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Background/objectives: Lactose-[(15)N, (15)N]-ureide is used to study the fate of the colonic urea-nitrogen metabolism. During the passage through the gastrointestinal tract, lactose ureide is hydrolysed to glucose ureide, which is absorbed to a limited extent from the small intestine and is excreted urinarily. In the present study, a procedure has been developed to quantify the urinary excretion of glucose-[(15)N, (15)N]-ureide. In addition, urine and faecal samples obtained during a dietary intervention study with the prebiotic lactulose were retrospectively analysed.Subjects/methods: The glucose ureide and lactose ureide content was measured by GC-MS in 19 healthy volunteers. After consumption of a standard test meal containing 75 mg lactose-[(15)N, (15)N]-ureide, six healthy volunteers performed a fractionated 24 h urine collection to investigate the urinary excretion of glucose-[(15)N, (15)N]-ureide. In 13 volunteers, the effect of lactulose administration on the urinary excretion of glucose-[(15)N, (15)N]-ureide was analysed.Results: The urinary excretion of glucose-[(15)N, (15)N]-ureide reached its maximum level in the 3-6 h urine collection and decreased in the 6-9 h urine. The label was still detectable in the 9-24 h urine collection. The cumulative excretion of (15)N-labelled glucose ureide after 24 h amounted 12.91%. No significant differences in glucose-[(15)N, (15)N]-ureide excretion were found in either of the urine fractions after administration of lactulose, compared with baseline. In none of the urine samples lactose-[(15)N, (15)N]-ureide was detected.Conclusions: In conclusion, the results obtained in the present study indicated that the percentage dose glucose-[(15)N, (15)N]-ureide recovered in urine is rather constant and not influenced by the presence of lactulose. [ABSTRACT FROM AUTHOR]

Background/Objectives:Lactose-[15N, 15N]-ureide is used to study the fate of the colonic urea-nitrogen metabolism. During the passage through the gastrointestinal tract, lactose ureide is hydrolysed to glucose ureide, which is absorbed to a limited extent from the small intestine and is excreted urinarily. In the present study, a procedure has been developed to quantify the urinary excretion of glucose-[15N, 15N]-ureide. In addition, urine and faecal samples obtained during a dietary intervention study with the prebiotic lactulose were retrospectively analysed.Subjects/Methods:The glucose ureide and lactose ureide content was measured by GC-MS in 19 healthy volunteers. After consumption of a standard test meal containing 75 mg lactose-[15N, 15N]-ureide, six healthy volunteers performed a fractionated 24 h urine collection to investigate the urinary excretion of glucose-[15N, 15N]-ureide. In 13 volunteers, the effect of lactulose administration on the urinary excretion of glucose-[15N, 15N]-ureide was analysed.Results:The urinary excretion of glucose-[15N, 15N]-ureide reached its maximum level in the 3-6 h urine collection and decreased in the 6-9 h urine. The label was still detectable in the 9-24 h urine collection. The cumulative excretion of 15N-labelled glucose ureide after 24 h amounted 12.91%. No significant differences in glucose-[15N, 15N]-ureide excretion were found in either of the urine fractions after administration of lactulose, compared with baseline. In none of the urine samples lactose-[15N, 15N]-ureide was detected.Conclusions:In conclusion, the results obtained in the present study indicated that the percentage dose glucose-[15N, 15N]-ureide recovered in urine is rather constant and not influenced by the presence of lactulose. [ABSTRACT FROM AUTHOR]

