Asthma and COPD: Smoking, Atopy and Corticosteroid responsiveness

The aim of this thesis was to describe, investigate and compare the effects of smoking and atopy in asthma and COPD. A part of the research focused on asthmatic patients with ageing and smoking COPD phenotype, resulting in difficulties to discriminate between these two disorders. The following conclusions can be drawn: • Pathologists are able to differentiate between asthma and COPD, on condition they use a number of pathological criteria, and take the clinical setting into account, particularly the use of inhaled corticosteroids (ICS). • Prevalence of atopy is significantly higher in COPD patients who are males, have overweight and lower age. Atopy significantly associates with higher prevalence of respiratory symptoms and higher likelihood to lose cough upon treatment with busedonide. • Absence of atopy and non-ICS use contribute independently to higher numbers of IL-17 expressing cells. IL17-positive cells were found to be predominantly neutrophils. • CCL20 levels are higher in sputum of asthmatics who use ICS, whereas glucocorticoids increase the release of CCL20 by primary bronchial epithelial cells in vitro. • Smoking associates with higher epithelial HDAC-2 expression in airway biopsies from asthmatics, independent of ICS-use. • Increased Eosinophil Peroxidase (EPX) immunopositivity in airway biopsies from asthmatic subjects associates significantly with lower intact epithelium, particularly in uncontrolled asthma. In summary: heterogeneous populations of asthma and COPD patients determine the broad spectrum of obstructive airway diseases. Smoking and atopy may modulate the underlying inflammatory and clinical phenotype, and affect corticosteroid responsiveness. This heterogeneity should be taken into account when designing clinical studies

Towards early recognition of hypogammaglobulinaemia:New insights into clinical presentation patterns and screening tools

Publiekssamenvatting Herhaaldelijke infecties van de luchtwegen komen veel voor; een onderliggende afweerstoornis is zeldzaam. Dat maakt het lastig om patiënten bij wie een afweerstoornis een rol zou kunnen spelen te onderscheiden van patiënten waarbij dit niet het geval is. Als de infecties heel vaak optreden of afwijkend verlopen, moet aan een onderliggende afweerstoornis worden gedacht. Van alle afweerstoornissen komt een tekort aan antistoffen - ook wel immuunglobulinen genoemd - het meest voor (primaire antistof deficiëntie, PAD), maar dit is nog steeds erg zeldzaam. De bekendste PAD is ‘common variable immunodeficiency’ (CVID). Deze diagnose wordt gesteld als er meerdere klassen van antistoffen verlaagd zijn, meestal immuunglobuline A (IgA) en immuunglobuline G (IgG) of soms verlaagd immuunglobuline M (IgM) en de patiënt na vaccinatie niet in staat is tot het aanmaken van antistoffen. Echter, veel meer patiënten met PAD voldoen niet precies aan deze criteria. Wij verwijzen naar deze vorm van PAD als ‘unclassified antibody deficiency’ (unPAD), een afweerstoornis die wordt beschouwd als milder. De kennis over deze groep afweerstoornissen is gering. De meeste artsen die niet gespecialiseerd zijn in afweerstoornissen, denken niet aan een onderliggende afweerstoornis bij patiënten met herhaaldelijke ‘normale’ infecties en/of chronische vermoeidheid. De diagnose wordt bij deze patiënten daarom vaak pas laat gesteld, met als gevolg dat er vaak al onherstelbare schade is ontstaan, zoals verwijde en ontstoken luchtwegen. Daarom is het belangrijk om PADs tijdig te herkennen. Hoofddoelen van deze thesis zijn: 1) PADs eerder herkennen, en 2) meer inzicht krijgen in de klachten waarmee PAD-patiënten bij de arts komen voordat de diagnose wordt gesteld. Dit proefschrift heeft aangetoond dat patiënten met ‘mildere’ PADs, vaak genegeerd worden in de literatuur en vaak niet volledig geanalyseerd of nauwkeurig beschreven worden. Het is echter belangrijk om ook deze patiëntgroep op tijd te herkennen en behandelen, omdat bij unPAD vaak ook andere ziekten voorkomen; 44% van de patiënten in ons algemeen ziekenhuis cohort had al schade aan de luchtwegen bij diagnose en hun kwaliteit van leven was verminderd op alle domeinen. In onze meta-analyse tonen we aan dat met de huidige waarschuwingssignalen, 25% van alle CVID-patiënten gemist worden. Naast deze medische aspecten kunnen ook niet-medische aspecten helpen om patiënten met PAD te onderscheiden van de patiënten met chronisch vermoeidheid syndroom of onschuldige infecties. Dit proefschrift heeft namelijk aangetoond dat patiënten met PAD hun klachten neigen te negeren en zoveel mogelijk doorgaan met hun normale leven. Dit verschilt van bijvoorbeeld patiënten met chronisch vermoeidheid syndroom, die vaker gebruik maken van passieve coping strategieën. Tenslotte toont ons proefschrift de bruikbaarheid van een screeningstest (23-valente Pneumokokken IgG test) aan om PAD eerder op te sporen. Onderzoek van een groter unPAD cohort is belangrijk om onze resultaten te bevestigen en klinische presentatie patronen beter in kaart te brengen. Hiervoor zal gebruik gemaakt worden van een reeds bestaande Europese patiëntenregistratie die opgezet is door de European Society for Immunodeficiencies (ESID online Database). Een groot cohort maakt daarnaast ook onderscheid van potentiele subgroepen mogelijk, waardoor bepaald kan worden welke patiëntencategorieën risico hebben op ernstigere complicaties en dus meer strikte follow-up en/of andere behandelingen nodig hebben. Om deze reden is de Europese multi-centrum ‘unPAD study’ ontwikkeld, waarbij gebruik wordt gemaakt van de ESID online Database en waarvan de dataverzameling nog steeds loopt

