Women with female infertility seeking medically assisted reproduction are not at increased risk of developing multiple sclerosis.

STUDY QUESTION: Is female infertility among women seeking medically assisted reproduction (MAR) associated with prevalent as well as incident multiple sclerosis (MS)? SUMMARY ANSWER: Women with a record of female infertility did not have an increased risk of developing MS compared with apparent fertile women; however, the prevalence of MS was slightly higher among women undergoing MAR compared with women who had a child without MAR, but this was not related to origin of infertility (i.e. male versus female factor infertility). WHAT IS KNOWN ALREADY: Women with MS have fewer children compared with women without MS. Persons with MS more often have other coexisting autoimmune disorders including hypothyroidism compared with the general population. Thyroid dysfunction is associated with ovarian cause of infertility, miscarriage and ovarian failure. Conversely, women with endometriosis, that is highly associated with infertility, also more often have other coexisting autoimmune diseases including MS and hypothyroidism compared with the general population. However, whether the low fertility rate among women with MS is due to a genetically predisposition to other autoimmune and endocrine disorders that leads to reduced fertility, or an active choice of the woman, disease-related pathology or treatment-specific effect on endocrine and/or ovarian function, is not completely understood. STUDY DESIGN, SIZE, DURATION: A register-based cohort study of a total of 310 357 women from 1996 to 2018. A cross-sectional design was used for analysing prevalence of MS, whereas a cohort design with up to 24 years of follow-up was used for analysing incidence of MS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three cohorts were included in the study (i) 55 404 women with a female infertility diagnosis registered in the Danish IVF register; (ii) 25 096 women with only male factor infertility recorded in the IVF register and thus no female infertility diagnosis and (iii) 229 857 age- and calendar-matched women with a record of first child birth in the Danish Medical Birth Register (DMBR) and no record ever in the IVF register. The prevalence and incidence of MS in the female infertility cohort were compared with the two control cohorts of apparent fertile women using log-binomial regression and Cox proportional hazard regression, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: The crude prevalence of having MS per 1000 persons was 3.2 for women who had undergone MAR treatment regardless of origin of infertility (i.e. male versus female factor infertility) and 2.3 for fertile DMBR controls. The age, calendar and educational level adjusted prevalence ratio of having a diagnosis of MS at the first MAR treatment was 1.27 (95% CI 1.07-1.52) for infertile women compared with fertile DMBR controls, and 1.00 (95% CI 0.77-1.31) for comparison to women with a male partner with infertility who had also undergone MAR treatment. We found no association between incident MS and female infertility compared with either of the control groups of fertile women. LIMITATIONS, REASON FOR CAUTION: The cohort of infertile women is highly selected on the basis of their choice of having fertility treatment and thus does not include women with unestablished infertility or women who, for some reason, have chosen not to have MAR treatment. Additionally, due to the nature of the observational study design, we cannot exclude the possibility of unmeasured and/or residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that women with MS may undergo MAR treatment more often than women without MS due to more awareness about the possibility of MAR treatments, sexual dysfunction related to MS disease, but also need for timing of the pregnancy to avoid an unnecessary long time period without disease modifying therapy-especially of high efficacy-and hence a wish to conceive quickly. These findings are important for clinicians dealing with women with MS of childbearing age. STUDY FUNDING/COMPETING INTEREST(S): The authors received no financial support for the study. T.I.K. has served on a scientific advisory board for Novartis and has received support for congress participation from Biogen. M.M. has served on scientific advisory boards for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie and Alexion. She has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi and Genzyme and has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck and Novartis. The remaining authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Serum ghrelin is associated with early feeding readiness but not growth in premature infants.