Background and Aims: Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is associated with an increased cardiovascular risk, particularly the myeloperoxidase AAV serotype (MPO-AAV). Distinct alterations in monocyte phenotypes may cause accelerated atherosclerotic disease in AAV., Methods: A cohort including 43 AAV patients and 19 healthy controls was included for downstream analyses. Extensive phenotyping of monocytes and monocyte-derived macrophages was performed using bulk RNA-sequencing and flow cytometry. An in vitro transendothelial migration assay reflecting intrinsic adhesive and migratory capacities of monocytes was employed. Subsequent sub-analyses were performed to investigate differences between serological subtypes., Results: Monocyte subset analysis showed increased classical monocytes during active disease, whereas non-classical monocytes were decreased compared to healthy controls (HC). RNA-sequencing revealed upregulation of distinct inflammatory pathways and lipid metabolism-related markers in monocytes of active AAV patients. No differences were detected in the intrinsic monocyte adhesion and migration capacity. Compared to proteinase-3(PR3)-AAV, monocytes of MPO-AAV patients in remission expressed genes related to inflammation, coagulation, platelet-binding and interferon signalling, whereas the expression of chemokine receptors indicative of acute inflammation and monocyte extravasation (i.e., CCR2 and CCR5) was increased in monocytes of PR3-AAV patients. During active disease, PR3-AAV was linked with elevated serum CRP and increased platelet counts compared to MPO-AAV., Conclusions: These findings highlight changes in monocyte subset composition and activation, but not in the intrinsic migration capacity of AAV monocytes. MPO-AAV monocytes are associated with sustained upregulation of inflammatory genes, whereas PR3-AAV monocytes exhibit chemokine receptor upregulation. These molecular changes may play a role in elevating cardiovascular risk as well as in the underlying pathophysiology of AAV., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Diagnosing lactose malabsorption is usually based on hydrogen excretion in breath after a lactose challenge. However, a proportion of subjects with lactose malabsorption will not present a rise in hydrogen. Measuring excretion of methane or stable isotope labeled 13 CO 2 after ingestion of 13 C-lactose has been proposed to mitigate this problem., Objective: The aim of the study was to assess the performance of measuring methane and 13 CO 2 in individuals with normal hydrogen excretion compared to a genetic lactase non-persistence test., Methods: Individuals referred for lactose breath testing and healthy controls were included. Participants received 13 C-enriched lactose, performed breath testing, and underwent genotyping for a marker of lactase non-persistence (13910C*T). Using genotype as gold standard, the performance of measuring methane and 13 CO 2 excretion was assessed., Results: 151 subjects participated in the study, 50 of which presented a lactase non-persistent genotype. Of these, 72% were correctly diagnosed through hydrogen excretion of ≥ 20 ppm above baseline. In subjects with normal hydrogen excretion, cumulative 13 C excretion had an area under the curve (AUC) of the receiver operating characteristics (ROC) curve of 0.852. Sensitivity was 93% and specificity was 51% for the current cutoff of 14.5%. The optimal cutoff was 12.65% (sensitivity 93%, specificity 70%). The ROC curve of peak methane had an AUC of 0.542 (sensitivity of 14%, specificity of 91% for cutoff ≥ 10 ppm)., Conclusions: In individuals with genetically demonstrated lactase non-persistence and negative hydrogen breath test, the use of 13 C-lactose with measurement of 13 CO 2 excretion and hydrogen is a well-performing test to detect the lactose malabsorption and performs better than methane in our cohort., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Durán, Riera-Arnau, Abtahi, Pajouheshnia, Hoxhaj, Gamba, Alsina, Martin-Perez, Garcia-Poza, Llorente-Garcia, Gonzalez-Bermejo, Ibánez, Sabaté, Vidal, Ballarín, Sanfélix-Gimeno, Rodríguez-Bernal, Peiró, García-Sempere, Sanchez-Saez, Ientile, Ingrasciotta, Guarneri, Tanaglia, Tari, Herings, Houben, Swart-Polinder, Holthuis, Huerta, Gini, Roberto, Bartolini, Paoletti, Limoncella, Girardi, Hyeraci, Andersen, Kristiansen, Hallgreen, Klungel and Sturkenboom.)

