Quantitative analysis of contribution of mild and moderate hyperthermia to thermal ablation and sensitization of irreversible electroporation of pancreatic cancer cells.

INTRODUCTION: Irreversible electroporation (IRE) is an ablation modality that applies short, high-voltage electric pulses to unresectable cancers. Although considered a non-thermal technique, temperatures do increase during IRE. This temperature rise sensitizes tumor cells for electroporation as well as inducing partial direct thermal ablation. AIM: To evaluate the extent to which mild and moderate hyperthermia enhance electroporation effects, and to establish and validate in a pilot study cell viability models (CVM) as function of both electroporation parameters and temperature in a relevant pancreatic cancer cell line. METHODS: Several IRE-protocols were applied at different well-controlled temperature levels (37 °C ≤ T ≤ 46 °C) to evaluate temperature dependent cell viability at enhanced temperatures in comparison to cell viability at T = 37 °C. A realistic sigmoid CVM function was used based on thermal damage probability with Arrhenius Equation and cumulative equivalent minutes at 43 °C (CEM43°C) as arguments, and fitted to the experimental data using "Non-linear-least-squares"-analysis. RESULTS: Mild (40 °C) and moderate (46 °C) hyperthermic temperatures boosted cell ablation with up to 30% and 95%, respectively, mainly around the IRE threshold Eth,50% electric-field strength that results in 50% cell viability. The CVM was successfully fitted to the experimental data. CONCLUSION: Both mild- and moderate hyperthermia significantly boost the electroporation effect at electric-field strengths neighboring Eth,50%. Inclusion of temperature in the newly developed CVM correctly predicted both temperature-dependent cell viability and thermal ablation for pancreatic cancer cells exposed to a relevant range of electric-field strengths/pulse parameters and mild moderate hyperthermic temperatures.

Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Factors affecting use of magnesium sulphate for pre-eclampsia or eclampsia: a qualitative evidence synthesis.

BACKGROUND: Hypertensive disorders account for 14% of global maternal deaths. Magnesium sulphate (MgSO4 ) is recommended for prevention and treatment of pre-eclampsia/eclampsia. However, MgSO4 remains underused, particularly in low- and middle-income countries (LMICs). OBJECTIVE: This qualitative evidence synthesis explores perceptions and experiences of healthcare providers, administrators and policy-makers regarding factors affecting use of MgSO4 to prevent or treat pre-eclampsia/eclampsia. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Emcare, CINAHL, Global Health and Global Index Medicus, and grey literature for studies published between January 1995 and June 2021. SELECTION CRITERIA: Primary qualitative and mixed-methods studies on factors affecting use of MgSO4 in healthcare settings, from the perspectives of healthcare providers, administrators and policy-makers, were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We applied a thematic synthesis approach to analysis, using COM-B behaviour change theory to map factors affecting appropriate use of MgSO4 . MAIN RESULTS: We included 22 studies, predominantly from LMICs. Key themes included provider competence and confidence administering MgSO4 (attitudes and beliefs, complexities of administering, knowledge and experience), capability of health systems to ensure MgSO4 availability at point of use (availability, resourcing and pathways to care) and knowledge translation (dissemination of research and recommendations). Within each COM-B domain, we mapped facilitators and barriers to physical and psychological capability, physical and social opportunity, and how the interplay between these domains influences motivation. CONCLUSIONS: These findings can inform policy and guideline development and improve implementation of MgSO4 in clinical care. Such action is needed to ensure this life-saving treatment is widely available and appropriately used. TWEETABLE ABSTRACT: Global qualitative review identifies factors affecting underutilisation of MgSO4 for pre-eclampsia and eclampsia.

Outcomes to measure the effects of pharmacological interventions for pain management for women during labour and birth: a review of systematic reviews and randomised trials.

