ESHRE good practice recommendations on recurrent implantation failure.

STUDY QUESTION: How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed? SUMMARY ANSWER: This is the first ESHRE good practice recommendations paper providing a definition for RIF together with recommendations on how to investigate causes and contributing factors, and how to improve the chances of a pregnancy. WHAT IS KNOWN ALREADY: RIF is a challenge in the ART clinic, with a multitude of investigations and interventions offered and applied in clinical practice, often without biological rationale or with unequivocal evidence of benefit. STUDY DESIGN SIZE DURATION: This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, if available, and the results of a previously published survey on clinical practice in RIF and the expertise of the working group. A literature search was performed in PubMed and Cochrane focussing on 'recurrent reproductive failure', 'recurrent implantation failure', and 'repeated implantation failure'. PARTICIPANTS/MATERIALS SETTING METHODS: The ESHRE Working Group on Recurrent Implantation Failure included eight members representing the ESHRE Special Interest Groups for Implantation and Early Pregnancy, Reproductive Endocrinology, and Embryology, with an independent chair and an expert in statistics. The recommendations for clinical practice were formulated based on the expert opinion of the working group, while taking into consideration the published data and results of the survey on uptake in clinical practice. The draft document was then open to ESHRE members for online peer review and was revised in light of the comments received. MAIN RESULTS AND THE ROLE OF CHANCE: The working group recommends considering RIF as a secondary phenomenon of ART, as it can only be observed in patients undergoing IVF, and that the following description of RIF be adopted: 'RIF describes the scenario in which the transfer of embryos considered to be viable has failed to result in a positive pregnancy test sufficiently often in a specific patient to warrant consideration of further investigations and/or interventions'. It was agreed that the recommended threshold for the cumulative predicted chance of implantation to identify RIF for the purposes of initiating further investigation is 60%. When a couple have not had a successful implantation by a certain number of embryo transfers and the cumulative predicted chance of implantation associated with that number is greater than 60%, then they should be counselled on further investigation and/or treatment options. This term defines clinical RIF for which further actions should be considered. Nineteen recommendations were formulated on investigations when RIF is suspected, and 13 on interventions. Recommendations were colour-coded based on whether the investigations/interventions were recommended (green), to be considered (orange), or not recommended, i.e. not to be offered routinely (red). LIMITATIONS REASONS FOR CAUTION: While awaiting the results of further studies and trials, the ESHRE Working Group on Recurrent Implantation Failure recommends identifying RIF based on the chance of successful implantation for the individual patient or couple and to restrict investigations and treatments to those supported by a clear rationale and data indicating their likely benefit. WIDER IMPLICATIONS OF THE FINDINGS: This article provides not only good practice advice but also highlights the investigations and interventions that need further research. This research, when well-conducted, will be key to making progress in the clinical management of RIF. STUDY FUNDING/COMPETING INTERESTS: The meetings and technical support for this project were funded by ESHRE. N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); Honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update, and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles, or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online, and Editor in Chief of Journal Gynäkologische Endokrinologie. He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update, immediate past Coordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online. B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose. DISCLAIMER: This Good Practice Recommendations (GPR) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation. ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type. Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE.

Leading hadronic contribution to the muon magnetic moment from lattice QCD.

The standard model of particle physics describes the vast majority of experiments and observations involving elementary particles. Any deviation from its predictions would be a sign of new, fundamental physics. One long-standing discrepancy concerns the anomalous magnetic moment of the muon, a measure of the magnetic field surrounding that particle. Standard-model predictions1 exhibit disagreement with measurements2 that is tightly scattered around 3.7 standard deviations. Today, theoretical and measurement errors are comparable; however, ongoing and planned experiments aim to reduce the measurement error by a factor of four. Theoretically, the dominant source of error is the leading-order hadronic vacuum polarization (LO-HVP) contribution. For the upcoming measurements, it is essential to evaluate the prediction for this contribution with independent methods and to reduce its uncertainties. The most precise, model-independent determinations so far rely on dispersive techniques, combined with measurements of the cross-section of electron-positron annihilation into hadrons3-6. To eliminate our reliance on these experiments, here we use ab initio quantum chromodynamics (QCD) and quantum electrodynamics simulations to compute the LO-HVP contribution. We reach sufficient precision to discriminate between the measurement of the anomalous magnetic moment of the muon and the predictions of dispersive methods. Our result favours the experimentally measured value over those obtained using the dispersion relation. Moreover, the methods used and developed in this work will enable further increased precision as more powerful computers become available.

