Burning plasma achieved in inertial fusion.

Obtaining a burning plasma is a critical step towards self-sustaining fusion energy1. A burning plasma is one in which the fusion reactions themselves are the primary source of heating in the plasma, which is necessary to sustain and propagate the burn, enabling high energy gain. After decades of fusion research, here we achieve a burning-plasma state in the laboratory. These experiments were conducted at the US National Ignition Facility, a laser facility delivering up to 1.9 megajoules of energy in pulses with peak powers up to 500 terawatts. We use the lasers to generate X-rays in a radiation cavity to indirectly drive a fuel-containing capsule via the X-ray ablation pressure, which results in the implosion process compressing and heating the fuel via mechanical work. The burning-plasma state was created using a strategy to increase the spatial scale of the capsule2,3 through two different implosion concepts4-7. These experiments show fusion self-heating in excess of the mechanical work injected into the implosions, satisfying several burning-plasma metrics3,8. Additionally, we describe a subset of experiments that appear to have crossed the static self-heating boundary, where fusion heating surpasses the energy losses from radiation and conduction. These results provide an opportunity to study α-particle-dominated plasmas and burning-plasma physics in the laboratory.

Internal evaluation of risk stratification tool using serial procalcitonin and clinical risk factors in pediatric febrile neutropenia: The non-interventional, single institution experience prior to clinical implementation.

Risk stratification of pediatric febrile neutropenia (FN) is an established concept, yet clinical risk tools misclassify nearly 5% of clinical standard-risk episodes with severe outcomes. The internal evaluation of a clinical risk tool before implementation has not been well-described. In this noninterventional cohort study, we evaluated a study decision rules (SDR) tool; a clinical risk tool with serial procalcitonin. The study standard-risk (SSR) group met clinical standard-risk criteria with two serial procalcitonin <0.4 ng/mL. The study high-risk (SHR) group met clinical high-risk criteria or clinical standard-risk with a procalcitonin ≥0.4 ng/mL. Descriptive and bivariate statistics compared the groups and outcomes. Clinical criteria alone identified 39.1% (238/608) standard-risk episodes; 5.9% (14/238) had severe events. Prospectively using the SDR, the SHR group encompassed 76.6% (92/120) of episodes; severe events occurred in 20% (3/15) of standard-risk episodes included due to elevated procalcitonin ≥0.4 ng/mL. The SHR group had more blood stream infections [21.7% (20/92) vs. 0% (0/28); P = 0.007] and intensive care admissions [13% (12/92) vs. 3.6% (1/28); P = 0.158]. In conclusion, the SDR with serial procalcitonin aided in identifying severe events in clinical standard-risk episodes, but analysis was limited. Institutions may consider similar internal evaluation methodology before FN episode risk stratification.

Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

Mechanism of Bismuth Stimulated Bottom-up Gold Feature Filling.

The mechanism underlying Bi 3+-stimulated bottom-up Au filling and self-passivation in trenches and vias in slightly alkaline Na 3 Au(SO 3)2 + Na 2 SO 3 electrolytes is explored. The impacts of electrolyte components Na 3 Au(SO 3)2, Na 2 SO 3 and Bi 3+ and potential-dependent kinetic factors on the rate of Au electrodeposition are quantified experimentally. Derived parameters are applied within the surfactant conservation Curvature Enhanced Accelerator Coverage model to simulate the filling of high aspect ratio trenches. It is observed that Bi adsorption accelerates the Au deposition rate with a non-linear dependence occurring around a critical coverage. Further, the impact of electrolyte composition is such that gradients of A u ( S O 3 ) 2 3 - and S O 3 2 - derived from reduction of A u ( S O 3 ) 2 3 - during deposition accentuate deposition farther from the feature opening. These factors and surface area reduction at the bottoms of filling features localize active deposition to feature bottoms. Ultimately, weakening of the concentration gradients and associated kinetics as bottom-up feature filling progresses reduces the Bi coverage on the growth front below the critical value and bottom-up growth terminates. Good agreement is observed with key experimental features including the incubation period of conformal deposition, transition to bottom-up growth, subsequent bottom-up filling and finally self-passivation as the growth front nears the field.

