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1.
  • Andersen, Claus Yding, et al. (author)
  • Preovulatory progesterone concentration associates significantly to follicle number and LH concentration but not to pregnancy rate
  • 2011
  • In: Reproductive BioMedicine Online. - : Elsevier BV. - 1472-6491 .- 1472-6483. ; 23:2, s. 187-195
  • Journal article (peer-reviewed)abstract
    • Using data from a large prospective randomized controlled trial that evaluated the effect of recombinant LH (rLH) co-administration for ovarian stimulation, the present study assessed whether progesterone concentration on the day of human chorionic gonadotrophin (HCG) administration was associated with pregnancy outcome. Progesterone concentration was measured on stimulation day 1 and on the day of HCG administration in 475 patients who underwent IVF/intracytoplasmic sperm injection treatment following ovarian stimulation with gonadotrophin-releasing hormone (GnRH) agonist and recombinant FSH with or without rLH administration from day 6 of stimulation. There was no significant association between the late-follicular-phase progesterone concentration and the clinical pregnancy rate. However, progesterone concentration was strongly associated with the number of follicles and retrieved oocytes. Late-follicular-phase LH concentration also showed a significant positive association with progesterone concentration (P = 0.018). Administration of rLH during ovarian stimulation did not affect progesterone concentration. The present study does not support an association between progesterone concentration on the day of HCG administration and the probability of clinical pregnancy in women undergoing ovarian stimulation with GnRH agonists and gonadotrophins for assisted reproduction treatment. Instead, late-follicular-phase progesterone concentration appears to be governed by the number of preovulatory follicles and LH concentration. (C) 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
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2.
  • Godoy, Patricio, et al. (author)
  • Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
  • 2013
  • In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
  • Research review (peer-reviewed)abstract
    • This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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3.
  • Nilsson, Lars, et al. (author)
  • Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'.
  • 2010
  • In: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 89:6, s. 828-31
  • Journal article (peer-reviewed)abstract
    • To enhance oocyte yield and pregnancy outcome in poor responder women undergoing IVF treatment, daily low dose GnRH antagonist administration was given during the late luteal phase to induce luteolysis and possibly secure a more synchronous cohort of recruitable follicles. An open extended pilot study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when < or = 5 follicles developed in a preceding cycle following a long agonist protocol with the use of > 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5 before expected start of menstruation and continued for 4-7 days. On cycle day 2-3 a starting dose of rFSH (300-400 IU/day) was given. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until final oocyte maturation was induced with 10,000 IU hCG. GnRH antagonist only marginally affected the intercycle FSH rise; basal levels of FSH remained similar to those seen after 4 days of antagonist administration. The protocol effectively induced low LH levels and luteolysis, but daily administration of 350 IU rFSH (median) for 11 days only led to the collection of 3 oocytes in 49 oocyte retrievals resulting in 5 pregnancies (4 delivered). Despite GnRH antagonist administration in the late luteal phase and menstrual bleeding, FSH was not sufficiently reduced to secure a more synchronic cohort of recruitable follicles. Novel GnRH antagonists more specifically targeting FSH release may improve the stimulation results in poor responders.
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4.
  • Arlien-Soborg, Mai C., et al. (author)
  • Acromegaly management in the Nordic countries: A Delphi consensus survey
  • 2024
  • In: Clinical Endocrinology. - : WILEY. - 0300-0664 .- 1365-2265.
  • Journal article (peer-reviewed)abstract
    • ObjectiveAcromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.MethodsA Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as >= 80% of panelists rating their agreement as >= 5 or <= 3 on the Likert-type scale.ResultsConsensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.ConclusionThis consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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5.
  • Arlien-Søborg, Mai C., et al. (author)
  • Acromegaly management in the nordic countries : a Delphi consensus survey
  • 2024
  • In: Clinical Endocrinology. - : John Wiley & Sons. - 0300-0664 .- 1365-2265.
  • Journal article (peer-reviewed)abstract
    • Objective: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.Methods: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1−7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale.Results: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.Conclusion: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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7.
  • Benatar, Michael, et al. (author)
  • Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
  • 2024
  • In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
  • Journal article (peer-reviewed)abstract
    • Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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8.
  • Björvang, Richelle D., et al. (author)
  • Mixtures of persistent organic pollutants are found in vital organs of late gestation human fetuses
  • 2021
  • In: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 283
  • Journal article (peer-reviewed)abstract
    • Persistent organic pollutants (POPs) are industrial chemicals with long half-lives. Early life exposure to POPs has been associated with adverse effects. Fetal exposure is typically estimated based on concentrations in maternal serum or placenta and little is known on the actual fetal exposure. We measured the concentrations of nine organochlorine pesticides (OCPs), ten polychlorinated biphenyl (PCB) congeners, and polybrominated diphenyl ether (PBDE) congeners by gas chromatography – tandem mass spectrometry in maternal serum, placenta, and fetal tissues (adipose tissue, liver, heart, lung and brain) in 20 pregnancies that ended in stillbirth (gestational weeks 36–41). The data were combined with our earlier data on perfluoroalkyl substances (PFASs) in the same cohort (Mamsen et al. 2019). HCB, p,p’-DDE, PCB 138 and PCB 153 were quantified in all samples of maternal serum, placenta and fetal tissues. All 22 POPs were detected in all fetal adipose tissue samples, even in cases where they could not be detected in maternal serum or placenta. Tissue:serum ratios were significantly higher in later gestations, male fetuses, and pregnancies with normal placental function. OCPs showed the highest tissue:serum ratios and PFAS the lowest. The highest chemical burden was found in adipose tissue and lowest in the brain. Overall, all studied human fetuses were intrinsically exposed to mixtures of POPs. Tissue:serum ratios were significantly modified by gestational age, fetal sex and placental function. Importantly, more chemicals were detected in fetal tissues compared to maternal serum and placenta, implying that these proxy samples may provide a misleading picture of actual fetal exposures.
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9.
  • Blauenfeldt, Rolf Ankerlund, et al. (author)
  • Remote Ischemic Conditioning for Acute Stroke : The RESIST Randomized Clinical Trial
  • 2023
  • In: JAMA. - 0098-7484. ; 330:13, s. 1236-1246
  • Journal article (peer-reviewed)abstract
    • Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P =.67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P =.68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.
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10.
  • Borgbo, Tanni, et al. (author)
  • Genotyping common FSHR polymorphisms based on competitive amplification of differentially melting amplicons (CADMA).