Exercise-induced respiratory symptoms in childhood.

Background Exercise-induced symptoms (EIS) are common in childhood and can lead to physical activity avoidance, reduced quality of life, and overtreatment with inhaled corticosteroids if mistakenly diagnosed as asthma. Diagnosis of EIS can be difficult because different aetiologies share similar clinical presentations. Reported symptoms can be helpful to identify the correct diagnosis, as certain symptoms are typically associated with specific diagnoses (e.g. expiratory wheeze for exercise-induced bronchoconstriction, and throat tightness for inducible laryngeal obstruction (ILO)). Only few studies have investigated diagnosis, diagnostic evaluations, and reported symptoms in children with EIS. Aims: The overall aim of this PhD thesis were to gain epidemiological knowledge about diagnosis, diagnostic investigations, and reported symptoms in children with EIS. Specifically, I aimed to 1) set up a prospective study including children referred to paediatric respiratory outpatient clinics with respiratory symptoms 2) study diagnosis, diagnostic investigations and management in children referred for EIS 3) study if parent reported EIS are helpful to distinguish different diagnoses and 4) study EIS reported by physicians in the clinical history and assess agreement with parent-reported symptoms. 5) Additionally, I aimed to validate a model to predict asthma in preschool children. Methods To address the aims of this PhD thesis, I used data from the Swiss Paediatric Airway Cohort (SPAC), a longitudinal observational clinical study of children referred with respiratory symptoms to paediatric respiratory outpatient clinics in Switzerland. I used data from medical records to get information on referral diagnosis, final diagnosis, diagnostic investigations and proposed management from the outpatient clinics. I used data from parental questionnaires to get information about symptoms. For publication 5, I used data from the Leicestershire Respiratory Cohort (LRC) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Results The main body of this thesis consists of 5 articles (2 published, 1 in review, and 2 to be submitted). These are the main findings in summary: Publication 1: The SPAC study is a novel longitudinal observational cohort study of children with respiratory symptoms. By January 7, 2020, the SPAC study includes 1893 children 5 recruited from 10 pulmonology clinics. The SPAC study will provide real-life data from paediatric pulmonology clinics in Switzerland and will serve as a platform for nested studies. Publication 2: Diagnosis given at the paediatric respiratory outpatient clinic differed from suspected referral diagnosis in half of the children referred primarily for EIS. Dysfunctional breathing was a common diagnosis at the outpatient clinic but rarely suspected at time of referral. Diagnostic evaluation, management, and follow-up were inconsistent between clinics and diagnostic groups. Publication 3: Parent reported EIS (including information on type of symptoms, activities triggering EIS, and characteristics of symptoms) can help to distinguish different diagnoses in children seen with EIS. Publication 4: Physicians reported EIS in the medical records in almost all children referred for EIS. Activities triggering EIS and characteristics of EIS (e.g. localisation of symptoms, respiratory phase, and onset and duration of symptoms) were reported only in around half of the children. Agreement with parent questionnaire reported EIS ranged from poor to moderate. Publication 5: PARC predicted asthma at school age equally well in the validation cohort, ALSPAC (AUC 0.77), compared with the development cohort, LRC (AUC 0.78). Apart from severity of wheeze and cough, family history of symptoms, age, and sex, also exercise as trigger for respiratory symptoms predicted asthma at school age in the development and validation cohort. The discriminative ability of the PARC appeared to be robust to changes in inclusion criteria, scoring variables, and outcome definitions. PARC may need recalibration when applied in other populations. Additionally, I contributed to further publications, which are included in this PhD thesis as related publications. Conclusion In summary, diagnosis, diagnostic investigations, and management in children with EIS differed between outpatient clinics and diagnosis groups, indicating a need for diagnostic guidelines. Parental reported symptoms can help to distinguish diagnoses in children with EIS. Future studies should focus on developing an algorithm for diagnosing children seen with EIS including both reported symptoms and objective diagnostic tests.