Objectives: ANCA-associated vasculitis (AAV) has been associated with increased risk of cardiovascular (CV) events. The aim was to assess traditional and disease-related CV risk determinants in a two-centre prospective cohort of AAV patients., Methods: Patients were recruited from centres in the Netherlands and Canada. A comprehensive CV risk assessment was performed at inclusion. Subjects were followed up yearly for 3-5 years until the first CV event, death or end of follow-up. Cox proportional hazards analyses were performed to relate baseline characteristics to the first CV event., Results: A total of 144 patients were included (mean age 62 years, female sex 44%, median Framingham risk score 14.3%). Insulin resistance was present in 73% of patients tested at inclusion, independent of concurrent prednisone therapy. After a median follow-up of 2.90 years, 16 patients (11%) experienced a CV event (14 non-fatal and 2 fatal). The incidence of CV events was 5.45 per 100 patient-years. Age, Framingham risk score, HbA1c level, Diabetes Mellitus (DM), and previous CV event were significantly associated with CV events. Other factors, such as sex, impaired renal function, dyslipidemia, hypertension, smoking history and microalbuminuria, or disease-specific variables, like ANCA serotype or disease activity, were not significantly related to CV events in univariable or age-adjusted cox regression analysis., Conclusions: Determinants of an increased CV risk were identified. Disease-related factors and treatments can further modify individual risk factors, such as for steroids causing chronic insulin resistance and DM. Treatment of risk factors is essential to optimize long-term outcomes in AAV patients., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: GPs have been shown to be important providers of medical care during pregnancy, however, little evidence exists on their awareness of pregnancy when prescribing medication to women., Aim: To assess GPs' awareness of pregnancy and its association with prescribing medication with potential safety risks., Design and Setting: Population-based study using confirmed pregnancy records linked to GP records from the PHARMO Perinatal Research Network., Method: GPs' awareness of pregnancy, defined as the presence of a pregnancy confirmation in the GP information system during pregnancy, was assessed from 2004 to 2020. GP prescriptions of medication with potential safety risks were selected during pregnancy and its association with GPs' awareness of pregnancy was assessed using multivariable logistic regression., Results: A pregnancy confirmation was present in the GP records for 48% ( n = 67 496/140 976) of selected pregnancies, increasing from 28% ( n = 34/121) in 2004 to 63% in 2020 ( n = 5763/9124). During 3% ( n = 4489/140 976) of all pregnancies, the GP prescribed highly hazardous medication with teratogenic effects that should have been (temporarily) avoided. Pregnancy was GP confirmed for only 13% ( n = 585/4489) at the first occurrence of such a prescription. Comparative analyses showed that women without a pregnancy confirmation were 59% more likely to be prescribed this highly hazardous medication (odds ratio [OR] 1.59, 95% confidence interval [CI] = 1.49 to 1.70) compared with those with a confirmed pregnancy., Conclusion: Results of this study indicate a potential issue with GP awareness about pregnancy status at the time medication with potential safety risks is prescribed. Although pregnancy registration by GPs improved over the years, inadequate use still seems to be made of the available information systems for appropriate drug surveillance., (© The Authors.)

TNF signaling is an essential regulator of cellular homeostasis. Through its two receptors TNFR1 and TNFR2, soluble versus membrane-bound TNF enable cell death or survival in a variety of cell types. TNF-TNFRs signaling orchestrates important biological functions such as inflammation, neuronal activity as well as tissue de- and regeneration. TNF-TNFRs signaling is a therapeutic target for neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD), but animal and clinical studies yielded conflicting findings. Here, we ask whether a sequential modulation of TNFR1 and TNFR2 signaling is beneficial in experimental autoimmune encephalomyelitis (EAE), an experimental mouse model that recapitulates inflammatory and demyelinating aspects of MS. To this end, human TNFR1 antagonist and TNFR2 agonist were administered peripherally at different stages of disease development in TNFR-humanized mice. We found that stimulating TNFR2 before onset of symptoms leads to improved response to anti-TNFR1 therapeutic treatment. This sequential treatment was more effective in decreasing paralysis symptoms and demyelination, when compared to single treatments. Interestingly, the frequency of the different immune cell subsets is unaffected by TNFR modulation. Nevertheless, treatment with only a TNFR1 antagonist increases T-cell infiltration in the central nervous system (CNS) and B-cell cuffing at the perivascular sites, whereas a TNFR2 agonist promotes Treg CNS accumulation. Our findings highlight the complicated nature of TNF signaling which requires a timely balance of selective activation and inhibition of TNFRs in order to exert therapeutic effects in the context of CNS autoimmunity., (© 2023. The Author(s).)

