Intra-individual variation in Galium odoratum is affected by experimental drought and shading.

BACKGROUND AND AIMS: Climate-change induced warmer spring temperatures advance tree leaf-out and result in earlier shading of the forest floor. Climate change also leads to more frequent droughts. Forest understorey herbs may respond to these environmental changes by varying traits at different hierarchical levels of organization. While trait mean variation at the inter-individual level in response to environmental changes is well-studied, little is known about how variation at the intra-individual level responds. METHODS: We sampled genets of the forest understorey herb Galium odoratum from 21 populations in three regions in Germany, varying in microclimatic conditions. The genets were transplanted into a common garden, where we applied shading and drought treatments. We measured plant height and leaf length and width, and calculated the coefficient of variation (CV) at different hierarchical levels: intra-population, intra-genet, intra-ramet and intra-shoot. KEY RESULTS: Variance partitioning showed that intra-shoot CV represented most of the total variation, followed by intra-ramet CV. We found significant variation in CV of plant height and leaf width among populations of origin, indicating that CV is at least partly genetically based. The soil temperature at populations' origins correlated negatively with CV in plant height, suggesting adaptation to local conditions. Furthermore, we observed that early shade led to increased intra-ramet CV in leaf length, while drought reduced intra-shoot CV in leaf width. Finally, intra-shoot leaf width mean and CV were independent under control conditions but correlated under drought. CONCLUSIONS: Our experimental results reveal correlations of intra-individual variation with soil temperature, indicating that intra-individual variation can evolve and may be adaptive. Intra-individual variation responded plastically to drought and shading, suggesting functional changes to improve light capture and reduce evapotranspiration. In conclusion, intra-individual variation makes up the majority of total trait variation in this species and can play a key role in plant adaptation to climatic change.

Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling.

The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi-Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.

Low prevalence of oral and nasal human papillomavirus in employees performing CO2-laser evaporation of genital warts or loop electrode excision procedure of cervical dysplasia.

Risk of human papillomavirus (HPV) transmission during laser vaporisation of genital warts or loop electrode excision procedure is controversial. An oral rinse, a nasal swabs, history of HPV related diseases and data on HPV exposure were collected from 287 employees at departments of dermato-venerology and gynaecology in Denmark. A mucosal HPV type was found among 5.8% of employees with experience of laser treatment of genital warts as compared to 1.7% of those with no experience (p = 0.12). HPV prevalence was not higher in employees participating in electrosurgical treatment or cryotherapy of genital warts, or loop electrode excision procedure compared with those who did not. HPV 6 or 11 were not detected in any samples. Hand warts after the age of 24 years was more common among dermatology than among non-dermatology personnel (18% vs. 8.0%, p = 0.03). Mucosal HPV types are infrequent in the oral and nasal cavity of health care personnel, however, employees at departments of dermato-venereology are at risk of acquiring hand warts.

Higher thermal plasticity in flowering phenology increases flowering output.

Ongoing climate change poses an increasing threat to biodiversity. To avoid decline or extinction, species need to either adjust or adapt to new environmental conditions or track their climatic niches across space. In sessile organisms such as plants, phenotypic plasticity can help maintain fitness in variable and even novel environmental conditions and is therefore likely to play an important role in allowing them to survive climate change, particularly in the short term. Understanding a species' response to rising temperature is crucial for planning well-targeted and cost-effective conservation measures. We sampled seeds of three Hypericum species (H. maculatum, H. montanum, and H. perforatum), from a total of 23 populations originating from different parts of their native distribution areas in Europe. We grew them under four different temperature regimes in a greenhouse to simulate current and predicted future climatic conditions in the distribution areas. We measured flowering start, flower count, and subsequent seed weight, allowing us to study variations in the thermal plasticity of flowering phenology and its relation to fitness. Our results show that individuals flowered earlier with increasing temperature, while the degree of phenological plasticity varied among species. More specifically, the plasticity of H. maculatum varied depending on population origin, with individuals from the leading range edge being less plastic. Importantly, we show a positive relationship between higher plasticity and increased flower production, indicating adaptive phenological plasticity. The observed connection between plasticity and fitness supports the idea that plasticity may be adaptive. This study underlines the need for information on plasticity for predicting species' potential to thrive under global change and the need for studies on whether higher phenotypic plasticity is currently being selected as natural populations experience a rapidly changing climate.

Preoperative staging of endometrial cancer using TVS, MRI, and hysteroscopy.