Association between asthma during pregnancy and postpartum depression

Il a été démontré dans plusieurs études épidémiologiques qu’il existe un risque important de dépression chez les femmes souffrant d'asthme en dehors de la grossesse. Cependant, on en connait peu sur l'association entre l'asthme pendant la grossesse et la dépression post-partum. Par conséquent, le but de cette étude était de quantifier la force de l’association entre l'asthme pendant la grossesse et la dépression post-partum. À l’aide des bases de données administratives du Québec, nous avons construit une cohorte de 35,520 grossesses de femmes asthmatiques et 197,057 grossesses de femmes non asthmatiques qui ont accouchées entre 1998 et 2009. Les femmes asthmatiques ont été identifiées à l'aide d’une définition opérationnelle validée. Nous avons utilisé la définition de Statistiques Canada pour détecter la dépression post-partum. Cette définition se base sur les codes diagnostics de la dépression enregistrés dans les bases de données de la RAMQ et de MED-ECHO dans l’année suivant l’accouchement. Un modèle d'équations généralisées a été utilisé pour estimer les ratios de cotes (RC) brutes et ajustés et les intervalles de confiance (IC) à 95% entre l’asthme pendant la grossesse et la dépression post-partum. La proportion de femmes ayant eu une dépression post-partum au cours de l’année suivant l’accouchement était plus élevée chez les asthmatiques que chez les non-asthmatiques (6,1% contre 2,9%). Après ajustement pour les variables potentiellement confondantes, nous avons observé que les femmes asthmatiques étaient 58% plus susceptibles de souffrir de dépression post-partum que les femmes non-asthmatiques (RC ajusté : 1,58 ; IC 95%, 1,50 à 1,67). Les résultats de notre étude suggèrent un risque accru de dépression post-partum chez les femmes asthmatiques. Une attention particulière devrait être accordée aux symptômes dépressifs chez les femmes asthmatiques dans l’année suivant l’accouchement pour détecter la dépression post-partum plus rapidement et intervenir plus efficacement.There is evidence from several epidemiological studies on the increased risk of depression among women with asthma outside of pregnancy. However, we found no studies designed to investigate the association between asthma during pregnancy and postpartum depression. Therefore, the purpose of this study was to assess the association between asthma during pregnancy and postpartum depression. Based on Quebec administrative databases, we constructed a cohort of 35,520 pregnancies from asthmatic women and 197,057 pregnancies from non-asthmatic women who delivered between 1998 and 2009. Asthmatic women were identified using a validated operational definition. Postpartum depression was defined and specified with diagnostic codes for depression from the definition of Statistics Canada recorded in the RAMQ or MED-ECHO databases and assessed 1 year postpartum. A generalized estimating equation model was used to estimate the crude and adjusted odds ratios (ORs) of postpartum depression and 95% confidence intervals (CI) comparing women with and without asthma during pregnancy. The proportion of postpartum depression 1 year after delivery was higher among asthmatic compared to non-asthmatic pregnant women (6.1% vs. 2.9%). After adjusting for potential confounders, we observed that women with asthma were 58% more likely to have postpartum depression (adjusted OR: 1.58; 95%CI, 1.50-1.67) than women without asthma during pregnancy. The findings of our study suggest an increased risk of postpartum depression among asthmatic women. Attention should be given to depressive symptoms in asthmatic women in the year postpartum to detect postpartum depression more rapidly and intervene more efficiently