  • 2014
  • In: Journal of Assisted Reproduction and Genetics. - : Springer Science and Business Media LLC. - 1058-0468 .- 1573-7330. ; 31:11, s. 1427-1436
  • Journal article (peer-reviewed)abstract
    • To provide an improved platform for simple, reliable, and cost-effective genotyping. Modern fertility treatments are becoming increasingly individualized in an attempt to optimise the follicular response and reproductive outcome, following controlled ovarian stimulation. As the field of pharmacogenetics evolve, genetic biomarkers such as polymorphisms of the follicle stimulating hormone receptor (FSHR) may be included as a predictive tool for individualized fertility treatment. However, the currently available genotyping methods are expensive, time-consuming or have a limited analytical sensitivity. Here, we present a novel version of "competitive amplification of differentially melting amplicons" (CADMA), providing an improved platform for simple, reliable, and cost-effective genotyping. Two CADMA based assays were designed for the two common polymorphisms of the FSHR gene: rs6165 (c.919A > G, p. Thr307Ala, FSHR 307) and rs6166 (c.2039A > G, p. Asn680Ser, FSHR 680). To evaluate the reliability of the new CADMA-based assays, the genotyping results were compared with two conventional PCR based genotyping methods; allele-specific PCR (AS-PCR) and Sanger sequencing. The genotype frequencies for both polymorphisms were 35 % (TT), 42 % (CT), and 23 % (CC), respectively. A 100 % accordance was observed between the CADMA-based genotyping results and sequencing results, whereas 5 discrepancies were observed between the AS-PCR results and the CADMA-based genotyping results. Comparing the CADMA-based assays to (AS-PCR) and Sanger sequencing, the CADMA based assays showed an improved analytical sensitivity and a wider applicability. The new assays provide a reliable, fast and user-friendly genotyping method facilitating a wider implication in clinical practise.
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11.
  • Bungum, Leif, et al. (author)
  • Circadian variation in concentration of anti-Mullerian hormone in regularly menstruating females: relation to age, gonadotrophin and sex steroid levels.
  • 2011
  • In: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 26, s. 678-684
  • Journal article (peer-reviewed)abstract
    • BACKGROUND Anti-Müllerian hormone (AMH) is a promising marker of ovarian reserve. The aim of the study is to assess the circadian variation in AMH, and to evaluate its clinical relevance and biological aspects as an effect of age and other endocrine mechanisms involved in the regulation of AMH secretion. METHODS Nineteen healthy non-smoking, regularly menstruating female volunteers with body mass index below 30 kg/m(2), 10 aged 20-30 years (Group A) and 9 aged 35-45 (Group B) were included. Blood sampling, initiated at 8:00 a.m. on Days 2-6 of the menstrual cycle, was continued every second hour until 8:00 a.m. the following day. Serum levels of AMH, FSH, LH, progesterone and estradiol were measured. RESULTS With 8:00 a.m. values at the first day of investigation as a reference, the mean concentrations in the pooled data revealed a significantly lower level at 4:00 a.m. (P = 0.021) and 6:00 a.m. (P = 0.005) with a maximum mean difference of 1.9 pmol/l (10.6%). The same pattern was seen in both the age groups. Including both the age groups, the overall circadian variation of the AMH levels did not reach statistical significance (P = 0.059). A significant positive correlation between AMH and LH concentration was seen over the 24-h period (P < 0.001). CONCLUSIONS A slight decrease in serum AMH levels during the late night appears not clinically relevant. Co-variation in the levels of LH and AMH might indicate joint regulatory mechanisms for the latter hormone and gonadotrophins.
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12.
  • Christensen, Jeppe Brage, et al. (author)
  • Ionization quenching in scintillators used for dosimetry of mixed particle fields
  • 2019
  • In: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 64:9
  • Journal article (peer-reviewed)abstract
    • Ionization quenching in ion beam dosimetry is often related to the fluence- or dose-averaged linear energy transfer (LET). Both quantities are however averaged over a wide LET range and a mixed field of primary and secondary ions. We propose a novel method to correct the quenched luminescence in scintillators exposed to ion beams. The method uses the energy spectrum of the primaries and accounts for the varying quenched luminescence in heavy, secondary ion tracks through amorphous track structure theory. The new method is assessed against more traditional approaches by correcting the quenched luminescence response from the BCF-12, BCF-60, and 81-0084 plastic scintillators exposed to a 100 MeV pristine proton beam in order to compare the effects of the averaged LET quantities and the secondary ions. Calculations and measurements show that primary protons constitute more than 92% of the energy deposition but account for more than 95% of the luminescence signal in the scintillators. The quenching corrected luminescence signal is in better agreement with the dose measurement when the secondary particles are taken into account. The Birks model provided the overall best quenching corrections, when the quenching corrected signal is adjusted for the number of free model parameters. The quenching parameter kB for the BCF-12 and BCF-60 scintillators is in agreement with literature values and was found to be kB = (10.6 +/- 0.1) x 10(-2) mu m keV(-1) for the 81-0084 scintillator. Finally, a fluence threshold for the 100 MeV proton beam was calculated to be of the order of 10(10) cm(-2), corresponding to 110 Gy, above which the quenching increases non-linearly and the Birks model no longer is applicable.
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13.
  • Christensen, Jeppe Brage, et al. (author)
  • Quenching-free fluorescence signal from plastic-fibres in proton dosimetry : understanding the influence of Cerenkov radiation
  • 2018
  • In: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 63:6
  • Journal article (peer-reviewed)abstract
    • The origin of photons emitted in optical fibres under proton irradiation has been attributed to either entirely Cerenkov radiation or light consisting of fluorescence with a substantial amount of Cerenkov radiation. The source of the light emission is assessed in order to understand why the signal from optical fibres irradiated with protons is reportedly quenching-free. The present study uses the directional emittance of Cerenkov photons in 12 MeV and 20 MeV electron beams to validate a Monte Carlo model for simulating the emittance and transmission of Cerenkov radiation in optical fibres. We show that fewer than 0.01 Cerenkov photons are emitted and guided per 225 MeV proton penetrating the optical fibre, and that the Cerenkov signal in the optical fibre is completely negligible at the Bragg peak. Furthermore, on taking the emittance and guidance of both fluorescence and Cerenkov photons into account, it becomes evident that the reported quenching-free signal in PMMA-based optical fibres during proton irradiation is due to fluorescence.
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14.
  • Christensen, Lise Lotte, et al. (author)
  • The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population
  • 2008
  • In: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 9, s. 52-
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Mutations in the mismatch repair genes hMLH1 and hMSH2 predispose to hereditary non-polyposis colorectal cancer (HNPCC). Genetic screening of more than 350 Danish patients with colorectal cancer (CRC) has led to the identification of several new genetic variants (e.g. missense, silent and non-coding) in hMLH1 and hMSH2. The aim of the present study was to investigate the frequency of these variants in hMLH1 and hMSH2 in Danish patients with sporadic colorectal cancer and in the healthy background population. The purpose was to reveal if any of the common variants lead to increased susceptibility to colorectal cancer. METHODS: Associations between genetic variants in hMLH1 and hMSH2 and sporadic colorectal cancer were evaluated using a case-cohort design. The genotyping was performed on DNA isolated from blood from the 380 cases with sporadic colorectal cancer and a sub-cohort of 770 individuals. The DNA samples were analyzed using Single Base Extension (SBE) Tag-arrays. A Bonferroni corrected Fisher exact test was used to test for association between the genotypes of each variant and colorectal cancer. Linkage disequilibrium (LD) was investigated using HaploView (v3.31). RESULTS: Heterozygous and homozygous changes were detected in 13 of 35 analyzed variants. Two variants showed a borderline association with colorectal cancer, whereas the remaining variants demonstrated no association. Furthermore, the genomic regions covering hMLH1 and hMSH2 displayed high linkage disequilibrium in the Danish population. Twenty-two variants were neither detected in the cases with sporadic colorectal cancer nor in the sub-cohort. Some of these rare variants have been classified either as pathogenic mutations or as neutral variants in other populations and some are unclassified Danish variants. CONCLUSION: None of the variants in hMLH1 and hMSH2 analyzed in the present study were highly associated with colorectal cancer in the Danish population. High linkage disequilibrium in the genomic regions covering hMLH1 and hMSH2, indicate that common genetic variants in the two genes in general are not involved in the development of sporadic colorectal cancer. Nevertheless, some of the rare unclassified variants in hMLH1 and hMSH2 might be involved in the development of colorectal cancer in the families where they were originally identified.
