The pharmacotherapy team: A novel strategy to improve appropriate in-hospital prescribing using a participatory intervention action method.

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

Explorative Prospective Evaluation of Short-Term Subjective Effects of Hormonal Treatment in Trans People-Results from the European Network for the Investigation of Gender Incongruence.

INTRODUCTION: Although many studies on the short- and long-term effects of hormonal treatment (HT) in trans people focus on objective changes such as body composition or bone density, few studies have evaluated self-reported effects of HT. AIM: To evaluate self-reported symptoms during the first year of HT in trans people. METHODS: This study is part of the European Network for the Investigation of Gender Incongruence, a multicenter prospective cohort study. For this study, 205 trans women and 193 trans men from the gender clinics of Amsterdam, Ghent, and Florence, who were >18 years of age and started hormonal treatment were included. Questionnaires, self-developed based on the Menopause Rating scale and clinical experiences, were completed, and changes in symptom scores were analyzed using linear mixed models. MAIN OUTCOME MEASURES: Self-reported psycho vegetative symptoms, as well as physical, cognitive, emotional, sexual and genital complaints, and pain were evaluated at baseline and after 3, 6, and 12 months of HT using a 4-point Likert scale (no, mild, moderate, or severe complaints). RESULTS: In trans men, with a median age of 23, transient increases were reported in night sweats, weight gain, and clitoral pain. Persistent increases were reported for hot flashes, balding, voice instability, acne, and increase in sexual desire, whereas emotional instability, fear, and menses decreased. For trans women, with a median age of 29, hot flashes, night sweats, fatigue, weight gain, changes in olfactory sense, brittle nails, emotional instability, mood swings, and breast tenderness increased persistently during 12 months of HT, whereas a decrease was observed for balding and sexual desire. Sleeping difficulties decreased temporarily. No changes were observed in palpitations, dizziness, abdominal complaints, anxiety, panic attacks, cognition, and pain, except for clitoral and breast pain. CLINICAL IMPLICATIONS: Knowledge on the occurrence of these self-reported, subjective effects and their course over time may help physicians informing trans people starting with and during HT. STRENGTHS & LIMITATIONS: This study was performed in a large cohort of trans people. The follow-up period was limited to 12 months. CONCLUSION: Changes in self-reported symptoms were mentioned in all investigated areas, except cognition. Most symptoms were as expected and even desired, whereas others may be considered unpleasant by some trans people. van Dijk D, Dekker MJHJ, Conemans EB, et al. Explorative Prospective Evaluation of Short-Term Subjective Effects of Hormonal Treatment in Trans People-Results from the European Network for the Investigation of Gender Incongruence. J Sex Med 2019;16:1297-1309.

The Use of Remote Monitoring Technologies: A Review of Recent Regulatory Scientific Advices, Qualification Opinions, and Qualification Advices Issued by the European Medicines Agency.

Aims: Recently, the use of novel remote monitoring technologies (RMTs) in trials has gained much interest. To facilitate regulatory learning, we evaluated qualification opinions (QOs) and advices (QAs) and scientific advices (SAs) of the Committee for Medicinal Products for Human Use (CHMP) to gain insight in the types of devices that are intended to be used in clinical trials for supporting/submitting application for obtaining marketing authorization (registration trials) and the main recommendations of the CHMP. Methods: QOs, QAs, and SAs of the CHMP that assessed RMTs between 2013 and 2019 were eligible for our study. The following information was extracted from the documents: year of advice/opinion, device and endpoints used, type of endpoint (primary, secondary, exploratory, or safety), and main recommendations of the CHMP. Results: In total two QOs, four QAs, and 59 SAs were included in our study (total of SAs between 2013 and 2019 = 4,054). In the SAs, accelerometers to measure activity and/or sleep parameters (n = 31) were the most frequently used devices, followed by mobile applications (n = 6) and glucose monitoring devices (n = 6). Usually, these measures were proposed as secondary or exploratory endpoints (n = 32). The main recommendations of the CHMP were related to relevance of the (novel) outcome measure; validation; precision, accuracy, sensitivity, and specificity; compliance; sampling interval; and data handling and privacy. Conclusions: Although there was a trend toward an increased use over time, the use of RMTs in registration trials is still relatively rare. In the absence of formal European regulatory guidance on mHealth technologies, insight in the main recommendations of the CHMP may stimulate the use of novel RMTs in a regulatory context.