BACKGROUND: Pharmacological pain management options can relieve women's pain during labour and birth. Trials of these interventions have used a wide variety of outcomes, complicating meaningful comparisons of their effects. To facilitate better assessment of the effectiveness of labour pain management in trials and meta-analyses, consensus about key outcomes and the development of a core outcome set is essential. OBJECTIVE: To identify all outcomes used in studies of pharmacological pain management interventions during labour and birth. DESIGN: A review of systematic reviews and their included randomised controlled trials was undertaken. SEARCH STRATEGY: Cochrane CENTRAL was searched to identify all Cochrane systematic reviews describing pharmacological pain management options for labour and birth. Search terms included 'pain management', 'labour' and variants, with no limits on year of publication or language. SELECTION CRITERIA: Cochrane reviews and randomised controlled trials contained within these reviews were included, provided they compared a pharmacological intervention with other pain management options, placebo or no treatment. DATA COLLECTION AND ANALYSIS: All outcomes reported by reviews or trials were extracted and tabulated, with frequencies of individual outcomes reported. MAIN RESULTS: Nine Cochrane reviews and 227 unique trials were included. In total, 146 unique outcomes were identified and categorised into maternal, fetal, neonatal, child, health service, provider's perspective or economic outcome domains. CONCLUSIONS: Outcomes of pharmacological pain management interventions during labour and birth vary widely between trials. The standardisation of trial outcomes would permit the assessment of meta-analyses for best clinical practice. TWEETABLE ABSTRACT: Outcomes to measure pharmacological pain management options during labour are highly variable and require standardisation.

Rydberg Series Excitation of a Single Trapped

A complete set of spectroscopic data is indispensable when using Rydberg states of trapped ions for quantum information processing. We carried out Rydberg series spectroscopy for nS_{1/2} states with 38≤n≤65 and for nD_{5/2} states with 37≤n≤50 on a single trapped ^{40}Ca^{+} ion. We determined the ionization energy of 2 870 575.582(15) GHz, 60 times more accurately as compared to the accepted value and contradicting it by 7.5 standard deviations. We confirm quantum defect values of δ_{S_{1/2}}=1.802 995(5) and δ_{D_{5/2}}=0.626 888(9) for nS_{1/2} and nD_{5/2} states, respectively, which allow for unambiguous addressing of Rydberg levels of Ca^{+} ions. Our measurements confirm Rydberg ion scaling properties, e.g., for blackbody induced ionization, linewidths and excitation strengths.

NAD+-Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults.

BACKGROUND: Boosting NAD+ via supplementation with niacin equivalents has been proposed as a potential modality capable of promoting healthy aging and negating age-dependent declines of skeletal muscle mass and function. OBJECTIVES: We investigated the efficacy of NAD+-precursor supplementation (tryptophan, nicotinic acid, and nicotinamide) on skeletal muscle mitochondrial function in physically compromised older adults. METHODS: A randomized, double-blind, controlled trial was conducted in 14 (female/male: 4/10) community-dwelling, older adults with impaired physical function [age, 72.9 ± 4.0 years; BMI, 25.2 ± 2.3 kg/m2]. Participants were supplemented with 207.5 mg niacin equivalents/day [intervention (INT)] and a control product (CON) that did not contain niacin equivalents, each for 32 days. The primary outcomes tested were mitochondrial oxidative capacity and exercise efficiency, analyzed by means of paired Student's t-tests. Secondary outcomes, such as NAD+ concentrations, were analyzed accordingly. RESULTS: Following supplementation, skeletal muscle NAD+ concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD+-precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD+ metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD+-precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. CONCLUSIONS: Our findings are consistent with previous findings on NAD+ efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD+-precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034.

Improving the quality of maternal and newborn care in the Pacific region: A scoping review.

BACKGROUND: Quality care is essential for improving maternal and newborn health. Low- and middle-income Pacific Island nations face challenges in delivering quality maternal and newborn care. The aim of this review was to identify all published studies of interventions which sought to improve the quality of maternal and newborn care in Pacific low-and middle-income countries. METHODS: A scoping review framework was used. Databases and grey literature were searched for studies published between January 2000 and July 2019 which described actions to improve the quality of maternal and newborn care in Pacific low- and middle-income countries. Interventions were categorised using a four-level health system framework and the WHO quality of maternal and newborn care standards. An expert advisory group of Pacific Islander clinicians and researchers provided guidance throughout the review process. RESULTS: 2010 citations were identified and 32 studies included. Most interventions focused on the clinical service or organisational level, such as healthcare worker training, audit processes and improvements to infrastructure. Few addressed patient experiences or system-wide improvements. Enablers to improving quality care included community engagement, collaborative partnerships, adequate staff education and training and alignment with local priorities. CONCLUSIONS: There are several quality improvement initiatives in low- and middle-income Pacific Island nations, most at the point of health service delivery. To effectively strengthen quality maternal and newborn care in this region, efforts must broaden to improve health system leadership, deliver sustaining education programs and encompass learnings from women and their communities.