Microstructure and Texture in Copper Filled Millimeter Scale Through Silicon Vias.

The microstructure and crystallographic texture of copper electrodeposits in millimeter scale through silicon vias are characterized using electron backscatter diffraction. The deposits obtained from additive-containing CuSO4-H2SO4 electrolytes are characteristic of the superconformal deposition process, with growth textures and columnar grains consistent with previous findings in smaller TSV. The microstructure, like the filling evolution it records, changes substantially with chloride concentration for the concentrations of polymer suppressor used. With chloride concentrations of 80 µmol·L-1 and less, columnar grains of Cu capture the linear motion of the local growth front during filling with a strong <110> orientation along the elongated grain axes typical of deposition in chloride-containing Cu electrolytes. In the mid- and upper- via locations these columnar grains are angled upward from the sidewalls toward the center of the v-shaped growth front. In a limited region adjacent to the via bottom they extend vertically from the bottom surface. With millimolar chloride concentration, deposition also exhibits columnar grains with preferred <110> growth orientation in the lower region of the via and adjacent to the sidewalls. However, separation of the central deposit from the sidewalls results in a convex geometry of the growth front and spatially varying texture in most of the deposit.

Risk factors and outcomes associated with type of uterine rupture.

PURPOSE: To identify risk factors associated with the occurrence of complete uterine rupture (CUR) in comparison to partial uterine rupture (PUR) to further investigate to what extent a standardized definition is needed and what clinical implications can be drawn. METHODS: Between 2005 and 2017 cases with CUR and PUR at Charité University Berlin, Germany were retrospectively identified. Demographic, obstetric and outcome variables were analyzed regarding the type of rupture. Binary multivariate regression analysis was conducted to identify risk factors associated with CUR. In addition, the intended route of delivery (trial of labor after cesarean delivery (TOLAC) and elective repeat cesarean delivery (ERCD)), divided according to the type of rupture, was compared. RESULTS: 92 cases with uterine rupture were identified out of a total of 64.063 births (0.14%). Puerperal complications were more frequent in CUR (67.9 versus 41.1%, p = 0.021). Multiparity ≥ 3 was more frequent in CUR (31 versus 10.7%, p = 0.020). Factors increasing the risk for CUR were parity ≥ 3 (OR = 3.8, p = 0.025), previous vaginal birth (OR = 4.4, p = 0.011), TOLAC (OR = 6.5, p < 0.001) and the use of oxytocin (OR = 2.9, p = 0.036). After multivariate analysis, the only independent risk factor associated with CUR was TOLAC (OR = 7.4, p = 0.017). CONCLUSION: TOLAC is the only independent risk factor for CUR. After optimized antenatal counselling TOLAC and ERCD had comparable short-term maternal and fetal outcomes in a high resource setting. A high number of previous vaginal births does not eliminate the risk of uterine rupture. A clear distinction between CUR and PUR is essential to ensure comparability among studies.

[Oncologic follow-up in head and neck cancer patients]. / Onkologische Nachsorge von Kopf-Hals-Tumor-Patienten.

Despite medical treatment according to evidence-based guidelines, approximately 25-30% of all head and neck tumor patients suffer a disease relapse, depending on tumor stage and entity. The primary goal of systematic follow-up examinations is early detection and treatment of recurrent tumors or metachronous secondary tumors, but it also serves to rule out distant metastasis. Secondary goals are the diagnosis and management of treatment-associated side effects to optimize quality of life. Because of an especially high relapse risk in the first 2 years after treatment, close-knit clinical controls are recommended, e.g., quarterly. Later on, the clinical control interval can be extended to 6 months. Cross-sectional diagnostic imaging of the primary tumor region is performed annually and when screening for possible distant metastases, or upon clinical suspicion of recurrence. After 5 years without tumor recurrence, the structured clinical follow-up is usually completed.

Record Energetics for an Inertial Fusion Implosion at NIF.