Definition, diagnostic and therapeutic options in recurrent implantation failure: an international survey of clinicians and embryologists.

STUDY QUESTION: What is the global variability in recurrent implantation failure (RIF) definition, investigation and therapy, currently offered to patients undergoing IVF? SUMAMRY ANSWER: Definitions, diagnostic investigations and treatments offered to RIF patients differ widely amongst assisted reproduction healthcare professionals and clinical guidelines on RIF are urgently needed. WHAT IS KNOWN ALREADY: RIF affects around 10% of patients undergoing IVF worldwide. There is no consensus on the definition of RIF, its diagnostic investigations or the therapeutic options, which leads to inconsistencies in clinical practice. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of clinicians and embryologists was conducted between May and June 2020. The survey included 43 questions aimed at understanding participants' background and their current practice with regards to defining, investigating and managing RIF. The questions were designed by the European Society of Human Reproduction and Embryology (ESHRE) Special Interest Group (SIG) on implantation and early pregnancy following three consensus meetings. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 8579 ESHRE members from 6916 IVF centers were invited to participate using two global email calls based on their pre-specified interest in implantation and early pregnancy. SurveyMonkey and SPSS were used for data collection and analysis, respectively. Furthermore, differences were reported in the answers of European and non-European professionals, as well as between public and private settings and among clinicians clustered according to the average number of RIF patients treated per year. MAIN RESULTS AND THE ROLE OF CHANCE: The final data set included 735 clinicians and 300 embryologist or IVF-biologists. The majority defines RIF based on the number of failed embryo transfers (ETs) with the most common threshold adopted being three ETs both fresh and frozen. More than two-thirds take lifestyle factors into account, mainly drugs, smoking and BMI. The highest consensus on which diagnostic investigations should be performed was reached for anatomical malformations and gynecological aspects focusing on hydrosalpinx, Asherman's syndrome, endometrial thickness and endometriosis. Concerning treatment of RIF patients, the highest consensus was reached for preconceptional therapies, including BMI adjustment, smoking and endometritis followed by therapies during IVF procedures. LIMITATIONS, REASONS FOR CAUTION: The response rate was relatively low, but comparable to other surveys. WIDER IMPLICATIONS OF THE FINDINGS: A consensus on definition, diagnosis and treatment of RIF would help to reduce costly, time-consuming and poorly validated approaches. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used. B.T. received support from Bayer for Clinical trials concerning endometriosis and Ferring for clinical trials concerning ovarian stimulation. She received reimbursement for travel expenses from Astropharm, Ferring. Dr Kade and is a shareholder of Reprognostics. She is a board member of the Austrian Society for Obstetrics and Gynecology (OEGGG), the associate head of the 'Reproduktionsmedizinische Zentren Baden-Württemberg' (RZBW), a member of guideline group of the German Society for Obstetrics and Gynecology (DGGG) and an editorial board member of the following journals: American Journal of Reproductive Immunology (AJRI), Archives of Gynecology and Obstetrics. All the other authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Manifestation of migraine in adolescents: Does it change in puberty?

PURPOSE: To analyze the association between pubertal stage, menstrual cycle and migraine attacks in girls with migraine. In addition, headache frequency, accompanying symptoms, duration and onset in relation to the specific phase of the cycle were investigated. METHODS: Girls between 7 and 18 years old, diagnosed with headaches that met "International Classification of Headache Disorders II" diagnostic criteria for migraine without aura, kept a daily headache and menstrual cycle diary over 8 weeks. Ovulatory cycles were identified by weekly progesterone saliva tests. RESULTS: 47 girls participated in the study and were divided into three groups according to Tanner stage and onset of regular menstruation: pre- (n = 16), peri- (n = 19) and post-pubertal (n = 12). A significant difference in migraine frequency was found between pre- and post-pubertal girls (p = 0.005). No significant differences with regard to headache characteristics were detected. Interestingly, a higher frequency of attacks in follicular phase occurred compared to luteal phase in peri- and post-pubertal girls (p = 0.030). CONCLUSION: During puberty, migraine patterns in girls change to a typical adult pattern of migraine in a stepwise manner not clearly related to menarche. The first sign of this transition phase could be the higher frequency of migraine attacks in post-pubertal girls.