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15.
  • Eguíluz-Gracia, Ibon, et al. (author)
  • Long-Term persistence of human donor alveolar macrophages in lung transplant recipients
  • 2016
  • In: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 71:11, s. 1006-1011
  • Journal article (peer-reviewed)abstract
    • Background Alveolar macrophages (AMFs) are critical regulators of lung function, and may participate in graft rejection following lung transplantation. Recent studies in experimental animals suggest that most AMFs are self-maintaining cells of embryonic origin, but knowledge about the ontogeny and life span of human AMFs is scarce. Methods To follow the origin and longevity of AMFs in patients with lung transplantation for more than 100â €..weeks, we obtained transbronchial biopsies from 10 gender-mismatched patients with lung transplantation. These were subjected to combined in situ hybridisation for X/Y chromosomes and immunofluorescence staining for macrophage markers. Moreover, development of AMFs in humanised mice reconstituted with CD34+ umbilical cord-derived cells was assessed. Results The number of donor-derived AMFs was unchanged during the 2â €..year post-Transplantation period. A fraction of the AMFs proliferated locally, demonstrating that at least a subset of human AMFs have the capacity to self-renew. Lungs of humanised mice were found to abundantly contain populations of human AMFs expressing markers compatible with a monocyte origin. Moreover, in patients with lung transplantation we found that recipient monocytes seeded the alveoli early after transplantation, and showed subsequent phenotypical changes consistent with differentiation into proliferating mature AMFs. This resulted in a stable mixed chimerism between donor and recipient AMFs throughout the 2-year period. Conclusions The finding that human AMFs are maintained in the lung parenchyma for several years indicates that pulmonary macrophage transplantation can be a feasible therapeutic option for patients with diseases caused by dysfunctional AMFs. Moreover, in a lung transplantation setting, long-Term persistence of donor AMFs may be important for the development of chronic graft rejection.
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16.
  • Ejlertsen, Bent, et al. (author)
  • Improved outcome from substituting methotrexate with epirubicin : results from a randomised comparison of CMF versus CEF in patients with primary breast cancer
  • 2007
  • In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 43:5, s. 877-884
  • Journal article (peer-reviewed)abstract
    • We compared the efficacy of CEF (cyclophosphamide, epirubicin, and fluorouracil) against CMF (cyclophosphamide, methotrexate, and fluorouracil) in moderate or high risk breast cancer patients. We randomly assigned 1224 patients with completely resected unilateral breast cancer to receive nine cycles of three-weekly intravenous CMF or CEF. Patients were encouraged to take part in a parallel trial comparing oral pamidronate 150 mg twice daily for 4 years versus control (data not shown). Substitution of methotrexate with epirubicin significantly reduced the unadjusted hazard for disease-free survival (DFS) by 16% (hazard ratio 0.84; 95% CI; 0.71-0.99) and for overall survival by 21% (hazard ratio 0.79; 95% CI; 0.66-0.94). The risk of secondary leukaemia and congestive heart failure was similar in the two groups. Overall CEF was superior over CMF in terms of DFS and OS in patients with operable breast cancer without subsequent increase in late toxicities.
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17.
  • Fejrskov, Anja, et al. (author)
  • Novel biomarker profiles to improve individual diagnosis and prognosis in patients with suspected inflammatory bowel disease : protocol for the Nordic inception cohort study (NORDTREAT)
  • 2024
  • In: BMJ Open. - : BioMed Central (BMC). - 2044-6055. ; 14:5
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, can be challenging to diagnose, and treatment outcomes are difficult to predict. In the NORDTREAT cohort study, a Nordic prospective multicentre study, we aim to identify novel molecular biomarkers of diagnostic value by assessing the diagnostic test accuracy (cross-sectionally), as well as the prognostic utility when used as prognostic markers in the long-term (cohort study). In the diagnostic test accuracy study, the primary outcome is a successful diagnosis using one or more novel index tests at baseline compared with the ECCO criteria as the reference standard. The composite outcome of the prognostic utility study is 'severe IBD' within 52 weeks from inclusion, defined as one or more of the following three events: IBD-related surgery, IBD-related hospitalisation or IBD-related death.METHODS AND ANALYSIS: We aim to recruit 800 patients referred on suspicion of IBD to this longitudinal observational study, a collaboration between 11 inclusion sites in Denmark, Iceland, Norway and Sweden. Inclusion will occur from February 2022 until December 2023 with screening and baseline visits for all participants and three outcome visits at weeks 12, 26 and 52 after baseline for IBD-diagnosed patients. Biological material (blood, faeces, biopsies, urine and hair), clinical data and lifestyle information will be collected during these scheduled visits.ETHICS AND DISSEMINATION: This study will explore novel biomarkers to improve diagnostic accuracy and prediction of disease progression, thereby improving medical therapy and the quality of life for patients with IBD.The study is approved by the Ethics Committee (DK: S-20200051, v1.4, 16.10.2021; IS: VSNb2021070006/03.01, NO: 193064; SE: DNR 2021-05090) and the Danish Data Protecting Agency (20/54594). Results will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences.CLINICAL TRIAL REGISTRATION NUMBER: NCT05414578; Pre-results.
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18.
  • Gilbert, M. Thomas P., et al. (author)
  • Paleo-Eskimo mtDNA genome reveals matrilineal discontinuity in Greenland
  • 2008
  • In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 320:5884, s. 1787-1789
  • Journal article (peer-reviewed)abstract
    • The Paleo- Eskimo Saqqaq and Independence I cultures, documented from archaeological remains in Northern Canada and Greenland, represent the earliest human expansion into the New World's northern extremes. However, their origin and genetic relationship to later cultures are unknown. We sequenced a mitochondrial genome from a Paleo- Eskimo human by using 3400- to 4500- year- old frozen hair excavated from an early Greenlandic Saqqaq settlement. The sample is distinct from modern Native Americans and Neo- Eskimos, falling within haplogroup D2a1, a group previously observed among modern Aleuts and Siberian Sireniki Yuit. This result suggests that the earliest migrants into the New World's northern extremes derived from populations in the Bering Sea area and were not directly related to Native Americans or the later Neo- Eskimos that replaced them.
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19.
  • Hudson, Lawrence N, et al. (author)
  • The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
  • 2017
  • In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
  • Journal article (peer-reviewed)abstract
    • The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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20.
