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.

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.

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.

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.

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.

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.

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).

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.

Extracellular vesicles in blood, milk and body fluids of the female and male urogenital tract and with special regard to reproduction.

Extracellular vesicles (EVs) are released from almost all cells and tissues. They are able to transport substances (e.g. proteins, RNA or DNA) at higher concentrations than in their environment and may adhere in a receptor-controlled manner to specific cells or tissues in order to release their content into the respective target structure. Blood contains high concentrations of EVs mainly derived from platelets, and, at a smaller amount, from erythrocytes. The female and male reproductive tracts produce EVs which may be associated with fertility or infertility and are released into body fluids and mucosas of the urogenital organs. In this review, the currently relevant detection methods are presented and critically compared. During pregnancy, placenta-derived EVs are dynamically detectable in peripheral blood with changing profiles depending upon progress of pregnancy and different pregnancy-associated pathologies, such as preeclampsia. EVs offer novel non-invasive diagnostic tools which may reflect the situation of the placenta and the foetus. EVs in urine have the potential of reflecting urogenital diseases including cancers of the neighbouring organs. Several methods for detection, quantification and phenotyping of EVs have been established, which include electron microscopy, flow cytometry, ELISA-like methods, Western blotting and analyses based on Brownian motion. This review article summarises the current knowledge about EVs in blood and cord blood, in the different compartments of the male and female reproductive tracts, in trophoblast cells from normal and pre-eclamptic pregnancies, in placenta ex vivo perfusate, in the amniotic fluid, and in breast milk, as well as their potential effects on natural killer cells as possible targets.

Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.

STUDY QUESTION: What is the success rate in terms of ovarian activity (menstrual cycles) as well as pregnancy and delivery rates 1 year after orthotopic ovarian transplantations conducted in a three-country network? SUMMARY ANSWER: In 49 women with a follow-up >1 year after transplantation, the ovaries were active in 67% of cases and the pregnancy and delivery rates were 33 and 25%, respectively. WHAT IS KNOWN ALREADY: Cryopreservation of ovarian tissue in advance of cytotoxic therapies and later transplantation of the tissue is being performed increasingly often, and the total success rates in terms of pregnancy and delivery have been described in case series. However, published case series have not allowed either a more detailed analysis of patients with premature ovarian insufficiency (POI) or calculation of success rates based on the parameter 'tissue activity'. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of 95 orthotopic transplantations in 74 patients who had been treated for cancer, performed in the FertiPROTEKT network from 2008 to June 2015. Of those 95 transplantations, a first subgroup (Subgroup 1) was defined for further analysis, including 49 women with a follow-up period >1 year after transplantation. Of those 49 women, a second subgroup (Subgroup 5) was further analysed, including 40 women who were transplanted for the first time and who were diagnosed with POI before transplantation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Transplantation was performed in 16 centres and data were transferred to the FertiPROTEKT registry. The transplantations were carried out after oncological treatment had been completed and after a remission period of at least 2 years. Tissue was transplanted orthotopically, either into or onto the residual ovaries or into a pelvic peritoneal pocket. The success rates were defined as tissue activity (menstrual cycles) after 1 year (primary outcome) and as pregnancies and deliveries achieved. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of all transplanted 74 women was 31 ± 5.9 years at the time of cryopreservation and 35 ± 5.2 at the time of transplantation. Twenty-one pregnancies and 17 deliveries were recorded. In Subgroup 1, tissue was cryopreserved at the age of 30 ± 5.6 and transplanted at 34 ± 4.9 years. Ovaries remained active 1 year after transplantation in 67% of cases (n = 33/49), the pregnancy rate was 33% (n = 16/49) and the delivery rate was 25% (n = 12/49). In Subgroup 5, tissue was cryopreserved at the age 30 ± 5.9 years and transplanted at 34 ± 5.2 years. Ovaries remained active 1 year after transplantation in 63% of cases (n = 25/40), the pregnancy rate was 28% (n = 11/40) and the delivery rate was 23% (n = 9/40). The success rates were age dependant with higher success in women who cryopreserved at a younger age. In Subgroup 5, tissue was exclusively transplanted into the ovary in 10% (n = 4/40) of women and into a peritoneal pocket in 75% (n = 30/40), resulting in spontaneous conceptions in 91% of patients (n = 10/11). LIMITATIONS, REASONS FOR CAUTION: The data were drawn from a retrospective analysis. The cryopreservation and transplantation techniques used have changed during the study period. The tissue was stored in many tissue banks and many surgeons were involved, leading to heterogeneity of the procedures. However, this does reflect the realistic situation in many countries. Although patients with POI were evaluated before transplantation to allow specific analysis of the transplanted tissue itself, the possibility cannot be excluded that residual ovarian tissue was also reactivated. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest case series worldwide to date and it confirms that cryopreservation and transplantation of ovarian tissue can be a successful option for preserving fertility. Persistent tissue activity 12 months after transplantation suggests that the pregnancy and delivery rates may increase further in the future. As transplantation into the peritoneum results in a high success rate, this approach may be an alternative to transplantation into the ovary. However, in order to establish the best transplantation site, a randomized study is required. STUDY FUNDING/COMPETING INTEREST: This study was in part funded from the Deutsche Forschungsgemeinschaft (# DI 1525) and the Wilhelm Sander Foundation (2012.127.1) and did not receive any funding from a commercial company. No competing interests. TRIAL REGISTRATION NUMBER: None.

