Probing the energetic particle environment near the Sun.

NASA's Parker Solar Probe mission1 recently plunged through the inner heliosphere of the Sun to its perihelia, about 24 million kilometres from the Sun. Previous studies farther from the Sun (performed mostly at a distance of 1 astronomical unit) indicate that solar energetic particles are accelerated from a few kiloelectronvolts up to near-relativistic energies via at least two processes: 'impulsive' events, which are usually associated with magnetic reconnection in solar flares and are typically enriched in electrons, helium-3 and heavier ions2, and 'gradual' events3,4, which are typically associated with large coronal-mass-ejection-driven shocks and compressions moving through the corona and inner solar wind and are the dominant source of protons with energies between 1 and 10 megaelectronvolts. However, some events show aspects of both processes and the electron-proton ratio is not bimodally distributed, as would be expected if there were only two possible processes5. These processes have been very difficult to resolve from prior observations, owing to the various transport effects that affect the energetic particle population en route to more distant spacecraft6. Here we report observations of the near-Sun energetic particle radiation environment over the first two orbits of the probe. We find a variety of energetic particle events accelerated both locally and remotely including by corotating interaction regions, impulsive events driven by acceleration near the Sun, and an event related to a coronal mass ejection. We provide direct observations of the energetic particle radiation environment in the region just above the corona of the Sun and directly explore the physics of particle acceleration and transport.

Parkinson disease loci in the mid-western Amish.

Previous evidence has shown that Parkinson disease (PD) has a heritable component, but only a small proportion of the total genetic contribution to PD has been identified. Genetic heterogeneity complicates the verification of proposed PD genes and the identification of new PD susceptibility genes. Our approach to overcome the problem of heterogeneity is to study a population isolate, the mid-western Amish communities of Indiana and Ohio. We performed genome-wide association and linkage analyses on 798 individuals (31 with PD), who are part of a 4,998 member pedigree. Through these analyses, we identified a region on chromosome 5q31.3 that shows evidence of association (p value < 1 × 10(-4)) and linkage (multipoint HLOD = 3.77). We also found further evidence of linkage on chromosomes 6 and 10 (multipoint HLOD 4.02 and 4.35 respectively). These data suggest that locus heterogeneity, even within the Amish, may be more extensive than previously appreciated.

Needs and preferences for the prevention of intimate partner violence among Hispanics: a community's perspective.

Research suggest that Hispanics in the U.S. are disproportionately affected by the consequences of intimate partner violence. Nevertheless, few intimate partner violence prevention interventions have been developed to address the unique needs and preferences of this population. The Partnership for Domestic Violence Prevention is a community-based participatory research project that assessed the needs and preferences for prevention programs for Hispanics in Miami-Dade County. Nine focus groups with domestic violence service providers, victims and general community members were conducted (N = 76). Four major themes emerged from the focus groups. These included immigrants and teens as the highest priority groups to target in prevention efforts, culture as a double-edged sword, the system that helps and hurts the victim, and the need for wide-scale prevention programs that would reach Hispanics systematically. The results from this study have important implications for the development of intimate violence prevention interventions targeting Hispanics in the U.S.

The psychological impact of diagnostic food challenges to confirm the resolution of peanut or tree nut allergy.

BACKGROUND: Twenty percent of children outgrow peanut allergy and 10% outgrow tree nut allergy. Resolution can be confirmed by a food challenge. Little is known about the psychosocial impact of the challenge. We aimed to investigate effects of a food challenge on anxiety, stress and quality of life (QoL) in children and their mothers on the day of a food challenge to peanuts or nuts, and in the months following the challenge. METHODS: One hundred and three families participated. Forty children undergoing food challenges to access resolution of allergy, and their mothers, completed validated questionnaires to measure generic and food specific quality of life, stress and anxiety prior to challenge, on the day of investigation and 3-6 months later. Sixty-three children with no clinical indication to challenge (i.e. in the opinion of the allergist had persistent allergy) acted as comparison group completing questionnaires 3-6 months apart. RESULTS: Mothers reported raised anxiety on the day of challenge (P = 0.007), but children were less anxious. The children (P = 0.01) and mothers (P = 0.01) had improved food-related, but not general, QoL 3-6 months following challenge. Children reported lower anxiety levels following the challenge (P = 0.02), but anxiety remained unchanged in mothers. The improvements in maternal and children's QoL and anxiety levels were irrespective of the challenge outcome and despite co-existing food allergies in 50% of children. CONCLUSIONS: Mothers experienced increased anxiety on the day of food challenge, unlike the children, perhaps reflecting the differences in their perceived risks. Food challenges are associated with improved food-related QoL in the following months even in those with a positive challenge.