Correction to: Primary immunodeficiencies in Central and Eastern Europe-the power of networking Report on the activity of the Jeffrey Modell Foundation Centers Network in Central and Eastern Europe.

Due to authors' internal mistake they have misspelled the name of one of the co-authors in this article.

Aquaporin-1 Protein Expression of the Primary Tumor May Predict Cerebral Progression of Cutaneous Melanoma.

Brain metastasis is a frequent complication of the progression of malignant melanoma. In a previous study aquaporin 1 (AQP1) protein expression was found to be associated with increased mortality and decreased progression free survival in cutaneous melanoma. To explore further the potential of this marker we studied the AQP1 protein expression in 67 metastatic melanoma patients using immunohistochemistry. Primary tumor samples were acquired from patients with brain (BR) (n = 44) and extra-cranial (EC) (n = 23) metastases, while brain metastatic samples were collected during neurosurgical resection (n = 5). Patients with brain metastases had shorter overall survival (p = 0.02) and significantly higher AQP1 expression in the primary tumors (median H-score = 250 vs. 140, p = 0.044) as compared to patients of the EC metastasis group. AQP1 expression was found to be significantly lower in the brain metastases compared to the corresponding primary tumors (median H-score = 35 vs. 300 p = 0.01). However, in brain metastases AQP1 expression was heterogenous, AQP1 protein was more abundant in the melanoma cells far away from the capillaries as compared to tumor cells adjacent to vessels indicating a hypoxia-driven expression of AQP1. We suggest that AQP1 expression could well be a prognostic marker of brain metastatic potential of human cutaneous melanoma.

Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 2: Histopathological examination, Confocal microscopy and collagen quantification of the lung and pleural cavity.

The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

Evaluation of the exposure, dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 1: Experimental design, aerosol exposure, lung burdens and BAL.

This 90-day repeated-dose inhalation toxicology study of brake-dust (BD) (brakes manufactured with chrysotile) in rats provides a comprehensive understanding of the biokinetics and potential toxicology in the lung and pleura. Exposure was 6 h/d, 5d/wk., 13wks followed by lifetime observation (~20 % survival). Control groups included a particle control (TiO2), chrysotile, commercial crocidolite and amosite asbestos. Aerosol fiber distributions of the chrysotile, crocidolite and amosite were similar (fibers L > 20 µm/cm3: chrysotile-Low/High 29/72; crocidolite 24; amosite 47 fibers/cm3; WHO-fibers/cm3: chrysotile-Low/High 119/233; crocidolite 181; amosite 281 fibers/cm3). The number of particles/cm3 in the BD was similar to that in the chrysotile, crocidolite & amosite exposures (BD 470-715; chrysotile 495-614; crocidolite 415; amosite 417 particles/cm3). In the BD groups, few fibers L > 20 µm were observed in the lungs at the end of exposure and no fibers L > 20 µm at 90d post exposure. In the chrysotile groups, means of 204,000 and 290,000 fibers(L > 20 µm)/lung were measured at 89d. By 180d, means of 1 and 3.9 fibers were counted on the filter corresponding to 14,000 and 55,000 fibers(L > 20 µm)/lung. In the crocidolite and amosite groups mean lung concentrations were 9,055,000 and 11,645,000 fibers(L > 20 µm)/lung at 89d. At 180d the means remained similar with 8,026,000 and 11,591,000 fibers(L > 20 µm)/lung representing 10-13% of the total lung fibers. BAL determined the total number of macrophages, lymphocytes, neutrophils, eosinophils, epithelial-cells and IL-1 beta, TNF-alpha and TGF-beta. At the moderate aerosol concentrations used in this study, neutrophil counts increased ~5 fold in the amphibole asbestos exposure groups. All other groups and parameters showed no important differences at these exposure concentrations. The exposure and lung burden results provide a sound basis for assessing the potential toxicity of the brake dust in comparison to the TiO2 particle control and the chrysotile, crocidolite and amosite asbestos control groups. The BAL results provide an initial indication of the differential response. Part 2 presents the presentation and discussion of the histopathological and confocal microscopy findings in this study through 90 days post exposure.