OBJECTIVES: To evaluate the accuracy of different preoperative modalities for staging of endometrial cancer to restrict extensive surgery to patients at high risk of metastatic disease. SETTING: Aarhus University Hospital. POPULATION: 156 women referred in 2006-2011 because of atypical endometrial hyperplasia (G0) or endometrial cancer. METHODS: Patients were offered preoperative transvaginal ultrasonography (TVS), magnetic resonance imaging (MRI), and hysteroscopic-directed biopsies from the uterine tumor and cervix. Final pathology of the removed uterus was the reference standard. Patients were divided into low risk (<50% myometrial invasion, and grades 0, 1, 2, and no cervical invasion) or high risk (all others). MAIN OUTCOME MEASURES: Accuracy, sensitivity, specificity, positive/negative predictive value. RESULTS: Patients were aged 32-88 years, with a mean body mass index of 29. At final pathology 81% had cancer and 19% G0 or no residual tumor; 54% were high risk. Hysteroscopy-directed biopsies had a higher accuracy (92%) than endometrial biopsy (58%) for differentiating G0 from cancer (p < 0.001); grade 3 tumor identification had similar accuracy (93 vs. 92%). Deep myometrial invasion was estimated with higher accuracy by MRI (82%) than TVS (74%) (p < 0.02). For cervical involvement, hysteroscopy-directed biopsies had higher accuracy (94%) than MRI (84%,) and TVS (80%) (p < 0.02). Accuracy for identifying high-risk women was highest (83%) using a combination of MRI and hysteroscopic-directed biopsies, compared with TVS and endometrial biopsy (72%) (p < 0.05). CONCLUSION: Preoperative staging with MRI and hysteroscopy-directed biopsy can identify eight of 10 women with high risk of lymph node metastases and spare eight of 10 low-risk women extended surgery.

Dual intron-targeted CRISPR-Cas9-mediated disruption of the AML RUNX1-RUNX1T1 fusion gene effectively inhibits proliferation and decreases tumor volume in vitro and in vivo.

Oncogenic fusion drivers are common in hematological cancers and are thus relevant targets of future CRISPR-Cas9-based treatment strategies. However, breakpoint-location variation in patients pose a challenge to traditional breakpoint-targeting CRISPR-Cas9-mediated disruption strategies. Here we present a new dual intron-targeting CRISPR-Cas9 treatment strategy, for targeting t(8;21) found in 5-10% of de novo acute myeloid leukemia (AML), which efficiently disrupts fusion genes without prior identification of breakpoint location. We show in vitro growth rate and proliferation reduction by 69 and 94% in AML t(8;21) Kasumi-1 cells, following dual intron-targeted disruption of RUNX1-RUNX1T1 compared to a non t(8;21) AML control. Furthermore, mice injected with RUNX1-RUNX1T1-disrupted Kasumi-1 cells had in vivo tumor growth reduction by 69 and 91% compared to controls. Demonstrating the feasibility of RUNX1-RUNX1T1 disruption, these findings were substantiated in isolated primary cells from a patient diagnosed with AML t(8;21). In conclusion, we demonstrate proof-of-principle of a dual intron-targeting CRISPR-Cas9 treatment strategy in AML t(8;21) without need for precise knowledge of the breakpoint location.

Determination of the binding sites for oxaliplatin on insulin using mass spectrometry-based approaches.

Using insulin as a model protein for binding of oxaliplatin to proteins, various mass spectrometric approaches and techniques were compared. Several different platinum adducts were observed, e.g. addition of one or two diaminocyclohexane platinum(II) (Pt(dach)) molecules. By top-down analysis and fragmentation of the intact insulin-oxaliplatin adduct using nano-electrospray ionisation quadrupole time-of-flight mass spectrometry (nESI-Q-ToF-MS), the major binding site was assigned to histidine5 on the insulin B chain. In order to simplify the interpretation of the mass spectrum, the disulphide bridges were reduced. This led to the additional identification of cysteine6 on the A chain as a binding site along with histidine5 on the B chain. Digestion of insulin-oxaliplatin with endoproteinase Glu-C (GluC) followed by reduction led to the formation of five peptides with Pt(dach) attached. Identification of several of the binding sites was obtained using matrix-assisted laser desorption/ionization (MALDI)-ToF-ToF-MS and liquid chromatography-nESI-Q-ToF-MS. Upon comparing the top-down and bottom-up approaches, the suitability of the bottom-up approach for determining binding sites was questioned, as the release and possible re-association of Pt(dach) were demonstrated upon enzymatic digestion. The associated advantages and disadvantages of ESI and MALDI were also pointed out.