Can Pediatric Primary Care Practices Afford Integrated Behavioral Health? A Comparison of 5 Pediatric Practices.

Licensed behavioral health providers (LBHPs) were integrated into 5 pediatric primary care practices in southeast and east Texas from October 2018 through March 2020. LBHPs Licensed behavioral health providers across the sites were 3 licensed clinical social workers (LCSW), 1 psychologist, and 1 nurse practitioner (NP). Practices provided data for 6 to 15 months. Overall, 2769 units of behavioral health services were provided to 746 children over 2243 hours. Across 4 sites, 44.3% of behavioral health patients were diagnosed with trauma disorders, 22.1% with anxiety, 19.3% with attention-deficit hyperactivity disorder, 15.1% with depression, and 10.9% with disruptive behavior disorders. Overall, the model was financially successful at 2 sites (LCSWs) and unsuccessful at 1 site (NP). The other 2 sites demonstrated potential for financial sustainability with increased behavioral health patient volume. Overall, this model is a financially viable option for pediatric primary care practices with adequate patient volumes to provide integrated behavioral health services.

The psychosocial impact of food allergy and food hypersensitivity in children, adolescents and their families: a review.

Food allergy affects 6% of children but there is no cure, and strict avoidance of index allergens along with immediate access to rescue medication is the current best management. With specialist care, morbidity from food allergy in children is generally low, and mortality is very rare. However, there is strong evidence that food allergy and food hypersensitivity has an impact on psychological distress and on the quality of life (QoL) of children and adolescents, as well as their families. Until recently, the measurement of QoL in allergic children has proved difficult because of the lack of investigative tools available. New instruments for assessing QoL in food allergic children have recently been developed and validated, which should provide further insights into the problems these children encounter and will enable us to measure the effects of interventions in patients. This review examines the published impact of food allergy on affected children, adolescents and their families. It considers influences such as gender, age, disease severity, co-existing allergies and external influences, and examines how these may impact on allergy-related QoL and psychological distress including anxiety and depression. Implications of the impact are considered alongside avenues for future research.

DNA sequence and analysis of human chromosome 9.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

Protein kinase activity associated with stored messenger ribonucleoprotein particles of Xenopus oocytes.

As the oocytes of Xenopus laevis grow and develop they accumulate vast stores of mRNA for use during early embryogenesis. The stored mRNA is stabilized and may be prevented from being translated in oocytes by the binding of a defined set of oocyte-specific proteins to form messenger RNP (mRNP) particles. A key event in the interaction of protein with mRNA is the phosphorylation of those few polypeptides that bind directly to all classes of polyadenylated mRNA. In this study we show that the phosphorylating enzyme (protein kinase), in addition to its target phosphoproteins, is an integral component of the mRNP particles. This association extends through various stages in the formation and use of the mRNP particles. Examination of material from oocytes of an early developmental stage (early stage 1), when the level of accumulated mRNA is low, reveals an excess of protein particles free of RNA, sedimenting at 6-18 S, and containing protein kinase activity and mRNA-binding phosphoproteins. At stages of maximum rate of mRNA accumulation (stages 1 and 2), the phosphoproteins and kinase are found primarily in individual mRNP particles that sediment at 40-80 S. As ribosomes become abundant (stages 2 and 3), the mRNP particles tend to interact with ribosomal subunits, at least in vitro, to form blocked translation initiation complexes that sediment at 80-110 S. These results are compared with observation on stored mRNP in other developmental systems.

