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Introduction: Capnocytophaga is a genus of bacteria that are commensal to the oral microbiome of humans and some animals. Some Capnocytophaga species are found in the human oral cavity and rarely cause disease in people; the species found in animals are zoönotic and can be transmitted to people via saliva. This study describes the clinical and epidemiologic features of patients from whom Capnocytophaga spp. were isolated from blood and other clinical specimens at the California state Microbial Diseases Laboratory., Methods: Clinical information was obtained from laboratory submission forms and any accompanying medical records and/or from matching records in statewide hospital discharge and emergency department databases., Results: During the 17-year study period (2005-2021), Capnocytophaga spp. were isolated in 48 specimens from 47 patients. Capnocytophaga canimorsus, which is a zoönotic species, represented 85% of the Capnocytophaga spp. identified to the species level. The median age was 67 years (range: 30-88 years) for the 42 patients infected with a zoönotic species of Capnocytophaga and 36 years (range: 12-65 years) for the four patients infected with a non-zoönotic species. Twenty-five (60%) patients with zoönotic species infections were male, compared to two (50%) patients with non-zoönotic species infections. Capnocytophaga spp. were most frequently isolated from blood (88%), and the most common case presentation was sepsis (45%). A dog or cat bite prior to diagnosis was reported for 14% of patients infected with a zoönotic species of Capnocytophaga. Records for 45% of patients indicated at least one pre-existing health condition associated with depressed immune function., Conclusions: This study documented that Capnocytophaga spp. can cause rare, severe, invasive disease in mostly older or immunocompromised persons, often without documentation of a dog or cat bite. Providers are encouraged to consider Capnocytophaga spp. infection in immunocompromised pet owners presenting with sepsis, even in the absence of a known animal bite., (© 2025 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Herein, we explore the generation and characterization of the radical cations of glycylphenylalanylglycine, or [GFG]•+, formed via dissociative electron-transfer reaction from the tripeptide to copper(II) within a ternary complex. A comprehensive investigation employing isotopic labeling, infrared multiple-photon dissociation (IRMPD) spectroscopy, and density functional theory (DFT) calculations elucidated the details and energetics in formation of the peptide radical cations as well as their dissociation products. Unlike conventional aromatic-containing peptide radical cations that primarily form canonical π-radicals, our findings reveal that 75% of the population of the experimentally produced [GFG]•+ precursors are [GFα•G]+, where the radical resides on the middle α-carbon of the phenylalanyl residue. This unexpected isomeric ion has an enthalpy of 6.8 kcal/mol above the global minimum, which has an N-terminal captodative structure, [Gα•FG]+, comprising 25% of the population. The [b₂-H]•+ product ions are also present in a ratio of 75/25 from [GFα•G]+/ [Gα•FG]+, the results of which are obtained from matches between the IRMPD action spectrum and predicted IR absorption spectra of the [b₂-H]•+ candidate structures, as well as from IRMPD isomer population analyses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We often seek information without any explicit incentives or goals (i.e., noninstrumental information seeking, often noted as a manifestation of curiosity). Does noninstrumental information-seeking change with age? We tried to answer the question by making a critical distinction between two information-seeking behaviors: diversive information seeking (i.e., information seeking for topics a person knows little about) and specific information seeking (i.e., information seeking to deepen a person's existing knowledge of a topic). Five hundred participants (age range: 12-79 years old) spontaneously read new facts about different topics. After reading each fact, participants were given the choice to read more facts about the current topic or return to the selection menu to learn about a new topic. We found that with increasing age, participants chose to explore more facts within a topic (i.e., increased specific information seeking) and switched less frequently to new topics (i.e., decreased diversive information seeking). These results indicate that while young people seek out a broader range of information, as people grow older, they develop a preference to deepen their existing knowledge. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Frailty is a well-recognised predictor of outcomes after transcatheter aortic valve implantation (TAVI). Psoas muscle area (PMA) is a surrogate marker for sarcopaenia and is a validated assessment tool for frailty. The objective of this study was to examine frailty as a predictor of outcomes in TAVI patients and assess the prognostic usefulness of adding PMA to established frailty assessments., Methods: Frailty assessments were performed on 220 consecutive patients undergoing TAVI. These assessments used four markers (serum albumin, handgrip strength, gait speed, and a cognitive assessment), which were combined to form a composite frailty score. Preprocedural computed tomography scans were used to calculate cross-sectional PMA for each patient. The primary outcomes were all-cause mortality at 1-year and post-procedure length of hospital stay., Results: Frailty status, as defined by the composite frailty score, was independently predictive of length of hospital stay (p=0.001), but not predictive of 1-year mortality (p=0.161). Albumin (p=0.036) and 5-metre walk test (p=0.003) were independently predictive of 1-year mortality. The PMA, when adjusted for gender, and normalised according to body surface area, was not predictive of 1-year mortality. Normalised PMA was associated with increased post-procedure length of stay within the female population (p=0.031)., Conclusions: A low PMA is associated with increased length of hospital stay in female TAVI patients but does not provide additional predictive value over traditional frailty scores. The PMA was not shown to correlate with TAVI-related complications or 1-year mortality., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Residue-specific phosphorylation is a protein post-translational modification that regulates cellular functions. Experimental determination of the exact sites of protein phosphorylation provides an understanding of the signaling and processes at work for a given cellular state. Any experimental artifact that involves migration of the phosphate group during measurement is a concern, as the outcome can lead to erroneous conclusions that may confound studies on cellular signal transduction. Herein, we examine computationally the mechanism by which a phosphate group migrates from one serine residue to another serine in monoprotonated pentapeptides [B A -pSer-Gly-Ser-B B + H] + → [B A -Ser-Gly-pSer-B B + H] + (where B A and B B are different combinations of the three basic amino acids, histidine, lysine, and arginine). In addition to moving the phosphate group, the overall mechanism involves transferring a proton from the N-terminal amino acid, B A , to the C-terminal amino acid, B B . This is not a synchronous process, and there is a key high-energy intermediate, structure C , that is zwitterionic with both the basic amino acids protonated and the phosphate group attached to both serine residues and carrying a negative charge. The barriers to moving the phosphate group are calculated to be in the range of 219-274 kJ mol -1 at the B3LYP/6-31G(d) level. These barriers are systematically slightly lower and in good agreement with single-point energy calculations at both M06-2 X /6-311++G(d,p) and MP2/6-31++G(d,p) levels. The competitive reaction, loss of phosphoric acid from the protonated pentapeptides, has a barrier in the range of 176-202 kJ mol -1 at the B3LYP/6-31G(d) level. Extension of the theory to M06-2 X /6-311++G(d,p)//B3LYP/6-31G(d) and MP2/6-31++G(d,p)// B3LYP/6-31G(d) gives higher values for the loss of phosphoric acid, falling in the range of 196-226 kJ mol -1 ; these are comparable to the barriers against phosphate migration at the same levels of theory. For larger peptides His-pSer-(Gly) n -Ser-His, where n has values from 2 to 5, the barriers against the loss of phosphoric acid are higher than those against the phosphate group migration. This difference is most pronounced and significant when n = 4 and 5 (the differences are approximately 80 kJ mol -1 under the single-point energy calculations at the M06-2X and MP2 levels). Energy differences using two more recent functionals, M08-HX and MN15, on His-pSer-(Gly) n -Ser-His, where n = 1 and 5, are in good agreement with the M06-2X and MP2 calculations. These results provide the mechanistic rationale for phosphate migration versus other competing reactions in the gas phase under tandem mass spectrometry conditions.

Sinorhizobium meliloti is a model alpha-proteobacterium for investigating microbe-host interactions, in particular nitrogen-fixing rhizobium-legume symbioses. Successful infection requires complex coordination between compatible host and endosymbiont, including bacterial production of succinoglycan, also known as exopolysaccharide-I (EPS-I). In S. meliloti EPS-I production is controlled by the conserved ExoS-ChvI two-component system. Periplasmic ExoR associates with the ExoS histidine kinase and negatively regulates ChvI-dependent expression of exo genes, necessary for EPS-I synthesis. We show that two extracytoplasmic proteins, LppA (a lipoprotein) and JspA (a lipoprotein and a metalloprotease), jointly influence EPS-I synthesis by modulating the ExoR-ExoS-ChvI pathway and expression of genes in the ChvI regulon. Deletions of jspA and lppA led to lower EPS-I production and competitive disadvantage during host colonization, for both S. meliloti with Medicago sativa and S. medicae with M. truncatula. Overexpression of jspA reduced steady-state levels of ExoR, suggesting that the JspA protease participates in ExoR degradation. This reduction in ExoR levels is dependent on LppA and can be replicated with ExoR, JspA, and LppA expressed exogenously in Caulobacter crescentus and Escherichia coli. Akin to signaling pathways that sense extracytoplasmic stress in other bacteria, JspA and LppA may monitor periplasmic conditions during interaction with the plant host to adjust accordingly expression of genes that contribute to efficient symbiosis. The molecular mechanisms underlying host colonization in our model system may have parallels in related alpha-proteobacteria., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bustamante et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA., Methods: Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0., Results: The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice., Conclusion: POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

Purpose: To investigate the effectiveness of orthokeratology (ortho-k) lenses and corneal changes with increased compression factor for myopia control over a 2-year period., Methods: Young participants (age: 6-<12 years), with low myopia (0.50-4.00 D) and low astigmatism (≤1.25 D), were recruited and allowed to choose to wear either single-vision spectacles or ortho-k lenses (randomly assigned to compression factor of either 0.75 or 1.75 D). Axial length and cycloplegic refraction were measured at six monthly intervals for two years by a masked examiner. The myopia control effectiveness was determined by axial elongation., Results: A significant number of control (63 %) dropped out, mainly due to concern about myopia progression (58 %). A total of 75 participants (mean age: 9.3 ± 1.0 years; control: n = 11, ortho-k [0.75 D]: n = 29, ortho-k [1.75 D]: n = 35) completed the study. Considering ortho-k groups only, the mean axial elongation of participants wearing ortho-k lenses of conventional compression factor (0.75 D) and increased compression factor (1.75 D) were 0.53 ± 0.29 and 0.35 ± 0.29 mm, respectively, over the 2-year study period. The between-group differences in corneal health were not significant at all visits., Conclusion: Participants wearing ortho-k lenses of increased compression factor further slowed axial elongation by 34%, when compared with the conventional compression factor without compromising corneal health. Further investigations are warranted to confirm the potential mechanism of an increased compression factor for improved myopia control effectiveness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Background: Transcatheter aortic valve implantation (TAVI) is an established therapy for the treatment of aortic valve disease in appropriately selected patients. Previous studies using the self-expanding Portico transcatheter heart valve (THV), (Abbott Structural Heart, St Paul, MN, USA) have demonstrated the technical feasibility of this system albeit in the hands of relatively inexperienced Portico users. The objective of this study was to assess the real-world safety and efficacy of the Portico THV (with and without the FlexNav delivery system, Abbott Structural Heart) at the 30-day timepoint in an Australian cohort., Methods and Results: This study was a retrospective real-world cohort analysis of 269 consecutive patients with severe aortic valve disease who underwent TAVI at multiple centres within Australia between February 2015 and April 2021. Of the 269 patients, 51.7% were female, mean Society of Thoracic Surgeons (STS) score was 5.2 (±6.8) and 98.5% had successful implantations. Thirty (30)-day post-implantation all-cause mortality was observed in one (0.4%) patient, major vascular complications in two (0.7%) patients, more-than-mild paravalvular leak in six (2.2%) patients and requirement for new permanent pacemaker implantation in 27 (10.2%) patients. Haemodynamic parameters at 30 days included mean effective orifice area (EOA) of 2.3 (±0.9) cm 2 and mean aortic valve gradient (AVG) of 9.6 (±6.2) mmHg., Conclusion: This analysis of the Portico THV in a real-world setting suggested that the system is associated with satisfactory safety and efficacy parameters. Previously published datasets may not have found similar findings owing to lower operator experience with the Portico THV system., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: To investigate the repeatability and reproducibility of choroidal thickness measurements using Lenstar images in young myopic children before and after one-month orthokeratology (ortho-k) treatment., Method: Ocular biometry of 39 subjects were performed using the Lenstar 900. The first five measurements with maximum differences of 0.02 mm in axial length in the right eyes were saved and used for measurement of choroidal thickness. Subfoveal choroidal thickness were manually measured by identifying the signals from the retinal pigmented epithelium layer and chorioscleral interface. Repeatability was determined by comparing measurements of the same images made by the same observer on two separate occasions (four weeks apart), while reproducibility was calculated by comparing measurements of the same images made by two independent observers. Data was analysed using intra-class correlation coefficients (ICC) and non-parametric Bland and Altman plots., Results: The choroidal peaks could not be identified in all five measurements in all subjects. On average, only 71% subjects had at least four definable images. Compared with the use of fewer than four images, reliability using an average of four definable images improved statistically, but remained clinically unacceptable (>10 µm), although pre- and post-ortho-k ICC values were good to excellent for repeatability (0.867 and 0.975, respectively) and excellent and good for reproducibility (0.959 and 0.868, respectively). Non-parametric pre- and post-ortho-k limits of agreement (2.5% and 97.5% percentiles) obtained were -45.8 to 79.3 µm and -30.3 to 9.5 µm, respectively for repeatability, and -29.0 to 33.5 µm and -21.8 to 70.0 µm, respectively for reproducibility., Conclusion: Choroidal thickness measurements using the Lenstar did not show good reliability, despite the high ICC values, non-parametric Bland and Altman plots demonstrated a wide variability of measurement errors. Any changes in subfoveal choroidal thickness, measured by Lenstar, of <80 µm may not represent real changes., (Copyright © 2021 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Background The pathophysiological mechanism behind adverse outcomes associated with ischemia-inducing epicardial coronary stenoses and microcirculatory dysfunction remains unclear. Wall shear stress (WSS) plays an important role in atherosclerotic plaque progression and vulnerability. We aimed to evaluate the relationship between WSS, functionally significant epicardial coronary stenoses, and microcirculatory dysfunction. Methods and Results Patients undergoing invasive coronary physiology testing were included. Fractional flow reserve, instantaneous wave-free ratio, and the index of microcirculatory resistance were measured. Quantitative coronary angiography was used to obtain the lesion percentage diameter stenosis. Computational fluid dynamics analysis was performed to calculate WSS parameters. Multiple regression analysis was performed to calculate the standardized regression coefficient (β) for the coronary physiology indices. A total of 107 vessels from 88 patients were included. Fractional flow reserve independently predicted the total area of low WSS (β=-0.44; 95% CI, -0.62 to -0.25; P <0.001) and maximum lesion WSS (β=-0.53; 95% CI, -0.70 to -0.36; P <0.001) after adjusting for percentage diameter stenosis and index of microcirculatory resistance. Similarly, instantaneous wave-free ratio also independently predicted the total area of low WSS (β=-0.45; 95% CI, -0.62 to -0.28; P <0.001) and maximum lesion WSS (β=-0.58; 95% CI, -0.73 to -0.43; P <0.001). The index of microcirculatory resistance did not predict either low or high WSS. Conclusions Fractional flow reserve and instantaneous wave-free ratio independently predicted the total burden of low WSS and maximum lesion WSS in coronary arteries. No relationship was found between microcirculatory dysfunction and WSS.