Inertial confinement fusion seeks to create burning plasma conditions in a spherical capsule implosion, which requires efficiently absorbing the driver energy in the capsule, transferring that energy into kinetic energy of the imploding DT fuel and then into internal energy of the fuel at stagnation. We report new implosions conducted on the National Ignition Facility (NIF) with several improvements on recent work [Phys. Rev. Lett. 120, 245003 (2018)PRLTAO0031-900710.1103/PhysRevLett.120.245003; Phys. Rev. E 102, 023210 (2020)PRESCM2470-004510.1103/PhysRevE.102.023210]: larger capsules, thicker fuel layers to mitigate fuel-ablator mix, and new symmetry control via cross-beam energy transfer; at modest velocities, these experiments achieve record values for the implosion energetics figures of merit as well as fusion yield for a NIF experiment.

Transesophageal Echocardiography - Dysphagia Risk in Acute Stroke (TEDRAS): a prospective, blind, randomized and controlled clinical trial.

BACKGROUND AND PURPOSE: Dysphagia is common in acute stroke and leads to worse overall outcome. Transesophageal echocardiography (TEE) is used in the diagnostic evaluation of stroke with regard to its etiology and is a known cause of postoperative dysphagia in cardiac surgery. The prevalence of dysphagia in acute stroke patients undergoing TEE remains unknown. The aim of the Transesophageal Echocardiography - Dysphagia Risk in Acute Stroke (TEDRAS) study was to assess the influence of TEE on swallowing among patients who have experienced acute stroke. METHODS: The TEDRAS study was a prospective, blind, randomized, controlled trial that included two groups of patients with acute stroke. Simple unrestricted randomization was performed, and examiners were blinded to each other's results. Swallowing was tested using flexible endoscopic evaluation of swallowing (FEES) at three different time points in the intervention group (24 h before, immediately after and 24 h after TEE) and in the control group (FEES on three consecutive days and TEE earliest after the third FEES). Validated scales were used to assess dysphagia severity for all time points as primary outcome measures. RESULTS: A total of 34 patients were randomized: 19 to the intervention group and 15 to the control group. The key findings of the repeated-measures between-group comparisons were significant increases in the intervention group for the following dysphagia measures: (1) secretion severity score (immediately after TEE: P < 0.001; 24 h after TEE: P < 0.001) and (2) Penetration-Aspiration Scale score for saliva (immediately after TEE: P < 0.001; 24 h after TEE: P = 0.007), for small (immediately after TEE: P = 0.009) and large liquid boli (immediately after TEE: P = 0.009; 24 h after TEE: P = 0.025). CONCLUSION: The results indicate a negative influence of TEE on swallowing in acute stroke patients for at least 24 hours.

Effect of Chloride on Microstructure in Cu Filled Microscale Through Silicon Vias.

The microstructure of copper filled through silicon vias deposited in a CuSO4 + H2SO4 electrolyte containing micromolar concentrations of deposition rate suppressing poloxamine and chloride additives is explored using electron backscatter diffraction. Regions with distinct microstructures are observed in the vias, including conformal deposition and seam formation localized adjacent to the bottom that can transition to bottom-up filling higher in the features. The presence and extent of each microstructure depends on applied potential as well as additive concentration. Deposition in the presence of higher chloride concentration yields a strong (110) growth texture in regions where bottom-up filling exhibits a horizontal growth front profile while (110) textured or untextured growth is observed for different conditions where upward growth proceeds with a v-notch profile.

Conservative management of abnormally invasive placenta complicated by local hyperfibrinolysis and beginning disseminated intravascular coagulation.