Pinpointing differences in cisplatin-induced apoptosis in adherent and non-adherent cancer cells.

Platinum compounds are used in the treatment of cancer. We demonstrate that cisplatin-induced (10 µM) apoptosis (caspase-3 activity) is pronounced within 18 hours in non-adherent Ehrlich ascites tumour cells (EATC), whereas there is no increase in caspase-3 activity in the adherent Ehrlich Lettré ascites tumour cells (ELA). Loss of KCl and cell shrinkage are hallmarks in apoptosis and has been shown in EATC. However, we find no reduction in cell volume and only a minor loss of K(+) which is accompanied by net uptake of Na(+) following 18 hours cisplatin exposure in ELA. Glutathione and taurine have previously been demonstrated to protect cells from apoptosis. We find, however, that increase or decrease in the cellular content of glutathione and taurine has no effect on cisplatin-induced cell death in EATC and ELA. Nevertheless, knock-down of the taurine transporter TauT leads to a significant increase in apoptosis in ELA following cisplatin exposure. We find that cytosolic accumulation of cisplatin is similar in EATC and ELA. However, the nuclear accumulation and DNA-binding of cisplatin is significant lower in ELA compared to EATC. We suggest three putative reasons for the observed cisplatin insensitivity in the adherent tumor cells (ELA) compared to the non-adherent tumor cells (EATC): less nuclear cisplatin accumulation, increased TauT activity, and decreased anion and water loss.

[Abdominal ectopic pregnancy].

This review summarises the knowledge of abdominal ectopic pregnancy (AEP), which is a rare condition with higher morbidity and mortalilty than other types of ectopic pregnancies. The condition can be primary, if the pregnancy implants directly on to an abdominal site, or it can be secondary after a tubar abortion. AEP differs from tubal pregnancies by a normal level of human chorionic gonadotropin and rare vaginal bleeding, which causes a diagnostic delay. In an early pregnancy the treatment is laparoscopic removal, but in second and third trimester pregnancies laparotomy is preferred, if possible preceded by MRI for mapping of vascular involvement and location of placenta.

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate.

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.

Author Correction: SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Characterisation of tannin-containing herbal drugs by HPLC.

INTRODUCTION: Herbal drugs containing tannins are characterised in the European Pharmacopoeia by their tannin content analysed by the old, nonspecific, colorimetric Folin-Ciocalteu method. The result of the analysis is a single figure relating to the content of tannins, but this does not provide much information on the identity or status of the herbal drug. OBJECTIVE: In the present paper methods for obtaining more detailed information of the constituents in these herbal drugs are described. METHODOLOGY: The methods developed are based on a reversed-phase gradient HPLC system coupled to DAD, fluorescence, electrochemical and MS detectors. RESULTS: The HPLC system developed provides characteristic fingerprints of the herbal drugs when using UV detection at 250 nm. The fingerprints may be used for identification of tannin-containing herbal drugs. Methanolysis of the herbal drug generated methyl gallate and ellagic acid, which were analysed in the HPLC system. The molar ratio between methyl gallate and ellagic acid may also be used for the identification of herbal drugs. CONCLUSIONS: An HPLC system equipped with selective detectors was shown to be valuable in the identification of herbal tannin. Most promising was fingerprinting using UV detection, but methanolysis followed by HPLC also proved useful.

Reliability and validity of The Danish pediatric voice handicap index.

BACKGROUND: The pediatric voice handicap index (pVHI) questionnaire was developed in 2006 to provide parental information regarding the impact of a voice disorder on their child's life. OBJECTIVES: The aim of this study was to make a Danish version of the original American pVHI and to validate the Danish pVHI by evaluating its internal consistency and reliability. MATERIALS AND METHODS: The original version of the pVHI was translated into Danish. Nineteen parents of dysphonic children, diagnosed in a tertiary otolaryngology hospital department, and 43 parents of children without known voice disorder (control group) completed the questionnaire. The internal consistency, content validity including comparisons of the scores in the two groups and the test-retest reliability were assessed through statistical analysis. RESULTS: The total pVHI scores significantly differed between the group of parents with dysphonic children and the group of parents with children without known voice disorder (p < 0.001). The internal consistency showed an excellent consistency (Chronbach's α > 0.9) of the three subdomains score and the total pVHI score. The test-re-test reliability of the total pVHI score was "strong" with a Pearson's correlation coefficient of 0.97. CONCLUSIONS AND SIGNIFICANCE: The Danish pVHI is a valid and reliable instrument to assess the parents' perception of the impact of a voice disorder on a child's physical, social and emotional well-being.

