Phased plan for the implementation of the time-resolving magnetic recoil spectrometer on the National Ignition Facility (NIF).

The time-resolving magnetic recoil spectrometer (MRSt) is a transformative diagnostic that will be used to measure the time-resolved neutron spectrum from an inertial confinement fusion implosion at the National Ignition Facility (NIF). It uses a CD foil on the outside of the hohlraum to convert fusion neutrons to recoil deuterons. An ion-optical system positioned outside the NIF target chamber energy-disperses and focuses forward-scattered deuterons. A pulse-dilation drift tube (PDDT) subsequently dilates, un-skews, and detects the signal. While the foil and ion-optical system have been designed, the PDDT requires more development before it can be implemented. Therefore, a phased plan is presented that first uses the foil and ion-optical systems with detectors that can be implemented immediately-namely CR-39 and hDISC streak cameras. These detectors will allow the MRSt to be commissioned in an intermediate stage and begin collecting data on a reduced timescale, while the PDDT is developed in parallel. A CR-39 detector will be used in phase 1 for the measurement of the time-integrated neutron spectra with excellent energy-resolution, necessary for the energy calibration of the system. Streak cameras will be used in phase 2 for measurement of the time-resolved spectrum with limited spectral coverage, which is sufficient to diagnose the time-resolved ion temperature. Simulations are presented that predict the performance of the streak camera detector, indicating that it will achieve excellent burn history measurements at current yields, and good time-resolved ion-temperature measurements at yields above 3 × 1017. The PDDT will be used for optimal efficiency and resolution in phase 3.

Design of the ion-optics for the MRSt neutron spectrometer at the National Ignition Facility (NIF).

A new Magnetic Recoil Spectrometer (MRSt) is designed to provide time-resolved measurements of the energy spectrum of neutrons emanating from an inertial confinement fusion implosion at the National Ignition Facility. At present, time integrated parameters are being measured using the existing magnet recoil and neutron time-of-flight spectrometers. The capability of high energy resolution of 2 keV and the extension to high time resolution of about 20 ps are expected to improve our understanding of conditions required for successful fusion experiments. The layout, ion-optics, and specifications of the MRSt will be presented.

Inhibition of mitochondrial fission by Drp-1 blockade by short-term leptin and Mdivi-1 treatment improves white adipose tissue abnormalities in obesity and diabetes.

BACKGROUND: Obesity and type 2 diabetes are chronic diseases characterized by insulin resistance, mitochondrial dysfunction and morphological abnormalities. OBJECTIVE: We have investigated if dysregulation of mitochondrial dynamics and biogenesis is involved in an animal model of obesity and diabetes. METHODS: The effect of short-term leptin and mdivi-1 - a selective inhibitor of Drp-1 fission-protein - treatment on mitochondrial dynamics and biogenesis was evaluated in epididymal white adipose tissue (WAT) from male ob/ob mice. RESULTS: An increase in Drp-1 protein levels and a decrease in Mfn2 and OPA-1 protein expression were observed with enhanced and sustained mitochondrial fragmentation in ob/ob mice compared to wt C57BL/6 animals (p < 0.05). The content of mitochondrial DNA and PGC-1α mRNA expression -both parameters of mitochondrial biogenesis- were reduced in ob/ob mice (p < 0.05). Treatment with leptin and mdivi-1 significantly increased mitochondrial biogenesis, improved fusion-to-fission balance and attenuated mitochondrial dysfunction, thus inducing white-to-beige adipocyte transdifferentiation. Measurements of glucose and lipid oxidation in adipocytes revealed that both leptin and mdivi-1 increase substrates oxidation while in vivo determination of blood glucose concentration showed decreased levels by 50% in ob/ob mice, almost to the wt level. CONCLUSIONS: Pharmacological targeting of Drp-1 fission protein may be a potential novel therapeutic tool for obesity and type 2 diabetes.

Decidual stromal cells support tolerance at the human foetal-maternal interface by inducing regulatory M2 macrophages and regulatory T-cells.