Lattice Computation of the Nucleon Scalar Quark Contents at the Physical Point.

We present a QCD calculation of the u, d, and s scalar quark contents of nucleons based on 47 lattice ensembles with N_{f}=2+1 dynamical sea quarks, 5 lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and pion masses down to 120 MeV. Using the Feynman-Hellmann theorem, we obtain f_{ud}^{N}=0.0405(40)(35) and f_{s}^{N}=0.113(45)(40), which translates into σ_{πN}=38(3)(3) MeV, σ_{sN}=105(41)(37) MeV, and y_{N}=0.20(8)(8) for the sigma terms and the related ratio, where the first errors are statistical and the second errors are systematic. Using isospin relations, we also compute the individual up and down quark contents of the proton and neutron (results in the main text).

Effects of medical causes, role concepts and treatment stages on quality of life in involuntary childless men.

Goal of this study was to investigate differences in quality of life in men contingent upon various fertility treatment stages, infertility causes and adoption of roles. A quantitative study with n = 115 men in three German fertility centres was devised. Participants completed a standardised, fertility-specific questionnaire devised for men (TLMK), sociodemographic and role items. Men having experienced severe medical conditions, for example cancer, reported significant higher quality of life compared to men with other infertility reasons [F(1,56) = 12.77, P = 0.001]. Furthermore, allocating participants into distinctive groups by means of kind and duration of treatment revealed significant group differences [F(2,111) = 4.94, P = 0.009], with quality of life decreasing with the use of more invasive fertility methods. A higher satisfaction with life was also stated by men adopting many tasks in the treatment process. The high quality of life displayed by men having experienced severe medical conditions contains valuable and far-reaching information about possible resilience factors that need to be researched more in detail. The finding of decreasing quality of life in men with the use of more invasive methods in treatment applies for increased psychosocial services in fertility clinics.

Severe XLP Phenotype Caused by a Novel Intronic Mutation in the SH2D1A Gene.

We describe here a novel c.137 + 5G > A intronic mutation in the SH2D1A gene of the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in association with Epstein-Barr virus (EBV)-induced fatal infectious mononucleosis (FIM) in an 8-year-old male patient and his 3-year-old step brother. The mother and the maternal grandmother of the boys are healthy and heterozygous for this sequence variant. Genetic sequencing of blood-cell-derived cDNA in the younger patient revealed a 22 bp deletion in the SH2D1A cDNA. Immunoblot and flow cytometry analysis performed in this younger patient showed the lack of SAP protein expression in peripheral blood lymphocytes. These data suggest that the novel c.137 + 5G > A mutation results in loss of function of SAP protein and leads to typical X-linked lymphoproliferative disease phenotype. We propose that intron 1 and the c.137 + 5G may be the most frequent intronic hot spot for SH2D1A splicing mutation.

New generation of hydraulic pedotransfer functions for Europe.

A range of continental-scale soil datasets exists in Europe with different spatial representation and based on different principles. We developed comprehensive pedotransfer functions (PTFs) for applications principally on spatial datasets with continental coverage. The PTF development included the prediction of soil water retention at various matric potentials and prediction of parameters to characterize soil moisture retention and the hydraulic conductivity curve (MRC and HCC) of European soils. We developed PTFs with a hierarchical approach, determined by the input requirements. The PTFs were derived by using three statistical methods: (i) linear regression where there were quantitative input variables, (ii) a regression tree for qualitative, quantitative and mixed types of information and (iii) mean statistics of developer-defined soil groups (class PTF) when only qualitative input parameters were available. Data of the recently established European Hydropedological Data Inventory (EU-HYDI), which holds the most comprehensive geographical and thematic coverage of hydro-pedological data in Europe, were used to train and test the PTFs. The applied modelling techniques and the EU-HYDI allowed the development of hydraulic PTFs that are more reliable and applicable for a greater variety of input parameters than those previously available for Europe. Therefore the new set of PTFs offers tailored advanced tools for a wide range of applications in the continent.