  • Jensen, Christian Fuglesang S., et al. (author)
  • Microdissection Testicular Sperm Extraction Versus Multiple Needle-pass Percutaneous Testicular Sperm Aspiration in Men with Nonobstructive Azoospermia : A Randomized Clinical Trial
  • 2022
  • In: European Urology. - : Elsevier BV. - 0302-2838. ; 82:4, s. 377-384
  • Journal article (peer-reviewed)abstract
    • Background: Surgical extraction of testicular spermatozoa is needed in men with nonobstructive azoospermia (NOA) who wish to become biological fathers. Based on available uncontrolled studies with unspecific patient selection, microdissection testicular sperm extraction (mTESE), having a sperm retrieval rate (SRR) of 50%, is considered the most efficient sperm retrieval procedure. However, no randomized clinical trials for comparison of different sperm retrieval procedures exist. Testicular sperm aspiration (TESA) is simple and commonly used, and we hypothesized that this technique using multiple needle passes would give similar SRRs to mTESE. Objective: To compare mTESE and multiple needle-pass TESA in men with NOA. Design, setting, and participants: A randomized clinical trial was performed between June 2017 and April 2021, with inclusion of 100 men with NOA from four centers in Denmark and Sweden. All participants received treatment at the same institution. Intervention: Participants were randomized to mTESE (n = 49) or multiple needle-pass TESA (n = 51). Patients with failed multiple needle-pass TESA proceeded directly to salvage mTESE. Outcome measurements and statistical analysis: The primary outcome was SRR. Secondary outcomes included complications and changes in reproductive hormones after surgery. Results and limitations: Spermatozoa were retrieved in 21/49 (43%) men after mTESE and in 11/51 (22%) men after multiple needle-pass TESA (rate difference –0.21; 95% confidence interval –0.39 to –0.03; p = 0.02). The combined SRR for multiple needle-pass TESA + salvage mTESE was 15/51 (29%). No complications occurred after multiple needle-pass TESA only, while 5/89 (6%) men having mTESE experienced a complication requiring surgical intervention. Overall, no statistically significant differences in reproductive hormones were observed between groups after 6 mo. Limitations include the low number of patients in secondary outcome data. Conclusions: In direct comparison, SRR was higher in mTESE than in multiple needle-pass TESA. Patient summary: Men with azoospermia need surgical extraction of spermatozoa to become biological fathers. In this randomized trial, we compared two surgeries (microdissection testicular sperm extraction [mTESE] and testicular sperm aspiration [TESA]) and found that mTESE gives a higher sperm retrieval rate than multiple needle-pass TESA.
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21.
  • Jensen, Christian Fuglesang S., et al. (author)
  • Results from the first autologous grafting of adult human testis tissue : A case report
  • 2024
  • In: Human Reproduction. - 0268-1161. ; 39:2, s. 303-309
  • Journal article (peer-reviewed)abstract
    • Fertility restoration using autologous testicular tissue transplantation is relevant for infertile men surviving from childhood cancer and, possibly, in men with absent or incomplete spermatogenesis resulting in the lack of spermatozoa in the ejaculate (non-obstructive azoospermia, NOA). Currently, testicular tissue from pre-pubertal boys extracted before treatment with gonadotoxic cancer therapy can be cryopreserved with good survival of spermatogonial stem cells. However, strategies for fertility restoration, after successful cancer treatment, are still experimental and no clinical methods have yet been developed. Similarly, no clinically available treatments can help men with NOA to become biological fathers after failed attempts of testicular surgical sperm retrieval. We present a case of a 31-year-old man with NOA who had three pieces of testis tissue (each ∼2 × 4 × 2 mm3) extracted and cryopreserved in relation to performing microdissection testicular sperm extraction (mTESE). Approximately 2 years after mTESE, the thawed tissue pieces were engrafted in surgically created pockets bilaterally under the scrotal skin. Follow-up was performed after 2, 4, and 6 months with assessment of reproductive hormones and ultrasound of the scrotum. After 6 months, all engrafted tissue was extracted and microscopically analyzed for the presence of spermatozoa. Furthermore, parts of the extracted tissue were analyzed histologically and by immunohistochemical analysis. Active blood flow in the engrafted tissue was demonstrated by doppler ultrasound after 6 months. No spermatozoa were found in the extracted tissue. Histological and immunohistochemical analysis demonstrated graft survival with intact clear tubules and normal cell organization. Sertoli cells and spermatocytes with normal morphology were located near the basement membrane. MAGE-A and VASA positive spermatogonia/spermatocytes were detected together with SOX9 positive Sertoli cells. Spermatocytes and/or Sertoli cells positive for γH2AX was also detected. In summary, following autologous grafting of frozen-thawed testis tissue under the scrotal skin in a man with NOA, we demonstrated graft survival after 6 months. No mature spermatozoa were detected; however, this is likely due to the pre-existing spermatogenic failure.
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22.
  • Jensen, Christian Fuglesang Skjødt, et al. (author)
  • Sertoli and Germ Cells Within Atrophic Seminiferous Tubules of Men With Non-Obstructive Azoospermia
  • 2022
  • In: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13
  • Journal article (peer-reviewed)abstract
    • Background: Infertile men with non-obstructive azoospermia (NOA) have impaired spermatogenesis. Dilated and un-dilated atrophic seminiferous tubules are often present in the testes of these patients, with the highest likelihood of active spermatogenesis in the dilated tubules. Little is known about the un-dilated tubules, which in NOA patients constitute the majority. To advance therapeutic strategies for men with NOA who fail surgical sperm retrieval we aimed to characterize the spermatogonial stem cell microenvironment in atrophic un-dilated tubules. Methods: Testis biopsies approximately 3x3x3 mm3 were obtained from un-dilated areas from 34 patients. They were classified as hypospermatogenesis (HS) (n=5), maturation arrest (MA) (n=14), and Sertoli cell only (SCO) (n= 15). Testis samples from five fertile men were included as controls. Biopsies were used for histological analysis, RT-PCR analysis and immunofluorescence of germ and Sertoli cell markers. Results: Anti-Müllerian hormone mRNA and protein expression was increased in un-dilated tubules in all three NOA subtypes, compared to the control, showing an immature state of Sertoli cells (p<0.05). The GDNF mRNA expression was significantly increased in MA (P=0.0003). The BMP4 mRNA expression showed a significant increase in HS, MA, and SCO (P=0.02, P=0.0005, P=0.02, respectively). The thickness of the tubule wall was increased 2.2-fold in the SCO-NOA compared to the control (p<0.05). In germ cells, we found the DEAD-box helicase 4 (DDX4) and melanoma-associated antigen A4 (MAGE-A4) mRNA and protein expression reduced in NOA (MAGE-A: 46% decrease in HS, 53% decrease in MA, absent in SCO). In HS-NOA, the number of androgen receptor positive Sertoli cells was reduced 30% with a similar pattern in mRNA expression. The γH2AX expression was increased in SCO as compared to HS and MA. However, none of these differences reached statistical significance probably due to low number of samples. Conclusions: Sertoli cells were shown to be immature in un-dilated tubules of three NOA subtypes. The increased DNA damage in Sertoli cells and thicker tubule wall in SCO suggested a different mechanism for the absence of spermatogenesis from SCO to HS and MA. These results expand insight into the differences in un-dilated tubules from the different types of NOA patients.