INTRODUCTION: Abnormally invasive placenta (AIP) is often associated with high maternal morbidity. In surgical treatment, caesarean hysterectomy or partial uterine resection may lead to high perioperative maternal blood loss. A conservative treatment by leaving the placenta in utero after caesarean delivery of the baby is an option to preserve fertility and to reduce peripartum hysterectomy-related morbidity. Nevertheless, due to increased placental coagulation activity as well as consumption of clotting factors, a disseminated intravascular coagulation (DIC)-like state with secondary late postpartum bleeding can occur. PURPOSE: Systematic review after the presentation of a case of conservative management of placenta percreta with secondary partial uterine wall resection due to vaginal bleeding, complicated by local hyperfibrinolysis and consecutive systemic decrease in fibrinogen levels. METHODS: Systematic PubMed database search was done until August 2019 without any restriction of publication date or journal RESULTS: Among 58 publications, a total of 11 reported on DIC-like symptoms in the conservative management of AIP, in the median on day 59 postpartum. In most cases, emergency hysterectomy was performed, which led to an almost immediate normalization of coagulation status but was accompanied with high maternal blood loss. In two cases, fertility-preserving conservative management could be continued after successful medical therapy. CONCLUSION: Based on these results, we suggest routinely monitoring of the coagulation parameters next to signs of infection in the postpartum check-ups during conservative management of AIP. Postpartum tranexamic acid oral dosage should be discussed when fibrinogen levels are decreasing and D-Dimers are increasing.

Ramp compression of diamond to five terapascals.

The recent discovery of more than a thousand planets outside our Solar System, together with the significant push to achieve inertially confined fusion in the laboratory, has prompted a renewed interest in how dense matter behaves at millions to billions of atmospheres of pressure. The theoretical description of such electron-degenerate matter has matured since the early quantum statistical model of Thomas and Fermi, and now suggests that new complexities can emerge at pressures where core electrons (not only valence electrons) influence the structure and bonding of matter. Recent developments in shock-free dynamic (ramp) compression now allow laboratory access to this dense matter regime. Here we describe ramp-compression measurements for diamond, achieving 3.7-fold compression at a peak pressure of 5 terapascals (equivalent to 50 million atmospheres). These equation-of-state data can now be compared to first-principles density functional calculations and theories long used to describe matter present in the interiors of giant planets, in stars, and in inertial-confinement fusion experiments. Our data also provide new constraints on mass-radius relationships for carbon-rich planets.

Simulation of Copper Electrodeposition in Through-Hole Vias.

Copper electrodeposition processes for filling metallized through-hole (TH) and through-silicon vias (TSV) depend on spatially selective breakdown of a co-adsorbed polyether-chloride adlayer within the recessed surface features. In this work, a co-adsorption-dependent suppression model that has previously captured experimental observations of localized Cu deposition in TSV is used to explore filling of TH features. Simulations of potentiodynamic and galvanostatic TH filling are presented. An appropriate applied potential or current localizes deposition to the middle of the TH. Subsequent deposition proceeds most rapidly in the radial direction leading to sidewall impingement at the via center creating two blind vias. The growth front then evolves primarily toward the two via openings to completely fill the TH in a manner analogous to TSV filling. Applied potentials, or currents, that are overly reducing result in metal ion depletion within the via and void formation. Simulations in larger TH features (i.e., diameter = 85 µm instead of 10 µm) indicate that lateral diffusional gradients within the via can lead to fluctuations between active and passive deposition along the metal/electrolyte interface.

Altered T cell receptor beta repertoire patterns in pediatric ulcerative colitis.

The antigenic specificity of T cells occurs via generation and rearrangement of different gene segments producing a functional T cell receptor (TCR). High-throughput sequencing (HTS) allows in-depth assessment of TCR repertoire patterns. There are limited data concerning whether TCR repertoires are altered in inflammatory bowel disease. We hypothesized that pediatric ulcerative colitis (UC) patients possess unique TCR repertoires, resulting from clonotypical expansions in the gut. Paired blood and rectal samples were collected from nine newly diagnosed treatment-naive pediatric UC patients and four healthy controls. DNA was isolated to determine the TCR-ß repertoire by HTS. Significant clonal expansion was demonstrated in UC patients, with inverse correlation between clinical disease severity and repertoire diversity in the gut. Using different repertoire variables in rectal biopsies, a clear segregation was observed between patients with severe UC, those with mild-moderate disease and healthy controls. Moreover, the overlap between autologous blood-rectal samples in UC patients was significantly higher compared with overlap among controls. Finally, we identified several clonotypes that were shared in either all or the majority of UC patients in the colon. Clonal expansion of TCR-ß-expressing T cells among UC patients correlates with disease severity and highlights their involvement in mediating intestinal inflammation.