Primary immunodeficiencies in Central and Eastern Europe-the power of networking Report on the activity of the Jeffrey Modell Foundation Centers Network in Central and Eastern Europe.

Jeffrey Modell Foundation centers' network activities in Central and Eastern Europe (JMF CEE) have contributed to the development of care for patients with primary immunodeficiencies. On the data continuously collected from individual centers in participating countries since 2011, we demonstrate a steady improvement in a number of aspects concerning complex care for patients with primary immunodeficiencies. The presented data show an improvement of awareness about these rare diseases across the whole Central and Eastern European region, an increase in newly diagnosed patients as well as genetically confirmed cases, earlier establishment of diagnosis, and improved access to clinical treatment. We also present an active patient involvement that is reflected in the expansion of patient organization centers and their activities. The cooperation within the JMF CEE network has also contributed to greater international exposure of participating centers and further to the gradual development of research activities in the rapidly evolving field of primary immunodeficiencies. The improvement of all important aspects of the complex field of primary immunodeficiencies within the JMF CEE network documents the strength and advantages of the joint and coordinated networking.

The impact of previous live births on peripheral and uterine natural killer cells in patients with recurrent miscarriage.

BACKGROUND: Peripheral and uterine natural killer cells (pNK and uNK cells) are key players in the establishment and maintenance of pregnancy and are disturbed in patients with recurrent miscarriage (RM). Different immunologic risk factors have been proposed between patients with primary RM (pRM, no previous live birth) and secondary RM (sRM, ≥ 1 previous live birth). However, so far, the study populations mainly consisted of small subgroups. Therefore, we aimed to analyse pNK and uNK cells in a large, well defined study population within a prospective study. METHODS: In total, n = 575 RM patients (n = 393 pRM, n = 182 sRM) were screened according to a standard protocol for established risk factors as well as pNK and uNK cells. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined by flow cytometry and uterine CD56+ NK cells by immunohistochemistry in mid-luteal non-pregnant RM patients. Exclusion of patients with ≥1 established risk factor revealed n = 248 idiopathic RM patients (iRM, n = 167 primary iRM (ipRM), n = 81 secondary iRM (isRM)). RESULTS: Patients with pRM and ipRM showed significant higher absolute numbers and percentages of pNK cells compared to sRM and isRM patients (pRM/ipRM vs sRM/isRM, mean ± SD /µl: 239.1 ± 118.7/244.9 ± 112.9 vs 205.1 ± 107.9/206.0 ± 105.6, p = 0.004/ p = 0.009; mean ± SD %: 12.4 ± 5.5/12.8 ± 5.4 vs 11.1 ± 4.6/11.1 ± 4.3, p = 0.001; p = 0.002). Only patients with isRM showed significantly higher uNK levels compared to patients with ipRM (mean ± SD /mm2 288.4 ± 239.3 vs 218.2 ± 184.5, p = 0.044). CONCLUSIONS: The demonstrated differences in pNK and uNK cells in RM patients depending on previous live birth might indicate differences in NK cell recruitment and potentially different underlying immune disorders between pRM and sRM. As there is an overlap in the distribution of the NK cell results, further studies with focus on NK cell function are needed in order to clearly identify RM patients with distinct immune abnormalities. The clinical relevance of our findings should be interpreted cautiously until specificity and sensitivity are further evaluated.

Effectiveness of the Gerundium Youth Educating Program in Hungary.

The acceptance of brain death and the legitimation of organ transplantation is very much dependent on the general knowledge of the society. In Hungary, the legislation of brain death is based on presumed consent. There is no structural education about the topic so far. AIM: The role of the Gerundium program is to educate high school students about the importance of transplantation and the meaning of brain death. The goal of this study was to evaluate the effectiveness of the Gerundium contemporary educational program in a pilot study. METHOD: The education was held by medical students who successfully completed a preparatory elective course consisting of relevant information in the topic. Medical students used simple language during the 45-minute presentations. Two tests with simple but representative questions created by experts were completed by high school students: one directly before contemporary education and another 5 to 6 weeks after the lecture. RESULTS: A total of 147 tests were completed: 78 before and 69 after the presentation in the city of Debrecen and 294 before the lecture in the city of Gyor. In Debrecen, the overall correct answers increased by 6.05% (P < .05; before vs after). The results show that the knowledge transfer is highly effective in this manner and the students know significantly more weeks after the lectures. CONCLUSION: There is much to do to broadly inform society about transplantation and brain death, but we will continue to increase the number of students and measure the dynamic change of the students' knowledge.

Psychometric characteristics of the FertiQoL questionnaire in a German sample of infertile individuals and couples.

BACKGROUND: FertiQoL is a questionnaire internationally developed to measure fertility-specific quality of life. It has been validated with infertile populations in many countries and used in several studies focusing on the psychosocial consequences of infertility in Europe, Asia, and North America. METHODS: Over a period of two years, 596 infertile women and men took part in the study conducted at three German fertility clinics. Psychometric properties of FertiQoL were tested by performing confirmatory factor analyses, calculating average variance extracted values, reliability and correlation coefficients. Hierarchical regression analyses were conducted to determine the relations between FertiQoL subscales and both sociodemographic and medical variables. Individual and cross-partner effects were tested for. RESULTS: The confirmatory factor analyses conducted on our FertiQoL data supported the original four-factor solution for both women and men but, resulted in some unsatisfactory indices. Family and friends' support items loaded weakly on the Social subscale of FertiQoL (.27 and .34 in women, .32 and .19 in men). The Emotional and Mind/Body subscales revealed a strong intercorrelation (r = .77, p < .001 in women, r = .74, p < .001 in men). Women scored lower than men on the Emotional and Mind/Body subscales only, and they reported better fertility-specific relational QoL. In women, the perceived cause of infertility and already mothering a child related significantly to individual FertiQoL scores, while in men, age, educational level, and the duration of their wish for a child had an impact on the FertiQoL subscales (all p < .05). The men's educational level, the women's educational level, and the subjective perceived medical cause of fertility problems exerted cross-partner effects on QoL (all p < .05). CONCLUSIONS: Our study results represent a contribution both to research and clinical practice. The findings suggest the importance of considering the personal experience of infertility in different cultural and gender specific settings and that the strong connections between the emotional, physical, and cognitive aspects of an individual's fertility-specific quality of life should be regarded as a more coherent system. TRIAL REGISTRATION: DRKS: DRKS00014707 . Registered 1 May 2018 (retrospectively registered).

Hadronic Vacuum Polarization Contribution to the Anomalous Magnetic Moments of Leptons from First Principles.

We compute the leading, strong-interaction contribution to the anomalous magnetic moment of the electron, muon, and tau using lattice quantum chromodynamics (QCD) simulations. Calculations include the effects of u, d, s, and c quarks and are performed directly at the physical values of the quark masses and in volumes of linear extent larger than 6 fm. All connected and disconnected Wick contractions are calculated. Continuum limits are carried out using six lattice spacings. We obtain a_{e}^{LO-HVP}=189.3(2.6)(5.6)×10^{-14}, a_{µ}^{LO-HVP}=711.1(7.5)(17.4)×10^{-10} and a_{τ}^{LO-HVP}=341.0(0.8)(3.2)×10^{-8}, where the first error is statistical and the second is systematic.

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant.