BACKGROUND: Feeding tolerance among premature infants is unpredictable using clinical parameters. Ghrelin, a peptide hormone, acts on the hypothalamus to increase hunger and gut motility. It is present in fetal tissues, promotes intestinal maturation, and is secreted in milk. We hypothesized that higher serum ghrelin levels on days 0-7 are associated with improved feeding tolerance and growth in premature infants. METHODS: Infants (< 1500 g birth weight, n = 36) were recruited on day (D) 0-7. Serum ghrelin was measured by ELISA on D 0-7, D 10-14, and D 24-32, and milk ghrelin in a feeding concurrent with each serum sample. Feeding tolerance was assessed as days to first and full enteral feeds. Growth was quantified as both weight and adipose and muscle deposition by ultrasound. RESULTS: Mean serum ghrelin levels decreased from D 0-7 to D 24-32. Higher ghrelin levels on D 0-7 were correlated with shorter time to first enteral feeding, but not with time to full enteral feeds, rate of weight gain, or rate of accretion of muscle or adipose tissue. Milk ghrelin was not related to serum ghrelin or growth. Abdominal and suprascapular muscle and adipose increased during the first month, but weight gain correlated only with the rate of accretion of abdominal adipose. CONCLUSIONS: Elevated serum ghrelin in the first days of life may contribute to gut motility and readiness to feed. Weight gain in premature infants may primarily indicate abdominal fat accumulation, suggesting that ultrasound measurement of muscle accretion is a better marker for lean body growth.

Complications after benign hysterectomy, according to procedure: a population-based prospective cohort study from the Danish hysterectomy database, 2004-2015.

OBJECTIVE: To compare the risk of complications associated with benign hysterectomy according to surgical procedure. DESIGN: Register-based prospective cohort study. SETTING: Danish Hysterectomy Database, 2004-2015. POPULATION: All Danish women with benign elective hysterectomy (n = 51 141). METHODS: Multivariate log-binomial regression to compute relative risks (RRs) stratified by calendar period, and adjusted for age, height, weight, smoking habits, use of alcohol, comorbidity, indications, uterine weight and adhesions. Multiple imputation and 'intention to treat' analyses were performed. MAIN OUTCOME MEASURES: Major (grades III-V) and minor (grades I-II) Clavien-Dindo modified complications within 30 days. RESULTS: Overall, major complications occurred in 3577 (7.0%) hysterectomies and minor complications occurred in 4788 (9.4%). The proportions of major and minor complications according to type of hysterectomy were: 10.3 and 9.6% for abdominal hysterectomy (AH); 4.1 and 12.1% for laparoscopic hysterectomy (LH); and 4.9 and 8.0% for vaginal hysterectomy (VH) for non-prolapse, and 2.3 and 6.4% for prolapse. In multivariate analyses, compared with VH for non-prolapse, the risk of major complications was higher for AH (RR 1.82, 95% CI 1.63-2.03) but lower for both LH (RR 0.78, 95% CI 0.68-0.90) and VH for prolapse (RR 0.55; 95% CI 0.41-0.75). For LH, the risk of major complications reduced from a RR of 0.96 (95% CI 0.75-1.22) in the time period 2004-2009 to an RR of 0.72 (95% CI 0.60-0.87) between 2010 and 2015. CONCLUSION: Laparoscopic hysterectomy and VH for uterine prolapse are associated with fewer major complications, and AH is associated with more major complications, compared with VH performed in the absence of uterine prolapse. TWEETABLE ABSTRACT: Laparoscopic hysterectomy has fewer major complications compared with vaginal hysterectomy, in the absence of uterine prolapse.

Oxygen vacancies and hydrogen doping in LaAlO3/SrTiO3 heterostructures: electronic properties and impact on surface and interface reconstruction.

We investigate the effect of oxygen vacancies and hydrogen dopants at the surface and inside slabs of [Formula: see text], [Formula: see text], and [Formula: see text]/[Formula: see text] heterostructures on the electronic properties by means of electronic structure calculations as based on density functional theory. Depending on the concentration, the presence of these defects in a [Formula: see text] slab can suppress the surface conductivity. In contrast, in insulating [Formula: see text] slabs already very small concentrations of oxygen vacancies or hydrogen dopant atoms induce a finite occupation of the conduction band. Surface defects in insulating [Formula: see text]/[Formula: see text] heterostructure slabs with three [Formula: see text] overlayers lead to the emergence of interface conductivity. Calculated defect formation energies reveal strong preference of hydrogen dopant atoms for surface sites for all structures and concentrations considered. Strong decrease of the defect formation energy of hydrogen adatoms with increasing thickness of the [Formula: see text] overlayer and crossover from positive to negative values, taken together with the metallic conductivity induced by hydrogen adatoms, seamlessly explains the semiconductor-metal transition observed for these heterostructures as a function of the overlayer thickness. Moreover, we show that the potential drop and concomitant shift of (layer resolved) band edges is suppressed for the metallic configuration. Finally, magnetism with stable local moments, which form atomically thin magnetic layers at the interface, is generated by oxygen vacancies either at the surface or the interface, or by hydrogen atoms buried at the interface. In particular, oxygen vacancies in the [Formula: see text] interface layer cause drastic downshift of the 3d e g states of the Ti atoms neighboring the vacancies, giving rise to strongly localized magnetic moments, which add to the two-dimensional background magnetization.