Background: Brief nonharmful ischemia, remote ischemic preconditioning (RIPC) has been proposed to confer benefit to patients with coronary artery disease via unknown mechanisms., Objectives: We aimed to investigate the effect of RIPC on circulating levels of extracellular vesicles (EVs) and global coagulation and fibrinolytic factors in patients with coronary disease., Patients/methods: Blood samples were taken from 60 patients presenting for coronary angiography enrolled in a randomized, controlled trial before and after RIPC (3 × 5 min administration of 200 mmHg sphygmomanometer on the arm, n = 31) or sham (n = 29) treatment. Most patients (n = 48) had significant coronary artery disease and all were taking at least one antiplatelet agent., Results: Remote ischemic preconditioning significantly decreased circulating levels of EVs expressing platelet markers CD41 and CD61 detected by flow cytometry in plasma, whereas no such effect was found on EVs expressing phosphatidylserine, CD62P, CD45, CD11b, CD144, CD31 + /CD41 - , or CD235a. RIPC had no effect on the overall hemostatic potential assay or circulating antigen levels of tissue plasminogen activator, urokinase, plasminogen activator inhibitor-1, or plasminogen. Sham treatment had no effect on any studied parameter. Statin use inhibited the effect of RIPC on CD61 + EVs, diabetes modified the effect of RIPC on CD45 + and CD11b + EVs, and hypertension modified the effect of RIPC on CD235a + EVs., Conclusions: Remote ischemic preconditioning decreased circulating levels of platelet-derived EVs in patients with coronary disease taking conventional antiplatelet therapy. This may reflect increased EV clearance/uptake or change in production. Clinical variables may alter the effectiveness of RIPC., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Transcatheter aortic valve implantation (TAVI) has become the standard-of-care for treatment of severe symptomatic aortic stenosis and is also being increasingly recommended for low-risk patients. While TAVI boasts positive post-procedural outcomes, it is also associated with cognitive complications, namely delirium and cognitive decline. There is a pressing need for accurate risk tools which can identify TAVI patients at risk of delirium and cognitive decline, as risk scores designed for general cardiovascular surgery fall short. The present effect-finding exploratory study will assess the utility of various measures in the context of aging and frailty in predicting who will and who will not develop delirium or cognitive impairment following TAVI. The measures we propose include gait, visual symptoms, voice, swallowing, mood and sleep. Methods: This is an observational prospective cohort study focused on identifying pre-procedural risk factors for the development of delirium and cognitive decline following TAVI. Potential risk factors will be measured prior to TAVI. Primary outcomes will be post-procedure cognitive decline and delirium. Secondary outcomes include activities of daily living, quality of life, and mortality. Delirium presence will be measured on each of the first 2 days following TAVI. All other outcomes will be assessed at 3-, 6-, and 12-months post-operatively. A series of logistic regressions will be run to investigate the relationship between potential predictors and outcomes (presence vs. absence of either delirium or cognitive decline). Discussion: This study will assess the strengths of associations between a range of measures drawn from frailty and aging literature in terms of association with cognitive decline and delirium following TAVI. Identified measures can be used in future development of TAVI risk prediction models, which are essential for the accurate identification of cognitive at-risk patients and successful application of pre-procedural interventions. Clinical Trial Registration: This trial is registered with the Australian New Zealand Clinical Trials Registry. [https://bit.ly/2PAotP5], [ACTRN12618001114235]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ghezzi, Psaltis, Loetscher, Davis, Montarello, Lau, Delacroix, Bourke, McLoughlin, Keage and Keage.)

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a university hospital in Hong Kong. Patients were reviewed up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis.&nbsp;A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) were included. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo + ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted + ICI).&nbsp;A significantly higher proportion of patients using targeted + ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (≥65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. This large, real-world cohort demonstrates that targeted + ICI has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is essential in older populations.

A set of fentanyl molecules when subjected to vacuum UV atmospheric pressure photoionization (VUV-APPI) in the presence of dopants (ammonia and anisole) shows two major bands in the ion mobility-mass spectrometry (IMS-MS) spectrum corresponding to (a) the protonated fentanyl, [M+H] + and (b) a unique [M-74] + ion. For the parent fentanyl, the [M-74] + ion is at m / z 262 but, in the absence of ammonia, the product ion is shifted to m / z 245, corresponding to a difference of NH 3 . Collision-induced dissociations (CID) of the [M-74] + ions for all the different fentanyls examined here show the same pattern of neutral losses, namely NH 3 and HN=CH 2 , and the dominant product ion is at m / z 84 (shifted to m / z 98 for 3-methylfentanyl and m / z 142 and 231 for carfentanyl). Dissociation of the [M-74-NH 3 ] + ion derived from the fentanyls yields the same product ions as found in the electron impact (EI) ionization spectra of the fentanyls. The dissociation products of the [M-74-HN=CH 2 ] + ion are different, include the ion at m / z 84, and correspond to the fragmentation products of protonated norfentanyls. Theoretical modeling supports the opening of new fragmentation channels as a result of the reaction of the initially formed iminium cation with ammonia at atmospheric pressure.

Radical cations of an aliphatic tripeptide prolyl-glycyl-glycine (PGG •+ ) and its sequence ions [a 3 + H] •+ and [b 2 - H] •+ have been generated by collision-induced dissociation of the [Cu(Phen)(PGG)] •2+ complex, where Phen = 1,10-phenanthroline. Infrared multiple photon dissociation spectroscopy, ion-molecule reaction experiments, and theoretical calculations have been used to investigate the structures of these ions. The unpaired electron in these three radical cations is located at different α-carbons. The PGG •+ radical cation has a captodative structure with the radical at the α-carbon of the proline residue and the proton on the oxygen of the first amide group. This structure is at the global minimum on the potential energy surface (PES). By contrast, the [a 3 + H] •+ and [b 2 - H] •+ ions are not the lowest-energy structures on their respective PESs, and their radicals are formally located at the C-terminal and second α-carbons, respectively. Density functional theory calculations on the structures of the ternary copper(II) complex ion suggest that the charge-solvated isomer of the metal complex is the precursor ion that dissociates to give the PGG •+ radical cation. The isomer of the complex in which PGG is bound as a zwitterion dissociates to give the [a 3 + H] •+ and [b 2 - H] •+ ions.

Background: The last visual survey of older adults in Hong Kong was a district-level study in 2002, with no assessment of behavioral and medical risk factors for visual impairment (VI). Our objectives were to determine the latest VI prevalence among older adults, significance of any spatial and temporal differences on the prevalence, and any associations of sociodemographic, behavioral and medical risk factors with VI from a multi-perspective analysis., Methods: Community-based pilot survey of residents from a suburb of Hong Kong, aged ≥50, using a standardized questionnaire, was conducted in 2016., Results: Of the 222 subjects, crude rates of bilateral and unilateral VI were 9.46 and 32.88%, respectively, or corresponding age-and-gender-adjusted rates of 6.89 and 30.5%. Older age and lower educational were associated with higher risk for unilateral VI, while older age, temporary housing, obesity and hyperlipidemia were associated with higher risk for bilateral VI. Smoking and alcohol-drinking status were not associated with unilateral or bilateral VI. Relative changes in ORs of hypertension or educational level on unilateral or bilateral VI were >  10% after adjusting for age. Interaction term between hyperlipidemia and gender or obesity was significant for unilateral VI. Gender, hypertension and cataract were not associated with unilateral or bilateral VI in general population of pooled analysis but were identified as risk factors in specific subgroups of stratified analysis. Refractive error (myopia or hyperopia) was significantly associated with VI in the eye-level analysis after adjusting the inter-eye correlation., Conclusions: Sociodemographic and medical risk factors contributed to VI, but behavioral risk factors did not. Sociodemographic disparities of visual health existed. Age was the confounders of the VI-hypertension or VI-educational level relationships. Gender and obesity were more likely to have multiplicative effect on unilateral VI when combined with hyperlipidemia. Stratified analysis should be conducted to provide further insight into the risk factors for VI in specific populations. Uncorrected refractive error remains a significant cause of impaired vision. The spatial and temporal differences in bilateral VI prevalence from the previous local study indicates a territory-wide survey is needed to assess regional differences and overall prevalence of VI in Hong Kong.

Objectives: To assess the proportions of respondents in the general community having heard or awareness, and their knowledge level, of three common eye diseases: age-related macular degeneration, cataract, and glaucoma. We also attempted to assess for risk factors that may be associated with any variations, which will help identify the areas of inadequate knowledge and demographics of potential audiences for focused health education., Methods: We conducted a community-based pilot survey for the residents from a southern suburb of Hong Kong in early 2016, by inviting all aged 50 or above to complete a standardized questionnaire in the local community hall., Results: Most of the 222 respondents have heard, or awareness, of cataract (92.79% or 81.98%, respectively), followed by glaucoma (86.94% or 52.70%, respectively), and age-related macular degeneration (51.35% or 29.28%, respectively). The results of Cronbach's alpha (α > 0.7) and Spearman's correlation coefficient (p < 0.01) suggested that the internal consistency, convergent and discriminant validities of the questionnaire were acceptable for the study population. Compared to a previous Hong Kong survey in 2002, the proportions of having heard of the three eye diseases were greater, but the overall knowledge remained limited. From a maximum knowledge score of 29, the median scores for age-related macular degeneration, cataract, and glaucoma were 9, 13, and 14, respectively. Except for the treatment of cataract, the knowledge level in most areas was low. Sociodemographic factors and medical history, rather than behavioral factors, were more likely to be associated with having a higher knowledge level. Subjects with family or friends with a history of glaucoma or age-related macular degeneration were more aware and knowledgeable, but not for subjects who were current and past smokers or alcohol drinkers. For age-related macular degeneration, gender modified the effect between age and knowledge level, while age was a confounder of having medical history, and having heard or awareness, of the disease., Conclusion: Despite a larger proportion of the community having heard or awareness since 15 years ago, much effort remains for improving health knowledge of these three eye diseases in Hong Kong. We recommend targeting respondents with higher lifestyle risks, such as current and past smokers or alcohol drinkers, as a focused audience, and utilizing family members, relatives, or friends as another way of distributing health information., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