Erratum: Fast Domain Wall Motion Governed by Topology and Œrsted Fields in Cylindrical Magnetic Nanowires [Phys. Rev. Lett. 123, 217201 (2019)].

This corrects the article DOI: 10.1103/PhysRevLett.123.217201.

Fast Domain Wall Motion Governed by Topology and Œrsted Fields in Cylindrical Magnetic Nanowires.

While the usual approach to tailor the behavior of condensed matter and nanosized systems is the choice of material or finite-size or interfacial effects, topology alone may be the key. In the context of the motion of magnetic domain walls (DWs), known to suffer from dynamic instabilities with low mobilities, we report unprecedented velocities >600 m/s for DWs driven by spin-transfer torques in cylindrical nanowires made of a standard ferromagnetic material. The reason is the robust stabilization of a DW type with a specific topology by the Œrsted field associated with the current. This opens the route to the realization of predicted new physics, such as the strong coupling of DWs with spin waves above >600 m/s.

Shuttling of Rydberg Ions for Fast Entangling Operations.

We introduce a scheme to entangle Rydberg ions in a linear ion crystal, using the high electric polarizability of the Rydberg electronic states in combination with mutual Coulomb coupling of ions that establishes common modes of motion. After laser initialization of ions to a superposition of ground and Rydberg states, the entanglement operation is driven purely by applying a voltage pulse that shuttles the ion crystal back and forth. This operation can achieve entanglement on a sub-µs timescale, more than 2 orders of magnitude faster than typical gate operations driven by continuous-wave lasers. Our analysis shows that the fidelity achieved with this protocol can exceed 99.9% with experimentally achievable parameters.

[Update on Li-Fraumeni syndrome]. / Ein Update zum Li-Fraumeni-Syndrom.

The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with a high interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in a significantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .

Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy.

Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton therapy (PBS-PT). However, the risk of brainstem necrosis has not yet been reported. In this study, we evaluate the rate of brainstem necrosis in pediatric patients with CNS malignancies treated with PBS-PT.Material and methods: Pediatric patients with non-hematologic CNS malignancies treated with PBS-PT who received dose to the brainstem were included. All procedures were approved by the institutional review board. Brainstem necrosis was defined as symptomatic toxicity. The actuarial rate was analyzed by the Kaplan Meier method.Results: One hundred and sixty-six consecutive patients were reviewed. Median age was 10 years (range 0.5-21 years). Four patients (2.4%) had prior radiation. Median maximum brainstem dose in the treated course was 55.4 Gy[RBE] (range 0.15-61.4 Gy[RBE]). In patients with prior RT, cumulative median maximum brainstem dose was 98.0 Gy [RBE] (range 17.0-111.0 Gy [RBE]). Median follow up was 19.6 months (range, 2.0-63.0). One patient who had previously been treated with twice-daily radiation therapy and intrathecal (IT) methotrexate experienced brainstem necrosis. The actuarial incidence of brainstem necrosis was 0.7% at 24 months (95% CI 0.1-5.1%).Conclusion: The rate of symptomatic brainstem necrosis was extremely low after treatment with PBS-PT in this study. Further work to clarify clinical and dosimetric parameters associated with risk of brainstem necrosis after PBS-PT is needed.

The burden of severe maternal outcomes and indicators of quality of maternal care in Nigerian hospitals: a secondary analysis comparing two large facility-based surveys.

OBJECTIVE: To compare severe maternal outcomes (SMOs) from two multi-centre surveys in Nigerian hospitals, and to evaluate how the SMO burden affects quality of secondary and tertiary hospital care. DESIGN: Two facility-based surveys of women experiencing SMO (maternal near-miss or maternal deaths). SETTING: Sixteen secondary and five tertiary facilities in Nigeria [WHO Multi-Country Survey on Maternal and Newborn Health (WHOMCS)] and 42 public tertiary facilities in Nigeria (Nigeria Near-Miss and Maternal Death Survey). POPULATION: 371 women in WHOMCS-Nigeria and 2449 women in Nigeria Near-Miss and Maternal Death Survey who experienced SMO. METHODS: Secondary analysis and comparison of SMO data from two surveys, stratified by facility level. MAIN OUTCOME MEASURES: Maternal mortality ratio (MMR) per 100 000 livebirths (LB), maternal near-miss (MNM) ratio per 1000 LB, SMO ratio per 1000 LB and mortality index (deaths/SMO). RESULTS: Maternal mortality ratio and mortality indices were highest in tertiary facilities of the WHOMCS-Nigeria (706 per 100 000; 26.7%) and the Nigeria Near-Miss and Maternal Death Survey (1088 per 100 000; 40.8%), and lower in secondary facilities of the WHOMCS-Nigeria (593 per 100 000; 17.9%). The MNM ratio and SMO ratio were highest in secondary WHOMCS-Nigeria facilities (27.2 per 1000 LB; 33.1 per 1000 LB). CONCLUSIONS: Tertiary-level facilities in Nigeria experience unacceptably high maternal mortality rates, but secondary-level facilities had a proportionately higher burden of severe maternal outcomes. Common conditions with a high mortality index (postpartum haemorrhage, eclampsia, and infectious morbidities) should be prioritised for action. Surveillance using SMO indicators can guide quality improvement efforts and assess changes over time. TWEETABLE ABSTRACT: 2820 Nigerian women with severe maternal outcomes: high mortality in tertiary level hospitals, higher burden in secondary level.

