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Marika T Leving,1 Job FM van Boven,2– 4 Sinthia Z Bosnic-Anticevich,5,6 Joyce van Cooten,1 Jaime Correia de Sousa,7 Biljana Cvetkovski,5 Richard Dekhuijzen,8 Lars Dijk,1 Marina García Pardo,9 Asparuh Gardev,10 Rados&lstrok;aw Gawlik,11 Iris van der Ham,1 Elisabeth Sophia Hartgers-Gubbels,10 Ymke Janse,1 Federico Lavorini,12 Tiago Maricoto,13 Jiska Meijer,1 Boyd Metz,1 David B Price,14,15 Miguel Roman-Rodríguez,9 Kirsten Schuttel,1 Nilouq Stoker,1 Ioanna Tsiligianni,16 Omar S Usmani,17 Janwillem H Kocks1,2,15,18 1General Practitioners Research Institute, Groningen, the Netherlands; 2University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, the Netherlands; 3University Medical Centre Groningen, Department of Clinical Pharmacy & Pharmacology, University of Groningen, Groningen, the Netherlands; 4Medication Adherence Expertise Centre of the Northern Netherlands (MAECON), Groningen, the Netherlands; 5Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia; 6Sydney Local Health District, Sydney, Australia; 7Life and Health Sciences Research Institute (ICVS), PT Government Associate Laboratory, School of Medicine, University of Minho, Braga, Portugal; 8Radboud University Medical Centre, Nijmegen, Netherlands; 9Primary Care Respiratory Research Unit, Instituto De Investigación Sanitaria De Baleares (IdISBa), Palma de Mallorca, Spain; 10Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 11Department of Internal Medicine, Allergology, Clinical Immunology, Medical University of Silesia, Katowice, Poland; 12Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy; 13Faculty of Health Sciences, University of Beira Interior, Covilha, Portugal; 14Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 15Observational and Pragmatic Research Institute, Singapore; 16Department of Social Medicine, Health Planning Unit, Faculty of Medicine, University of Crete, Rethymno, Greece; 17Airway Disease, National Heart and Lung Institute (NHLI), Imperial College London and Royal Brompton Hospital, London, UK; 18Department of Pulmonology, University of Groningen, University Medical Centre Groningen, Groningen, the NetherlandsCorrespondence: Janwillem H Kocks, General Practitioners Research Institute, Professor Enno Dirk Wiersmastraat 5, Groningen, 9713 GH, the Netherlands, Tel +31 50 211 3898, Email janwillem@gpri.nlPurpose: To assess the relationship between suboptimal Peak Inspiratory Flow (sPIF), inhalation technique errors, and non-adherence, with Healthcare Resource Utilisation (HCRU) in Chronic Obstructive Pulmonary Disease (COPD) patients receiving maintenance therapy via a Dry Powder Inhaler (DPI).Patients and methods: The cross-sectional, multi-country PIFotal study included 1434 COPD patients (≥ 40 years) using a DPI for maintenance therapy. PIF was measured with the In-Check DIAL G16, and sPIF was defined as a typical PIF lower than required for the device. Inhalation technique was assessed by standardised evaluation of video recordings and grouped into 10 steps. Patients completed the “Test of Adherence to Inhalers” questionnaire. HCRU was operationalised as COPD-related costs for primary healthcare, secondary healthcare, medication, and total COPD-related costs in a 1-year period.Results: Participants with sPIF had higher medication costs compared with those with optimal PIF (cost ratio [CR]: 1.07, 95% CI [1.01, 1.14]). Multiple inhalation technique errors were associated with increased HCRU. Specifically, “insufficient inspiratory effort” with higher secondary healthcare costs (CR: 2.20, 95% CI [1.37, 3.54]) and higher total COPD-related costs (CR: 1.16, 95% CI 1.03– 1.31). “no breath-hold following the inhalation manoeuvre (< 6 s)” with higher medication costs (CR: 1.08, 95% CI [1.02, 1.15]) and total COPD-related costs (CR 1.17, 95% CI [1.07, 1.28]), and “not breathing out calmly after inhalation” with higher medication costs (CR: 1.19, 95% CI [1.04, 1.37]). Non-adherence was not significantly associated with HCRU.Conclusion: sPIF and inhalation technique errors were associated with higher COPD-related healthcare utilisation and costs in COPD patients on DPI maintenance therapy.Keywords: chronic obstructive pulmonary disease, Dry Powder Inhaler, health economics, cost analysis, healthcare resource utilisation

Rationale Many depressed women continue antidepressant treatment during pregnancy. Selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy increases the risk for abnormal social development of the child, including increased aggressive or defiant behavior, with unknown effects on sexual behavior. Objectives Our aim was to investigate the effects of perinatal SSRI treatment and maternal depression, both separately and combined, on aggressive and sexual behavior in male rat offspring. Methods Heterozygous serotonin transporter (SERT± ) knockout dams exposed to early life stress (ELSD) were used as an animal model of maternal depression. Early life stress consisted of separating litters from their mother for 6 h a day on postnatal day (PND)2–15, resulting in a depressive-like phenotype in adulthood. Depressive-like dams were treated with fluoxetine (FLX, 10 mg/kg) or vehicle throughout pregnancy and lactation (gestational day 1 until PND 21). Male offspring were tested for aggressive and sexual behavior in adulthood. As lifelong reductions in SERT expression are known to alter behavioral outcome, offspring with normal (SERT+/+) and reduced (SERT± ) SERT expression were assessed. Results Perinatal FLX treatment reduced offensive behavior and the number of animals attacking and increased the latency to attack, especially in SERT+/+ offspring. Perinatal FLX treatment reduced the mounting frequency in SERT+/+ offspring. ELSD increased offensive behavior, without affecting sexual behavior in SERT± offspring. Conclusions Overall, our research demonstrates that perinatal FLX treatment and ELSD have opposite effects on aggressive behavior, with little impact on sexual behavior of male offspring.

Many women diagnosed with a major depression continue or initiate antidepressant treatment during pregnancy. Both maternal stress and selective serotonin inhibitor (SSRI) antidepressant treatment during pregnancy have been associated with changes in offspring behavior, including increased anxiety and depressive-like behavior. Our aim was to investigate the effects of the SSRI fluoxetine (FLX), with and without the presence of a maternal depression, on affective behavior in male and female rat offspring. As reduced serotonin transporter (SERT) availability has been associated with altered behavioral outcome, both offspring with normal (SERT+/+) and reduced (SERT+/-) SERT expression were included. For our animal model of maternal depression, SERT+/- dams exposed to early life stress were used. Perinatal FLX treatment and early life stress in dams (ELSD) had sex- and genotype-specific effects on affective behavior in the offspring. In female offspring, perinatal FLX exposure interacted with SERT genotype to increase anxiety and depressive-like behavior in SERT+/+, but not SERT+/-, females. In male offspring, ELSD reduced anxiety and interacted with SERT genotype to decrease depressive-like behavior in SERT+/-, but not SERT+/+, males. Altogether, SERT+/+ female offspring appear to be more sensitive than SERT+/- females to the effects of perinatal FLX exposure, while SERT+/- male offspring appear more sensitive than SERT+/+ males to the effects of ELSD on affective behavior. Our data suggest a role for offspring SERT genotype and sex in FLX and ELSD-induced effects on affective behavior, thereby contributing to our understanding of the effects of perinatal SSRI treatment on offspring behavior later in life.