Effect of Chloride Concentration on Copper Deposition in Through Silicon Vias.

Bottom-up Cu deposition in metallized through silicon vias (TSV) depends on a co-adsorbed polyether-Cl- suppressor layer that selectively breaks down within recessed surface features. This work explores Cu deposition when formation of the suppressor blocking layer is limited by the flux of Cl-. This constraint leads to a transition from passive surfaces to active deposition partway down the via sidewall due to coupling between suppressor formation and breakdown as well as surface topography. The impact of Cl- concentration and hydrodynamics on the formation of the suppressor surface phase and its potential-dependent breakdown is examined. The onset of suppression breakdown is related to the local Cl- coverage as determined by the adsorption isotherm or transport limited flux. A two-additive co-adsorption model is presented that correlates the voltammetric potential of suppression breakdown with the depth of the passive-active transition during TSV filling under conditions of transport limited flux and incorporation of Cl-. The utility of potential waveforms to optimize the feature filling process is demonstrated. At higher Cl- concentrations (≥80 µmol/L), sidewall breakdown during Cu deposition occurs near the bottom of the via followed by a shift to bottom-up growth like that seen at higher Cl- concentrations.

[Evidence-based treatment recommendations for familial Mediterranean fever : A joint statement by the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. / Evidenzbasierte Therapieempfehlungen für das familiäre Mittelmeerfieber : Eine gemeinsame Stellungnahme der Gesellschaft für Kinder- und Jugendrheumatologie und der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Familial Mediterranean fever (FMF) in Germany is a rare, genetically linked disease of childhood and adolescence, which is characterized by recurrent febrile episodes and clinical signs of peritonitis, pleuritis and arthritis. Treatment with colchicine is effective and well-tolerated in the majority of patients; however, some patients do not sufficiently respond to this treatment or are intolerant to colchicine. For these patients first-line treatment with biologics which block interleukin-1 can be used. OBJECTIVE: The aim was to formulate evidence-based treatment recommendations for patients with an insufficient response and intolerance to colchicine treatment. METHODS: Based on a literature search and the European League Against Rheumatism (EULAR) recommendations on FMF from 2016 the appointed members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Rheumatology (DGRh) convened to work out and form a consensus in a joint statement on evidence-based treatment recommendations on FMF. RESULTS: After intensive discussions all decisions were in concordance. A total of 5 superordinate principles and 10 recommendations were agreed upon. DISCUSSION: The joint activities of the GKJR and the DGRh were successfully concluded in a timely manner. The recommendations form a good basis for optimal treatment of all age groups of patients with FMF.

Superconformal Nickel Deposition in Through Silicon Vias: Experiment and Prediction.

This work examines the filling of Through Silicon Vias (TSV) by Ni deposition from a NiSO4 + NiCl2 + H3BO3 electrolyte containing a branched polyethyleneimine suppressor. Feature filling occurs due to the interaction of transport limited suppressor adsorption and its consumption by potential dependent metal deposition. The interaction between surface topography and suppressor transport yields a sharp transition from passive to active deposition within the TSV. The transition is associated with significant incorporation of the suppressor, or its components, within the Ni deposit that results in grain refinement evident by electron backscatter diffraction (EBSD). Potential waveforms that progressively shift the location of the passive-active transition upward to optimize feature filling were examined. The evolution of feature filling and deposit microstructure are compared to predictions of a three-dimensional model that reflect critical behavior associated with suppressor-derived, S-shaped negative differential resistance (S-NDR). The model uses adsorption and consumption kinetics obtained from voltammetric measurements of the critical potential associated with suppression breakdown. Good agreement between experiment and simulation is demonstrated.

Statistical controversies in clinical research: building the bridge to phase II-efficacy estimation in dose-expansion cohorts.

BACKGROUND: Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics-prevalence, size, and number-their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established. METHODS: We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design. RESULTS: Adaptively updating the MTD during the DEC improved true positive rates by 8-43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance. CONCLUSION: A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping.