Electron stimulated desorption from condensed benzene.

The electron induced dissociation of condensed benzene (C6H6) in thin films deposited on a Pt substrate is investigated by electron stimulated desorption (ESD) of anions and cations. The desorbed yields are recorded as a function of incident electron energy in the range of 10 to 950 eV for a fixed film thickness of 2 monolayers (ML) and for a fixed energy of 950 eV, as well as a function of film thickness from 0.5 to 8 monolayers (ML) for anions, and from 0.5 to 12ML for cations. Both energy and thickness dependencies are discussed in terms of the three main mechanisms yielding positively and/or negatively charged fragments: dissociative electron attachment (DEA), dipolar dissociation (DD) and dissociative ionization (DI) processes. At the probed energies, DD is the major mechanism, while DEA is predominantly induced by secondary electrons from the Pt substrate. Desorption of the parent positive ion is strongly suppressed. Similar qualitative behaviours are observed for the energy dependence of both anion and cation ESD yields, while some discrepancies exist in the thickness dependence, including a very significant systematic magnitude difference found between such ions formation. An estimation of the effective DD cross-section including the desorption probability is obtained. Feasible mechanisms behind the observed energy and thickness dependences for anion and cation yields are proposed. These results highlight the need for further investigations to better understand the underlying processes of electron induced dissociation in condensed matter.

The Interplay of Conflicting and Complementing Institutional Logics in Sustainability Practices.

The impact of institutional environments on sustainability is well documented in the international business literature. However, how multiple and occasionally conflicting institutional logics shape sustainability as it is practiced by individuals across countries remains undertheorized. Our study contributes to this line of research by examining how multiple institutional logics inform the comprehension of sustainability practices in two high-hazard organizations in the Republic of Serbia and Canada. In doing so, our findings explicate three multi-level mechanisms - pulling down (1st level), relating (2nd level), and aligning (2nd level) - through which individuals in these organizations across two countries construct a localized understanding of sustainability. In both countries, individuals pull down elements of the state and organizational logics to construct meso-level logics they use to comprehend sustainability practices, albeit differently. In Serbia, due to the conflict between the current state logic and dominant high-hazard organizational logic, individuals pull down elements of the high-hazard organizational logic and the enduring legacy state logic to construct a community logic and align sustainability practices with it. In Canada, the state logic complements the high-hazard organizational logic, resulting in individuals pulling down elements of both logics to construct the professional logic and aligning their practice with it. In both countries, due to the dominance of the high-hazard organizational logic, individuals relate their practices to the well-being of others. Based on our comparative case analysis, we create a general model and a country-specific model depicting how individuals embed multiple institutional logics into their sustainability practices.

The emergence of a value transformation strategic initiative in the healthcare context.

How do strategic initiatives emerge? Despite rich tradition in the emergent strategy literature-focused on significant organizational change-surprisingly little insight exists on the dynamics of a new initiative's emergence. This is particularly relevant in healthcare because of the increasing pressure to implement value transformation models focused on maximizing value at the point of care. The value transformation model prioritizes the decisions of the frontline providers and thus requires their expertise and commitment for the model's implementation and success. In our case study of a dental organization, "OptiPlex," we trace the emergence of a value transformation strategic initiative from its origination at the point of care to its formalization into the organization's strategic plan. Using qualitative methods, we identify three phases in the emergence of the value transformation strategic initiative, each embodying different championing behaviors necessary for the initiative's emergence. In doing so, we explicate the nature of these behaviors and how they link up across the organizational hierarchy to drive the value transformation strategic initiative's emergence and implementation.

Effect of a 12-Week Mixed Training on Body Quality in People Living with HIV: Does Age and HIV Duration Matter?