Characterization and calibration of a multilayer coated Wolter optic for an imager on the Z-machine at Sandia National Laboratories.

The need for a time-resolved monochromatic x-ray imaging diagnostic at photon energies >15 keV has motivated the development of a Wolter optic to study x-ray sources on the Z-machine at Sandia National Laboratories. The work is performed in both the LLNL's x-ray calibration facility and SNL's micro-focus x-ray lab. Characterizations and calibrations include alignment, measurement of throughput within the field of view (FOV), the point-spread function within the FOV both in and out of focus, and bandpass in the FOV. These results are compared with ray tracing models, showing reasonable agreement.

Design and raytrace simulations of a multilayer-coated Wolter x-ray optic for the Z machine at Sandia National Laboratories.

Recent breakthroughs in the fabrication of small-radii Wolter optics for astrophysics allow high energy density facilities to consider such optics as novel x-ray diagnostics at photon energies of 15-50 keV. Recently, the Lawrence Livermore National Laboratory, Sandia National Laboratories (SNL), the Smithsonian Astrophysical Observatory, and the NASA Marshall Space Flight Center jointly developed and fabricated the first custom Wolter microscope for implementation in SNL's Z machine with optimized sensitivity at 17.5 keV. To achieve spatial resolution of order 100-200 microns over a field of view of 5 × 5 × 5 mm3 with high throughput and narrow energy bandpass, the geometry of the optic and its multilayer required careful design and optimization. While the geometry mainly influences resolution and the field of view of the diagnostic, the mirror coating determines the spectral response and throughput. Here we outline the details of the design and fabrication process for the first multilayer-coated Wolter I optic for SNL's Z machine (Z Wolter), including its W/Si multilayer, and present results of raytrace simulations completed to predict and verify the performance of the optic.

An x-ray optic calibration facility for high energy density diagnostics.

A facility to calibrate x-ray imaging optics was built at Lawrence Livermore National Laboratory to support high energy density (HED) and inertial confinement fusion (ICF) diagnostics such as those at the National Ignition Facility and the Sandia Z-Machine. Calibration of the spectral reflectivity and resolution of these x-ray diagnostics enable absolute determination of the x-ray flux and wavelengths generated in the HED and ICF experiments. Measurement of the optic point spread function is used to determine spatial resolution of the optic. This facility was constructed to measure (1) the x-ray reflectivity to ±5% over a spectral range from 5 to 60 keV; (2) point spread functions with a resolution of 50 µm (currently) and 13 µm (future) in the image plane; and (3) optic distance relative to the x-ray source and detector to within ±100 µm in each dimension. This article describes the capabilities of the calibration facility, concept of operations, and initial data from selected x-ray optics.

A Wolter imager on the Z machine to diagnose warm x-ray sources.

A new Wolter x-ray imager has been developed for the Z machine to study the emission of warm (>15 keV) x-ray sources. A Wolter optic has been adapted from observational astronomy and medical imaging, which uses curved x-ray mirrors to form a 2D image of a source with 5 × 5 × 5 mm3 field-of-view and measured 60-300-µm resolution on-axis. The mirrors consist of a multilayer that create a narrow bandpass around the Mo Kα lines at 17.5 keV. We provide an overview of the instrument design and measured imaging performance. In addition, we present the first data from the instrument of a Mo wire array z-pinch on the Z machine, demonstrating improvements in spatial resolution and a 350-4100× increase in the signal over previous pinhole imaging techniques.