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23.
  • Jensen, Pernille Linnert, et al. (author)
  • Proteomic Analysis of Human Blastocoel Fluid and Blastocyst Cells
  • 2013
  • In: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 22:7, s. 1126-1135
  • Journal article (peer-reviewed)abstract
    • Human embryonic stem cells (hESCs) are derived from the inner cell mass (ICM) of the blastocyst and can differentiate into any cell type in the human body. These cells hold a great potential for regenerative medicine, but in order to obtain enough cells needed for medical treatment, culture is required on a large scale. In the undifferentiated state, hESCs appear to possess an unlimited potential for proliferation but optimal, defined and safe culture conditions remains a challenge. The aim of the present study was to identify proteins in the natural environment of undifferentiated hESCs, namely the blastocoel fluid, which is in contact with all the cells in the blastocyst, including hESCs. Fifty-three surplus human blastocysts were donated after informed consent and blastocoel fluid was isolated by micromanipulation. Using highly sensitive nano high pressure liquid chromatography tandem mass spectrometry, 286 proteins were identified in the blastocoel fluid and 1307 proteins in the corresponding cells of the blastocyst. Forty-two were previously uncharacterized proteins - eight of these originated from the blastocoel fluid. Furthermore, several heat shock proteins (Hsp27, Hsp60, Hsc70 and Hsp90) were identified in blastocoel fluid together with zona pellucida proteins (ZP2-4), Vitamin D binding protein and Retinol binding protein. Proteins that regulate ciliary assembly and function were also identified, including Bardet-biedl syndrome protein 7. This study has identified numerous proteins which cells from the ICM of the human blastocyst are exposed to via the blastocoel fluid. These results can be an inspiration for the development of improved culture conditions for hESCs.
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24.
  • Kehler, Jan, et al. (author)
  • Discovery and Development of C-11-Lu AE92686 as a Radioligand for PET Imaging of Phosphodiesterase10A in the Brain
  • 2014
  • In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:9, s. 1513-1518
  • Journal article (peer-reviewed)abstract
    • Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-C-11-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (C-11-Lu AE92686) and its tritiated analog H-3-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and C-11-labeled compounds were synthesized. 3H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and C-11-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: C-11-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3H-Lu AE92686. The binding of C-11-Lu AE92686 and 3H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BPND) of C-11-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BPND was found to be high and reproducible-that is, BP(ND)s were 6.5 +/- 0.3 (n = 3) and 7.5 +/- 1.0 (n = 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that C-11-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.
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25.
  • Kristensen, Bent, et al. (author)
  • Bisphosphonate treatment in primary breast cancer : results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer
  • 2008
  • In: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 47:4, s. 740-6
  • Journal article (peer-reviewed)abstract
    • PURPOSE AND PATIENTS: During the period from January 1990 to January 1996 a total of 953 patients with lymph node negative primary breast cancer were randomised to oral pamidronate (n=460) 150 mg twice daily for 4 years or no adjuvant pamidronate (n=493) in order to investigate whether oral pamidronate can prevent the occurrence of bone metastases and fractures. The patients received adjuvant chemotherapy, loco-regional radiation therapy, but no endocrine treatment. RESULTS: During the follow-up period the number of patients with pure bone metastases was 35 in the control group and 31 in the pamidronate group. The number of patients with a combination of bone and other distant metastases were 22 in the control group and 20 in the pamidronate group. The hazard rate ratio for recurrence in bone in the pamidronate group compared to the control group was 1.03 (95% confidence interval 0.75-1.40) and p=0.86. No effect was observed on overall survival. In a small subgroup of 27 patients from the study, 12 of whom were treated with pamidronate a significant bone preserving effect was observed on bone mineral density in the lumbar spine, but not in the proximal femur. CONCLUSION: The results from the trial do not support a beneficial effect of oral pamidronate on the occurrence of bone metastases or fractures in patients with primary breast cancer receiving adjuvant chemotherapy.
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26.
  • Mamsen, Linn Salto, et al. (author)
  • Concentration of perfluorinated compounds and cotinine in human foetal organs, placenta, and maternal plasma
  • 2017
  • In: Science of the Total Environment. - : Elsevier BV. - 0048-9697. ; 596-597, s. 97-105
  • Journal article (peer-reviewed)abstract
    • Background Perfluoroalkyl substances (PFASs) are bio-accumulative pollutants, and prenatal exposure to PFASs is believed to impact human foetal development and may have long-term adverse health effects later in life. Additionally, maternal cigarette smoking may be associated with PFAS levels. Foetal exposure has previously been estimated from umbilical cord plasma, but the actual concentration in foetal organs has never been measured. Objectives The concentrations of 5 PFASs and cotinine – the primary metabolite of nicotine – were measured in human foetuses, placentas, and maternal plasma to evaluate to what extent these compounds were transferred from mother to foetus and to determine if the PFAS concentrations were associated with maternal cigarette smoking. Methods Thirty-nine Danish women who underwent legal termination of pregnancy before gestational week 12 were included; 24 maternal blood samples were obtained together with 34 placental samples and 108 foetal organs. PFASs and cotinine were assayed by liquid chromatography/triple quadrupole mass spectrometry. Results In foetal organs, the average concentrations of perfluorooctanesulphonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDa), and perfluorodecanoic acid (PFDA) were 0.6 ng/g, 0.2 ng/g, 0.1 ng/g, 0.1 ng/g, and 0.1 ng/g, respectively. A significant positive correlation was found between the exposure duration, defined as foetal age, and foetal to maternal ratio for all five PFASs and cotinine. Smokers presented 99 ng/g cotinine in plasma, 108 ng/g in placenta, and 61 ng/g in foetal organs. No correlation between the maternal cotinine concentrations and PFAS concentrations was found. Conclusions PFASs were transferred from mother to foetus, however, with different efficiencies. The concentrations of PFOS, PFOA, PFNA, PFUnDA, and PFDA in foetal organs were much lower than the maternal concentrations. Furthermore, a significant correlation between the exposure duration and all of the evaluated PFASs was found. The health-compromising concentrations of these substances during foetal development are unknown.
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27.