BACKGROUND: The impact of HIV duration on exercise adaptations has not yet been studied. Moreover, the age at which subjects living with HIV are the most responsive to exercise is not clear. AIMS: Investigate the effect of a mixed exercise training program on physical performance changes in individuals living with HIV and explore if age or HIV duration influence these adaptations in men. METHODS: In this feasibility study, participants followed a 12-week mixed exercise training program, three times/week, 45 min/session. Physical performance including functional capacities (normal 4-m walking test, 6min walking test), grip strength (hand dynamometer), muscle power, body composition (android and gynoid fat masses, appendicular lean mass) were evaluated pre- and post-intervention. Subgroup analysis according to the median age of the participants (age<50yrs vs. age≥50yrs) and median HIV duration (HIV<20yrs vs. HIV≥20yrs) were performed in men. RESULTS: A total of 27 participants (age: 54.5±6.8yrs, men: 85%; HIV duration: 19.3±7.6yrs) were included. At the end of the intervention, significant increases compared to baseline were seen in grip strength (p=0.017), leg power (p<0.001), normal walking speed (p<0.001) and 6-min walking distance (p=0.003). Following the intervention, parameters improved similarly in both age groups. However improvement was greater in those with HIV>20yrs than those with a shorter infection duration, with change (%) on total (p<0.001), android (p=0.02), and gynoid (p=0.05) fat masses as well as appendicular lean mass index (p=0.03). CONCLUSION: Mixed exercise training seems to be an effective intervention to improve physical performance in individuals living with HIV. In addition, this study suggests that neither age nor HIV duration has influence on the effect of mixed training in this population.

Targeting the complexity of ERBB2 biology in gastroesophageal carcinoma.

ERBB2 is the most prominent therapeutic target in gastroesophageal adenocarcinoma (GEA). For two decades, trastuzumab was the only treatment available for GEA overexpressing ERBB2. Several drugs showing evidence of efficacy over or in complement to trastuzumab in breast cancer failed to show clinical benefit in GEA. This resistance to anti-ERBB2 therapy is peculiarly recurrent in GEA and is mostly due to tumor heterogeneity with the existence of low expressing ERBB2 tumor clones and loss of ERBB2 over time. The development of new ERBB2 testing strategies and the use of antibody-drug conjugates having a bystander effect are providing new tools to fight heterogeneity in ERBB2-positive GEA. Co-amplifications of tyrosine kinase receptors, alterations in mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways and in proteins controlling cell cycle are well known to contribute resistance to anti-ERBB2 therapy, and they can be targeted by dual therapy. Recently described, NF1 mutations are responsible for Ras phosphorylation and activation and can also be targeted by MEK/ERK inhibition along with anti-ERBB2 therapy. Multiple lines of evidence suggest that immune mechanisms involving antibody-dependent cell-mediated cytotoxicity are preponderant over intracellular signaling in anti-ERBB2 therapy action. A better comprehension of these mechanisms could leverage immune action of anti-ERBB2 therapy and elucidate efficacy of combinations associating immunotherapy and anti-ERBB2 therapy, as suggested by the recent intermediate positive results of the KEYNOTE-811 trial.

Shared accountability in distributed leadership for improved healthcare access: a study of a US dental institution.

PURPOSE: Accountability within distributed leadership (DL) is critical for DL to drive positive outcomes in health services organizations. Despite this, how accountability emerges in DL is less clear. This study aims to understand how accountability emerges in DL so that distributed leaders can drive improvements in healthcare access - an increasingly important outcome in today's health services environment. DESIGN/METHODOLOGY/APPROACH: The authors use an instrumental case study of a dental institution in the USA, "Environ," as it underwent a strategic change to improve healthcare access to rural populations. The authors focused on DL occurring within the strategic change and collected interview, observation and archival data. FINDINGS: The findings demonstrate accountability in DL emerged as shared accountability and has three elements: personal ownership, agentic actions and a shared belief system. Each of these was necessary for DL to advance the strategic change for improved healthcare access. PRACTICAL IMPLICATIONS: Top managers should be cognizant of the emergence processes driven by DL. This includes enabling pockets of employees to connect, align and link up so that ideas, processes and practices can emerge and allow for shared accountability in DL. ORIGINALITY/VALUE: The overarching contribution of this research is identifying shared accountability in DL and its three elements: personal ownership, agentic actions and a shared belief system. These elements serve as a platform to demonstrate "how DL works" in a healthcare organization.

Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a disease with dismal treatment outcomes. Response to neoadjuvant chemoradiation (CRT) varies greatly. Although the underlying mechanisms of CRT resistance are not identified, accumulating evidence indicates an important role for local antitumor immunity. To explore the immune microenvironment in relation to response to CRT we performed an in-depth analysis using multiplex immunohistochemistry, flow cytometry and mRNA expression analysis (NanoString) to generate a detailed map of the immunological landscape of pretreatment biopsies as well as peripheral blood mononuclear cells (PBMCs) of EAC patients. Response to CRT was assessed by Mandard's tumor regression grade (TRG), disease-free- and overall survival. Tumors with a complete pathological response (TRG 1) to neoadjuvant CRT had significantly higher tumor-infiltrating T cell levels compared to all other response groups (TRG 2-5). These T cells were also in closer proximity to tumor cells in complete responders compared to other response groups. Notably, immune profiles of near-complete responders (TRG 2) showed more resemblance to non-responders (TRG 3-5) than to complete responders. A high CD8:CD163 ratio in the tumor was associated with an improved disease-free survival. Gene expression analyses revealed that T cells in non-responders were Th2-skewed, while complete responders were enriched in cytotoxic immune cells. Finally, complete responders were enriched in circulating memory T cells. preexisting immune activation enhances the chance for a complete pathological response to neoadjuvant CRT. This information can potentially be used for future patient selection, but also fuels the development of immunomodulatory strategies to enhance CRT efficacy.

Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.

BACKGROUND: Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. RESULTS: Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. CONCLUSIONS: These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

Handling, infectious agents and physiological condition influence survival and post-release behaviour in migratory adult coho salmon after experimental displacement.

For Pacific salmon captured and released by fisheries, post-release behaviour and survival may be influenced by their health and condition at time of capture. We sought to characterize the interactions between infectious agent burden, fish immune and stress physiology and fisheries stressors to investigate the potential for capture-mediated pathogen-induced mortality in adult coho salmon Oncorhynchus kisutch. We used radio-telemetry paired with high-throughput qPCR of non-lethal gill biopsies for infectious agents and host biomarkers from 200 tagged fish experimentally displaced and exposed to various experimental fisheries treatments (gill net entanglement, recreational angling and recreational angling with air exposure vs. non-sampled control). We characterized relationships among post-release behaviour and survival, infectious agent presence and loads, physiological parameters and transcription profiles of stress and immune genes. All infectious agents detected were endemic and in loads consistent with previous adult Pacific salmon monitoring. Individuals exposed to fisheries treatments were less likely to reach spawning habitat compared to controls, and handling duration independent of fisheries gear had a negative effect on survival. High infectious agent burden was associated with accelerated migration initiation post-release, revealing behavioural plasticity in response to deteriorating condition in this semelparous species. Prevalence and load of infectious agents increased post-migration as well as transcription signatures reflected changes in immune and stress profiles consistent with senescence. Results from this study further our understanding of factors associated with fisheries that increase risk of post-release mortality and characterize some physiological mechanisms that underpin migratory behaviour.

Low energy (6-18 eV) electron scattering from condensed thymidine (dT) III: absolute electronic excitation cross sections.

Absolute cross sections (CSs) for electronic excitation by low-energy electron (LEE) scattering, from condensed thymidine (dT) in the 6-18 eV incident energy range, were measured by high-resolution electron energy loss spectroscopy (HREELS). Various electron energy loss (EEL) spectra were acquired using 1 ML of dT condensed on a multilayer film of Ar held at about 20 K under ultra-high vacuum (∼1 × 10-11 Torr). dT is one of the most complex DNA constituents to be studied by HREELS and these spectra provide the first LEE energy-loss data for electronic excitation of a nucleoside. CSs for transitions to the states 13A', 13A'', 23A', 21A', 33A', 23A'', 43A', 33A'', 53A' and 51A' of dT were extracted from the EEL spectra. These states correlate to those previously measured for the thymine moiety. Two broad resonances are observed in the energy dependence of the CSs at around 8 and 10 eV; these energies are close to those found in earlier gas- and solid-phase studies on the interaction of LEEs with dT, thymine and related molecules. A quantitative comparison between the electronic CSs of dT and those of thymine and tetrahydrofuran indicates that no variation is induced in the electronic CSs of thymine upon chemically binding to a deoxyribose group.