Patients with recurrent miscarriage (RM) show up-regulated cytotoxic natural killer (NK) cells that are suspected to play a causal role in abortion. In the present study, we investigated counter-regulating inhibitory mechanisms and compared the results in RM patients with those of healthy controls (HC), patients with end-stage renal disease (ESRD) and kidney transplant recipients late post-transplant (TX). NK, NK T and T cell subsets were analysed in the peripheral blood of 31 RM, 14 female ESRD and nine female TX patients as well as 21 female HC using eight-colour fluorescence flow cytometry. Compared with HC, RM patients showed significantly higher absolute numbers of CD56+ NK cells co-expressing the phenotype interferon (IFN)-γR+ , IL-4+ , transforming growth factor (TGF)-ß+ , IL-4+ human leucocyte antigen D-related (HLA-DR)+ , TGF-ß+ HLA-DR+ , IL-4+ TGF-ß+ , IL-4+ TGF-ß- , IFN-γ+ and/or IL-10- IFN-γ+ (all P ≤ 0·01), more IL-17+ CD56bright (P = 0·028) NK cells and more CD56dim CD16+ NK cells co-expressing IFN-γR, IFN-γ, IL-4 and/or TGF-ß (all P ≤ 0·01). When the same cell subsets were analysed in ESRD or TX patients, cytokine-producing NK cell subsets were not significantly different from those of HC. RM patients showed significantly higher absolute numbers of CD158a+ , CD158b+ , CD158a- CD158e+ (all P < 0·05), NKG2D+ NKG2A+ , NKG2D + NKG2A- , NKG2D+ and/or NKG2A+ (all P ≤ 0·01) CD56+ NK cells and higher CD158a+ , CD158b+ (all P < 0·05), NKG2D+ and/or NKG2A+ (all P < 0·01) CD56dim+ CD16+ NK cells than HC. In contrast, ESRD patients had normal and TX recipients had lower CD158a+ and NKG2D+ NKG2A- CD56+ NK cells and lower CD158a+ CD56dim+ CD16+ NK cells (all P < 0·05) than HC. RM patients have abnormally high circulating NK cells expressing inhibitory cytokines and inhibitory surface receptors which might contribute to the pathogenesis of RM.

Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to chrysotile or crocidolite asbestos in a 28-day quantitative inhalation toxicology study.

This study provides an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake-dust (brakes manufactured with chrysotile). The design included a 28-day repeated multi-dose inhalation exposure (6 h/d, 5 d/wk, 4 wks) followed by 28-days without exposure. Fiber control groups included a similar grade chrysotile as used in the brakes and a commercial crocidolite asbestos. Aerosol fiber distributions of the chrysotile and crocidolite were similar (fiber-length > 20 µm/cm3: Chrysotile-low/high 42/62; Crocidolite-low/high 36/55; WHO-fibers/cm3: Chrysotile-low/high 192/219; Crocidolite-low/high 211/255). The total number of aerosol particles/cm3 in the brake-dust was similar to that in the chrysotile (Brake-dust 710-1065; Chrysotile 532-1442). Brake-dust at particle exposure levels equal to or greater than chrysotile or crocidolite caused no indication of microgranulomas, epithelial hyperplasia, or fibrosis (Wagner score < 1.7) or changes in bronchoalveolar lavage (BAL) indices from the air control. Chrysotile BAL indices did not differ from the air control. Pathologically, there was low level of inflammation and epithelial hyperplasia, but no fibrosis (Wagner score ≤ 3). Crocidolite induced elevated neutrophils and cell damage (BAL), persistent inflammation, microgranulomas, and fibrosis (Wagner scores 4) which persisted through the post exposure period. Confocal microscopy of snap-frozen chestwalls showed no difference between control, brake-dust and chrysotile-HD groups or in thickness of visceral or parietal pleural. The crocidolite exposure resulted in extensive inflammatory response, collagen development and adhesions between the visceral and parietal surfaces with double the surface thickness. These results provide essential information for the design of a subsequent subchronic study.

Health-related quality of life in patients with polycystic ovary syndrome: validation of the German PCOSQ-G.