Utilizing Consumer Health Posts for Pharmacovigilance: Identifying Underlying Factors Associated with Patients’ Attitudes Towards Antidepressants

Non-adherence to antidepressants is a major obstacle to antidepressants therapeutic benefits, resulting in increased risk of relapse, emergency visits, and significant burden on individuals and the healthcare system. Several studies showed that non-adherence is weakly associated with personal and clinical variables, but strongly associated with patients’ beliefs and attitudes towards medications. The traditional methods for identifying the key dimensions of patients’ attitudes towards antidepressants are associated with some methodological limitations, such as concern about confidentiality of personal information. In this study, attempts have been made to address the limitations by utilizing patients’ self report experiences in online healthcare forums to identify underlying factors affecting patients attitudes towards antidepressants. The data source of the study was a healthcare forum called “askapatients.com”. 892 patients’ reviews were randomly collected from the forum for the four most commonly prescribed antidepressants including Sertraline (Zoloft) and Escitalopram (Lexapro) from SSRI class, and Venlafaxine (Effexor) and duloxetine (Cymbalta) from SNRI class. Methodology of this study is composed of two main phases: I) generating structured data from unstructured patients’ drug reviews and testing hypotheses concerning attitude, II) identification and normalization of Adverse Drug Reactions (ADRs), Withdrawal Symptoms (WDs) and Drug Indications (DIs) from the posts, and mapping them to both The UMLS and SNOMED CT concepts. Phase II also includes testing the association between ADRs and attitude. The result of the first phase of this study showed that “experience of adverse drug reactions”, “perceived distress received from ADRs”, “lack of knowledge about medication’s mechanism”, “withdrawal experience”, “duration of usage”, and “drug effectiveness” are strongly associated with patients attitudes. However, demographic variables including “age” and “gender” are not associated with attitude. Analysis of the data in second phase of the study showed that from 6,534 identified entities, 73% are ADRs, 12% are WDs, and 15 % are drug indications. In addition, psychological and cognitive expressions have higher variability than physiological expressions. All three types of entities were mapped to 811 UMLS and SNOMED CT concepts. Testing the association between ADRs and attitude showed that from twenty-one physiological ADRs specified in the ASEC questionnaire, “dry mouth”, “increased appetite”, “disorientation”, “yawning”, “weight gain”, and “problem with sexual dysfunction” are associated with attitude. A set of psychological and cognitive ADRs, such as “emotional indifference” and “memory problem were also tested that showed significance association between these types of ADRs and attitude. The findings of this study have important implications for designing clinical interventions aiming to improve patients\u27 adherence towards antidepressants. In addition, the dataset generated in this study has significant implications for improving performance of text-mining algorithms aiming to identify health related information from consumer health posts. Moreover, the dataset can be used for generating and testing hypotheses related to ADRs associated with psychiatric mediations, and identifying factors associated with discontinuation of antidepressants. The dataset and guidelines of this study are available at https://sites.google.com/view/pharmacovigilanceinpsychiatry/hom

Atopic dermatitis in adults : epidemiological studies of comorbidity and studies of patients on systemic treatment