Incidental bilateral calcaneal fractures following overground walking with a wearable robotic exoskeleton in a wheelchair user with a chronic spinal cord injury: is zero risk possible?

Many individuals with spinal cord injury (SCI) rely on wheelchairs as their primary mode of locomotion leading to reduced weight-bearing on the lower extremities, which contributes to severe bone loss and increased risk of fragility fractures. Engaging in a walking program may reverse this vicious cycle, as this promotes lower extremity weight-bearing and mobility, which may reduce bone loss and fragility fracture risk. However, fragility fracture risk associated with the use of wearable robotic exoskeletons (WREs) in individuals with SCI needs consideration. A 35-year-old man with chronic complete sensorimotor SCI (neurological level = T6) and low initial bone mineral density enrolled in a 6- to 8-week WRE-assisted walking program after successfully completing an initial clinical screening process and two familiarization sessions with the WRE. However, after the first training session with the WRE, he developed bilateral localized ankle edema. Training was suspended, and a CT-scan revealed bilateral calcaneal fractures, which healed with conservative treatment over a 12-week period. Opportunities for improving clinical screening and WRE design are explored. The relevance of developing clinical practice guidelines for safe initiation and progression of intensity during WRE-assisted walking programs is highlighted. This case of bilateral calcaneal fractures illustrates that aiming for "zero risk" during WRE-assisted walking programs may not be realistic. Although WREs are a relatively new technology, current evidence confirms their potential to greatly improve health and quality of life in individuals with chronic SCI. Hence, ensuring their safe use remains a key priority.

Low energy (1-19 eV) electron scattering from condensed thymidine (dT) I: absolute vibrational excitation cross sections.

Absolute cross sections (CSs) for vibrational excitation by electrons of energy between 1-19 eV scattering from condensed thymidine (dT) were measured by means of high-resolution electron energy loss spectroscopy (HREELS). The CSs were extracted from electron energy loss spectra of dT condensed on multilayers film of Ar held at about 20 K under ultra-high vacuum (∼1 × 10-11 Torr). dT is one of the most complex molecules to be studied in condensed phase by HREELS. The magnitudes of the vibrational CSs lie within the 10-17 cm2 range. Structures observed in the energy dependence of the vibrational CSs under 3 eV and around 4 eV were compared with previous results of gas- and solid-phase studies on dT and related molecules (e.g., thymine and tetrahydrofuran). These structures were attributed to the formation of shape resonances.

Low energy (1-19 eV) electron scattering from condensed thymidine (dT) II: comparison of vibrational excitation cross sections with those of tetrahydrofuran and the recalibrated values of thymine.

Recent measurements of absolute vibrational cross sections (CSs) for low-energy electron (LEE) scattering from condensed thymidine (dT) allows comparison with CSs of its constituents; thymine and tetrahydrofuran (THF). To facilitate this comparison, the vibrational CSs of condensed thymine were remeasured at six electron incident energies and a correction was applied to the earlier thymine CS values measured by Lévesque et al. [Nucl. Instrum. Methods Phys. Res., Sect. B, 2003, 208, 225]. The incident energy dependence of the CS of each vibrational mode of dT is compared with the corresponding modes in thymine and/or THF. It is found that the magnitude of the CSs of the thymine breathing mode and the C-C stretch mode of THF are greatly attenuated in dT. Finally, the magnitudes of the total vibrational CSs of each molecule are compared. Below 4 eV, the total vibrational CSs of dT is greater than each of its two constituents. Interestingly, at higher energy (>6 eV), the magnitude of the total vibrational CS of dT is roughly equal to that of THF and is greater than thymine by only 15% at 10 eV, showing that the CSs of dT cannot be approximated by the addition of the CSs of its constituents over the entire energy range. These comparisons are discussed in terms of the basic principles involved in the formation and decay of shape resonances, which are known to be responsible for major enhancements of LEE-induced vibrational excitation at low electron energies.

Absolute cross section for DNA damage induced by low-energy (10 eV) electrons: Experimental refinements and sample characterization by AFM.

