Aims The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice.Methods and results Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, pro-arrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for Complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-alpha prevented electrical remodelling and AF susceptibility, while IL-1 beta inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke.Conclusion These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling. Graphical Abstract

ACTN2 gene encodes α-actinin 2 protein, which binds actin. In cardiac muscle, α-actinin 2 is located in the Z-disc of the sarcomere, where it anchors myofibrillar actin filaments. A 48-years old female presented with out-of-hospital ventricular fibrillation arrest. Echocardiogram showed stage II diastolic dysfunction, elevated RVSP, and abnormal global longitudinal strain consistent with early LV systolic dysfunction. Cardiopulmonary testing indicated AHA functional class IV HF. Genetic testing identified a missense heterozygous variant of unknown significance in ACTN2 (gene previously associated with HCM and DCM), and SCNB2 (β-2 subunit of type II voltage-gated sodium channel).

The fragment separator FRS has been used for the first time to measure the (n, p)- and (p, n)-type isobaric charge-exchange cross sections of stable Sn-112,Sn-124 isotopes accelerated at 1A GeV with an uncertainty of 3% and to separate quasielastic and inelastic components in the missing-energy spectra of the ejectiles. The inelastic contribution can be associated to the excitation of isobar Delta(1232) resonances and to the pion emission in s wave, in both the target and projectile nuclei, while the quasielastic contribution is associated with the nuclear spin-isospin response of nucleon-hole excitations. The data lead to interesting results, where we observe a clear quenching of the quasielastic component, and their comparisons to theoretical calculations demonstrate that the baryonic resonances can be excited in the target and projectile nuclei. To go further in this investigation, we propose to study the excitation of baryonic resonances, taking advantage of the combination of high-resolving power magnetic spectrometers with the Wide Angle Shower Apparatus (WASA) calorimeter. These new measurements will allow us to determine the momenta of the ejectiles and pions emitted in coincidence after the single isobaric charge-exchange collisions, providing us unique opportunities to study the evolution of the baryonic resonance dynamics with the neutron-proton asymmetry through the use of exotic radioactive ion beams.

Isobaric single charge-exchange reactions, changing nuclear charges by one unit but leaving the mass partitions unaffected, have been for the first time investigated by peripheral collisions of 112Sn ions accelerated up to 1A GeV at the GSI facilities. The high-resolving power of the FRS spectrometer allows us to obtain (p,n)-type isobaric charge-exchange cross sections with an uncertainty of 3.5% and to separate quasi-elastic and inelastic components in the missing-energy spectra of the ejectiles. The inelastic component is associated to the excitation of the Δ(1232) isobar resonance and the emission of pions in s-wave both in the target and projectile nucleus, while the quasi-elastic contribution is associated to the nuclear spin-isospin response of nucleon-hole excitations. An apparent shift of the Δ-resonance peak of ∼63 MeV is observed when comparing the missing-energy spectra obtained from the measurements with proton and carbon targets. A detailed analysis, performed with a theoretical model for the reactions, indicates that this observation can be simply interpreted as a change in the relative magnitude between the contribution of the excitation of the resonance in the target and in the projectile.

Isobaric charge-exchange reactions induced by beams of 112Sn have been investigated at the GSI facility using the fragment separator FRS. The high-resolving power of this spectrometer makes it possible to obtain the isobaric charge-exchange cross sections with an uncertainty of 3.5% and to separate quasi-elastic and inelastic contributions in the missing-energy spectra, in which the inelastic component is associated to the in-medium excitation of baryonic resonances such as the Δ resonance. We report on the results obtained for the (p,n) channel excited by using different targets that cover a large range in neutron excess. In addition, we also compare the missing-energy spectra with an intranuclear cascade model coupled to a de-excitation code to investigate the in-medium effects in the production of baryonic resonances.

Oxidative damage is implicated in atrial fibrillation (AF), but antioxidants are ineffective therapeutically. The authors tested the hypothesis that highly reactive lipid dicarbonyl metabolites, or isolevuglandins (IsoLGs), are principal drivers of AF during hypertension. In a hypertensive murine model and stretched atriomyocytes, the dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) prevented IsoLG adducts and preamyloid oligomers (PAOs), and AF susceptibility, whereas the ineffective analog 4-hydroxybenzylamine (4-HOBA) had minimal effect. Natriuretic peptides generated cytotoxic oligomers, a process accelerated by IsoLGs, contributing to atrial PAO formation. These findings support the concept of pre-emptively scavenging reactive downstream oxidative stress mediators as a potential therapeutic approach to prevent AF.

Isobaric charge-exchange reactions induced by beams of Sn-112 have been investigated at the GSI facilities using the fragment separator FRS. The high-resolving power of this spectrometer makes it possible to obtain the isobaric charge-exchange cross sections with an accuracy of 3% and to separate quasi-elastic and inelastic contributions in the missing-energy spectra, in which the inelastic component is associated to the in-medium excitation of baryonic resonances such as the Delta resonance. We report on the results obtained for the (p, n) and (n, p) channels excited by using different targets that cover a large range in neutron excess.

Genomic medicine is transforming patient care. However, the speed of development has left a knowledge gap between discovery and effective implementation into clinical practice. Since 2010, the Training Residents in Genomics (TRIG) Working Group has found success in building a rigorous genomics curriculum with implementation tools aimed at pathology residents in postgraduate training years 1-4. Based on the TRIG model, the interprofessional Undergraduate Training in Genomics (UTRIG) Working Group was formed. Under the aegis of the Undergraduate Medical Educators Section of the Association of Pathology Chairs and representation from nine additional professional societies, UTRIG's collaborative goal is building medical student genomic literacy through development of a ready-to-use genomics curriculum. Key elements to the UTRIG curriculum are expert consensus-driven objectives, active learning methods, rigorous assessment and integration.

CONTEXT.—:Developing skills related to use of computer-based tools is critical for practicing genomic pathology. However, given the relative novelty of genomics education, residency programs may lack faculty members with adequate expertise and/or time to implement training. A virtual team-based learning (TBL) environment would make genomic pathology education available to more trainees.OBJECTIVE.—:To translate an extensively implemented in-person TBL genomic pathology workshop into a virtual environment and to evaluate both knowledge and skill acquisition.DESIGN.—:Using a novel interactive simulation approach, online modules were developed translating aspects of the TBL experience into the virtual environment with a goal of acquisition of necessary computer-related skills. The modules were evaluated at 10 postgraduate pathology training programs using a pre-post test design with participants deidentified. A postmodule anonymous survey obtained participant feedback on module quality and efficacy.RESULTS.—:There were 147 trainees who received an email request to voluntarily participate in the study. Of these, 43 trainees completed the pretest and 15 (35%) subsequently completed the posttest. Mean overall scores were 45% on the pretest compared with 70% on the posttest ( P < .001; effect size = 1.4). Posttest improvement of results was similar for questions testing acquisition of knowledge versus skills. Regarding the 19 participants who took the survey, 18 (95%) would recommend the modules to others and believed they met the stated objectives.CONCLUSIONS.—:A simulation-based approach allows motivated pathology trainees to acquire computer-related skills for practicing genomic pathology. Future work can explore efficacy in a nonvoluntary setting and adaptation to different specialties, learners, and computer tools.

Production cross sections of residual nuclei obtained by knockout and fragmentation reactions of different tin isotopes accelerated at 1A GeV have been measured with the fragment separator (FRS) at GSI, Darmstadt. The new measurements are used to investigate the neutron-excess dependence of the neutron- and proton-knockout cross sections. These cross sections are compared toGlauber model calculations coupled to a nuclear de-excitation code in order to investigate the role of the remnant excitations. This bench marking shows an overestimation of the cross sections for the removal of deeply bound nucleons. A phenomenological increase in the excitation energy induced in the remnants produced in these cases allows us to reproduce the measured cross sections.

Isobaric charge-exchange reactions induced by different tin isotopes have been investigated at GSI. The high-resolving power of the FRS spectrometer made it possible to separate elastic and inelastic components in the missing-energy spectra of the ejectiles. The inelastic component was associated to the in-medium excitation of nucleon resonances such as the Delta and Roper resonances. These data are expected to contribute to better understand the in-medium properties of baryon resonances but also to investigate the abundance of protons and neutrons at the nuclear periphery.