Anomalous impact in reaction-diffusion financial models.

We generalize the reaction-diffusion model A+B→0 in order to study the impact of an excess of A (or B) at the reaction front. We provide an exact solution of the model, which shows that the linear response breaks down: the average displacement of the reaction front grows as the square root of the imbalance. We argue that this model provides a highly simplified but generic framework to understand the square-root impact of large orders in financial markets.

Severe skin inflammation and filaggrin mutation similarly alter the skin barrier in patients with atopic dermatitis.

BACKGROUND: Filaggrin (FLG) deficiency is a well-known predisposing factor for the development of atopic dermatitis (AD). Decreased FLG expression can be the result of haploinsufficiency or severe inflammation, which can cause acquired FLG alterations. FLG mutations are related to several clinical and laboratory parameters of AD; however, some recent data seem to contradict these associations. OBJECTIVES: Our aim was to determine which clinical and biochemical parameters are connected to FLG haploinsufficiency and which ones are also associated with acquired FLG alterations due to severe skin symptoms in patients with AD. METHODS: We introduced a novel classification of patients with AD, based on FLG mutations and SCORAD (SCORing Atopic Dermatitis). Based on these parameters, we created three groups of patients with AD: mild-to-moderate wild-type (A), severe wild-type (B) and severe mutant (C). In all groups, we assessed laboratory and clinical parameters and performed immunohistochemical analyses. RESULTS: Groups B and C contained patients with equally severe symptoms based on the SCORAD. The two severe groups did not differ significantly with respect to barrier-specific parameters, whereas group A had significantly better results for the barrier function measurements. However, significant differences were detected between groups B and C with respect to the allergic sensitization-specific parameters. CONCLUSIONS: These findings suggest that skin barrier function correlates with the severity of skin inflammation and can be equally impaired in patients with FLG mutant- and wild-type AD with severe symptoms. Nevertheless, our results also suggest that patients with FLG mutant-type AD may have a higher risk of allergic sensitization compared with patients with the wild-type.

The success of assisted reproduction technologies in relation to composition of the total regulatory T cell (Treg) pool and different Treg subsets.

