of both pharmacists and pharmacy technicians. This thesis emphasizes the importance of providing clear and appropriate information to patients, addressing patient emotions and concerns, and effective communication to enhance medication use in challenging situations. It is crucial to recognize and address emotions in pharmacy practice and education, as this can contribute to the further professionalization of the profession.

This thesis focuses on real-world studies of biological treatment in severe asthma. We studied the real-world effectiveness of the expensive biologics, adding to the knowledge derived from randomized controlled trials. In addition, we connected several real-world population-based registries across Europe, paving the way for future real-world studies analyzing data from thousands of patients in Europe in a privacy-protected way. One of our studies is the first study using this approach, demonstrating the real-world effectiveness of mepolizumab in almost a thousand patients. Furthermore, we focused on the prediction of response to the expensive biologics. We found that adding an early evaluation significantly adds to the prediction of future response. Lastly, we focused on patient-tailored outcomes and found that a large proportion of patients experience a waning of the effect of their biologic over the course of the dosing interval. This study opens the way for future studies that work towards even better biological treatment of patients with severe asthma.

Rationale & Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting & Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P < 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P < 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P < 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P < 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted.

Introduction: Due to the COVID-19 vaccination campaign, national pharmacovigilance (PV) centres had to deal with high volumes of Individual Case Safety Reports (ICSRs) that needed to be processed and assessed in a short time span. This necessitated the development of a dedicated system to enable near real-time vaccine safety monitoring at the Dutch PV Centre Lareb. Objectives: To describe infrastructure, processes and Adverse Events Following Immunisation (AEFIs) reported for vaccine safety monitoring of COVID-19 vaccines during a large-scale vaccination campaign in the Netherlands. Methods: A COVID-19 tailored vaccine web-based reporting form collected information on the vaccine administered, AEFIs and other (medical) information. A fully automated process for ICSRs enabled the handling of the majority of common and known reported AEFIs. All other ICSRs were triaged daily and processed separately. There were daily signal detection meetings and weekly reports for batch analysis. Results: In 2021, Lareb received 184,411 ICSRs, a reporting rate of 0.67% for vaccines given in the Netherlands. 887,954 AEFIs were reported, mostly well-known, nonserious AEFIs; 2.4% were serious and 0.3% were fatal. 33.1% of all ICSRs were processed fully automatically. Based on the daily triage, 4.2% were flagged as ‘high priority’; 62.7% as ‘low-priority’. Twenty-seven signals and news stories about the COVID-19 vaccines were disseminated. Conclusions: Due to automatic processing of well-known AEFIs, daily triage and signal detection meetings, 99.9% of the ICSRs were processed within the compliance timeframe to Eudravigilance, and signal detection was performed during a large-scale vaccination campaign. These experiences may serve as a blueprint for future mass vaccination programs.