During pregnancy, the semi-allogeneic nature of the foetus requires maternal immune adaption and acquisition of tolerance at the foetal-maternal interface. Macrophages with regulatory properties and regulatory T (Treg) cells are central in promoting foetal tolerance and are enriched in the decidua (the uterine endometrium during pregnancy). Although tissue-resident decidual stromal cells (DSC) have been implicated in regulatory functions, it is not known if they are able to induce the regulatory phenotype of macrophages and T-cells. In this study we report that maternally derived DSC are able to induce homeostatic M2 macrophages and Treg cells. CD14+ monocytes and CD4+ T-cells from healthy non-pregnant women were cultured in the presence or absence of conditioned medium (CM) from DSC isolated from 1st trimester and term placentas. DSC-CM alone was able to promote the survival of macrophages and to induce a regulatory CD14brightCD163+CD209+CD86dim phenotype, typical for decidual macrophages and similar to that induced by M-CSF. Interestingly, DSC-CM was also able to overrule the pro-inflammatory effects of GM-CSF by upregulating CD14, CD163 and CD209. Protein-profiling showed that M-CSF was secreted by DSC, and blocking of M-CSF partially reversed the M2 phenotype and reduced viability. DSC-CM also expanded CD25brightFoxp3+ Treg cells, an expansion that was abolished by a SMAD3-inhibitor, indicating the contribution of TGF-ß signaling. In conclusion, our findings collectively emphasize the role of tissue-resident stromal cells in shaping the tolerogenic environment at the foetal-maternal interface.

Top-level physics requirements and simulated performance of the MRSt on the National Ignition Facility.

The time-resolving Magnetic Recoil Spectrometer (MRSt) for the National Ignition Facility (NIF) has been identified by the US National Diagnostic Working Group as one of the transformational diagnostics that will reshape the way inertial confinement fusion (ICF) implosions are diagnosed. The MRSt will measure the time-resolved neutron spectrum of an implosion, from which the time-resolved ion temperature, areal density, and yield will be inferred. Top-level physics requirements for the MRSt were determined based on simulations of numerous ICF implosions with varying degrees of alpha heating, P2 asymmetry, and mix. Synthetic MRSt data were subsequently generated for different configurations using Monte-Carlo methods to determine its performance in relation to the requirements. The system was found to meet most requirements at current neutron yields at the NIF. This work was supported by the DOE and LLNL.

Development of Microbiome Biobanks - Challenges and Opportunities.

The microbiome research field is rapidly evolving, but the required biobanking infrastructure is currently fragmented and not prepared for the biobanking of microbiomes. The rapid advancement of technologies requires an urgent assessment of how biobanks can underpin research by preserving microbiome samples and their functional potential.

Mapping of a New Deformation Region around

We performed the first direct mass measurements of neutron-rich scandium, titanium, and vanadium isotopes around the neutron number 40 at the RIKEN RI Beam Factory using the time-of-flight magnetic-rigidity technique. The atomic mass excesses of ^{58-60}Sc, ^{60-62}Ti, and ^{62-64}V were measured for the first time. The experimental results show that the two-neutron separation energies in the vicinity of ^{62}Ti increase compared to neighboring nuclei. This shows that the masses of Ti isotopes near N=40 are affected by the Jahn-Teller effect. Therefore, a development of Jahn-Teller stabilization appears below the Cr isotopes, and the systematics in Sc, Ti, and V isotopes suggest that ^{62}Ti is located close to the peak of the Jahn-Teller effect.

Author Correction: Low-molecular-weight-heparin increases Th1- and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial.

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

Fetal heart rate variability responsiveness to maternal stress, non-invasively detected from maternal transabdominal ECG.