Energetic charged particles in the uranian magnetosphere.

During the encounter with Uranus, the cosmic ray system on Voyager 2 measured significant fluxes of energetic electrons and protons in the regions of the planets magnetosphere where these particles could be stably trapped. The radial distribution of electrons with energies of megaelectron volts is strongly modulated by the sweeping effects ofthe three major inner satellites Miranda, Ariel, and Umbriel. The phase space density gradient of these electrons indicates that they are diffusing radially inward from a source in the outer magnetosphere or magnetotail. Differences in the energy spectra of protons having energies of approximately 1 to 8 megaelectron volts from two different directions indicate a strong dependence on pitch angle. From the locations of the absorption signatures observed in the electron flux, a centered dipole model for the magnetic field of Uranus with a tilt of 60.1 degrees has been derived, and a rotation period of the planet of 17.4 hours has also been calculated. This model provides independent confirmaton of more precise determinations made by other Voyager experiments.

Energetic Charged Particles in Saturn's Magnetosphere: Voyager 2 Results.

Results from the cosmic-ray system on Voyager 2 in Saturn's magnetosphere are presented. During the inbound pass through the outer magnetosphere, the >/= 0.43-million-electron-volt proton flux was more intense, and both the proton and electron fluxes were more variable, than previously observed. These changes are attributed to the influence on the magnetosphere of variations in the solar wind conditions. Outbound, beyond 18 Saturn radii, impulsive bursts of 0.14- to > 1.0- million-electron-volt electrons were observed. In the inner magnetosphere, the charged particle absorption signatures of Mimas, Enceladus, and Tethys are used to constrain the possible tilt and offset of Saturn's internal magnetic dipole. At approximately 3 Saturn radii, a transient decrease was observed in the electron flux which was not due to Mimas. Characteristics of this decrease suggest the existence of additional material, perhaps another satellite, in the orbit of Mimas.

Energetic Charged Particles in Saturn's Magnetosphere: Voyager 1 Results.

Voyager 1 provided the first look at Saturn's magnetotail and magnetosphere during relatively quiet interplanetary conditions. This report discusses the energetic particle populations of the outer magnetosphere of Saturn and absorption features associated with Titan and Rhea, and compares these observations with Pioneer 11 data of a year earlier. The trapped proton fluxes had soft spectra, represented by power laws E(-gamma) in kinetic energy E, with gamma approximately 7 in the outer magnetosphere and gamma approximately 9 in the magnetotail. Structure associated with the magnetotial was observed as close as 10 Saturn radii (R(s)) on the outbound trajectory. The proton and electron fluxes in the outer magnetosphere and in the magnetotail were variable and appeared to respond to changes in interplanetary conditions. Protons with energies >/= 2 million electron volts had free access to the magnetosphere from interplanetary space and were not stably trapped outside approximately 7.5 R(s).

Voyager 2: energetic ions and electrons in the jovian magnetosphere.

The Voyager 2 encounter has enhanced our understanding of earlier results and provided measurements beyond 160 Jupiter radii (R(J)) in the magnetotail. Significant fluxes of energetic sulfur and oxygen nuclei (4 to 15 million electron volts per nucleon) of Jovian origin were observed inside 25 R(J), and the gradient in phase space density at 12 R(J) indicates that the ions are diffusing inward. A substantially longer time delay versus distance was found for proton flux maxima in the active hemisphere in the magnetotail at Jovicentric longitudes lambda(III), = 260 degrees to 320 degrees than in the inactive hemisphere at lambda(III), = 85 degrees to l10 degrees . These delays can be related to the radial motion of plasma expanding into the magnetotail, and differences in the expansion speeds between the active and inactive hemispheres can produce rarefaction regions in trapped particles. It is suggested that the 10-hour modulation of interplanetary Jovian electrons may be associated with the arrival at the dawn magnetopause of a rarefaction region each planetary rotation.