Background: There is a need for updated incidence rates (IRs) of Lyme borreliosis (LB) in Europe, including the Netherlands. We estimated LB IRs stratified by geographic area, year, age, sex, immunocompromised status, and socioeconomic status (SES). Methods: All subjects registered in the PHARMO General Practitioner (GP) Database without prior diagnosis of LB or disseminated LB and having ≥1 year of continuous database enrolment were included. IRs and corresponding confidence intervals (CIs) of GP-recorded LB, erythema migrans (EM), and disseminated LB were estimated during the period 2015‒2019. Results: We identified 14,794 events (suspected, probable, or confirmed) with a diagnostic code for LB that included 8219 with a recorded clinical manifestation: 7985 (97%) with EM and 234 (3%) with disseminated LB. National annual LB IRs were relatively consistent, ranging from 111 (95% CI 106‒115) in 2019 to 131 (95% CI 126‒136) in 2018 per 100,000 person-years. Incidence of LB showed a bimodal age distribution, with peak IRs observed among subjects aged 5‒14 and 60‒69 years in men and women. Higher LB incidence was found in subjects who were residents of the provinces of Drenthe and Overijssel, immunocompromised, or of lower SES. Similar patterns were observed for EM and disseminated LB. Conclusions: Our findings confirm that LB incidence remains substantial throughout the Netherlands with no indication of decline in the past 5 years. Foci in two provinces and among vulnerable populations suggest potential initial target groups for preventive strategies such as vaccination.

Early diagnosis of invasive aspergillosis is an important factor to improve survival but remains challenging. The detection of Aspergillus antigens is included in the consensus case definitions of the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycoses Study Group as a criterion of "probable" invasive aspergillosis. JF5, a mouse IgG3 monoclonal antibody detecting an Aspergillus mannoprotein, has already been implemented as a lateral flow device (LFD). Now, also a JF5-based enzyme-linked immunosorbent assay (EIA) is commercialized (Aspergillus specific galactomannoprotein [GP] EIA, Euroimmun Medizinische Labordiagnostika AG). In this study, we analyzed the diagnostic performance of GP in 63 bronchoalveolar lavage fluid (BALf) samples and 224 serum samples and compared it to performance of the galactomannan (GM) (Platelia Aspergillus enzyme immunoassay (EIA) (Bio-Rad, Marnes-la-Coquette, France)) and the JF5-based LFD (AspLFD; OLM Diagnostics, Newcastle Upon Tyne, United Kingdom). The diagnostic performance of GP and GM correlated well with both having high specificity. With an optimized cutoff threshold for positivity of 0.4-deviating from the 0.5 threshold recommended by the manufacturer-sensitivity of GP in serum is not significantly different than that of GM. However, in BALf sensitivity of GP is significantly less than for GM.

Oncostatin M (OSM) is an IL-6 family member which exerts neuroprotective and remyelination-promoting effects after damage to the central nervous system (CNS). However, the role of OSM in neuro-inflammation is poorly understood. Here, we investigated OSM's role in pathological events important for the neuro-inflammatory disorder multiple sclerosis (MS). We show that OSM receptor (OSMRβ) expression is increased on circulating lymphocytes of MS patients, indicating their elevated responsiveness to OSM signalling. In addition, OSM production by activated myeloid cells and astrocytes is increased in MS brain lesions. In experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, OSMRβ-deficient mice exhibit milder clinical symptoms, accompanied by diminished T helper 17 (Th17) cell infiltration into the CNS and reduced BBB leakage. In vitro, OSM reduces BBB integrity by downregulating the junctional molecules claudin-5 and VE-cadherin, while promoting secretion of the Th17-attracting chemokine CCL20 by inflamed BBB-endothelial cells and reactive astrocytes. Using flow cytometric fluorescence resonance energy transfer (FRET) quantification, we found that OSM-induced endothelial CCL20 promotes activation of lymphocyte function-associated antigen 1 (LFA-1) on Th17 cells. Moreover, CCL20 enhances Th17 cell adhesion to OSM-treated inflamed endothelial cells, which is at least in part ICAM-1 mediated. Together, these data identify an OSM-CCL20 axis, in which OSM contributes significantly to BBB impairment during neuro-inflammation by inducing permeability while recruiting