We report herein the first detailed study of the mechanism of redox reactions occurring during the gas-phase dissociative electron transfer of prototypical ternary [Cu II (dien)M]˙ 2+ complexes (M, peptide). The two final products are (i) the oxidized non-zwitterionic π-centered [M]˙ + species with both the charge and spin densities delocalized over the indole ring of the tryptophan residue and with a C-terminal COOH group intact, and (ii) the complementary ion [Cu I (dien)] + . Infrared multiple photon dissociation (IRMPD) action spectroscopy and low-energy collision-induced dissociation (CID) experiments, in conjunction with density functional theory (DFT) calculations, revealed the structural details of the mass-isolated precursor and product cations. Our experimental and theoretical results indicate that the doubly positively charged precursor [Cu II (dien)M]˙ 2+ features electrostatic coordination through the anionic carboxylate end of the zwitterionic M moiety. An additional interaction exists between the indole ring of the tryptophan residue and one of the primary amino groups of the dien ligand; the DFT calculations provided the structures of the precursor ion, intermediates, and products, and enabled us to keep track of the locations of the charge and unpaired electron. The dissociative one-electron transfer reaction is initiated by a gradual transition of the M tripeptide from the zwitterionic form in [Cu II (dien)M]˙ 2+ to the non-zwitterionic M intermediate, through a cascade of conformational changes and proton transfers. In the next step, the highest energy intermediate is formed; here, the copper center is 5-coordinate with coordination from both the carboxylic acid group and the indole ring. A subsequent switch back to 4-coordination to an intermediate IM1, where attachment to GGW occurs through the indole ring only, creates the structure that ultimately undergoes dissociation.

Single-cell RNA sequencing (scRNA-seq) is the leading technique for characterizing the transcriptomes of individual cells in a sample. The latest protocols are scalable to thousands of cells and are being used to compile cell atlases of tissues, organs and organisms. However, the protocols differ substantially with respect to their RNA capture efficiency, bias, scale and costs, and their relative advantages for different applications are unclear. In the present study, we generated benchmark datasets to systematically evaluate protocols in terms of their power to comprehensively describe cell types and states. We performed a multicenter study comparing 13 commonly used scRNA-seq and single-nucleus RNA-seq protocols applied to a heterogeneous reference sample resource. Comparative analysis revealed marked differences in protocol performance. The protocols differed in library complexity and their ability to detect cell-type markers, impacting their predictive value and suitability for integration into reference cell atlases. These results provide guidance both for individual researchers and for consortium projects such as the Human Cell Atlas.

Objective: To present the study design and the baseline data of a prospective cohort study investigating the safety, refractive correction and effectiveness of myopia control in subjects fitted with orthokeratology (ortho-k) lenses of different compression factors., Methods and Analysis: This study is a 2-year longitudinal, double-masked, partially randomised study. Myopic children aged between 6 and 10 years are recruited and they may choose to participate in either the ortho-k or spectacle-wearing group. Subjects in the ortho-k group are randomly assigned to wear ortho-k lenses of either conventional compression factor (CCF, 0.75 D) or increased compression factor (ICF, 1.75 D). For the ortho-k subjects, the time and between-group effects within the first month of lens wear were analysed., Results: Sixty-nine ortho-k subjects (CCF: 34; ICF: 35) and 30 control subjects were recruited. There were no significant differences in baseline demographic data among the three groups of subjects (p>0.19). At the 1-month visit, the first fit success rates were 97% and 100% in the CCF and ICF ortho-k group, respectively. A higher percentage of ICF subjects could achieve full correction (CCF: 88.2%; ICF: 94.3%). The change in axial length was significantly higher in the ICF group (CCF, 0.003 mm; ICF, -0.031 mm) (p<0.05). No significant between-group differences in daytime vision or in the coverage and depth of corneal staining between the two ortho-k groups (p>0.05) were observed at any visit., Conclusion: ICF did not compromise the corneal integrity and the lens centration within the first month of lens wear. The preliminary performance of ortho-k lenses with ICF of 1.00D shows that it was safe to be used in the longer term for the investigation of myopia control., Trial Registration Number: NCT02643342., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We investigated whether remote ischemic preconditioning (RIPC) inhibits agonist-induced conformational activation of platelet α IIb β 3 in patients with coronary artery disease already receiving conventional antiplatelet therapy., Patients/methods: Consecutive patients with angiographically confirmed coronary artery disease were randomized to RIPC or sham treatment. Venous blood was collected before and immediately after RIPC/sham. Platelet aggregometry (ADP, arachidonic acid) and whole blood platelet flow cytometry was performed for CD62P, CD63, active α IIb β 3 (PAC-1 binding) before and after stimulation with ADP, thrombin ± collagen, or PAR-1 thrombin receptor agonist., Results: Patients (25 RIPC, 23 sham) were well matched, 83% male, age (mean ± standard deviation) 63.3 ± 13.2 years, 95% aspirin, 81% P2Y 12 inhibitor. RIPC did not affect platelet aggregation, nor agonist-induced expression of CD62P, but selectively and significantly decreased α IIb β 3 activation after stimulation with either PAR-1 agonist peptide or the combination of thrombin + collagen, but not after ADP nor thrombin alone. The effect of RIPC on platelet α IIb β 3 activation was evident in patients receiving both aspirin and P2Y 12 inhibitor, and was not associated with an increase in vasodilator-stimulated phosphoprotein phosphorylation., Conclusions: Remote ischemic preconditioning inhibits conformational activation of platelet α IIb β 3 in response to exposure to thrombin and collagen in patients with coronary artery disease receiving dual antiplatelet therapy. These findings indicate agonist-specific inhibition of platelet activation by RIPC in coronary artery disease that is not obviated by the prior use of P2Y 12 inhibitors., (© 2020 International Society on Thrombosis and Haemostasis.)

Purpose: This retrospective longitudinal study aimed to examine the relationship between ocular higher-order aberrations (HOA) and axial eye growth in young myopic children undergoing orthokeratology (ortho-k) treatment., Methods: Axial length and ocular HOA, measured under cycloplegia annually over a 2-year period from the right eyes of myopic children, who previously completed ortho-k clinical trials, were retrieved. Linear mixed model analyses were applied to determine the association between ocular HOA, other known confounding variables (age, sex, and refractive error), and axial eye growth., Results: Data from 103 subjects were analyzed. The root-mean square (RMS) values of total ocular HOA (third to sixth orders combined), spherical (\({\rm{Z}}&#95;4^0\) and \({\rm{Z}}&#95;6^0\) combined), and comatic (\({\rm{Z}}&#95;3^{ - 1}\), \({\rm{Z}}&#95;3^1\), \({\rm{Z}}&#95;5^{ - 1}\), and \({\rm{Z}}&#95;5^1\) combined) aberrations increased by approximately 3, 9, and 2 times, respectively, after 2 years of ortho-k treatment. After adjusting for age, sex, and refractive error, higher RMS values of total HOA and spherical aberrations were associated with both longer axial length and slower axial elongation (all P < 0.01). For individual Zernike term coefficients, a higher level of positive spherical aberration (\({\rm{Z}}&#95;4^0\)) was also associated with longer axial length and slower axial elongation (both P < 0.01), after adjusting for baseline HOA., Conclusions: Ortho-k for myopia control significantly increases the Zernike coefficients and therefore the RMS values for a range of total ocular HOA terms or metrics in children. These findings suggest the potential role of HOA, particularly spherical aberration, as the possible mechanism of slowing axial elongation in ortho-k treatment.

