Omgaan met digitale nationale beleidskaarten

In dit werkdocument worden de resultaten besproken van een casestudy die onderdeel is van het project GeO3 - Omgaan met onzekerheid binnen Ruimtelijke Ordening. De directie Platteland van het ministerie van LNV heeft bij het publiceren van het meerjarenprogramma van Agenda Vitaal Platteland geen digitale viewer gepubliceerd omdat men bang was voor verkeerde interpretatie van de digitale kaarten. In dit project is gekeken naar methoden en cartografische oplossingen om voortaan zonder angst voor misinterpretaties digitale nationale beleidskaarten te kunnen verspreiden. De oplossing is gezocht in het opstellen van een handreiking, zodat kaarten ook daadwerkelijk weergeven wat er bedoeld is door de maker

Feasibility of assessment of skeletal muscle mass on a single cross-sectional image at the level of the fourth thoracic vertebra

Background Skeletal muscle mass (SMM) determined on computed tomography (CT) is emerging as a novel imaging biomarker. Cross-sectional area (CSA) of SMM at the level of the third lumbar vertebra (L3) on abdominal imaging is considered the clinical reference standard for measuring SMM. In certain patient groups, such as those with oncological or non-oncological lung disease like COVID-19, a chest CT may be available while an abdominal CT is not. The purpose of this study was to investigate whether determining SMM on a chest CT is a feasible alternative to abdominal CT.  Research question What is the correlation between SMM measurements at the level of L3 and the level of the fourth thoracic vertebra (Th4)?  Study design and methods  In this study we retrospectively analyzed abdominal and thoracic series of whole-body CT-scans of trauma patients (N = 47) and head and neck cancer patients (N = 194). All abdominal muscles were delineated on a single axial slice at the level of L3. The erector spinae, levator scapulae, rhomboideus minor and major and pectoralis minor and major muscles were delineated on a single axial slice at the level of Th4. CSA of the muscles at Th4 and the L3 level were compared using linear regression, and a multivariate linear regression model was established.  Results Muscle CSA at level Th4 strongly correlates with L3 muscle CSA (r = 0.791, p < 0.05). A multivariate model incorporating the patient characteristics arm positioning, age, sex, and weight achieved a stronger correlation (r = 0.856, p < 0.05). Interpretation: Skeletal muscle CSA measured at the level of Th4 is a feasible alternative to measurements at L3. This allows diagnosing low SMM using clinically available thoracic CT-scans. SMM measurements at the level of Th4 may become a prognostic or triage tool when faced with mechanical ventilator shortage

Towards a framework PCR-based map of onion (Allium cepa L.)

Genetic analysis of onion has been hampered by a lack of portable co-dominant markers based on the polymerase chain reaction (PCR). The public release of a relatively large set of non-redundant onion expressed sequence tags (ESTs) in 2003 has provided the opportunity to develop such markers for use in Allium research and industry. We have mined this collection for simple sequence repeats (SSRs) and screened over 200 primer sets designed to flank SSRs for their ability to amplify low-copy polymorphic products in Allium cepa and A. roylei. Screening to date confirms that these are a rich source of polymorphic markers in Allium. Half of the sets reveal polymorphism between onion and A. roylei, ~40% reveal putative allelic variation in a small set of onion germplasm and 20% reveal polymorphism in a single F2 family in the cross `W202A¿ x `Texas Grano 438¿. Mapping common markers has permitted alignment with the RFLP map developed in the `Brigham Yellow Globe 15-23¿ x `Alisa Craig 43¿ population. Preliminary studies show these markers are effective in distinguishing variation in allelic diversity among a set of inbred and open-pollinated onion varieties. Our results suggest that these markers will enable effective genome scanning and analysis of genetic diversity and identity in cultivated onion

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH)

STUDY QUESTION: Does endometnal scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between - 0.7% and 9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/11 I for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials

Is home-based monitoring of ovulution to time frozen embryo transfer a cost-effective alternative for hospital-based monitoring of ovulation? Study protocol of the multicentre, non-inferiority Antarctica-2 randomised controlled trial

STUDY QUESTION: The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman’s point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN, SIZE, DURATION: This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTEREST(S): The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE: 23 July 2017 DATE OF FIRST PATIENT’S ENROLMENT: 10 April 201

Identification of an ATP/P2X7/Mast Cell Pathway Mediating Ozone-Induced Bronchial Hyperresponsiveness

Ozone is a highly reactive environmental pollutant with well-recognized adverse effects on lung health. Bronchial hyperresponsiveness (BHR) is one consequence of ozone exposure, particularly for individuals with underlying lung disease. Our data demonstrated that ozone induced substantial ATP release from human airway epithelia in vitro and into the airways of mice in vivo and that ATP served as a potent inducer of mast cell degranulation and BHR, acting through P2X7 receptors on mast cells. Both mast cell-deficient and P2X7 receptor-deficient (P2X7-/-) mice demonstrated markedly attenuated BHR to ozone. Reconstitution of mast cell-deficient mice with WT mast cells and P2X7-/- mast cells restored ozone-induced BHR. Despite equal numbers of mast cells in reconstituted mouse lungs, mice reconstituted with P2X7-/- mast cells demonstrated significantly less robust BHR than mice reconstituted with WT mast cells. These results support a model where P2X7 on mast cells and other cell types contribute to ozone-induced BHR

Enhanced delivery of peptide-morpholino oligonucleotides with a small molecule to correct splicing defects in the lung

Pulmonary diseases offer many targets for oligonucleotide therapeutics. However, effective delivery of oligonucleotides to the lung is challenging. For example, splicing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect a significant cohort of Cystic Fibrosis (CF) patients. These individuals could potentially benefit from treatment with splice switching oligonucleotides (SSOs) that can modulate splicing of CFTR and restore its activity. However, previous studies in cell culture used oligonucleotide transfection methods that cannot be safely translated in vivo. In this report, we demonstrate effective correction of a splicing mutation in the lung of a mouse model using SSOs. Moreover, we also demonstrate effective correction of a CFTR splicing mutation in a pre-clinical CF patient-derived cell model. We utilized a highly effective delivery strategy for oligonucleotides by combining peptide-morpholino (PPMO) SSOs with small molecules termed OECs. PPMOs distribute broadly into the lung and other tissues while OECs potentiate the effects of oligonucleotides by releasing them from endosomal entrapment. The combined PPMO plus OEC approach proved to be effective both in CF patient cells and in vivo in the mouse lung and thus may offer a path to the development of novel therapeutics for splicing mutations in CF and other lung diseases