Background: Atopic dermatitis (AD) is one of the most common chronic skin disorders globally. It is an itchy inflammatory skin disease that can have a detrimental impact on health-related quality of life. In recent years, AD has been associated with non-atopic conditions, though this requires further exploration. Novel understanding of AD pathogenesis has recently led to development of the first biological treatment. The overall aims of the thesis were to assess cardiovascular disease (CVD), autoimmune disease and depression among adults with AD, and to investigate the response to, and some adverse events from, systemic treatment that includes the first biological for AD. Methods: Register-based, case-control studies were conducted to assess CVD and autoimmune comorbidity among patients with AD. The source population comprised the entire Swedish population aged ≥ 15 years. Cases, including all those with an inpatient diagnosis of AD (from 1968) and/or a specialist outpatient diagnosis of AD (from 2001) through 2016, were matched by sex and age to healthy controls (104,832 cases of AD, 1,022,435 controls). Patients were classified as having severe AD if they had received systemic pharmacotherapy for AD or had been treated in a dermatological ward with AD as the main diagnosis. Otherwise, AD was classified as non-severe. The clinical cohort studies and the case-series used data from a register containing prospectively collected data from adult patients with AD on systemic treatment at the Karolinska University Hospital from 2017. The register was launched for national use in 2019. Result: Studies I–II: After multivariable adjustments for comorbidities and socioeconomic status, AD was associated with angina pectoris (adjusted odds ratio (aOR) 1.13, 95% confidence interval (CI) 1.08–1.19). Non-severe AD was associated with myocardial infarction (aOR 1.15, 95% CI 1.07–1.23) among men. Severe AD was associated with ischaemic stroke, with similar estimates in men and women (aOR 1.19, 95% CI 1.07–1.33). Diabetes mellitus, hyperlipidaemia, and hypertension were more prevalent in patients with severe AD than in controls, and hyperlipidaemia and hypertension were also more prevalent in patients with non-severe AD than in controls. Having AD was significantly associated with having one or more autoimmune diseases as compared with controls: (aOR 1.97, 95% CI 1.93–2.01), and this association was significantly stronger for having multiple autoimmune diseases than for having only one. The association was strongest for autoimmune disorders involving the skin, the gastrointestinal tract or the connective tissue. Studies III–V: In a caseseries of 10 patients with severe, long-lasting AD and most often also previous eye disease, 9/10 developed eye complications during dupilumab treatment, most commonly conjunctivitis (7/10). In a cohort study of patients treated with dupilumab (n = 12), weight gain (mean 6.1 kg, range 0.1–18.0 kg, p = 0.002) was seen after 1 year on treatment. In spite of these adverse events, dupilumab was very effective and safe. More than half of patients with moderate-to-severe AD eligible for systemic treatment (n = 60) had depressive symptoms, 25% of whom presented with moderate-to-severe depression and 5% of whom had pronounced suicidal ideation. Systemic treatment for AD significantly reduced depressive symptoms, in addition to relieving symptoms of AD. Conclusion: AD was associated with CVD and several autoimmune disorders. More than half of the patients with moderate-to-severe AD in routine dermatological care had depressive symptoms. Dupilumab was very effective and safe overall, but was associated with ocular adverse events and weight gain in these small studies. Systemic treatment for AD significantly reduced depressive symptoms in parallel with reducing AD symptoms

Front-Line Physicians' Satisfaction with Information Systems in Hospitals

Day-to-day operations management in hospital units is difficult due to continuously varying situations, several actors involved and a vast number of information systems in use. The aim of this study was to describe front-line physicians' satisfaction with existing information systems needed to support the day-to-day operations management in hospitals. A cross-sectional survey was used and data chosen with stratified random sampling were collected in nine hospitals. Data were analyzed with descriptive and inferential statistical methods. The response rate was 65 % (n = 111). The physicians reported that information systems support their decision making to some extent, but they do not improve access to information nor are they tailored for physicians. The respondents also reported that they need to use several information systems to support decision making and that they would prefer one information system to access important information. Improved information access would better support physicians' decision making and has the potential to improve the quality of decisions and speed up the decision making process.Peer reviewe

European position paper on rhinosinusitis and nasal polyps 2020

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included

Viral infections in 47 CVID patients in allergy and immunology department of Rasool E Akram hospital in Tehran

Background: CVID is a heterogeneous primary immune deficiency with infectious, autoimmune and autoinflamatory features. It is most common symptomatic PID in Iran, with prevalence of 1 in 25000 to 50000 people. CVID has been divided into some phenotypes to produce more homogenized subpopulations. CVID is not a pure Ab deficiency .and because of both abnormalities in Tcell and innate immunity in combination with B cell dysfunction these patients are predisposed to viral and opportunistic infections. Method: prevalence of viral infections is reported in 47 CVID patients registered in Rasool E Akram hospital in Tehran. Patients have been diagnosed as CVID with the PAGID-ESID diagnostic criteria in our department or referred from other clinics for follow up and treatment. Diagnosis of viral germs has been made by clinical signs, pathological significances and in some cases by PCR. Cases: 9 patients (19%) had problems with viral infections. Infections occurred befor diagnosis of CVID in some cases or after that. Four patients (8.5 %) had problems with wart. Sever mucocutaneus HSV infection has occurred in 3 (6 %), recurrent zona in one (2 %) and CMV infection as colitis or pneumonitis in 3(6 %) patients. Sever progressive lethal CNS infection with JC virus occurred in one patient. Conclusion: evidences show that CVID is not a pure B cell defect, and we should be aware of opportunistic and viral infections that in some cases may be fatal

European Position Paper on Rhinosinusitis and Nasal Polyps 2020

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise. The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included.Peer reviewe