Th17 cells via enhanced endothelial CCL20 secretion and integrin activation. Therefore, care should be taken when considering OSM as a therapeutic agent for treatment of neuro-inflammatory diseases such as MS., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS)., Methods: Following European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion., Results: Four overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering., Conclusion: These recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases., Competing Interests: Competing interests: GCD, DV, EH, LB, SB, DTB, NB, GK, FM, CM, MR-C, KS, SS, VPvH, GJM, MMW and MN have nothing to declare. FA: research grants from BMS, Celgene, Novartis and Sandoz and consulting fees from AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and Sanofi-Aventis, all unrelated to this manuscript; INB: grant from GSK paid to institution, consulting fees from Astra Zeneca, GSK, Eli lilly, UC, MSD paid to institution, support for attending meetings and/or travel from GSK, participation on a data safety monitoring board/or advisory board from Aurinia, Astra Zeneca and ILTOO paid to institution, all unrelated to this manuscript; MÁG-G: grants/research support from AbbVie, MSD, Jansen and Roche paid to institution and personal consulting fees/participation in company sponsored speakers bureau from AbbVie, Pfizer, Roche, Celgene, MSD, Novartis, SOBI and Sanofi, all unrelated to this manuscript; SJ: grants from BMS paid to institution, personal consulting fees from Astra Zeneca, and personal fees from Danish Medicolegal Council, all unrelated to this manuscript; NS: grants paid to institution from Astrazeneca, Boehringer Ingelheim and Roche Diagnostics, personal consulting fees from Afimmune, Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharamceuticals, MSD, Novartis, Novo Nordisk, Pfizer and Sanofi, all unrelated to this manuscript; ES: grant from Merck and honoraria from Janssen, all unrelated to this manuscript; ZS: research grants from Pfizer paid to institution and personal consulting fees from Pfizer, MSD, Lilly, Novartis, Roche, Gedeon Richter, Boehringer Ingelheim, Abbvie, all unrelated to this manuscript; A-KT: speakers fee from Berlin Chemie Menarini, Novarti and personal fees and non-financial support from AstraZeneca and Grünenthal, all unrelated to this manuscript; AT: consulting fees from Magenta Therapeutics and personal fees from Novartis and Idorsia for participation on a Data Safety Monitoring Board or Advisory Board, all unrelated to this manuscript; AV: personal consulting fees from Astra Zeneca and GS, all unrelated to this manuscript; MGT: research grants from Genesis, GSK, MSD, Pfizer and UCB paid to institution, and personal consulting fees from Genesis, GSK and Novartis, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Direct oral anticoagulants are available for patients with atrial fibrillation., Objective: This study compared adherence and persistence of once-daily (QD) vs twice-daily (BID) direct oral anticoagulants in patients with atrial fibrillation., Methods: A cohort study was conducted in three databases in the Netherlands, Italy and Germany. Patients with AF starting direct oral anticoagulants after drug approval date were included. The index date was the date of first dispensing. Study patients were restricted to those aged ≥ 18 years, ≥ 1 year database history and ≥ 1 year follow-up. Adherence to treatment was defined as the proportion of days covered ≥ 80% between the index date and the date of last dispensing of the index regimen (i.e. exposure period). The proportion of days covered was also determined during the 12-month follow-up. Persistence was defined as continuous use from index to treatment discontinuation., Results: In the Netherlands, Italy and Germany, respectively, 6068, 32,260 and 167,445 patients were included. The mean age of the patients was 70, 77 and 74 years, and 31%, 40% and 61% were QD users, all respectively. Among QD/BID users, 93/90%, 88/86% and 77/58%, respectively were adherent during the exposure period. Persistence rates at 1 year in QD/BID users were 60/59%, 13/14% and 46/31%, respectively., Conclusions: Adherence to treatment was high. In Germany, adherence was markedly higher in QD users compared with BID users. In Italy and the Netherlands, these differences were marginal. Persistence was low in all countries, but discontinuation was temporary. Only in Germany, persistence was markedly lower in BID users vs QD users., (© 2022. The Author(s).)