Dr. Dan Hays, distinguished pediatric surgeon, scholar, father, and grandfather, passed away quietly at his home in Riverside, California on April 7, 2016, at the age of 97. Dan was a pioneer in academic pediatric surgery and will be greatly missed by his family, colleagues, and friends. Dr. Hays was born in Reading, Pennsylvania, while his parents were visiting his mother's childhood home. His childhood was spent in Riverside, California, where his father was the owner and editor of the Riverside Press-Enterprise, a respected daily newspaper. The Hays family owned and operated the paper from 1928 to 1997. They also owned the Glacier Park Transportation Company, and Dan spent his summers living in East Glacier, Montana, between the ages of 8 years and 21 years, ending in 1941. He experienced a childhood growing up among the writers, editors, and reporters of the newspaper, along with the drivers of the red cars on the Going-to-the-Sun Road in Glacier Park, which likely led to his life-long curiosity and extraordinary accomplishments as an academic pediatric surgeon. Dan completed his undergraduate education at Stanford University in 1941. He enrolled at Cornell University Medical College in New York City just prior to WW II, graduating in 1944. He was a captain in the U. S. Army Medical Corps from 1941 to 1947, serving during his medical training and later in post-war Germany. Dr. Hays developed his interest in pediatric surgery during an internship at the Boston Children's Hospital from 1944 to 1945. During this time, he was trained by Dr. William Ladd, Robert Gross, both significant figures in the history of pediatric surgery, and Sydney Farber, who was pioneering the use of chemotherapy in children. Dr. Hays spent a year in pathology at Peter Brent Brigham Hospital 1947–1948 and subsequently moved back to New York and completed surgical training at New York Hospital 1948–1954. He met his wife, Esther Fincher Hays, when both were residents at New York Hospital, and they married in 1951. Following training, they moved to Los Angeles in 1954, and he joined the staff of Good Samaritan Hospital and then Children's Hospital Los Angeles working with William Snyder, the Chief of Surgery. Esther joined the faculty at UCLA as a hematologist. Dr. Hays practiced academic pediatric surgery at Children's Hospital of Los Angeles from 1955 until his retirement in 2001. During this long tenure, Dr. Hays had many accomplishments, but his greatest achievement was his impact in the treatment of children with cancer. He recognized that children with lethal malignancies would benefit from combinations of surgery with other modalities such as chemotherapy and radiation. He also noted that outcomes for many childhood malignancies varied based upon tumor location, histology, and other markers, initiating the early phase of what is now being pursued today as individualized cancer care. Dr. Hays was successful in broadly engaging pediatric surgeons in the Children's Cancer Study Group (the precursor to the Children's Oncology Group), the Intergroup Rhabdomysarcoma Group, and other entities to standardize surgery and surgical care of children more than 20 years as the chairman of these important efforts. His early collaboration with Drs. Farber and William Newton of Columbus, OH, spurred the acceptance of cooperative group multidisciplinary cancer care. The impact of this work was significant worldwide, as pediatric surgeons in Japan, Europe, and Australia accepted Dr. Hay's work. His work not only led to improved survival of children with cancer but also contributed to the knowledge of the impact of childhood cancer upon survivors through his long-term follow-up clinic and studies concerning the transition of childhood survivors into adulthood. He was a continuously funded investigator for the NIH for more than 30 years and was published extensively in the literature with more than 150 scientific publications in peer-reviewed textbooks and a textbook on biliary tract disease. “More than any one individual, Dan Hays helped set the standard for the specialty of modern pediatric cancer surgery,” said Stuart E. Siegel, M.D., former head of the Division of Hematology/Oncology and Director of the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles, and professor of pediatrics at the USC Keck School of Medicine. Dr. Hays had a very significant relationship with many Japanese surgeons and fellows. His interest in liver disease led to a mid-career sabbatical in Japan, where he observed the Japanese approach to infants with biliary atresia, studying with Professors Suruga (in Tokyo) and Kasai (in Sendai). This experience led to a book published by Dr. Hays (with the assistance of Dr. Ken Kimura) which accelerated the adoption of the Kasai procedure in the United States with much improved results. Dr. Hays was a diplomate of the American Board of Surgery, a Fellow of the American College of Surgeons, and was elected to membership in the American Pediatric Surgical Association, Section on Surgery-American Academy of Pediatrics, and Pacific Association of Pediatric Surgeons. In recognition of his many accomplishments, Dan received the Coe Medal from the Pacific Association of Pediatric Surgeons in 1994 and the William E Ladd Medal from the Surgical Section of the American Academy of Pediatrics in 2004. Dan was a visionary regarding the future of childhood cancer care and devoted much of his professional career to this effort. He was a gentleman and a scholar, a valued teacher, colleague, and friend and will be missed. Dr. Hays is survived by his wife Esther, son Jonathan Hays of Santa Monica, daughters Sarah Hays of Los Angeles, Elizabeth Hays of Mount Vernon, Maine, Margaret Hays Van Kan of Auckland, New Zealand, and seven grandchildren. The family asks that in lieu of flowers, memorial donations be made to The Children's Oncology Group Foundation, 3720 Spruce St., No 506, Philadelphia, PA 19104.