Electronic properties of LaAlO3/SrTiO3 n-type interfaces: a GGA+U study.

The role of electronic correlation effects for a realistic description of the electronic properties of [Formula: see text]/[Formula: see text] heterostructures as covered by the on-site Coulomb repulsion within the GGA+U approach is investigated. Performing a systematic variation of the values of the Coulomb parameters applied to the Ti 3d and La 4f orbitals we put previous suggestions to include a large value for the La 4f states into perspective. Furthermore, our calculations provide deeper insight into the band gap landscape in the space spanned by these Coulomb parameters and the resulting complex interference effects. In addition, we identify important correlations between the local Coulomb interaction within the La 4f shell, the band gap, and the atomic displacements at the interface. In particular, these on-site Coulomb interactions influence buckling within the LaO interface layer, which via its strong coupling to the electrostatic potential in the LAO overlayer causes considerable shifts of the electronic states at the surface and eventually controls the band gap.

Artificial atoms based on correlated materials.

Low-dimensional electron systems fabricated from quantum matter have in recent years become available and are being explored with great intensity. This article gives an overview of the fundamental properties of such systems and summarizes the state of the field. We furthermore present and consider the concept of artificial atoms fabricated from quantum materials, anticipating remarkable scientific advances and possibly important applications of this new field of research. The surprising properties of these artificial atoms and of molecules or even of solids assembled from them are presented and discussed.

In vitro screening of inhibition of PPAR-γ activity as a first step in identification of potential breast carcinogens.

Alcohol consumption and increased estrogen levels are major risk factors for breast cancer, and peroxisome proliferator-activated receptor γ (PPAR-γ) plays an important role in alcohol-induced breast cancer. PPAR-γ activity is inhibited by ethanol, leading to increased aromatase activity and estrogen biosynthesis ultimately leading to breast cancer. If other organic solvents inhibit PPAR-γ activity, they should also lead to increased oestrogen biosynthesis and thus be potential breast carcinogens. Ten commonly used hydrophilic organic solvents were first tested in a cell-based screening assay for inhibitory effects on PPAR-γ transactivation. The chemicals shown to inhibit PPAR-γ were tested with vectors encoding PPAR-γ with deleted AB domains and only the ligand-binding domain to rule out unspecific toxicity. Next, the effects on biosynthesis of estradiol, testosterone and oestrone sulphate were measured in the H295R steroidogenesis assay after incubation with the chemicals. Ethylene glycol, ethyl acetate, and dimethyl sulphoxide inhibited PPAR-γ transactivation in a dose-dependent manner. The inhibitory effect on PPAR-γ was specific for PPAR-γ since the AB domain of PPAR-γ was required for the inhibitory effect. In the second step, ethylene glycol significantly increased production of oestradiol by 19% (p < 0.05) and ethyl acetate inhibited production of testosterone (p < 0.05). We here show that screening of 10 commonly used organic solvents for the ability to inhibit PPAR-γ transactivation followed by a well-established steroidogenesis assay for production of sex hormones in exposed H295 R cells may provide a screening tool for potential breast carcinogens. This initial screening thus identified ethylene glycol and possibly ethyl acetate as potential breast carcinogens.

Fractional quantization of the magnetic flux in cylindrical unconventional superconductors.

The magnetic flux threading a conventional superconducting ring is typically quantized in units of Φ0=hc/2e. The factor of 2 in the denominator of Φ0 originates from the existence of two different types of pairing states with minima of the free energy at even and odd multiples of Φ0. Here we show that spatially modulated pairing states exist with energy minima at fractional flux values, in particular, at multiples of Φ0/2. In such states, condensates with different center-of-mass momenta of the Cooper pairs coexist. The proposed mechanism for fractional flux quantization is discussed in the context of cuprate superconductors, where hc/4e flux periodicities were observed.

Direct k-space mapping of the electronic structure in an oxide-oxide interface.