Background: Anti-seizure medications (ASMs) are used to treat conditions such as epilepsy and bipolar disorder. Some of these drugs are associated with an increased risk of congenital malformations and adverse developmental outcomes., Objectives: To examine trends in use of ASMs among pregnant women in the Netherlands according to medication safety profile., Methods: Using population-based data from the PHARMO Perinatal Research Network, we assessed trends in use of ASMs among pregnant women in the Netherlands between 1999 and 2019, stratified by medication safety profile. Individual treatment patterns were also assessed., Results: In total, 671,709 pregnancies among 446,169 women were selected, of which 2405 (3.6 per 1000) were ASM-exposed. Over the study period, a significant increase was observed for use of known safest ASMs (0.7-18.0 per 10,000 pregnancies) as well as for those with uncertain risk (5.3-13.4 per 10,000 pregnancies). Use of ASMs with higher risk of congenital malformations decreased significantly (24.8-14.5 per 10,000 pregnancies), except for topiramate (0-6.7 per 10,000 pregnancies). Switches between ASM safety risk categories before and during pregnancy were uncommon; women rather discontinued treatment or switched within the same category. There was no clear change for the proportion using polytherapy during pregnancy (12% overall), however a non-significant trend toward inclusion of known safest ASMs was observed over time (1.9-3.6%)., Conclusions: Over the last two decades, there has been an increase in use of known safest ASMs among pregnant women, together with a trend toward newer ASMs with uncertain risk. Only a small proportion of women switched to a safer alternative before or during pregnancy. Altogether, this highlights the need for an expansion of ASM risk knowledge and communication to healthcare providers and women of reproductive age to improve preconception counseling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Pharmacological treatment of peripheral arterial disease (PAD) comprises of antiplatelet therapy (APT), blood pressure control and cholesterol optimisation. Guidelines provide class-I recommendations on the prescription, but there are little data on the actual prescription practices. Our study provides insight into the prescription of medication among patients with PAD in the Netherlands and reports a 'real-world' patient journey through primary and secondary care., Design: We conducted a cohort study among patients newly diagnosed with PAD between 2010 and 2014., Setting: Data were obtained from the PHARMO Database Network, a population-based network of electronic pharmacy, primary and secondary healthcare setting records in the Netherlands. The source population for this study comprised almost 1 million individuals., Participants: 'Newly diagnosed' was defined as a recorded International Classification of Primary Care code for PAD, a PAD-specific WCIA examination code or a diagnosis recorded as free text episode in the general practitioner records with no previous PAD diagnosis record and no prescription of P2Y12 inhibitors or aspirin the preceding year. The patient journey was defined by at least 1 year of database history and follow-up relative to the index date., Results: Between 2010 and 2014, we identified 3677 newly diagnosed patients with PAD. Most patients (91%) were diagnosed in primary care. Almost half of all patients (49%) had no APT dispensing record. Within this group, 33% received other anticoagulant therapy (vitamin K antagonist or direct oral anticoagulant). Mono-APT was dispensed as aspirin (40% of patients) or P2Y12 inhibitors (2.5% of patients). Dual APT combining aspirin with a P2Y12 inhibitor was dispensed to 8.5% of the study population., Conclusion: Half of all patients with newly diagnosed PAD are not treated conforming to (international) guideline recommendations on thromboembolism prevention through APT. At least 33% of all patients with newly diagnosed PAD do not receive any antithrombotic therapy. Evaluation and improvement of APT prescription and thereby improved prevention of (secondary) cardiovascular events is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Extremely preterm (EP) infants have high rates of respiratory morbidity and correspondingly high healthcare resource utilization., Objectives: Data from the PHARMO Perinatal Research Network were analyzed to quantify the burden of EP birth in the Netherlands., Methods: A retrospective analysis included infants <28 weeks gestational age with a birth record in the Perinatal Registry (1999-2015) and data in the PHARMO Database Network. Outcomes of interest included select comorbidities, hospital readmissions, and costs of hospitalization and medication up to 1- and 2-years corrected age. Outcomes were stratified by birth period (1999-2005, 2000-2009, 2010-2015) and by diagnosis of bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD)., Results: The cohort included 168 EP infants (37 born 1999-2005, 51 born 2006-2009, 80 born 2010-2015). Median (Q1-Q3) birth weights decreased by birth period from 970 (840-1,035) g in 1999-2005 to 853 (695-983) g in 2010-2015. Overall, BPD and CLD were reported during the birth hospitalization in 40% and 29% of infants, respectively; rates of BPD increased and rates of CLD decreased by birth period. Eighty-four percent of EP infants had an additional comorbidity. Mean (standard deviation) costs of birth hospitalization were €110,600 (€73,000) for 1999-2005, €119,350 (€60,650) for 2006-2009, and €138,800 (€130,100) for 2010-2015. Birth hospitalization and total costs for up to 1- and 2-years corrected age were higher for infants with BPD and/or CLD than for those without either complication., Conclusion: Healthcare resource utilization and costs for EP infants, especially for those with respiratory morbidities, increased between 1999 and 2015. Future cost-effectiveness analyses are essential to determine the economic impact of this change and underscore the need for new therapeutic interventions to decrease clinical sequelae in this vulnerable population.