  • Mamsen, Linn Salto, et al. (author)
  • Concentrations of perfluoroalkyl substances (PFASs) in human embryonic and fetal organs from first, second, and third trimester pregnancies
  • 2019
  • In: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 124, s. 482-492
  • Journal article (peer-reviewed)abstract
    • Background: The persistent environmental contaminants perfluoroalkyl substances (PFASs) have gained attention due to their potential adverse health effects, in particular following early life exposure. Information on human fetal exposure to PFASs is currently limited to one report on first trimester samples. There is no data available on PFAS concentrations in fetal organs throughout all three trimesters of pregnancy. Methods: We measured the concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnA), and perfluorohexane sulfonic acid (PFHxS) in human embryos and fetuses with corresponding placentas and maternal serum samples derived from elective pregnancy terminations and cases of intrauterine fetal death. A total of 78 embryos and fetuses aged 7–42 gestational weeks were included and a total of 225 fetal organs covering liver, lung, heart, central nervous system (CNS), and adipose tissue were analyzed, together with 71 placentas and 63 maternal serum samples. PFAS concentrations were assayed by liquid chromatography/triple quadrupole mass spectrometry. Results: All evaluated PFASs were detected and quantified in maternal sera, placentas and embryos/fetuses. In maternal serum samples, PFOS was detected in highest concentrations, followed by PFOA > PFNA > PFDA = PFUnA = PFHxS. Similarly, PFOS was detected in highest concentrations in embryo/fetal tissues, followed by PFOA > PFNA = PFDA = PFUnA. PFHxS was detected in very few fetuses. In general, PFAS concentrations in embryo/fetal tissue (ng/g) were lower than maternal serum (ng/ml) but similar to placenta concentrations. The total PFAS burden (i.e. the sum of all PFASs) was highest in lung tissue in first trimester samples and in liver in second and third trimester samples. The burden was lowest in CNS samples irrespective of fetal age. The placenta:maternal serum ratios of PFOS, PFOA and PFNA increased across gestation suggesting bioaccumulation in the placenta. Further, we observed that the ratios were higher in pregnancies with male fetuses compared to female fetuses. Conclusions: Human fetuses were intrinsically exposed to a mixture of PFASs throughout gestation. The compounds were detected in all analyzed tissues, suggesting that PFASs reach and may affect many types of organs. Collectively, our results demonstrate that PFASs pass the placenta and deposit to embryo and fetal tissues, calling for risk assessment of gestational exposures.
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28.
  • Müller, Catharina, et al. (author)
  • Early extracellular matrix changes are associated with later development of bronchiolitis obliterans syndrome after lung transplantation
  • 2017
  • In: BMJ Open Respiratory Research. - : BMJ. - 2052-4439. ; 4:1
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Chronic lung allograft dysfunction in the form of bronchiolitis obliterans syndrome (BOS) is the main cause of death beyond 1-year post-lung transplantation. The disease-initiating triggers as well as the molecular changes leading to fibrotic alterations in the transplanted lung are largely unknown. The aim of this study was to identify potential early changes in the extracellular matrix (ECM) in different compartments of the transplanted lung prior to the development of BOS.METHODS: Transbronchial biopsies from a cohort of 58 lung transplantation patients at the Copenhagen University hospital between 2005 and 2006, with or without development of BOS in a 5-year follow-up, were obtained 3 and 12 months after transplantation. Biopsies were assessed for total collagen, collagen type IV and biglycan in the alveolar and small airway compartments using Masson's Trichrome staining and immunohistochemistry.RESULTS: A time-specific and compartment-specific pattern of ECM changes was detected. Alveolar total collagen (p=0.0190) and small airway biglycan (p=0.0199) increased between 3 and 12 months after transplantation in patients developing BOS, while collagen type IV (p=0.0124) increased in patients without BOS. Patients with early-onset BOS mirrored this increase. Patients developing grade 3 BOS showed distinct ECM changes already at 3 months. Patients with BOS with treated acute rejections displayed reduced alveolar total collagen (p=0.0501) and small airway biglycan (p=0.0485) at 3 months.CONCLUSIONS: Patients with future BOS displayed distinct ECM changes compared with patients without BOS. Our data indicate an involvement of alveolar and small airway compartments in post-transplantation changes in the development of BOS.
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29.
  • Mörse, Helena, et al. (author)
  • Acute onset of ovarian dysfunction in young females after start of cancer treatment.
  • 2013
  • In: Pediatric Blood & Cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 60:4, s. 676-681
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Female childhood cancer survivors are at risk of ovarian failure and premature ovarian insufficiency. We hereby present an interim analysis of a prospective observational study of ovarian function during cancer treatment of young females in relation to clinical factors. PROCEDURE: Thirty-four consecutive female cancer patients aged 0-18 year were included after informed consent. Serum/Plasma levels of anti-Müllerian hormone (AMH), inhibin B, FSH, LH, and oestradiol (E2) were measured at diagnosis and every 3-4 months during and after treatment. RESULTS: All patients had detectable AMH levels at diagnosis. Eleven patients had reached menarche (mean age 14½ years) and the remaining patients had a mean age of 6½ years. They all showed a rapid decline in AMH after 3 months of treatment, regardless of AMH at diagnosis, age, menarche, or treatment given. Those given radiotherapy below the diaphragm and/or stem cell transplantation (SCT) (n = 9) had no ovarian recovery during or 1½-year after treatment. However, recovery was observed in those given standard treatment for acute lymphatic leukemia (n = 7) already during maintenance chemotherapy. For the remaining patients, longer follow-up is required for analysis of ovarian recovery after treatment. CONCLUSIONS: Rapid ovarian dysfunction is observed in all females after initiation of cancer treatment as measured by AMH and inhibin B. Our data regarding those who require abdominal radiotherapy and/or SCT confirms the recommendations in the Nordic countries where these patients are eligible for cryopreservation of ovarian cortical tissue before start of cancer treatment. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
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30.
  • Mörse, Helena, et al. (author)
  • Reliability of AMH in Serum after Long-term Storage at -80°C and an Extended Thawing Episode
  • 2016
  • In: Annals of Clinical and Laboratory Research. - 2386-5180. ; 4:1
  • Journal article (peer-reviewed)abstract
    • Background: Measurement of anti-Müllerian hormone (AMH) is a valuable clinical tool for evaluating ovarian function. The present study aims to evaluate the reliability of AMH measurements obtained from samples kept for long-term storage with or without intermittent thawing.Methods and findings: Serum samples from 35 young female cancer patients were prospectively collected and stored at -80°C from 2007 until 2010. In 2011, AMH was analyzed with the DSL assay. During storage, the samples were exposed to a freezer error in 2013 that resulted in their being thawed up to 11°C for a maximum of 21 days and then refrozen. In 2014, the same samples (new aliquots) were analyzed with the Ansh-AMH assay. To test the reliability of the results from 2014, we conducted a thawing experiment on serum samples from 10 randomly selected females and compared the Ansh-AMH results for samples stored in a freezer with aliquots from the same samples that were stored at 11°C for 1, 3, 7, 14, and 21 days, respectively. Average AMH levels were 1.6 times higher when assayed with the Ansh-AMH compared with the DSL-AMH, which is in line with reported agreement between these types of assays. The same difference between the assays was found in samples that differed two years in storage time. The Ansh-AMH levels from ten serum samples without long-term storage were not influenced by exposure to 11°C for up to 21 days.Conclusions: The results indicate that long-term storage at -80°C and episodes of thawing have little impact on AMH levels analyzed with current methods. These data are reassuring and enable longitudinal studies to be planned that will analyze all collected serum samples simultaneously.
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31.