Purpose: To evaluate changes in refractive and corneal responses in myopic children wearing orthokeratology (ortho-k) lenses with conventional compression factor (CCF, 0.75 D) and increased compression factor (ICF, 1.75 D)., Methods: This was a double-blind self-controlled study. Subjects were randomly fitted with CCF in one eye and ICF in the fellow eye. Weekly monitoring of refraction, visual acuity (VA), external ocular health, and corneal responses were performed over one month of lens wear and after discontinuation of lens wear until stabilization was achieved., Results: Twenty-five subjects, aged 9.4 ± 1.0 years, completed one-month lens wear, of whom 23 completed the washout period. The first fit success rates for CCF and ICF were 93% and 96%, respectively. Myopia, unaided VA, central corneal thickness, anterior corneal curvatures (K), apical power (AP), and corneal resistance factor (CRF) all changed significantly during the study period (P <  0.003). Between-eye difference was significant only for myopia reduction (P =  0.001). About 4% and 8% of ICF and CCF eyes were under-corrected. The attempted target was achieved in about 80% of CCF and 60% of ICF eyes at week 4. At the end of the washout period (3 weeks), myopia, K, and AP were significantly different compared to baseline (P <  0.001)., Conclusion: Increasing the compression factor did not affect the first fit success rate and external ocular health, but did allow faster correction of refractive error within one month of lens wear. Further investigation is warranted to investigate the long-term effects of ICF on myopia control compared to CCF., (Copyright © 2019 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Background: To investigate the influence of compression factor upon changes in ocular higher-order aberrations (HOAs) in young myopic children undergoing orthokeratology treatment., Methods: Subjects aged between six and < 11 years, with low myopia (0.50-4.00 D inclusive), low astigmatism (≤ 1.25 D), and anisometropia (≤ 1.00 D), were randomly assigned to wear orthokeratology lenses of different compression factors in each eye (one eye 0.75 D and the fellow eye 1.75 D). HOAs were measured weekly over one month of lens wear. Wavefront analysis was conducted over a 5-mm pupil using a sixth order Zernike polynomial expansion. Linear mixed models were used to examine the individual Zernike co-efficients and specific root-mean-square (RMS) error (spherical, comatic, total HOAs) metrics and their changes between the two eyes during the study period., Results: Twenty-eight myopic (mean manifest spherical equivalent refraction: -2.10 ± 0.58 D) children (median [range] age: 9.3 [7.8-11.0] years) were analysed. Significant interocular differences in HOAs at baseline were observed for Z 6 - 6 and Z 6 - 4 only (both p < 0.05). During the lens wear period, eyes fitted with the increased compression factor showed greater changes in primary spherical aberration ( Z 4 0 , p = 0.04) and RMS values for spherical and total HOAs (both p < 0.01). Considering data from both eyes together, after adjusting for the paired nature of the data, some other Zernike terms ( Z 3 1 and Z 6 0 , both p < 0.01) and the RMS value of comatic aberrations (p < 0.001) significantly increased after one month of orthokeratology treatment. The increase in primary spherical aberration ( Z 4 0 ) was positively correlated with the reduction in spherical equivalent refractive error, but only in eyes fitted with the increased compression factor (r = 0.69, p < 0.001)., Conclusions: Increasing the orthokeratology compression factor by 1.00 D significantly altered some HOAs, particularly spherical aberration. Given the association between positive spherical aberration and eye growth in children, further research investigating the influence of orthokeratology compression factor on axial eye growth is warranted., (© 2019 Optometry Australia.)

The current study investigated the cognitive and neural substrates that underpin writing ability. We explored similarities and differences in writing numbers and words and compared these to language and manual actions in a large group of sub-acute, stroke patients (n = 740). The behavioral data showed association and dissociation in the ability to write words and numbers. Comorbidities of writing deficits with both language and motor impairments were prevalent, with less than a handful showing deficits restricted to the writing tasks. A second analysis with a subset of patients (n = 267) explored the neural networks that mediate writing abilities. Lesion to right temporal contributed to writing words, while lesions to left postcentral contributed to writing numbers. Overlapping neural mechanisms included the bilateral prefrontal cortex, right inferior parietal, left middle occipital and the right cerebellum. With the former regions associated with error pattern typical to writing based on prior knowledge (the lexical route), while lesion to left MOG was associated with errors to the phonological (non-lexical) route. Using principle components extracted from the behavioral data, we showed that right prefrontal and right parietal contributed to the ability to use pen, while lesion to bilateral prefrontal, inferior temporal and cerebellum supported unique use of pen for writing. The behavioral and imaging data suggested that writing numbers and words primarily relied on overlapping cognitive and neural functions. Incidents of pure writing deficits, in the absence of motor or language deficits were rare. Nevertheless, the PCA and neural data suggested that writing abilities were associated with some unique neuro-cognitive functions, specifically dedicated to the use of pen and the ability to transform meaning to motor command.

[a 3 + H] 2+ ions generated from Ln 3+ /tripeptide complexes, where Ln = La or Ce, have similar structures to the linear [a n ] + ions but with protonation at both the terminal NH 2 and N═CH 2 groups. Ion stability is favored by having the basic secondary amine of the proline residue at the N-terminus and by an amino acid residue accommodating one of the protons on the side chain. Dissociation of [a 3 + H] 2+ ions derived from peptides containing only aliphatic residues is by cleavage of the second amide bond to give [b 2 ] + or [a 2 ] + ions along with internal [a 1 ] + ions. For [a 3 + H] 2+ ions containing a tryptophan residue in the central location, in addition to cleavage of the amide bond, losses of neutrals NH 3 , HN═CHR, (NH 3 + CO), and HNCO were observed. Dissociations of some unsolvated Ln 3+ /tripeptide complexes gave [b 3 + H] 2+ ions in low abundance; formation of these [b 3 + H] 2+ ions was favored by the presence of a proline residue at the N-terminus and by either a histidine or tryptophan residue in the central position. Dissociation of these [b 3 + H] 2+ ions was by the loss of (H 2 O + CO) and not only CO, indicating that these ions did not have the same type of oxazolone structure as found for [b n ] + ions. Density functional theory calculations suggest that the observed [b 3 + H] 2+ ions of ProGlyGly were formed from [Ce(ProGlyGly)] 3+ complexes in which the peptide was bound to the metal ion as an enolate. Dissociation of the slightly lower-energy complex, where the peptide is bound in the keto form, would produce an oxazolone but the high barrier required to create this isomer of the [b 3 + H] 2+ ion would be sufficient to result in further dissociation. Two isomers of the [b 3 + H] 2+ ion of ProHisGly have been created, one from the [Ce(ProHisGly)] 3+ complex that characteristically dissociates by the combined loss of (H 2 O + CO) and the other by the loss of glycine from [ProHisGlyGly + 2H] 2+ . The [b 3 + H] 2+ ion derived from [ProHisGlyGly + 2H] 2+ dissociated by the loss of only CO.