Aims: Recent population-based data on drug utilization around pregnancy are lacking. This study aims to examine the prevalence of drug exposure in the Netherlands during the preconception, pregnancy and postpartum periods, with special emphasis on trends of potentially harmful medication over the years., Methods: A population-based study was conducted using records from the PHARMO Perinatal Research Network. From 1999 to 2017, the proportion of pregnancies during which women used any medication or potentially harmful medication was assessed, overall and stratified by timing of exposure relative to pregnancy and by the year of delivery., Results: Overall, 357 226 (73%) and 166 484 (34%) of 487 122 selected pregnancies were exposed to any and potentially harmful medication, respectively. Among these 487 122 pregnancies, preconception prevalence for use of potentially harmful medication was 43%, 24% during the first trimester, 19% during the second, 16% during the third, and 45% postpartum. A declining trend was observed for exposure to any medication, from 84% in 1999 to 68% in 2017. No clear changes were observed over time for the proportion of pregnancies exposed to potentially harmful medication., Conclusions: Our study shows that the use of potentially harmful medication was high over the last two decades. Although there was a declining trend over the years in overall medication use, during a steady one-third of pregnancies, women used potentially harmful medication. Our findings highlight the need for an increased sense of urgency among both healthcare providers and women of reproductive age regarding potential risks associated with pharmacological treatment during pregnancy., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: The aim was to determine the antibody response against SARS-CoV-2 spike protein and nucleoprotein using four automated immunoassays and three ELISAs for the detection of total Ig antibodies (Roche) or IgG (Abbott, Diasorin, Snibe, Euroimmun, Mikrogen) in COVID-19 patients., Methods: Sensitivity and dynamic trend to seropositivity were evaluated in 233 samples from 114 patients with moderate, severe or critical COVID-19 confirmed with PCR on nasopharyngeal swab. Specificity was evaluated in 113 samples collected before January 2020, including 24 samples from patients with non-SARS coronavirus infection., Results: Sensitivity for all assays was 100% (95% confidence interval 83.7-100) 3 weeks after onset of symptoms. Specificity varied between 94.7% (88.7-97.8) and 100% (96.1-100). Calculated at the cut-offs that corresponded to a specificity of 95% and 97.5%, Roche had the highest sensitivity (85.0% (79.8-89.0) and 81.1% (76.6-85.7), p < 0.05 except vs. Abbott). Seroconversion occurred on average 2 days earlier for Roche total Ig anti-N and the three IgG anti-N assays (Abbott, Mikrogen, Euroimmun) than for the two IgG anti-S assays (Diasorin, Euroimmun) (≥50% seroconversion day 9-10 vs. day 11-12 and p < 0.05 for percent seropositive patients day 9-10 to 17-18). There was no significant difference in the IgG antibody time to seroconversion between critical and non-critical patients., Discussion: Seroconversion occurred within 3 weeks after onset of symptoms with all assays and on average 2 days earlier for assays detecting IgG or total Ig anti-N than for IgG anti-S. The specificity of assays detecting anti-N was comparable to anti-S and excellent in a challenging control population., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)