The interface between LaAlO(3) and SrTiO(3) hosts a two-dimensional electron system of itinerant carriers, although both oxides are band insulators. Interface ferromagnetism coexisting with superconductivity has been found and attributed to local moments. Experimentally, it has been established that Ti 3d electrons are confined to the interface. Using soft x-ray angle-resolved resonant photoelectron spectroscopy we have directly mapped the interface states in k space. Our data demonstrate a charge dichotomy. A mobile fraction contributes to Fermi surface sheets, whereas a localized portion at higher binding energies is tentatively attributed to electrons trapped by O vacancies in the SrTiO(3). While photovoltage effects in the polar LaAlO(3) layers cannot be excluded, the apparent absence of surface-related Fermi surface sheets could also be fully reconciled in a recently proposed electronic reconstruction picture where the built-in potential in the LaAlO(3) is compensated by surface O vacancies serving also as a charge reservoir.

Supercurrent through grain boundaries of cuprate superconductors in the presence of strong correlations.

Strong correlations are known to severely reduce the mobility of charge carriers near half filling and thus have an important influence on the current carrying properties of grain boundaries in the high-T(c) cuprates. In this Letter we present an extension of the Gutzwiller projection approach to treat electronic correlations below as well as above half filling consistently. We apply this method to investigate the critical current through grain boundaries with a wide range of misalignment angles for electron- and hole-doped systems. For the latter excellent agreement with experimental data is found. We further provide a detailed comparison to an analogous weak-coupling evaluation.

[Evaluation of cancer therapy from the perspective of a statutory health insurance]. / Bewertung onkologischer Therapien aus Sicht einer Kasse.

Increasing life expectancy, the introduction of costly new drugs and contributions from the health fund which do not cover overall costs, all contribute to financial problems for statutory health insurances (SHI) in oncology. Only an evidence-based approach can help to address these problems. In a first step patient-relevant benefits have to be substantiated as a necessary prerequisite for coverage of any treatment by SHIs. For products with no additional benefit compared to established forms of therapy the price will be limited by the established cost-benefit ratio. For products with additional benefits pricing is more difficult. For this situation the Institute for Quality and Efficiency in Healthcare (IQWiG) has developed general methods for the assessment of the relation of benefits to costs. Pricing based on this health economic evaluation is developed using efficiency frontier plots. However, this method is prone to manipulation and needs to be refined. Therapies without comparators, so-called soloists, cannot be priced in this way. New approaches to increase cost efficiency need to be developed in order to ensure the availability of high quality care in the future.

Very large capacitance enhancement in a two-dimensional electron system.

Increases in the gate capacitance of field-effect transistor structures allow the production of lower-power devices that are compatible with higher clock rates, driving the race for developing high-κ dielectrics. However, many-body effects in an electronic system can also enhance capacitance. Onto the electron system that forms at the LaAlO(3)/SrTiO(3) interface, we fabricated top-gate electrodes that can fully deplete the interface of all mobile electrons. Near depletion, we found a greater than 40% enhancement of the gate capacitance. Using an electric-field penetration measurement method, we show that this capacitance originates from a negative compressibility of the interface electron system. Capacitance enhancement exists at room temperature and arises at low electron densities, in which disorder is strong and the in-plane conductance is much smaller than the quantum conductance.

Surgical management of congenital heart disease: correlation between hospital costs and the Aristotle complexity score.

BACKGROUND: Hospital costs are expected to correlate with clinical complexity. Do costs for congenital heart surgery correlate with Aristotle complexity scores? METHODS: 442 inpatient stays in 2008 were evaluated. Aristotle scores and levels were determined. Costs were estimated according to the German Institute for Hospital Reimbursement system. Pearson and Spearman R correlation coefficients and corresponding goodness-of-fit regression coefficients R2 were calculated. RESULTS: Mean basic and comprehensive Aristotle scores were 7.60 +/- 2.74 and 9.23 +/- 2.94 points, respectively. Mean expenses per hospital stay amounted to 29,369 +/- 30,823 Euros. Aristotle basic and comprehensive scores and levels were positively correlated with hospital costs. With a Spearman R of 1 and related R2 of 0.9436, scores of the 6 Aristotle comprehensive levels correlated best. Mean hospital reimbursement was 26,412 +/- 17,962 Euros. Compensation was higher than expenses for patients in comprehensive levels 1 to 3, but much lower for those in levels 4 to 6. CONCLUSIONS: Aristotle comprehensive complexity scores were highly correlated with hospital costs. The Aristotle score could be used as a scale to establish the correct reimbursement after congenital heart surgery.