Timing of heparin prophylaxis and bleeding complications in hysterectomy a nationwide prospective cohort study of 9,949 Danish women.

OBJECTIVE: To examine bleeding complications and thromboembolic events in relation to timing of heparin prophylaxis after hysterectomy. DESIGN: Nationwide prospective cohort study with 30 days post-operative follow-up within the Danish Hysterectomy Database (DHD). SETTING: All gynecological departments in Denmark (n=31). SAMPLE: 9,949 women who had an elective hysterectomy for benign indication between October 2003 and May 2006 and were reported to DHD (national response rate: 88-99% throughout 2004-2005). MAIN OUTCOME MEASURES: Odds ratios (OR) of peri-operative bleeding complications (> or =1,000 ml bleeding during surgery or post-operative wound/vaginal-vault/intraabdominal bleeding or hematoma) and number of events of venous thromboembolism. Logistic regression analysis adjusting for: age, body mass index, alcohol, smoking, meno-/metrorrhagia, uterine weight, department volume, surgeon's experience, route and type of hysterectomy and additional surgery, and stratification on assistant's experience, peri-operative pain prophylaxis with NSAID and daily use of Acetyl Salicylic Acid (ASA)/NSAID. RESULTS: 9,051 women (92%) received thromboprophylaxis with heparin, initiated pre-operatively in 48% and post-operatively in 52%. At least one bleeding complication was noted in 881 women (10%). Post-operative heparin administration was associated with a reduced risk of bleeding complications; OR=0.85 (95% confidence interval 0.73-0.99) compared to pre-operative administration. Excluding cases with potential impaired hemostasis at baseline, the OR was 0.78 (0.64-0.94). There was no fatal embolism. Three of seven pulmonary embolisms and one of three symptomatic deep venous thromboses occurred with the post-operative heparin administration. CONCLUSION: Post-operative rather than pre-operative administration of heparin prophylaxis may reduce the risk of bleeding complications after hysterectomy without apparent risk of increased thromboembolic events.

Establishment of a national Danish hysterectomy database: preliminary report on the first 13,425 hysterectomies.

OBJECTIVE: To describe the concept and early results from the Danish Hysterectomy Database (DHD). DESIGN: Nationwide prospective cohort. SETTING: Denmark. POPULATION: All women who had undergone an elective hysterectomy for benign indication carried out in 2004-2006. METHODS: Structured data are registered prospectively by the surgeons involved in the treatment. Data is reported using the Danish National Patient Registry (LPR) and feedback is provided as clinical indicators with well-defined goals. The DHD concept includes annual plenary meetings, elaboration of national clinical guidelines and parallel causal studies. MAIN OUTCOME MEASURES: Completeness, data validation and department-identifiable clinical indicators (surgical volume, method of hysterectomy, use of antibiotic and thromboembolic prophylaxis, postoperative hospitalization and bleeding complications, surgical infections, reoperations, readmissions and death within 30 days postoperatively). RESULTS: A total of 13,425 hysterectomies were performed in Denmark from 2004 to 2006. In 2005, all gynecological departments in Denmark (n=31) were included in the database collaboration and the national response rate was 99%. Data validity was good in general (82-100% agreement and kappa=0.40-1.00) and data completeness was high (92-100% in 2006). From 2004 to 2006, two clinical guidelines were implemented, the postoperative hospitalization was stable at median 2 days, the rate of postoperative surgical infections was reduced from 4 to 2%, the rate of bleeding complications from 8 to 6%, the reoperation rate from 5 to 4%, and the readmission rate from 7 to 5%. CONCLUSIONS: Clinical performance indicators, audit meetings and nationwide collaboration are useful in monitoring and improving outcome after hysterectomy on a national level. In addition, the DHD offers scope for causal studies about perioperative management.

The use of inductively coupled plasma mass spectrometry as a detector in drug metabolism studies.