Sex Proportionality in Pre-clinical and Clinical Trials: An Evaluation of 22 Marketing Authorization Application Dossiers Submitted to the European Medicines Agency.

This study assessed to what extent women were included in all phases of drug development; whether the clinical studies in the marketing authorization application dossiers include information per sex; and explored whether there are differences between women and men in the drugs' efficacy and safety. Data were extracted from dossiers submitted to the European Medicines Agency. Twenty-two dossiers of drugs approved between 2011 and 2015 for the treatment of various diseases were included. Female animals were included in only 9% of the pharmacodynamics studies, but female and male animals were included in all toxicology studies. Although fewer women than men were included in the clinical studies used to evaluate pharmacokinetics (PK) (29 to 40% women), all dossiers contained sex-specific PK parameter estimations. In the phase III trials, inclusion of women was proportional to disease prevalence for depression, epilepsy, thrombosis, and diabetes [participation to prevalence ratio (PPR) range: 0.91-1.04], but women were considered underrepresented for schizophrenia, hepatitis C, hypercholesterolemia, HIV, and heart failure (PPR range: 0.49-0.74). All dossiers contained sex-specific subgroup analyses of efficacy and safety. There seemed to be higher efficacy for women in one dossier and a trend toward lower efficacy in another dossier. More women had adverse events in both treatment (73.0 vs. 70.6%, p < 0.001) and placebo groups (69.5 vs. 65.5%, p < 0.001). In conclusion, women were included throughout all phases of clinical drug research, and sex-specific information was available in the evaluated dossiers. The included number of women was, however, not always proportional to disease prevalence rates.

Effect of glucocorticoid receptor gene polymorphisms in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a postinfectious immune-mediated polyneuroradiculopathy in which host factors influence disease susceptibility and clinical course. Single-nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene influence the sensitivity to glucocorticoids and are related to both microbial colonization and susceptibility to develop auto-immune disease. This genetic variation may therefore also influence the chance to develop GBS. In this study, we genotyped 318 GBS patients and 210 control subjects for five known SNPs in the GR gene. We could distinguish six different GR haplotypes of which two carried the BclI polymorphism: haplotype 1, which consists of the minor allele of BclI in combination with the common variant of TthIIII and haplotype 2, which carries the minor allele of BclI as well as the minor allele of TthIIII. The GR haplotypes were not related to susceptibility to develop GBS. Carriers of haplotype 2 had more frequently preceding diarrhea, serum antibodies to GM1 and GD1a, and more severe muscle weakness at entry. Haplotype 1 carriers had a significantly better prognosis. In conclusion, GR haplotypes are not a susceptibility factor for GBS. However, haplotypes carrying the minor allele of the BclI polymorphism were related to the phenotype and outcome of GBS.

Alignment of European Regulatory and Health Technology Assessments: A Review of Licensed Products for Alzheimer's Disease.

Aims: To facilitate regulatory learning, we evaluated similarities and differences in evidence requirements between regulatory and health technology assessment (HTA) bodies of Alzheimer's disease (AD) approved products. Methods: The European marketing authorisation application dossiers and European public assessment reports (EPARs) of the licensed AD drugs were screened to identify the phase III randomised controlled trials (RCTs) and outcomes used. We also screened the assessment reports of the National Institute of Health and Care Excellence (NICE, England) and the National Health Care Institute (ZiN, the Netherlands) to identify the studies and outcomes used in HTA assessments. Results: The application dossiers of donepezil, galantamine, rivastigmine, and memantine contained 16 phase III RCTs in total. These trials were also included in HTA assessments except that NICE excluded studies that were not published (n = 2) or trials that included patients with other types of dementia (n = 3). In the regulatory assessments the focus was on cognitive and global outcomes, and to some extent on function. In the HTA assessments of clinical effectiveness other domains were also covered including: function, behaviour and mood, and, occasionally, quality of life. In the economic analyses of NICE the domains cognition, function, and quality of life were included. Conclusion: There was a large overlap in inclusion of trials in regulatory and HTA assessments, although the focus on specific outcomes slightly differed. Understanding the methods and perceptions of both authorities can stimulate regulatory and HTA cross-talk and further alignment, and therefore more rapid patient access to new treatments.

Lack of Association of the 11beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia.