PURPOSE: Prenatal stress (PS) during pregnancy affects in utero- and postnatal child brain-development. Key systems affected are the hypothalamic-pituitary-adrenal axis and the autonomic nervous system (ANS). Maternal- and fetal ANS activity can be gauged non-invasively from transabdominal electrocardiogram (taECG). We propose a novel approach to assess couplings between maternal (mHR) and fetal heart rate (fHR) as a new biomarker for PS based on bivariate phase-rectified signal averaging (BPRSA). We hypothesized that PS exerts lasting impact on fHR. METHODS: Prospective case-control study matched for maternal age, parity, and gestational age during the third trimester using the Cohen Perceived Stress Scale (PSS-10) questionnaire with PSS-10 over or equal 19 classified as stress group (SG). Women with PSS-10 < 19 served as control group (CG). Fetal electrocardiograms were recorded by a taECG. Coupling between mHR and fHR was analyzed by BPRSA resulting in fetal stress index (FSI). Maternal hair cortisol, a memory of chronic stress exposure for 2-3 months, was measured at birth. RESULTS: 538/1500 pregnant women returned the questionnaire, 55/538 (10.2%) mother-child pairs formed SG and were matched with 55/449 (12.2%) consecutive patients as CG. Maternal hair cortisol was 86.6 (48.0-169.2) versus 53.0 (34.4-105.9) pg/mg (p = 0.029). At 36 + 5 weeks, FSI was significantly higher in fetuses of stressed mothers when compared to controls [0.43 (0.18-0.85) versus 0.00 (- 0.49-0.18), p < 0.001]. CONCLUSION: Prenatal maternal stress affects the coupling between maternal and fetal heart rate detectable non-invasively a month prior to birth. Lasting effects on neurodevelopment of affected offspring should be studied. TRIAL REGISTRATION: Clinical trial registration: NCT03389178.

The effect of orthopaedic surgeons' and interventional radiologists' availability on the priority treatment sequence for hemodynamically unstable pelvic fractures: a survey of US Level I trauma centers.

BACKGROUND: Most guidelines recommend both pelvic packing (PP) and angioembolization for hemodynamically unstable pelvic fractures, however their sequence varies. Some argue to use PP first because orthopaedic surgeons are more available than interventional radiologists; however, there is no data confirming this. METHODS: This cross-sectional survey of 158 trauma medical directors at US Level I trauma centers collected the availability of orthopaedic surgeons and interventional radiologists, the number of orthopaedic trauma surgeons trained to manage pelvic fractures, and priority treatment sequence for hemodynamically unstable pelvic fractures. The study objective was to compare the availability of orthopaedic surgeons to interventional radiologists and describe how the availability of orthopaedic surgeons and interventional radiologists affects the treatment sequence for hemodynamically unstable pelvic fractures. Fisher's exact, chi-squared, and Kruskal-Wallis tests were used, alpha = 0.05. RESULTS: The response rate was 25% (40/158). Orthopaedic surgeons (86%) were on-site more often than interventional radiologists (54%), p = 0.003. Orthopaedic surgeons were faster to arrive 39% of the time, and interventional radiologists were faster to arrive 6% of the time. There was a higher proportion of participants who prioritized PP before angioembolization at centers with above the average number (> 3) of orthopaedic trauma surgeons trained to manage pelvic fractures, as among centers with equal to or below average, p = 0.02. Arrival times for orthopaedic surgeons did not significantly predict prioritization of angioembolization or PP. CONCLUSIONS: Our results provide evidence that orthopaedic surgeons typically are more available than interventional radiologists but contrary to anecdotal evidence most participants used angioembolization first. Familiarity with the availability of orthopaedic surgeons and interventional radiologists may contribute to individual trauma center's treatment sequence.

Low-molecular-weight-heparin increases Th1- and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial.

Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. Although in vitro studies have suggested additional immunological effects, these are debated. We therefore investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomised controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analysed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. Mixed linear models test on LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p < 0.001) and the Th17-associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Subsequent Student's t-test showed significantly higher plasma levels of CXCL10 and CXCL11 in treated than untreated women at gw 28 and 34. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance.

Gradient over Melody valve in left AV valve position reduces with beta blockade.

The Melody valve, designed for implantation into the pulmonary outflow tract, can also be used to treat the pathology of atrioventricular (AV) valves. Increasing gradients are seen as an indication for re-dilating the valve. Our case demonstrates the heart rate dependency of the gradient across a Melody implanted in the left AV valve position in an infant. Beta blockers were used to lower both heart rate and gradient.

Magic Nature of Neutrons in

We perform the first direct mass measurements of neutron-rich calcium isotopes beyond neutron number 34 at the RIKEN Radioactive Isotope Beam Factory by using the time-of-flight magnetic-rigidity technique. The atomic mass excesses of ^{55-57}Ca are determined for the first time to be -18650(160), -13510(250), and -7370(990) keV, respectively. We examine the emergence of neutron magicity at N=34 based on the new atomic masses. The new masses provide experimental evidence for the appearance of a sizable energy gap between the neutron 2p_{1/2} and 1f_{5/2} orbitals in ^{54}Ca, comparable to the gap between the neutron 2p_{3/2} and 2p_{1/2} orbitals in ^{52}Ca. For the ^{56}Ca nucleus, an open-shell property in neutrons is suggested.