PURPOSE: Patients with polycystic ovary syndrome (PCOS) report a decreased health-related quality of life (HRQOL) and higher levels of psychological distress. Validated questionnaires are necessary to assess the impact of PCOS on patients' lives. The aim of the present study was to evaluate the German "Polycystic Ovary Syndrome Questionnaire" (PCOSQ-G). METHODS: The psychometric properties of the PCOSQ-G were investigated in PCOS patients with item-total correlation, internal consistency and test-retest reliability. Correlations with the Short-Form-36 Health Survey (SF-36) and the Hospital Anxiety and Depression Scale (HADS-D) were calculated to evaluate the validity of the PCOSQ-G. Discriminatory validity was investigated through a receiver operating characteristic curve and independent sample t tests compared with healthy controls. RESULTS: Good psychometric properties were found for most items. Acceptable to high internal consistency was found for the total score (α = 0.94-0.95) and all subscales (α = 0.70-0.97). High test-retest reliability was found for the total score (0.86) and all subscales (0.81-0.90). The validity analyses showed that the PCOSQ-G total score was positively correlated with both SF-36 summary scales and was negatively correlated with both HADS subscales. Patients reported significantly lower values for the PCOSQ-G total score (p < 0.001) and all subscales, and the PCOSQ-G discriminated well between patients and healthy controls (AUC = 0.81, p < 0.001). CONCLUSIONS: PCOSQ-G is a reliable and valid tool to assess the HRQOL in patients with PCOS and can be used in future clinical research. Patients with PCOS exhibited an impaired HRQOL, which indicates the need for psychosomatic counseling.

Effect of feed deprivation on selected parameters of lipid mobilisation and hepatic function in healthy Akhal Teke horses.

BACKGROUND: Gastrointestinal and other systemic diseases of Equidae are often characterised by partial or complete inappetence. The catabolic processes may lead to lipid mobilisation and other metabolic disturbances. Evidence from earlier studies has revealed that during feed deprivation/inappetence, the conjugation of bilirubin is reduced causing a substantial rise of the total bilirubin and its unconjugated fraction. OBJECTIVES: We hypothesised that during feed deprivation, the serum concentration of free fatty acids (FFA), triglycerides (TG), blood urea nitrogen (BUN), total bilirubin (tBIL), total bile acids (tBA) and activity of GGT and GLDH increases, while the concentration of insulin and direct bilirubin (dBIL) decreases. STUDY DESIGN: Observational experiment. METHODS: Eleven horses were feed deprived for 96 h. Animals were closely monitored while blood samples were taken at the beginning, and then at 72, 84 and 96 h later. Variables of interest included serum FFA, TG, insulin, GGT, GLDH, total and direct BIL (t&dBIL), tBA and BUN. The data were analysed by descriptive statistics, paired t-test and one-way repeated measures ANOVA with post-hoc HSD test, and P≤0.05 was considered significant. RESULTS: Horses tolerated feed restriction without complications. During this time, the concentration of TG, FFA, BUN, dBIL and insulin significantly increased (P≤0.05), as well as the activity of serum GGT, while the concentration of tBIL, tBA and the activity of GLDH did not change significantly (P>0.05). MAIN LIMITATIONS: Sample size, lack of serum volatile fatty acid, cortisol and blood glucose measurements may have limited the value of the study. CONCLUSIONS: Healthy Akhal Teke horses did not develop a catabolic crisis following 4 days of feed restriction and hyperlipaemia did not occur. Total BIL and tBA did not increase, thus were not useful indicators of inappetence in this group of horses.

Higher prevalence of colonization with Gardnerella vaginalis and gram-negative anaerobes in patients with recurrent miscarriage and elevated peripheral natural killer cells.