This work describes multiple experimental improvements for measuring absolute cross sections of DNA damage induced by low-energy electrons in nanometer-thick films in vacuum. Measurements of such cross sections are particularly sensitive to film thickness and uniformity. Using atomic force microscopy in 70% ethanol, we present a novel and effective method to determine plasmid DNA film thickness and uniformity that combines height histograms and force-distance curves. We also investigate film deposition with DNA intercalated with 1,3-diaminopropane (Dap) on tantalum-coated substrates as a convenient and cost-effective alternative to the previously-used graphite substrate. The tantalum substrate permits deposition of films very similar to those formed on graphite. Using these refinements and further optimizations of the experimental procedure, we measure an absolute cross section of (7.4 ± 2.3) × 10-18 cm2 per nucleotide for conformational damage to a 3197 base-pair plasmid, induced by 10 eV electrons, which we believe should be considered as a reference value.

Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients.

Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

Absolute vibrational excitation cross sections for 1-18 eV electron scattering from condensed dimethyl phosphate (DMP).

Absolute cross sections (CSs) for vibrational excitation by 1-18 eV electrons incident on condensed dimethyl phosphate (DMP) were measured with a high-resolution electron energy loss (EEL) spectrometer. Absolute CSs were extracted from EEL spectra of DMP condensed on multilayer film of Ar held at about 20 K under ultra-high vacuum (∼1 × 10-11 Torr). Structures observed in the energy dependence of the CSs around 2, 4, 7, and 12 eV were compared with previous results of gas- and solid-phase experiments and with theoretical studies on dimethyl phosphate and related molecules. These structures were attributed to the formation of shape resonances.

Electron stimulated desorption from condensed pyrimidine and pyridazine.

Low energy electron (LEE) interactions and the formation of transient negative ions play a dominant role in radiation-induced dissociation of condensed-phase biomolecules (e.g. in radiotherapy). Here we present data on the LEE-induced dissociation and desorption of the DNA/RNA-base and radiosensitizing agent analogues pyrimidine and pyridazine. Vapors of each molecule were condensed on either a Pt or Ar substrate to form a multilayer film or a submonolayer molecular target, respectively. These were irradiated with electrons of 0-80 eV and the desorbing anionic and cationic fragments analysed via time of flight mass spectrometry. The detected cations are the same species seen in gas-phase mass spectra, albeit of differing relative intensity. Anion yield functions exhibit strong maxima, indicating that transient negative ions contribute significantly, via dissociative electron attachment (DEA), to molecular dissociation below 20 eV. For both molecules, the <5 eV shape resonances, seen experimentally and predicted by theory, do not result in fragment desorption. The main anionic fragments are H- and CN- for both molecules, additionally the fragments C-, CH- C2H- and CHN- desorb from pyrimidine and C- and C2H- from pyridazine, with some resonances lying above the ionization limit. Pyrimidine shows higher anion desorption yields than pyridazine for all species except H-. The anion signal also comprises dipolar dissociation (DD), investigated in both anionic and cationic yield functions. From analysis of anion and cation yields, fragmentation pathways are suggested. The direct ionization pathway provides information on the appearance energies for cations and their production processes in condensed phase.

A survey of microparasites present in adult migrating Chinook salmon (Oncorhynchus tshawytscha) in south-western British Columbia determined by high-throughput quantitative polymerase chain reaction.

Microparasites play an important role in the demography, ecology and evolution of Pacific salmonids. As salmon stocks continue to decline and the impacts of global climate change on fish populations become apparent, a greater understanding of microparasites in wild salmon populations is warranted. We used high-throughput, quantitative PCR (HT-qRT-PCR) to rapidly screen 82 adult Chinook salmon from five geographically or genetically distinct groups (mostly returning to tributaries of the Fraser River) for 45 microparasite taxa. We detected 20 microparasite species, four of which have not previously been documented in Chinook salmon, and four of which have not been previously detected in any salmonids in the Fraser River. Comparisons of microparasite load to blood plasma variables revealed some positive associations between Flavobacterium psychrophilum, Cryptobia salmositica and Ceratonova shasta and physiological indices suggestive of morbidity. We include a comparison of our findings for each microparasite taxa with previous knowledge of its distribution in British Columbia.