Voyager 1: energetic ions and electrons in the jovian magnetosphere.

The observations of the cosmic-ray subsystem have added significantly to our knowledge of Jupiter's magnetosphere. The most surprising result is the existence of energetic sulfur, sodium, and oxygen nuclei with energies above 7 megaelectron volts per nucleon which were found inside of Io's orbit. Also, significant fluxes of similarly energetic ions reflecting solar cosmic-ray composition were observed throughout the magnetosphere beyond 11 times the radius of Jupiter. It was also found that energetic protons are enhanced by 30 to 70 percent in the active hemisphere. Finally, the first observations were made of the magnetospheric tail in the dawn direction out to 160 Jupiter radii.

Energetic charged particles in the magnetosphere of neptune.

The Voyager 2 cosmic ray system (CRS) measured significant fluxes of energetic [>/=1 megaelectron volt (MeV)] trapped electrons and protons in the magnetosphere of Neptune. The intensities are maximum near a magnetic L shell of 7, decreasing closer to the planet because of absorption by satellites and rings. In the region of the inner satellites of Neptune, the radiation belts have a complicated structure, which provides some constraints on the magnetic field geometry of the inner magnetosphere. Electron phase-space densities have a positive radial gradient, indicating that they diffuse inward from a source in the outer magnetosphere. Electron spectra from 1 to 5 MeV are generally well represented by power laws with indices near 6, which harden in the region of peak flux to power law indices of 4 to 5. Protons have significantly lower fluxes than electrons throughout the magnetosphere, with large anisotropies due to radial intensity gradients. The radiation belts resemble those of Uranus to the extent allowed by the different locations of the satellites, which limit the flux at each planet.

Subband anticrossing and the spin Hall effect in quantum wires.

We report on numerical simulations of the intrinsic spin Hall effect in semiconductor quantum wires as a function of the Rashba spin-orbit coupling strength, the electron density, and the width of the wire. We find that the strength of the spin Hall effect does not depend monotonically on these parameters, but instead exhibits a local maximum. This behavior is explained by considering the dispersion relation of the electrons in the wire, which is characterized by the anticrossing of adjacent subbands. These results lead to a simple estimate of the optimal wire width for spin Hall transport experiments, and simulations indicate that this optimal width is independent of disorder. The anticrossing of adjacent subbands is related to a quantum phase transition in momentum space, and is accompanied by an enhancement of the Berry curvature and subsequently in the magnitude of the spin Hall effect.

A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC.

BACKGROUND: Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%. METHODS: We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation-positive, advanced NSCLC and PD-L1-positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab. RESULTS: Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient's tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern. CONCLUSIONS: Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

Altered glucose metabolism in childhood pre-B acute lymphoblastic leukaemia.

The cells of solid tumours are known to have an altered metabolism, with high rates of glucose uptake and glycolysis, which results in the excessive production of lactate. To date there has been no definitive research documenting metabolic changes in acute lymphoblastic leukaemia (ALL) cells. In order to investigate whether ALL cells have an altered metabolism, we initially compared the transcriptional profiles of 22 specimens from paediatric patients diagnosed with ALL to five CD34+ specimens isolated from bone marrow, which was verified in an independent cohort of 101 specimens. Profiling revealed the upregulation of genes facilitating glycolysis in the ALL specimens compared to the CD34+ specimens, while those involved in the tricarboxylic acid cycle were downregulated. Functional studies supported the microarray findings threefold: (1) higher expression of the glucose transport protein glucose transporter 1 in ALL compared to CD34+ specimens, (2) the excessive production of lactate in ALL cell lines and (3) sensitivity of ALL cell lines to the glycolysis inhibitor 2-deoxy-D-glucose. While metabolic alterations have been well documented in solid tumours, this is the first study to provide direct evidence for the existence of metabolic changes in the leukaemic cells of ALL patients. The finding offers new options for targeted therapy for ALL patients.