  • Mörse, Helena, et al. (author)
  • Severe gonadotoxic insult manifests early in young girls treated for Ewing sarcoma
  • 2016
  • In: Medicine. - 0025-7974. ; 95:33
  • Journal article (peer-reviewed)abstract
    • We prospectively investigated anti-Müllerian hormone (AMH) as a measure of ovarian insult in young females during and after treatment for Wilms tumor (WT), osteosarcoma (OS), and Ewing sarcoma (ES). Twenty-one female childhood cancer patients, with a mean age of 7.9 years (range 0.6-17), entered the study. Levels of AMH, follicle-stimulating hormone (FSH), and luteinizing hormone were monitored at diagnosis and every 3 to 4 months during, and regularly for a mean of 2.6 years after treatment. A profound decline in AMH was seen in the majority of the 21 study patients 3 to 4 months after the beginning of treatment, the exception being patients with WT, of whom 60% showed no such decline. During the remaining treatment, all patients except those with WT not treated with whole abdominal radiotherapy or stem cell transplantation (SCT) had AMH below detection limit. After completion of treatment, patients with OS and WT (without whole abdominal radiotherapy and SCT) recovered in AMH and had FSH in the normal range. In contrast, ES patients showed no AMH recovery and highly fluctuating FSH in the first years of follow-up, except for the 2 youngest patients, who had a late, slow AMH recovery. In conclusion, young female ES patients already showed signs of severe ovarian dysfunction during the first years after cancer treatment similar to patients treated with SCT and abdominal radiotherapy, in contrast to females with WT and OS. Fertility counseling and information concerning fertility preservation procedures should be considered before starting to treat young females with ES.
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32.
  • Osmanovic, Alma, et al. (author)
  • Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients
  • 2022
  • In: Genes. - : MDPI. - 2073-4425. ; 13:1
  • Journal article (peer-reviewed)abstract
    • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis.
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33.
  • Pla, Indira, et al. (author)
  • Proteome of fluid from human ovarian small antral follicles reveals insights in folliculogenesis and oocyte maturation
  • 2021
  • In: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 36:3, s. 756-770
  • Journal article (peer-reviewed)abstract
    • STUDY QUESTION: Is it possible to identify by mass spectrometry a wider range of proteins and key proteins involved in folliculogenesis and oocyte growth and development by studying follicular fluid (FF) from human small antral follicles (hSAF)?SUMMARY ANSWER: The largest number of proteins currently reported in human FF was identified in this study analysing hSAF where several proteins showed a strong relationship with follicular developmental processes.WHAT IS KNOWN ALREADY: Protein composition of human ovarian FF constitutes the microenvironment for oocyte development. Previous proteomics studies have analysed fluids from pre-ovulatory follicles, where large numbers of plasma constituents are transferred through the follicular basal membrane. This attenuates the detection of low abundant proteins, however, the basal membrane of small antral follicles is less permeable, making it possible to detect a large number of proteins, and thereby offering further insights in folliculogenesis.STUDY DESIGN, SIZE, DURATION: Proteins in FF from unstimulated hSAF (size 6.1 ± 0.4 mm) were characterised by mass spectrometry, supported by high-throughput and targeted proteomics and bioinformatics. The FF protein profiles from hSAF containing oocytes, capable or not of maturing to metaphase II of the second meiotic division during an IVM (n = 13, from 6 women), were also analysed.PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected FF from hSAF of ovaries that had been surgically removed from 31 women (∼28.5 years old) undergoing unilateral ovariectomy for fertility preservation.MAIN RESULTS AND THE ROLE OF CHANCE: In total, 2461 proteins were identified, of which 1108 identified for the first time in FF. Of the identified proteins, 24 were related to follicular regulatory processes. A total of 35 and 65 proteins were down- and up-regulated, respectively, in fluid from hSAF surrounding oocytes capable of maturing (to MII). We found that changes at the protein level occur already in FF from small antral follicles related to subsequent oocyte maturation.LIMITATIONS, REASONS FOR CAUTION: A possible limitation of our study is the uncertainty of the proportion of the sampled follicles that are undergoing atresia. Although the FF samples were carefully aspirated and processed to remove possible contaminants, we cannot ensure the absence of some proteins derived from cellular lysis provoked by technical reasons.WIDER IMPLICATIONS OF THE FINDINGS: This study is, to our knowledge, the first proteomics characterisation of FF from hSAF obtained from women in their natural menstrual cycle. We demonstrated that the analysis by mass spectrometry of FF from hSAF allows the identification of a greater number of proteins compared to the results obtained from previous analyses of larger follicles. Significant differences found at the protein level in hSAF fluid could predict the ability of the enclosed oocyte to sustain meiotic resumption. If this can be confirmed in further studies, it demonstrates that the viability of the oocyte is determined early on in follicular development and this may open up new pathways for augmenting or attenuating subsequent oocyte viability in the pre-ovulatory follicle ready to undergo ovulation.STUDY FUNDING/COMPETING INTEREST(S): The authors thank the financial support from ReproUnion, which is funded by the Interreg V EU programme. No conflict of interest was reported by the authors.TRIAL REGISTRATION NUMBER: N/A.
  •  
34.
  • Pla, Indira, et al. (author)
  • Proteomic Alterations in Follicular Fluid of Human Small Antral Follicles Collected from Polycystic Ovaries—A Pilot Study
  • 2022
  • In: Life. - : MDPI AG. - 0024-3019 .- 2075-1729. ; 12:3
  • Journal article (peer-reviewed)abstract
    • Polycystic ovaries (PCO) contain antral follicles that arrest growing around 3–11 mm in diameter, perturbing the dominant follicle’s selection and the subsequent ovulatory process. Proteomic alterations of PCO follicular fluid (FF) (i.e., microenvironment in which the oocyte develops until ovulation) have been studied from large follicles in connection with oocyte pickup during ovarian stimulation. The present study aimed to detect proteomic alterations in FF from unstimulated human small antral follicles (hSAF) obtained from PCO. After performing deep-sequencing label-free proteomics on 10 PCO and 10 non-PCO FF samples from unstimulated hSAF (4.6–9.8 mm), 1436 proteins were identified, of which 115 were dysregulated in PCO FF samples. Pathways and processes related to the immune system, inflammation, and oxidative stress appeared to be upregulated in PCO, while extracellular matrix receptors interactions, the collagens-containing extracellular matrix, and the regulation of signaling were downregulated. The secreted proteins SFRP1, THBS4, and C1QC significantly decreased their expression in PCO FF, and this downregulation was suggested to affect future oocyte competence. In conclusion, our study revealed, for the first time, evidence of proteomic alterations occurring in the FF of PCO hSAF that may be related to the dysfunction of follicular growth and subsequent oocyte competence.
  •  
35.
  • Rodriguez-Wallberg, Kenny A., et al. (author)
  • Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience
  • 2016
  • In: Acta Obstetricia et Gynecologica Scandinavica. - : WILEY-BLACKWELL. - 0001-6349 .- 1600-0412. ; 95:9, s. 1015-1026
  • Journal article (peer-reviewed)abstract
    • Introduction. The aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries. Material and methods. A questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation. Results. Among the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow-freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients' clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1: 3). Conclusions. Overall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.
  •  
36.