Congenital heart surgery: applicability of hospital reimbursement according to German diagnosis-related groups system in conformity with the Aristotle complexity score.

BACKGROUND: Scores of Aristotle comprehensive complexity (ACC) levels have been demonstrated to correlate with the case-mix index (CMI) (cost-weights) generated by the German Diagnosis-Related Groups (DRG) 2009 version (G-DRG 2009). The equation used was "y = 0.5591 + 0.939 x" whereby y stands for cost-weight and x for ACC score. We hypothesised that each ACC level could be assigned a DRG (ACC DRG) and be used to determine hospital reimbursement. METHODS: 185 patients underwent cardiac surgery between January and June 2009. The ACC scores of these 185 patients were grouped in ACC levels, based on the basic cost-weight value of their DRG. One ACC DRG was assigned to each group and a corresponding cost-weight calculated based on the aforementioned equation. The resulting ACC CMI was compared with the CMI generated by the G-DRG 2009 (G-DRG 2009 CMI). Finally, the ACC surgical performance (complexity x hospital survival) was used to calculate the cost-weight; the obtained CMI was called "effective ACC CMI". RESULTS: Mean ACC score was 9.515 +/- 3.611 points. Derived ACC CMI and related G-DRG 2009 CMI were 9.494 and 8.438, respectively. Hospital survival was 97.8 % (181/184). Therefore ACC surgical performance and "effective ACC CMI" were 9.306 and 9.297, respectively. For each ACC level, the number of patients (n), mean ACC score, ACC CMI and related G-DRG 2009 CMI were as follows: Level 1: n = 25, 4.024 +/- 0.879, 4.338 and 5.911; Level 2: n = 30, 6.563 +/- 0.574, 6.722 and 6.602; Level 3: n = 43, 8.665 +/- 0.540, 8.695 and 8.088; Level 4: n = 73, 11.730 +/- 1.690, 11.574 and 9.612; Level 5: n = 14, 16.710 +/- 1.380, 16.249 and 11.843, respectively. CONCLUSIONS: The Aristotle score can be used to adjust hospital reimbursement by assigning a DRG and cost-weight value to each ACC level. Missing figures for level 6 can be obtained from a previous study which showed a mean score of 22.11 +/- 1.24: the ACC CMI would be 21.320. The 6 ACC DRGs indicate the correct compensation based on the complexity of the procedure. Reimbursement using the German DRG 2009 appears to favour less complex cases, while procedures with a higher complexity are penalised. Reimbursement according to "effective ACC CMIs" would have a strong impact by supporting units providing high-quality care.

Analysis of four prevalent filaggrin mutations (R501X, 2282del4, R2447X and S3247X) in Austrian and German patients with atopic dermatitis.

BACKGROUND: Recently, mutations in the filaggrin gene (FLG) have been shown to be a major predisposing factor for atopic dermatitis (AD). OBJECTIVE: In this study, we evaluated the influence of four prevalent mutations (R501X, 2282del4, R2447X and S3247X) in a large cohort of 462 Austrian and German AD patients and in 402 control individuals. RESULTS: We found a strong association of the FLG mutations with AD. Subgroup analysis revealed a significantly higher proportion of patients with an early age of disease onset and significantly higher median serum IgE levels among mutation carriers. Furthermore, we observed an overrepresentation of null alleles in AD patients with concomitant asthma compared with those without this co-morbidity. CONCLUSION: Our data confirm and extend the knowledge of the influence of FLG mutations in AD.

Analysis of the prodynorphin promoter polymorphism in atopic dermatitis and disease-related pruritus.

Pruritus is one of the key symptoms in atopic dermatitis (AD). The prodynorphin polypeptide is a precursor protein of pruritus-modulating opioid peptides. It is encoded by the prodynorphin gene (PDYN). To investigate a possible correlation of PDYN promoter polymorphisms with intensity of pruritus in patients with AD, we genotyped 211 Austrian patients with AD and 197 nonatopic controls. No significant association of the PDYN promoter polymorphism with AD in general was found when patients with AD were compared with controls. The analysis of possible associations with pruritus intensity also showed no relevant difference in the allelic distribution between patients with different pruritus-score values. These data argue against an important role of the PDYN promoter polymorphism in AD in general and in the development of disease-related pruritus, although owing to our small sample size, a weak effect cannot be excluded. Additional studies are needed to further evaluate the influence of PDYN polymorphism in pruritus.