Excitation of the Isovector Spin Monopole Resonance via the Exothermic

The (^{12}N, ^{12}C) charge-exchange reaction at 175 MeV/u was developed as a novel probe for studying the isovector spin giant monopole resonance (IVSMR), whose properties are important for better understanding the bulk properties of nuclei and asymmetric nuclear matter. This probe, now available through the production of ^{12}N as a secondary rare-isotope beam, is exothermic, is strongly absorbed at the surface of the target nucleus, and provides selectivity for spin-transfer excitations. All three properties enhance the excitation of the IVSMR compared to other, primarily light-ion, probes, which have been used to study the IVSMR thus far. The ^{90}Zr(^{12}N,^{12}C) reaction was measured and the excitation energy spectra up to about 70 MeV for both the spin-transfer and non-spin-transfer channels were deduced separately by tagging the decay by γ emission from the ^{12}C ejectile. Besides the well-known Gamow-Teller and isobaric analog transitions, a clear signature of the IVSMR was identified. By comparing with the results from light-ion reactions on the same target nucleus and theoretical predictions, the suitability of this new probe for studying the IVSMR was confirmed.

Spectroscopy of Pionic Atoms in

We observed the atomic 1s and 2p states of π^{-} bound to ^{121}Sn nuclei as distinct peak structures in the missing mass spectra of the ^{122}Sn(d,^{3}He) nuclear reaction. A very intense deuteron beam and a spectrometer with a large angular acceptance let us achieve a potential of discovery, which includes the capability of determining the angle-dependent cross sections with high statistics. The 2p state in a Sn nucleus was observed for the first time. The binding energies and widths of the pionic states are determined and found to be consistent with previous experimental results of other Sn isotopes. The spectrum is measured at finite reaction angles for the first time. The formation cross sections at the reaction angles between 0° and 2° are determined. The observed reaction-angle dependence of each state is reproduced by theoretical calculations. However, the quantitative comparison with our high-precision data reveals a significant discrepancy between the measured and calculated formation cross sections of the pionic 1s state.

Interleukin-34 is present at the fetal-maternal interface and induces immunoregulatory macrophages of a decidual phenotype in vitro.

STUDY QUESTION: Is the newly discovered cytokine interleukin (IL)-34 expressed at the human fetal-maternal interface in order to influence polarization of monocytes into macrophages of a decidual immunoregulatory phenotype? SUMMARY ANSWER: IL-34 was found to be present at the fetal-maternal interface, in both fetal placenta and maternal decidua, and it was able to polarize monocytes into macrophages of a decidual phenotype. WHAT IS KNOWN ALREADY: IL-34 was shown to bind to the same receptor as macrophage-colony stimulating factor (M-CSF), which has an important immunomodulatory role at the fetal-maternal interface, for example by polarizing decidual macrophages to an M2-like regulatory phenotype. IL-34 is known to regulate macrophage subsets, such as microglia and Langerhans cells, but its presence at the fetal-maternal interface is unknown. STUDY DESIGN, SIZE, DURATION: The presence of IL-34 at the fetal-maternal interface was evaluated by immunohistochemistry (IHC) and ELISA in placental and decidual tissues as well as in isolated trophoblast cells and decidual stromal cells obtained from first trimester elective surgical terminations of pregnancy (n = 49). IL-34 expression was also assessed in third trimester placental biopsies from women with (n = 21) or without (n = 15) pre-eclampsia. The effect of IL-34 on macrophage polarization was evaluated in an in vitro model of blood monocytes obtained from healthy volunteers (n = 14). In this model, granulocyte macrophage-colony stimulating factor (GM-CSF) serves as a growth factor for M1-like polarization, and M-CSF as a growth factor for M2-like polarization. PARTICIPANTS/MATERIALS, SETTING, METHODS: First trimester placental and decidual tissues were obtained from elective pregnancy terminations. Placental biopsies were obtained from women with pre-eclampsia and matched controls in the delivery ward. Polarization of macrophages in vitro was determined by flow-cytometric phenotyping and secretion of cytokines and chemokines in cell-free supernatants by multiplex bead assay. MAIN RESULTS AND THE ROLE OF CHANCE: Our study shows that IL-34 is produced at the fetal-maternal interface by both placental cyto- and syncytiotrophoblasts and decidual stromal cells. We also show that IL-34, in vitro, is able to polarize blood monocytes into macrophages with a phenotype (CD14highCD163+CD209+) and cytokine secretion pattern similar to that of decidual macrophages. The IL-34-induced phenotype was similar, but not identical to the phenotype induced by M-CSF, and both IL-34- and M-CSF-induced macrophages were significantly different (P < 0.05-0.0001 depending on marker) from GM-CSF-polarized M1-like macrophages. Our findings suggest that IL-34 is involved in the establishment of the tolerant milieu found at the fetal-maternal interface by skewing polarization of macrophages into a regulatory phenotype. LIMITATIONS, REASONS FOR CAUTION: Although it is clear that IL-34 is present at the fetal-maternal interface and polarizes macrophages in vitro, its precise role in vivo remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The recently discovered cytokine IL-34 is present at the fetal-maternal interface and has immunomodulatory properties with regard to induction of decidual macrophages, which are important for a healthy pregnancy. Knowledge of growth factors related to macrophage polarization can potentially be translated to treatment of pregnancy complications involving dysregulation of this process. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by grants from the Medical Research Council (Grant K2013-61X-22310-01-04), the Research Council of South-East Sweden (FORSS), and the County Council of Östergötland, Sweden. No author has any conflicts of interest to declare.