The role of macrophages in fibrosing steatohepatitis is largely unclear. We characterized the origin and molecular mechanisms of macrophages and its targeted therapy of fibrosing steatohepatitis. Fibrosing steatohepatitis was established in Alms1 mutant (foz/foz) and C57BL/6J wildtype mice fed high-fat/high-cholesterol or methionine- and choline-deficient diet. Bone marrow transplantation was performed to track the macrophage origin in fibrosing steatohepatitis. Macrophages were depleted using liposomal clodronate. Primary macrophages were isolated from bone marrow for adoptive transfer into mice. We found that macrophage infiltration is induced in two mouse models of fibrosing steatohepatitis and human nonalcoholic steatohepatitis-fibrosis patients. Bone marrow-derived macrophages (BMMs) contribute to the hepatic macrophage accumulation in experimental fibrosing steatohepatitis. Depletion of hepatic BMMs by liposomal clodronate during liver injury attenuated fibrosing steatohepatitis, whilst BMMs depletion after liver injury delayed the regression of fibrosing steatohepatitis. The pro-fibrotic effect of macrophages was associated with reduced activation of hepatic stellate cells (HSCs), collagen deposition and hepatic expression of key pro-fibrotic factors (TIMP1, TIMP2, and TGFβ1) and endoplasmic reticulum stress markers (GRP78, IRE1α, and PDI). Conversely, adoptive transfer of BMMs significantly aggravated fibrosing steatohepatitis. Moreover, macrophage-conditioned medium directly promoted the phenotypic transition of primary quiescent HSCs to activated HSCs; it enhanced activation and proliferation but decreased apoptosis of HSC cell lines (LX-2 and HSC-T6). The effect of BMMs in promoting fibrosing steatohepatitis was mediated by inducing key pro-fibrosis factors and signaling pathways including cytokine/chemokine, TGFβ and complement cascade as assessed by cDNA expression array. Complement 3a receptor (C3ar1) was a predominant effector of macrophage mediated fibrosing steatohepatitis. Knockout of C3ar1 in mice blunted development of fibrosing steatohepatitis. In conclusion, BMMs promoted the progression of fibrosing steatohepatitis during injury, whereas macrophages reduced fibrosing steatohepatitis in the recovery phase of liver injury. Increasing anti-fibrotic macrophages and decreasing pro-fibrotic macrophages are promising approaches for fibrosing steatohepatitis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Purpose: To determine the influence of compression factor upon changes in axial length and choroidal thickness during and following orthokeratology treatment., Methods: Orthokeratology lenses of different compression factors (one eye with 0.75 D and the fellow eye with 1.75 D) were randomly assigned to 28 subjects (median [range] age: 9.3 [7.8-11.0] years). Ocular biometrics were measured weekly for 1 month of lens wear and after lens cessation until the refraction stabilized (mean duration: 2.8 ± 0.4 weeks). Changes between eyes, and the associations between axial shortening and choroidal thickening with other ocular biometrics were analyzed., Results: There were no significant between-eye differences in the changes of ocular biometrics (all P > 0.05). After adjusting for paired-eye data, axial length initially decreased by 26 ± 41 μm ( P = 0.03) at week 1, then gradually returned to its original length. An approximate antiphase relationship of choroidal thickness (mean change: 9 ± 12 μm, P < 0.001) with axial length was observed. A significant rebound in axial length, but not choroidal thickness, occurred during the cessation period. Central corneal thinning and choroidal thickening accounted for 70% of initial axial shortening., Conclusions: Increasing the compression factor by 1.00 D did not affect changes in ocular biometrics in short-term orthokeratology. Significant axial shortening and choroidal thickening were observed during early treatment period. Axial shortening could not be entirely explained by central corneal thinning and choroidal thickening, which warrants further investigation., Translational Relevance: Initial axial shortening in orthokeratology is transient and therefore axial length remains useful for long-term monitoring of axial elongation in children.

Structures of [Ce(GGG)] 3+ and [Ce(GGG ? H)] 2+ have been investigated by DFT calculations. The two lowest-energy structures of the triply charged metal complex have the peptide in either the iminol or conventional zwitterionic form, and these ions have almost identical energies. In the doubly charged complex, the iminol and charge-solvated structures are the best structures on the potential energy surface, but the latter is favored. In both iminol structures, the metal ion coordinates to the iminol oxygen rather than to the nitrogen, unlike in previously reported iminol-containing complexes. Triply charged [Ce(peptide)] 3+ complexes are fragile and not easily isolated in a mass spectrometer, whereas the doubly charged [Ce(peptide ? H)] 2+ complexes are more robust. Here, we studied the fragmentations of 37 [Ce(peptide ? H)] 2+ and 30 [Ce(peptide)(peptide ? H)] 2+ complexes and the results are systematically summarized. Losses of CO and/or H 2 O are the most commonly observed fragmentation channels for [Ce(peptide ? H)] 2+ complexes and these dissociation pathways are modeled by DFT calculations. For [Ce(peptide)(peptide ? H)] 2+ complexes the neutral peptide plays the role of a solvent molecule but, unlike in the dissociations of [Ce(CH 3 CN)(peptide ? H)] 2+ complexes, the loss of the solvent molecule is not observed. Instead, fragmentation occurs by cleavage of the second amide bond of the solvating peptide molecule.

Objectives: Anaemia is associated with increased mortality in acute pulmonary embolism (PE) patients. However, prior studies have not examined the prognostic impact of trends in plasma haemoglobin during admission. This study investigates the impact of changes in haemoglobin level on mortality during hospital stay in acute PE., Study Design: A retrospective observational study., Setting: Tertiary-referral centre in Australia., Participants: Consecutive patients from 2000 to 2012 admitted with confirmed acute PE were identified from a dedicated PE database. Haemoglobin levels on days 1, 3-4, 5-6 and 7 of admission were retrieved. Patients without both baseline haemoglobin and subsequent haemoglobin levels were excluded (n=327), leaving 1099 patients as the study cohort. Anaemia was defined as haemoglobin <130 g/L for men and <120 g/L for women. There were 576 patients without anaemia throughout admission, 65 with transient anaemia (anaemic on day 1, but subsequently normalised during admission), 122 with acquired anaemia (normal on day 1 but developed anaemia during admission) and 336 with persistent anaemia. A total of 71 patients received blood transfusion during admission., Main Outcome Measure: 6-month mortality was tracked from a state-wide death database and analysed using multivariable modelling., Results: After adjusting for transfusion, patietns with persistent anaemia had a significantly increased 6-month mortality risk (adjusted HR 1.97, 95% CI 1.26 to 3.09, p=0.003) compared with patients without anaemia. There was no difference in mortality between patients with transient or acquired anaemia and patients without anaemia., Conclusion: Among patients who had anaemia during their admission for acute PE, only the subgroup with persistent anaemia demonstrated worse outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the repeatability of choroidal thickness measurements determined from enhanced depth imaging optical coherence tomography (EDI-OCT) images of eyes after wearing single-vision spectacles (SV) and orthokeratology (ortho-k) lenses., Methods and Analysis: Two EDI-OCT images of 40 children (SV: 20, ortho-k: 20) taken at a single visit were analysed twice. Subjects in the ortho-k group had been wearing ortho-k for 1-4 weeks. The choroidal thickness was determined from each image using a graph theory-based software and, where appropriate, manual correction of choroidal boundaries was undertaken by an experienced examiner., Results: The mean (±SD) choroidal thickness was 227.3±42.2 µm for the SV subjects and 251.1±54.4 µm for the ortho-k subjects. The interimage differences in choroidal thickness were -0.99±3.54 and -1.14±5.03 µm for the SV and ortho-k subjects, respectively, and the limits of agreement were +5.96 to -7.93 and +8.72 to -11.00 µm, respectively., Conclusion: The coefficients of repeatability of choroidal thickness measurements from two EDI-OCT images taken at a single visit were 7.08 µm (SV) and 10.06 µm (ortho-k), suggesting that a change in choroidal thickness of less than 10 µm may not indicate a real change resulting from ortho-k lens wear., Competing Interests: Competing interests: None declared.

Two types of radical cations of tryptophan-the π-radical cation and the protonated tryptophan-N radical-have been studied in dipeptides AW and WA. The π-radical cation produced by removal of an electron during collision-induced dissociation of a ternary Cu(II) complex was only observed for the AW peptide. In the case of WA, only the ion corresponding to the loss of ammonia, [WA-NH 3 ] •+ , was observed from the copper complex. Both protonated tryptophan-N radicals were produced by N-nitrosylation of the neutral peptides followed by transfer to the gas phase via electrospray ionization and subsequent collision-induced dissociation. The regiospecifically formed N • species were characterized by infrared multiple-photon dissociation spectroscopy which revealed that the WA tryptophan-N • radical remains the nitrogen radical, while the AW nitrogen radical rearranges into the π-radical cation. These findings are supported by the density functional theory calculations that suggest a relatively high barrier for the radical rearrangement (N • to π) in WA (156.3 kJ mol -1 ) and a very low barrier in AW (6.1 kJ mol -1 ). The facile hydrogen atom migration in the AW system is also supported by the collision-induced dissociation of the tryptophan-N radical species that produces fragments characteristic of the tryptophan π-radical cation. Gas-phase ion-molecule reactions with n-propyl thiol have also been used to differentiate between the π-radical cations (react by hydrogen abstraction) and the tryptophan-N • species (unreactive) of AW.