The role of vaginal infections in recurrent miscarriage (RM) is discussed controversially and screening is not recommended in international guidelines. Peripheral and uterine NK cells (pNK, uNK) play an important role in the establishment of a healthy pregnancy and are targets of immune diagnostics in RM patients. The aim of this study was to analyze the composition of the vaginal microbiota in RM patients and to correlate the findings to clinical characteristics as well as NK cell parameters. In total, n=243 RM patients with ≥3 consecutive miscarriages were recruited between 11/2011 and 03/2016. Vaginal swabs were analyzed by microbiological culture. Further, a cervical swab was taken in n=187 patients and the presence of Chlamydia trachomatis was evaluated by a molecular assay. Peripheral blood levels of CD45+CD3-CD56+CD16+ pNK (determined by four-color fluorescence flow cytometry) and CD56+ uNK (uterine biopsy, determined by immunohistochemistry) were analyzed. The prevalence of Gardnerella vaginalis colonization in RM patients was 19.0%, gram-negative anaerobes 20.5%, Candida species 7.9%, group B Streptococcus 11.0% and Enterobacteriaceae 14.8%. Commensal lactobacilli were absent in 14.5% of the women. Chlamydia trachomatis was detected in n=1 case (0.53%). The prevalence of Gardnerella vaginalis and gram-negative anaerobes in RM patients with elevated pNK (>280/µl, n=69) was significantly higher (p=0.012, p=0.04) compared to patients with normal pNK (n=174). In conclusion, RM patients with elevated pNK suffer more often from colonization by Gardnerella vaginalis and gram-negative anaerobes. This might indicate an association between the vaginal microbiota, local inflammation, changes in immune parameters and miscarriage.

Infertile Partners' Coping Strategies Are Interrelated - Implications for Targeted Psychological Counseling.

Background Infertility patients often have high stress levels which, in some cases, represent a risk of developing depression or anxiety. The SCREENIVF questionnaire is a validated tool to evaluate such risks. Some coping strategies have been shown to be correlated with infertile couples' levels of stress. Determining which strategies are correlated with higher levels of risk for depression or anxiety could be useful to offer targeted psychological counseling to reduce the risk of depression or anxiety. Materials and Methods A total of 296 women and men who attended the Fertility Center at Heidelberg University Hospital completed the SCREENIVF questionnaire and the COMPI coping scales. Data were analyzed first on an individual basis and focused on the couple, using the Actor Partner Interdependence Model. Results On an individual level, active avoidance coping was positively correlated with a higher risk of depression or anxiety in women, while meaning-based coping was negatively correlated with risk in men. When the results of couples were viewed together, women and men using active avoidance coping exhibited higher risk scores as individuals (actor effect), as did their partners (partner effect). Women who used meaning-based coping had positive actor and partner effects. Women using active-confronting coping had a negative partner effect (higher risk score for men). Conclusions These findings indicate that some coping strategies may have a protective effect while others may increase the risk of emotional maladjustment in infertile couples. Further analysis of coping strategies could help to identify new counseling approaches for infertile patients.

The "killer cell story" in recurrent miscarriage: Association between activated peripheral lymphocytes and uterine natural killer cells.

Peripheral and uterine NK cells (pNK, uNK) can be distinguished according to their receptor expression. Recent studies indicate an association of elevated pNK and uNK with recurrent miscarriage (RM). This study aimed to analyze pNK and uNK in patients with RM and healthy controls. Out of n=590 RM patients screened according to a standard diagnostic protocol, n=268 couples with ≥3 consecutive RM were identified. Subgroups consisted of n=151 primary RM (pRM), n=85 secondary RM (sRM), n=32 tertiary RM (tRM) and n=42 healthy controls. Finally, n=147 idiopathic RM (iRM) and n=121 non-iRM patients were identified. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined in non-pregnant patients and controls in the mid-luteal phase by FACS. In n=129 RM patients a uterine biopsy was taken to evaluate CD56+ NK cells by immunohistochemistry. PRM showed higher absolute pNK than sRM (median/µl (Q1;Q3): 234 (147;306) vs 176 (128;245), p=0.02). Further a trend towards higher pNK percentages in pRM was detected. UNK numbers did not differ between RM subgroups and did not correlate with pNK. However, the rate of highly elevated uNK was increased in iRM compared to non-iRM patients (p=0.04). Further, higher numbers of CD45+CD3-DR+ (p<0.01) and CD45+CD3+CD8+DR+ (p=0.04) peripheral lymphocytes were associated with higher uNK numbers. In conclusion, elevated pNK were present in pRM patients. Although pNK and uNK numbers did not correlate, the association between high CD45+CD3-DR+ and CD45+CD3+CD8+DR+ peripheral lymphocytes and uNK might indicate that activated NK, B and T cells provide cytokines for the differentiation of uNK.