Transient thyrotoxicosis during nivolumab treatment.

Two patients presented with transient thyrotoxicosis within 2-4 weeks after starting treatment with nivolumab. This thyrotoxicosis turned into hypothyroidism within 6-8 weeks. Temporary treatment with a beta blocker may be sufficient.

Risk stratification for healthcare planning in women with gestational diabetes mellitus.

BACKGROUND: To identify relevant factors predicting the need for insulin therapy in women with gestational diabetes mellitus (GDM) and secondly to determine a potential 'low- risk' diet-treated group who are likely to have good pregnancy outcomes. METHODS: A retrospective analysis between 2011-2014. Multivariable backward stepwise logistic regression was used to identify the predictors of the need for insulin therapy. To identify a 'low-risk' diet-treated group, the group was stratified according to pregnancy complications. Diet-treated women with indications for induction in secondary care were excluded. RESULTS: A total of 820 GDM women were included, 360 (44%) women required additional insulin therapy. The factors predicting the need for insulin therapy were: previous GDM, family history of diabetes, a previous infant weighing ≥ 4500 gram, Middle-East/North-African descent, multiparity, pre-gestational BMI ≥ 30 kg/m2, and an increased fasting glucose level ≥ 5.5 mmol/l (OR 6.03;CI 3.56-10.22) and two-hour glucose level ≥ 9.4 mmol/l after a 75-gram oral glucose tolerance test at GDM diagnosis. In total 125 (54%) women treated with diet only had pregnancy complications. Primiparity and higher weight gain during pregnancy were the best predictors for complications (predictive probability 0.586 and 0.603). CONCLUSION: In this GDM population we found various relevant factors predicting the need for insulin therapy. A fasting glucose level ≥ 5.5 mmol/l at GDM diagnosis was by far the strongest predictor. Women with GDM who had good glycaemic control on diet only with a higher parity and less weight gain had a lower risk for pregnancy complications.

[Can Peers Achieve Access to Socially Burdened Families? Evaluation Results of the Programme 'Community Mothers in Berlin-Kreuzberg']. / Können Peers Zugänge zu sozial belasteten Familien schaffen? Ergebnisse der Evaluation des Projekts "Stadtteilmütter in Berlin-Kreuzberg".

This study evaluated a setting-based programme whose goal was to promote the healthy upbringing of children in a disadvantaged district through the empowerment of mothers. Women from the neighbourhood were trained as community mothers (CM) to impart their knowledge in home visitations to other mothers. 67 CMs were trained. They gained access to 118 families via home visits and to 191 families in single contacts. Information and support resulted in positive changes in all families available for interviews (n=44). The families also gained access to the professional help system.