The neurotransmitter acetylcholine (ACh) acts as an autocrine growth factor for human lung cancer. Several lines of evidence show that lung cancer cells express all of the proteins required for the uptake of choline (choline transporter 1, choline transporter-like proteins) synthesis of ACh (choline acetyltransferase, carnitine acetyltransferase), transport of ACh (vesicular acetylcholine transport, OCTs, OCTNs) and degradation of ACh (acetylcholinesterase, butyrylcholinesterase). The released ACh binds back to nicotinic (nAChRs) and muscarinic receptors on lung cancer cells to accelerate their proliferation, migration and invasion. Out of all components of the cholinergic pathway, the nAChR-signaling has been studied the most intensely. The reason for this trend is due to genome-wide data studies showing that nicotinic receptor subtypes are involved in lung cancer risk, the relationship between cigarette smoke and lung cancer risk as well as the rising popularity of electronic cigarettes considered by many as a "safe" alternative to smoking. There are a small number of articles which review the contribution of the other cholinergic proteins in the pathophysiology of lung cancer. The primary objective of this review article is to discuss the function of the acetylcholine-signaling proteins in the progression of lung cancer. The investigation of the role of cholinergic network in lung cancer will pave the way to novel molecular targets and drugs in this lethal malignancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Temporary-transvenous-cardiac-pacing (TTCP) is a potentially lifesaving procedure, however trends in its utilization and outcomes in unselected contemporary populations are all unknown., Methods: Consecutive patients requiring TTCP between July-1, 2000 and December-31, 2013 were identified from a statewide registry of admitted patients. In addition, all patients who underwent other cardiac procedures including permanent-pacemaker (PPM) implantation, automated-implantable-cardiac-defibrillator (AICD) implantation, percutaneous-coronary-intervention (PCI), or coronary-artery-bypass-graft (CABG) surgery were identified for comparative outcome analyses. Survival was tracked from a statewide death registry., Results: A total of 4838 patients (mean age [±standard deviation] 74.7 ± 12.7 years; 58.0% males) requiring TTCP were identified. The incidence for TTCP was 5.86 ± 1.06 cases per-100,000-persons-per-annum, declining by 46% between 2003 and 2013. During 4.2 ± 3.7 years of follow-up, 2594 (53.6%) patients died, of whom 569 (11.8%) died during the index admission. Weekend admission was associated with increased mortality compared to weekdays (hazard ratio: 1.15, 95% confidence interval [CI] 1.06-1.26, p = 0.002) and independently predicted all-cause death. After adjusting for age, gender, comorbidities, and referral source for admission, patients requiring TTCP had worse survival than those undergoing PPM (n = 17,988) or AICD (n = 5264) implantation, PCI (n = 46,859), or CABG surgery (n = 50,992) (adjusted hazard ratio [aHR]: 2.14, 95% CI 1.94-2.37; aHR: 1.61, 95% CI 1.41-1.83; aHR: 1.76, 95% CI 1.61-1.93; aHR: 2.09, 95% CI 1.98-2.21 respectively, all p < 0.001)., Conclusion: TTCP utilization is decreasing and is associated with substantial in-hospital and long-term mortality with weekend-weekday variation in outcome. Further studies are needed to develop strategies to better understand the determinants of adverse outcomes of these patients, as well as appropriate strategies for outcome improvement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background Remote ischemic preconditioning (RIPC) attenuates myocardial damage during elective and primary percutaneous coronary intervention. Recent studies suggest that coronary microcirculatory function is an important determinant of clinical outcome. The aim of this study was to assess the effect of RIPC on markers of microcirculatory function. Methods and Results Patients referred for cardiac catheterization and fractional flow reserve measurement were randomized to RIPC or sham. Operators and patients were blinded to treatment allocation. Comprehensive physiological assessments were performed before and after RIPC/sham including the index of microcirculatory resistance and coronary flow reserve after intracoronary glyceryl trinitrate and during the infusion of intravenous adenosine. Thirty patients were included (87% male; mean age: 63.1±10.0 years). RIPC and sham groups were similar with respect to baseline characteristics. RIPC decreased the calculated index of microcirculatory resistance (median, before RIPC: 22.6 [interquartile range [IQR]: 17.9-25.6]; after RIPC: 17.5 [IQR: 14.5-21.3]; P=0.007) and increased coronary flow reserve (2.6±0.9 versus 3.8±1.7, P=0.001). These RIPC-mediated changes were associated with a reduction in hyperemic transit time (median: 0.33 [IQR: 0.26-0.40] versus 0.25 [IQR: 0.20-0.30]; P=0.010). RIPC resulted in a significant decrease in the calculated index of microcirculatory resistance compared with sham (relative change with treatment [mean±SD] was -18.1±24.8% versus +6.1±37.5; P=0.047) and a significant increase in coronary flow reserve (+41.2% [IQR: 20.0-61.7] versus -7.8% [IQR: -19.1 to 10.3]; P<0.001). Conclusions The index of microcirculatory resistance and coronary flow reserve are acutely improved by remote ischemic preconditioning. This raises the possibility that RIPC confers cardioprotection during percutaneous coronary intervention as a result of an improvement in coronary microcirculatory function. Clinical Trial Registration URL: www.anzctr.org.au/ . Unique identifier: CTRN12616000486426.

Background and Objective: Blood transfusion has been associated with adverse outcomes in certain conditions. This study investigates the prevalence and outcomes of red blood cell (RBC) transfusion in patients with acute pulmonary embolism (PE)., Methods: Retrospective study of consecutive patients from 2000 to 2012 admitted to a tertiary hospital with a primary diagnosis of acute PE. Transfusion status during the hospital admission was ascertained. Mortality was tracked from a state-wide death database and analysed using multivariable modelling., Results: A total of 73 patients (5% of all patients admitted with PE) received RBC transfusion during their admission. These patients were significantly older, had more co-morbidities, worse haemodynamics, higher simplified pulmonary embolism severity index scores, and lower plasma sodium and haemoglobin (Hb) levels at admission. Unadjusted mortality for the transfused group was significantly higher at 30-day (19% vs 4%, P < 0.001) and 6-month (40% vs 10%, P < 0.001) follow-up. Multivariable modelling showed RBC transfusion to be a significant independent predictor of mortality at 30-day (odds ratio 3.06, 95% CI: 1.17-8.01, P = 0.02) and 6-month (hazard ratio (HR) 1.97, 95% CI: 1.12-3.46, P = 0.02). Sensitivity analysis confirmed that transfused patients had higher mortality than non-transfused patients in the subgroup of patients with Hb <100 g/L., Conclusion: RBC transfusion in patients hospitalized with acute PE is rare and appears to be associated with increased risk of short- and long-term mortality, independent of Hb level on admission. This finding underscores the need for future randomized controlled studies on the impact of RBC transfusion in the management of patients admitted with acute PE. [Correction added on 4 May 2018, after first online publication: the word 'serum' was changed to 'plasma' throughout the article where appropriate.]., (© 2018 Asian Pacific Society of Respirology.)

Collision-induced dissociation of isotopically labelled protonated pentaglycine produced two abundant [b5]+ ions, the products of the loss of water from the first and second amide groups, labelled [b5]+I and [b5]+II. IRMPD spectroscopy and DFT calculations show that these two [b5]+ ions feature N1-protonated 3,5-dihydro-4H-imidazol-4-one structures. 15N-Labelling established that some interconversion occurs between these two ions but dissociations are preferred. For both ions, DFT calculations show that the barrier to interconversion is slightly higher than those to dissociation. Dehydration of protonated hexaglycine produced three imidazolone ions. Ions [b6]+I and [b6]+II exhibit analogous CID spectra to those from [b5]+I and [b5]+II; however, the spectrum of the [b6]+III ion was dramatically different, showing losses predominantly of a further water molecule or cleavage of the second amide bond to give the glycyloxazolone (a deprotonated [b2]+ ion, labelled GlyGlyox (114 Da)) from the N-terminus. Protonated polyglycines [Glyn + H]+, where n = 7-9, all readily lose at least one water molecule. The corresponding [bn]+ ions lose either a further water molecule, an oxazolone from the N-terminus or a truncated peptide from the C-terminus. The number of amino acid residues in the latter two eliminated neutral molecules provides insight into the location of the imidazolone in the peptide chain and which oxygen was lost in the initial dehydration reaction. From this analysis, it appears that water loss from the longer protonated polyglycines is predominantly from the central residues.