STUDY QUESTION: Are there differences in composition of the total regulatory T cell (Treg) pool and distinct Treg subsets (naïve CD45RA(+)-Tregs, HLA-DR(-)- and HLA-DR(+)-memory Tregs) between successfully and non-successfully IVF/ICSI-treated women? SUMMARY ANSWER: Non-successfully IVF/ICSI-treated women have a decreased percentage of naïve CD45RA(+)-Tregs and an increased percentage of HLA-DR(-)-memory Tregs within the total Treg pool. WHAT IS KNOWN ALREADY: Immunosuppressive Tregs play a significant role in human reproduction and studies have shown that their number and function are reduced in reproductive failure and complications of pregnancy such as pre-eclampsia and preterm labor. However, no data exist concerning the importance of Tregs for a successful outcome following assisted reproduction technologies. STUDY DESIGN, SIZE, DURATION: Blood samples were obtained from 210 women undergoing IVF/ICSI treatment, where 14 patients were excluded due to biochemical pregnancy or missed abortion. Age control blood samples were collected from 20 neonates and 176 healthy female volunteers. The study was performed between October 2010 and March 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, we determined prospectively the quantity and composition of the total CD4(+)CD127(low+/-)CD25(+)FoxP3(+)-Treg pool and three different Treg subsets (naïve CD45RA(+)-Tregs, HLA-DR(-)- and HLA-DR(+)-memory Tregs) in all women undergoing IVF/ICSI treatment. We examined whether there were differences between those who became pregnant (n = 36) and those who did not (n = 160). The blood samples were collected within 1 h before the embryo transfer and analyzed by six-color flow cytometry. In order to evaluate these results with regard to the normal age-related changes in composition of the total Treg pool, the same analysis was performed using samples of umbilical cord blood and from healthy female volunteers aged between 17 and 76 years. The composition of the total Treg pool was documented for successfully IVF/ICSI-treated women (n = 5) throughout their pregnancy and we assessed the suppressive activity of each Treg subset in pregnant (n = 10) compared with non-pregnant women (n = 10) using suppression assays. MAIN RESULTS AND ROLE OF CHANCE: The percentage of CD4(+)CD127(low+/-)CD25(+)FoxP3(+)-Tregs within the total CD4(+)-T cell pool did not change with age and did not differ between IVF/ICSI-treated women who did or did not become pregnant. For the total Treg pool, the percentage of the naïve CD45RA(+)-Tregs decreased continuously, while the percentage of HLA-DR(-)- and HLA-DR(+)-memory Tregs increased with aging. From the age of about 40 years, the increase in HLA-DR(+)-memory Tregs in particular became less pronounced, indicating that conversion of naïve CD45RA(+)Tregs into HLA-DR(+)-memory Tregs decreases with age. Women who did not achieve a pregnancy with IVF/ICSI were older than those who did (P < 0.01). However, multiple logistic regression analysis revealed that irrespective of age, the percentage of naïve CD45RA(+)-Tregs within the total Treg pool was decreased (P < 0.05), while the percentage of HLA-DR(-)-memory Tregs was increased (P < 0.01) in women who did not become pregnant compared with those who did. At the beginning of pregnancy, naïve CD45RA(+)-Tregs showed a major decrease but increased again during pregnancy and these cells showed a higher suppressive activity (P < 0.0001) in pregnant compared with non-pregnant women. LIMITATIONS, REASONS FOR CAUTION: There was a large variation in the percentages of the Treg subsets within the total Treg pool between successfully and non-successfully IVF/ICSI-treated women. Therefore, their determination would not allow us to predict the IVF/ICSI outcome with sufficient specificity and sensitivity. We did not examine the antigen specificity of the Treg subsets and therefore could not discern whether the naïve CD45RA(+)-Tregs recognized maternal or paternal antigens. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that Tregs, especially the naïve CD45RA(+)-Treg subset, may play a role in determining the probability of both becoming pregnant and maintenance of the pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the German Research Council (DFG) grant STE 885/3-2 (to A.S.). All authors declare to have no conflict of interest.

Randomised comparison of three tools for improving compliance with occlusion therapy: an educational cartoon story, a reward calendar, and an information leaflet for parents.

BACKGROUND: We previously demonstrated that compliance with occlusion therapy for amblyopia was improved by the use of an educational programme, especially in children of parents of foreign origin and who spoke Dutch poorly. The programme consisted of: (i) a cartoon story for amblyopic children that explained without words why they should patch, (ii) a calendar with reward stickers, and (iii) an information leaflet for parents. In the current study, we assessed the individual effect of each component on compliance. METHODS: We recruited 120 3- to 6-year-old children who lived in a low socio-economic status (SES) area in The Hague and were starting occlusion therapy for the first time. They were randomised to receive one of the components (three intervention groups), or a picture to colour (control group). The randomisation was blinded for treating orthoptist and researcher. Compliance was measured electronically using the Occlusion Dose Monitor (ODM). Primary outcome was percentage of compliance (actual/prescribed occlusion time). Secondary outcome was absolute occlusion hours per day. Parental fluency in Dutch was rated on a five-point scale. RESULTS: Compliance could be measured electronically in 88 of the 120 children; in 32 others, it failed for various reasons. Parental fluency in Dutch was moderate or worse in 36.4 % (p = 0.327). Average compliance was 55 % standard deviation (SD) 40 (n = 18) in the control group, 89 % SD 25 in the group receiving the educational cartoon (n = 25, P = 0.002 compared with control group), 67 % SD 33 (n = 24, P = 0.301) in the reward-calendar group and 73 % SD 40 (n = 21, P = 0.119) in the parent-information-leaflet group. On average, children in the control group occluded 1:46 SD1:19 hours/day, 2:33 SD 1:18 hours/day in the group receiving the educational cartoon, 1:59 SD 1:13 hours/day in the reward-calendar group and 2:18 SD 1:13 hours/day in the parent-information-leaflet group. No child who received the cartoon story occluded less than 1 hour per day, against seven in the reward-calendar group, five in the parent-information-leaflet group and five in the control group. CONCLUSIONS: Although all three components of the programme improved compliance with occlusion therapy in children in low-SES areas, the educational cartoon had the strongest effect, as it explained without words to a 4- to 5-year-old child why it should wear the eye patch.