  • Schwartz, Franziska A., et al. (author)
  • Dynamics of a Staphylococcus aureus infective endocarditis simulation model
  • 2022
  • In: APMIS. - : Wiley. - 0903-4641 .- 1600-0463. ; 130:8, s. 515-523
  • Journal article (peer-reviewed)abstract
    • Infective endocarditis (IE) is a serious infection of the inner surface of heart, resulting from minor lesions in the endocardium. The damage induces a healing reaction, which leads to recruitment of fibrin and immune cells. This sterile healing vegetation can be colonized during temporary bacteremia, inducing IE. We have previously established a novel in vitro IE model using a simulated IE vegetation (IEV) model produced from whole venous blood, on which we achieved stable bacterial colonization after 24h. The bacteria were organized in biofilm aggregates and displayed increased tolerance towards antibiotics. In this current study, we aimed at further characterizing the time course of biofilm formation and the impact on antibiotic tolerance development. We found that a S. aureus reference strain, as well as three clinical IE isolates formed biofilms on the IEV after 6h. When treatment was initiated immediately after infection, the antibiotic effect was significantly higher than when treatment was started after the biofilm was allowed to mature. We could follow the biofilm development microscopically by visualizing growing bacterial aggregates on the IEV. The findings indicate that mature, antibiotic-tolerant biofilms can be formed in our model already after 6h, accelerating the screening for optimal treatment strategies for IE.
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37.
  • Sørensen, Thomas Lykke Møller, et al. (author)
  • Membrane-protein crystals for neutron diffraction
  • 2018
  • In: Acta Crystallographica Section D: Structural Biology. - 2059-7983. ; 74:12, s. 1208-1218
  • Research review (peer-reviewed)abstract
    • Neutron macromolecular crystallography (NMX) has the potential to provide the experimental input to address unresolved aspects of transport mechanisms and protonation in membrane proteins. However, despite this clear scientific motivation, the practical challenges of obtaining crystals that are large enough to make NMX feasible have so far been prohibitive. Here, the potential impact on feasibility of a more powerful neutron source is reviewed and a strategy for obtaining larger crystals is formulated, exemplified by the calcium-transporting ATPase SERCA1. The challenges encountered at the various steps in the process from crystal nucleation and growth to crystal mounting are explored, and it is demonstrated that NMX-compatible membrane-protein crystals can indeed be obtained.
  •  
38.
  • Thomassen, Mads, et al. (author)
  • A BRCA2 mutation incorrectly mapped in the original BRCA2 reference sequence, is a common West Danish founder mutation disrupting mRNA splicing
  • 2011
  • In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 128:1, s. 179-185
  • Journal article (peer-reviewed)abstract
    • Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G > A (c.7617+1G > A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally published genomic reference sequence. This reference sequence is generally used in many laboratories and it maps the mutation 16 base pairs inside intron 15. However, according to the recent reference sequences the mutation is located in the consensus donor splice sequence. By reverse transcriptase analysis, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most common BRCA2 mutation in West Denmark, while it is rare in Central and East Denmark and not identified in South Sweden. Haplotype analysis using dense SNP arrays indicated a common founder of the mutation approximately 1,500 years ago.
  •  
39.
  • Tornøe, Birte, et al. (author)
  • Specific strength training compared with interdisciplinary counseling for girls with tension-type headache : A randomized controlled trial
  • 2016
  • In: Journal of Pain Research. - 1178-7090. ; 9, s. 257-270
  • Journal article (peer-reviewed)abstract
    • Background: Childhood tension-type headache (TTH) is a prevalent and debilitating condition for the child and family. Low-cost nonpharmacological treatments are usually the first choice of professionals and parents. This study examined the outcomes of specific strength training for girls with TTH. Methods: Forty-nine girls aged 9–18 years with TTH were randomized to patient education programs with 10 weeks of strength training and compared with those who were counseled by a nurse and physical therapist. Primary outcomes were headache frequency, intensity, and duration; secondary outcomes were neck–shoulder muscle strength, aerobic power, and pericranial tenderness, measured at baseline, after 10 weeks intervention, and at 12 weeks follow-up. Health-related quality of life (HRQOL) questionnaires were assessed at baseline and after 24 months. Results: For both groups, headache frequency decreased significantly, P=0.001, as did duration, P=0.022, with no significant between-group differences. The odds of having headache on a random day decreased over the 22 weeks by 0.65 (0.50–0.84) (odds ratio [95% confidence interval]). For both groups, neck extension strength decreased significantly with a decrease in cervicothoracic extension/flexion ratio to 1.7, indicating a positive change in muscle balance. In the training group, shoulder strength increased ≥10% in 5/20 girls and predicted VO2max increased ≥15% for 4/20 girls. In the training group, 50% of girls with a headache reduction of ≥30% had an increase in VO2max >5%. For the counseling group, this was the case for 29%. A 24-month follow-up on HRQOL for the pooled sample revealed statistically significant improvements. Fifty-five percent of the girls reported little to none disability. Conclusion: The results indicate that both physical health and HRQOL can be influenced significantly by physical exercise and nurse counseling. More research is needed to examine the relationship between physical exercise, VO2max, and TTH in girls. Thus, empowering patient education to promote maximum possible outcomes for all children needs more attention.
  •  
40.
  • Villadsen, Sarah Fredsted, et al. (author)
  • Unlocking the mechanisms of change in the MAMAACT intervention to reduce ethnic disparity in stillbirth and newborns' health : integration of evaluation findings
  • 2024
  • In: Frontiers in health services. - : Frontiers Media S.A.. - 2813-0146. ; 4
  • Journal article (peer-reviewed)abstract
    • Ethnic disparities in stillbirth exist in Europe and suboptimal care due to miscommunication is one contributing cause. The MAMAACT intervention aimed to reduce ethnic disparity in stillbirth and newborns' health through improved management of pregnancy complications. The intervention encompassed training of antenatal care midwives in cultural competencies and intercultural communication combined with health education materials for the expecting parents about symptoms of pregnancy complications. The evaluation consisted of a qualitative in-depth implementation analysis and a process evaluation embedded in a cluster randomized trial including 19 of 20 maternity wards in Denmark. In this article, the findings from the different evaluation perspectives are integrated. The integration follows the principles of realist evaluation by analyzing to what extent the MAMAACT activities were generating mechanisms of change in interaction with the context. The integration analysis shows that the health education materials in the MAMAACT intervention contributed to heightened health literacy concerning pregnancy complications among pregnant women. Additionally, the training of midwives in cultural competency and intercultural communication raised awareness among midwives. Nonetheless, the exclusive emphasis on midwives and the inflexibility in care provision hindered them from changing their communication practices. To enhance the cultural competence in maternity care, it is essential to implement more comprehensive initiatives involving healthcare professionals in maternity care at all levels, from pregraduate to postgraduate. Adequate interpreter services and management support should also be ensured. Currently, the Danish antenatal care system faces challenges including inadequate information transfer between healthcare sectors, insufficient differentiation of care, and inflexibility in midwife scheduling. This results in a lack of responsiveness to the individual needs of women with immigrant backgrounds, potentially reproducing health inequities.
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