Auditory semantic networks for words and natural sounds.

Does lexical processing rely on a specialized semantic network in the brain, or does it draw on more general semantic resources? The primary goal of this study was to compare behavioral and electrophysiological responses evoked during the processing of words, environmental sounds, and non-meaningful sounds in semantically matching or mismatching visual contexts. A secondary goal was to characterize the dynamic relationship between the behavioral and neural activities related to semantic integration using a novel analysis technique, ERP imaging. In matching trials, meaningful-sound ERPs were characterized by an extended positivity (200-600 ms) that in mismatching trials partly overlapped with centro-parietal N400 and frontal N600 negativities. The mismatch word-N400 peaked later than the environmental sound-N400 and was only slightly more posterior in scalp distribution. Single-trial ERP imaging revealed that for meaningful stimuli, the match-positivity consisted of a sensory P2 (200 ms), a semantic positivity (PS, 300 ms), and a parietal response-related positivity (PR, 500-800 ms). The magnitudes (but not the timing) of the N400 and PS activities correlated with subjects' reaction times, whereas both the latency and magnitude of the PR was correlated with subjects' reaction times. These results suggest that largely overlapping neural networks process verbal and non-verbal semantic information. In addition, it appears that semantic integration operates across different time scales: earlier processes (indexed by the PS and N400) utilize the established meaningful, but not necessarily lexical, semantic representations, whereas later processes (indexed by the PR and N600) are involved in the explicit interpretation of stimulus semantics and possibly of the required response.

GALACTIC COSMIC RAYS IN THE LOCAL INTERSTELLAR MEDIUM: VOYAGER 1 OBSERVATIONS AND MODEL RESULTS.

Since 2012 August Voyager 1 has been observing the local interstellar energy spectra of Galactic cosmic-ray nuclei down to 3 MeV nuc-1 and electrons down to 2.7 MeV. The H and He spectra have the same energy dependence between 3 and 346 MeV nuc-1, with a broad maximum in the 10-50 MeV nuc-1 range and a H/He ratio of 12.2 ± 0.9. The peak H intensity is ~15 times that observed at 1 AU, and the observed local interstellar gradient of 3-346 MeV H is -0.009 ± 0.055% AU-1, consistent with models having no local interstellar gradient. The energy spectrum of electrons (e - + e +) with 2.7-74 MeV is consistent with E -1.30±0.05 and exceeds the H intensity at energies below ~50 MeV. Propagation model fits to the observed spectra indicate that the energy density of cosmic-ray nuclei with >3 MeV nuc-1 and electrons with >3 MeV is 0.83-1.02 eV cm-3 and the ionization rate of atomic H is in the range of 1.51-1.64 × 10-17 s-1. This rate is a factor >10 lower than the ionization rate in diffuse interstellar clouds, suggesting significant spatial inhomogeneity in low-energy cosmic rays or the presence of a suprathermal tail on the energy spectrum at much lower energies. The propagation model fits also provide improved estimates of the elemental abundances in the source of Galactic cosmic rays.

Observation of the 6°Fe nucleosynthesis-clock isotope in galactic cosmic rays.

Iron-60 ((60)Fe) is a radioactive isotope in cosmic rays that serves as a clock to infer an upper limit on the time between nucleosynthesis and acceleration. We have used the ACE-CRIS instrument to collect 3.55 × 10(5) iron nuclei, with energies ~195 to ~500 mega-electron volts per nucleon, of which we identify 15 (60)Fe nuclei. The (60)Fe/(56)Fe source ratio is (7.5 ± 2.9) × 10(-5) The detection of supernova-produced (60)Fe in cosmic rays implies that the time required for acceleration and transport to Earth does not greatly exceed the (60)Fe half-life of 2.6 million years and that the (60)Fe source distance does not greatly exceed the distance cosmic rays can diffuse over this time, ⪍1 kiloparsec. A natural place for (60)Fe origin is in nearby clusters of massive stars.