BACKGROUND: The inherent properties of element selectivity combined with high sensitivity and structure independent response, make inductively coupled plasma mass spectrometry (ICP-MS) an interesting alternative detection technique in drug metabolism studies. OBJECTIVE: The application of online separation with ICP-MS detection in drug metabolism studies is reviewed with focus on the merits and demerits of this detection technique. The prerequisite for inclusion in this review is that the study involves a separation technique hyphenated online to the ICP-MS detection. RESULT/CONCLUSION: ICP-MS detection is found to be advantageous for analysis of all drug substances detectable by ICP-MS compared to radiochemical detection. Detectable drugs are limited to halogen-, sulfur-, metal- and metalloid-containing compounds. The drawback of interference from endogenous compounds on quantitative mass balance estimations of non-metal drugs is addressed. The potential of determining the stoichiometry in metallo-drug biomolecule interactions is pointed out by presenting examples of simultaneous monitoring of metals in metallo-drugs and intrinsic ICP-MS detectable elements in biomolecules. It is concluded that ICP-MS detection is an indispensable technique in drug metabolism studies of metallo-drugs, although the applicability for traditional drugs is limited.

Effect of laxatives on gastrointestinal functional recovery in fast-track hysterectomy: a double-blind, placebo-controlled randomized study.

OBJECTIVE: The purpose of this study was to determine the effect of early oral bowel stimulation with osmotic laxatives on gastrointestinal function, postoperative nausea and vomiting (PONV) and pain in patients who undergo fast-track abdominal hysterectomy. STUDY DESIGN: This was a double-blind, placebo-controlled study of 53 women who were assigned randomly to either laxative (magnesium oxide + disodium phosphate) or placebo that was initiated 6 hours after the operation. Primary outcome was time to first defecation; the number of vomiting episodes; nausea and pain score were assessed on a visual analogue scale. RESULTS: Time to first postoperative defecation was a median of 45 hours in the laxative group and a median of 69 hours in the placebo group (P < .0001). There were no significant differences between groups in pain scores, PONV and the use of morphine or antiemetics. Postoperative hospitalization was a median of 1 day in the laxative group and of 2 days in the placebo group (P = .41). CONCLUSION: Laxative improves recovery of gastrointestinal function after fast-track hysterectomy but has no significant effect on pain and PONV.

Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 µM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 µM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.

Identification of differences in gene expression in primary cell cultures of human endometrial epithelial cells and trophoblast cells following their interaction.

BACKGROUND: The interaction between epithelial cells of endometrium and trophoblast cells during implantation is presumed to be accompanied by a change in gene expression in the cell types involved. The objective of this study was to identify such differentially expressed genes. METHODS: The interaction between the cell types was simulated in vitro by growing primary cell cultures of human endometrial epithelial cells and trophoblast cells together (co-culture) and separately (control cultures). Gene expression in the cell cultures was compared using the Differential Display method and confirmed using a modified Northern Blot method. RESULTS: Twelve transcripts were identified as being differentially expressed following the interaction between trophoblast and endometrial cells. Some of these sequences show homology to known human genes while other sequences are coding for potential novel genes: (1) one sequence was homologous to the to Homer 1 gene, (2) one identical to the mRNA for XP-G factor, (3) one similar to a hypothetical protein, (4) transcripts showing homologies to a mRNA coding for a cellular proapoptotic protein, and (5) sequences homologous to regions on human chromosomes 5 and 16. Besides, some differentially expressed transcripts have sequences, which could be translated into ribosomal proteins or possibly code for novel proteins. CONCLUSION: These sequences may be important to the course of events following the interaction between endometrial epithelial and trophoblast cells and responsible for implantation.

A review of medical records and discharge summary data found moderate to high predictive values of discharge diagnoses of venous thromboembolism during pregnancy and postpartum.

OBJECTIVE: To validate the discharge diagnoses of venous thromboembolism during pregnancy and postpartum, we examined the positive predictive value (PPV) of venous thromboembolic (VTE) discharge diagnoses associated with pregnancy or puerperium based on 311 cases registered in a Danish population-based hospital-discharge registry. STUDY DESIGN AND SETTING: Medical records and hospital discharge summaries were retrieved and reviewed using a standardized form. Standard and pregnancy-specific codes were used for 147 (49%) and 153 (51%) cases, respectively. RESULTS: The overall PPV of the selected codes was 87.3% (95% confidence interval [CI]: 83.0-90.9). When focusing on confirmed VTE events in relation to the pregnancy, the overall PPV was 79.3% (95% CI: 74.3-83.8). CONCLUSION: The overall PPVs of pregnancy-related VTE diagnoses were moderate to high. The predictive values varied substantially between the individual codes, however, and not all the registered VTE events occurred in relation to pregnancy. Thus, use of unvalidated registry-based pregnancy-related VTE diagnoses for epidemiological research may lead to biased results.