Essentials Procoagulant platelets can be detected using GSAO in human whole blood. Stable coronary artery disease is associated with a heightened procoagulant platelet response. Agonist-induced procoagulant platelet response is not inhibited by aspirin alone. Collagen plus thrombin induced procoagulant platelet response is partially resistant to clopidogrel., Summary: Background Procoagulant platelets are a subset of highly activated platelets with a critical role in thrombin generation. Evaluation of their clinical utility in thrombotic disorders, such as coronary artery disease (CAD), has been thwarted by the lack of a sensitive and specific whole blood assay. Objectives We developed a novel assay, utilizing the cell death marker, GSAO [(4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid], and the platelet activation marker, P-selectin, to identify procoagulant platelets in whole blood by flow cytometry. Patients/Methods Using this assay, we characterized the procoagulant platelet population in healthy controls and a cohort of patients undergoing elective coronary angiography. Results In patients with CAD, compared with patients without CAD, there was a heightened procoagulant platelet response to thrombin (25.2% vs. 12.2%), adenosine diphosphate (ADP) (7.8% vs. 2.7%) and thrombin plus collagen (27.2% vs. 18.3%). The heightened procoagulant platelet potential in CAD patients was not associated with other markers of platelet function, including aggregation, dense granule release and activation of α 2b β 3 integrin. Although dual antiplatelet therapy (DAPT) was associated with partial suppression of procoagulant platelets, this inhibitory effect on a patient level could not be predicted by aggregation response to ADP and was not fully suppressed by clopidogrel. Conclusions We report for the first time that procoagulant platelets can be efficiently detected in a few microliters of whole blood using the cell death marker, GSAO, and the platelet activation marker, P-selectin. A heightened procoagulant platelet response may provide insight into the thrombotic risk of CAD and help identify a novel target for antiplatelet therapies in CAD., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

This retrospective longitudinal analysis aimed to investigate the association between ocular higher-order aberrations (HOAs) and axial eye growth in Hong Kong children. Measures of axial length and ocular HOAs under cycloplegia were obtained annually over a two-year period from 137 subjects aged 8.8 ± 1.4 years with mean spherical equivalent refraction of -2.04 ± 2.38 D. A significant negative association was observed between the RMS of total HOAs and axial eye growth (P = 0.03), after adjusting for other significant predictors of axial length including age, sex and refractive error. Similar negative associations with axial elongation were found for the RMS of spherical aberrations ([Formula: see text] and [Formula: see text] combined) (P = 0.037). Another linear mixed model also showed that greater levels of vertical trefoil [Formula: see text], primary spherical aberration [Formula: see text] and negative oblique trefoil [Formula: see text] were associated with slower axial elongation and longer axial length (all P < 0.05). These findings support the potential role of HOAs, image quality and a vision-dependent mechanism in childhood eye growth.

Collision-induced dissociations of isotopically labeled protonated tetraglycines establish that the [b 4 ] + ion formed by loss of water from the second amide bond (structure II) rearranges to form N 1 -protonated 3,5-dihydro-4H-imidazol-4-one (structure I), the product of water loss from the first amide bond. Structure II is slightly higher in energy than I (ΔH at 0 K is 5.1 kJ mol -1 , as calculated at M06-2X/6-311++G-(d,p)), and the barrier to interconversion is 139.8 kJ mol -1 above I. The dominant dissociation pathway is the loss of methanimine (HN=CH 2 ) from ion I with a barrier of 167.1 kJ mol -1 , giving [GlyGlyGlyGly + H - H 2 O - HN=CH 2 ] + , ion III; a minor channel, loss of NH 3 , has a slightly higher barrier (181.5 kJ mol -1 ). Using labeled glycine ( 13 C α ) it was determined that loss of the imine is from the same residue as that from which water was initially lost. The collision-induced dissociation spectra of ion III derived from both I and II were identical, and their energy-resolved curves were also very similar. Ion III fragments by losses of a glycine molecule (the dominant channel), a water molecule, and a glycine residue (57 Da), giving ions IV, V, and VII, respectively. Isotopic labeling established the origins of each of the neutral molecules that are lost. Using glycine (2,2 D 2 ), rapid deuterium exchange was observed for both ions I and II for the α-hydrogens that are from the same residue as that from which the water had been eliminated.

In this case, prompt stenting of the dissection entry flap allowed for stabilization and eventual healing of a severe catheter-induced aortic dissection, without resort to surgical intervention.

Background: Despite guideline recommendation of dual antiplatelet therapy (DAPT) in treating ACS, DAPT is underutilized. Our objective was to determine independent predictors of DAPT non-prescription in ACS and describe pattern of DAPT prescription over time., Methods: Patients presenting to 41 Australian hospitals with an ACS diagnosis between 2009 and 2016 were stratified according to discharge prescription with DAPT and single antiplatelet therapy (SAPT) or no antiplatelet therapy. Multiple stepwise logistic regression, accounting for within hospital clustering, was used to determine the independent predictors of DAPT non-prescription, defined as discharge with SAPT alone or no antiplatelet agent., Results: 8939 patients survived to discharge with an ACS diagnosis. Of these, 6294 (70.4%) patients were discharged on DAPT, 2154 (24.1%) on SAPT and 491 (5.5%) on no antiplatelet agent. Independent predictors of DAPT non-prescription in the overall cohort were: in-hospital CABG (OR 0.09, 95%CI 0.05-0.14), discharge with warfarin (0.10 (0.07-0.14)), in hospital major bleeding (0.48 (0.34-0.67), diagnosis of unstable angina (0.35, (0.27-0.45)), non-ST-elevation myocardial infarction (0.67 (0.57-0.78)) [both vs. ST-segment elevation myocardial infarction], in hospital atrial arrhythmia (0.72 (0.60-0.86)), history of hypertension (0.83 (0.73-0.94)) and GRACE high risk (0.83 (0.71-0.98)). There was an increase in prescription of DAPT and a shift towards ticagrelor over clopidogrel for ACS from 2013 to 2016 (p<0.0001), but no overall change in the frequency of DAPT prescription over the entire study period., Conclusion: This study revealed high-risk ACS subgroups who do not receive optimal DAPT. Strategies are necessary to bridge the treatment gap in ACS antiplatelet management., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Discordance between angiography-based anatomical assessment of coronary stenosis severity and fractional flow reserve (FFR) has been attributed to several factors including lesion length and irregularity, and the myocardial territory supplied by the target vessel. We sought to examine if coronary arterial distensibility is an independent contributor to this discordance. There were two parts to this study. The first consisted of "in silico" models of 26 human coronary arteries. Computational fluid dynamics-derived FFR was calculated for fully rigid, partially distensible and fully distensible models of the 26 arteries. The second part of the study consisted of 104 patients who underwent coronary angiography and FFR measurement. Distensibility at the lesion site (DistensibilityMLA) and for the reference vessel (DistensibilityRef) was determined by analysing three-dimensional angiography images during end-systole and end-diastole. Computational fluid dynamics-derived FFR was 0.67±0.19, 0.70±0.18 and 0.75±0.17 (P<0.001) in the fully rigid, partially distensible and fully distensible models respectively. FFR correlated with both DistensibilityMLA (r = 0.36, P<0.001) and DistensibilityRef (r = 0.44, P<0.001). Two-way ANCOVA analysis revealed that DistensibilityMLA (F (1, 100) = 4.17, p = 0.031) and percentage diameter stenosis (F (1, 100) = 60.30, p < 0.01) were both independent predictors of FFR. Coronary arterial distensibility is a novel, independent determinant of FFR, and an important factor contributing to the discordance between anatomical and functional assessment of stenosis severity.

Background: Pulmonary embolism continues to be a significant cause of death. The aim was to derive and validate a risk prediction model for in-hospital death after acute pulmonary embolism to identify low risk patients suitable for outpatient management., Methods: A confirmed acute pulmonary embolism database of 1,426 consecutive patients admitted to a tertiary-center (2000-2012) was analyzed, with odd and even years as derivation and validation cohorts respectively. Risk stratification for in-hospital death was performed using multivariable logistic-regression modelling. Models were compared using receiver-operating characteristic-curve and decision curve analyses., Results: In-hospital mortality was 3.6% in the derivation cohort (n = 693). Adding day-1 sodium and bicarbonate to simplified Pulmonary Embolism Severity Index (sPESI) significantly increased the C-statistic for predicting in-hospital death (0.71 to 0.86, P = 0.001). The validation cohort yielded similar results (n = 733, C-statistic 0.85). The new model was associated with a net reclassification improvement of 0.613, and an integrated discrimination improvement of 0.067. The new model also increased the C-statistic for predicting 30-day mortality compared to sPESI alone (0.74 to 0.83, P = 0.002). Decision curve analysis demonstrated superior clinical benefit with the use of the new model to guide admission for pulmonary embolism, resulting in 43 fewer admissions per 100 presentations based on a risk threshold for admission of 2%., Conclusions: A risk model incorporating sodium, bicarbonate, and the sPESI provides accurate risk prediction of acute in-hospital mortality after pulmonary embolism. Our novel model identifies patients with pulmonary embolism who are at low risk and who may be suitable for outpatient management.