S. Bagchi1,2,∗ R. Kanungo1,† F. Ameil, J. Atkinson, Y. Ayyad, D. Cortina-Gil, I. Dillmann, A. Estradé, A. Evdokimov, F. Farinon, H. Geissel, G. Guastalla, W. Horiuchi, R. Janik, M. Kimura, R. Knöbel, J. Kurcewicz, Yu. A. Litvinov, M. Marta, M. Mostazo, I. Mukha, C. Nociforo, H. J. Ong, S. Pietri, A. Prochazka, C. Scheidenberger, B. Sitar, P. Strmen, Y. Suzuki, M. Takechi, J. Tanaka, I. Tanihata, S. Terashima, J. Vargas, H. Weick, and J. S. Winfield Saint Mary’s University, Halifax, Canada GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany Universidad de Santiago de Compostela, Santiago de Compostella, Spain Justus-Liebig University, Giessen, Germany Department of Physics, Hokkaido University, Sapporo, Japan Faculty of Mathematics and Physics, Comenius University, Bratislava, Slovakia RCNP, Osaka University, Mihogaoka, Ibaraki, Osaka, Japan Department of Physics, Niigata University, Niigata, Japan RIKEN Nishina Center, Wako, Saitama, Japan and School of Physics and Nuclear Energy Engineering and IRCNPC, Beihang University, Beijing, People’s Republic of China

Charge-changing cross sections at high energies are expected to provide useful information on nuclear charge radii. No reliable theory to calculate the cross section has yet been available. We develop a formula using Glauber and eikonal approximations and test its validity with recent new data on carbon isotopes measured at around 900A MeV. We first confirm that our theory reproduces the cross sections of C-12,C-13,C-14+C-12 consistently with the known charge radii. Next we show that the cross sections of C12-19 on a proton target are all well reproduced provided the role of neutrons is accounted for. We also discuss the energy dependence of the charge-changing cross sections.

Proton radii of ^{12-19}C densities derived from first accurate charge changing cross section measurements at 900A  MeV with a carbon target are reported. A thick neutron surface evolves from ∼0.5  fm in ^{15}C to ∼1  fm in ^{19}C. The halo radius in ^{19}C is found to be 6.4±0.7  fm as large as ^{11}Li. Ab initio calculations based on chiral nucleon-nucleon and three-nucleon forces reproduce the radii well.

Production cross sections of nitrogen isotopes from high-energy carbon isotopes on hydrogen and carbon targets have been measured for the first time for a wide range of isotopes. The fragment separator FRS at GSI was used to deliver C isotope beams. The cross sections of the production of N isotopes were determined by charge measurements of forward going fragments. The cross sections show a rapid increase with the number of neutrons in the projectile. Since the production of nitrogen is mostly due to charge exchange reactions below the proton separation energies, the present data suggests a concentration of Gamow-Teller and Fermi transition strength at low excitation energies for neutron-rich isotopes. It was also observed that the cross sections were enhanced much more strongly for neutron rich isotopes in the C-target data.

The adult respiratory distress syndrome (ARDS) developed in 2 patients with blastomycosis. In one, ARDS apparently followed the rupture of an infected subcarinal lymph node into a bronchus. Extensive involvement of alveoli with Blastomyces dermatitidis was noted at autopsy in both patients. Four additional cases of blastomycosis with definite or presumed ARDS are reviewed. The clinical course of these 6 patients was characterized by a prolonged prodrome (median, 36 days), consistent with pulmonary blastomycosis, and a rapid demise (median, 5 days) associated with ARDS.

Background Increasing evidence indicates that proteotoxicity plays a pathophysiologic role in experimental and human cardiomyopathy. In organ‐specific amyloidoses, soluble protein oligomers are the primary cytotoxic species in the process of protein aggregation. While isolated atrial amyloidosis can develop with aging, the presence of preamyloid oligomers (PAOs) in atrial tissue has not been previously investigated. Methods and Results Atrial samples were collected during elective cardiac surgery in patients without a history of atrial arrhythmias, congestive heart failure, cardiomyopathy, or amyloidosis. Immunohistochemistry was performed for PAOs using a conformation‐specific antibody, as well as for candidate proteins identified previously in isolated atrial amyloidosis. Using a myocardium‐specific marker, the fraction of myocardium colocalizing with PAOs (PAO burden) was quantified (green/red ratio). Atrial samples were obtained from 92 patients, with a mean age of 61.7±13.8 years. Most patients (62%) were male, 23% had diabetes, 72% had hypertension, and 42% had coronary artery disease. A majority (n=62) underwent aortic valve replacement, with fewer undergoing coronary artery bypass grafting (n=34) or mitral valve replacement/repair (n=24). Immunostaining detected intracellular PAOs in a majority of atrial samples, with a heterogeneous distribution throughout the myocardium. Mean green/red ratio value for the samples was 0.11±0.1 (range 0.03 to 0.77), with a value ≥0.05 in 74 patients. Atrial natriuretic peptide colocalized with PAOs in myocardium, whereas transthyretin was located in the interstitium. Adjusting for multiple covariates, PAO burden was independently associated with the presence of hypertension. Conclusion PAOs are frequently detected in human atrium, where their presence is associated with clinical hypertension.