CONTEXT: Recently, it was proposed that a combination of the 83,557insA polymorphism in the 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene and the R453Q polymorphism in the hexose-6-phosphate dehydrogenase (H6PD) gene interacts to cause cortisone reductase deficiency (CRD) when at least three alleles are affected. OBJECTIVE: The aim was to study the separate and combined effects of these polymorphisms on body composition, adrenal androgen production, blood pressure, glucose metabolism, and the incidence of dementia in the healthy elderly population. DESIGN/SETTING/PARTICIPANTS: The Rotterdam study (n = 6105) and the Frail Old Men study (n = 347) are population-based cohort studies in the elderly. MAIN OUTCOME MEASURES: Genotype distributions and influences of (combined) genotypes on body mass index, adrenal androgen production, waist to hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, and incidence of dementia were measured. RESULTS: No influence of the HSD11B1 83,557insA (allele frequencies 22.0 and 21.5%) and H6PD R453Q (allele frequencies 22.9 and 20.2%) variants was found for the different outcome measures that were investigated, either separately or when at least three alleles were affected. CONCLUSIONS: Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia. Moreover, the high frequencies observed for these two polymorphisms do not correspond to the low incidence of CRD observed in the general population. Altogether, it is unlikely that these polymorphisms cause CRD.

The Very Low-Dose Dexamethasone Suppression Test in the General Population: A Cross-Sectional Study.

Determinants of the hypothalamic-pituitary-adrenal (HPA) axis functioning are increasingly explored in population-based studies. However, functional tests measuring the negative feedback of the HPA axis cannot easily be implemented into large observational studies. Furthermore, high doses of dexamethasone often completely suppress the HPA axis in healthy persons. This study aimed to detect the effects of the health, lifestyle and sociodemographic factors, psychiatric problems and cognitive functions on the negative feedback of the HPA axis using a very low-dose (0.25 mg) dexamethasone suppression test (DST).We evaluated the associations of several determinants with the saliva cortisol concentrations after dexamethasone intake in a confounder-adjusted model also corrected for baseline saliva cortisol concentrations in the Rotterdam Study, a large population-based study (N = 1822). We found that female sex, low income, lack of exercise, instrumental disability and smoking were all independently associated with stronger suppression of the HPA axis. Even though there were no linear associations between psychiatric measures and cortisol suppression, we found that depressive symptoms and anxiety disorders were more common in persons with non-suppression of cortisol. Conversely, psychotropic medication use was related to enhanced suppression of cortisol after DST. In this large study, we found that female gender, low socioeconomic status and poor health were all related to suppression of the HPA axis. Non-linear associations were detected between the suppression of the HPA axis and common psychiatric disorders in community-dwelling persons.

Incidence and recurrence of late-life depression.

CONTEXT: Depression is common in old age. Nevertheless, few incidence studies have established how often depression occurs in elderly persons with and without a history of depression. OBJECTIVES: To determine the incidence and recurrence rates of depression in an elderly population. DESIGN, SETTING, AND PARTICIPANTS: A cohort study of community-dwelling elderly persons aged 56 years or older residing in Rotterdam, the Netherlands, performed between September 1993 and October 2005 and encompassing baseline and 2 follow-up examinations as well as continuous procedures. The study population consisted of 5653 participants free of dementia. Depression was identified through standardized psychiatric examinations, monitoring of medical records, registration of antidepressant use, and self-reported histories of depression. We categorized the depression as depressive syndromes, including DSM-IV-defined major depression, or clinically relevant depressive symptoms. MAIN OUTCOME MEASURES: Incidence and recurrence rates for depressive syndromes as well as for depressive syndromes and symptoms combined. In addition to overall rates, sex- and age-specific rates were calculated. RESULTS: During the follow-up period of 8 years on average, 566 depressive syndromes and 1073 episodes of clinically relevant depressive symptoms occurred. For depressive syndromes, the incidence rate was 7.0 (95% confidence interval, 6.0-8.3) per 1000 person-years and the recurrence rate was 27.5 (95% confidence interval, 23.7-32.1) per 1000 person-years. The incidence and recurrence rates more than doubled when episodes of depressive symptoms were included. The recurrence rate of depressive syndromes was equal for women and men, but all other rates were almost twice as high for women compared with men. No rates seemed to change with age. CONCLUSIONS: The incidence rate of depression in the elderly population is low except when episodes of clinically relevant depressive symptoms are accounted for. Most late-life depression occurs in persons with a history of depression. Moreover, the recurrence rate of depressive syndromes does not differ between men and women.