Sequential Deoxygenation of CO2 and NO2- via Redox-Control of a Pyridinediimine Ligand with a Hemilabile Phosphine.

The deoxygenation of environmental pollutants CO2 and NO2- to form value-added products is reported. CO2 reduction with subsequent CO release and NO2- conversion to NO are achieved via the starting complex Fe(PPhPDI)Cl2 (1). 1 contains the redox-active pyridinediimine (PDI) ligand with a hemilabile phosphine located in the secondary coordination sphere. 1 was reduced with SmI2 under a CO2 atmosphere to form the direduced monocarbonyl Fe(PPhPDI)(CO) (2). Subsequent CO release was achieved via oxidation of 2 using the NOx- source, NO2-. The resulting [Fe(PPhPDI)(NO)]+ (3) mononitrosyl iron complex (MNIC) is formed as the exclusive reduction product due to the hemilabile phosphine. 3 was investigated computationally to be characterized as {FeNO}7, an unusual intermediate-spin Fe(III) coupled to triplet NO- and a singly reduced PDI ligand.

Open-source Software Sustainability Models: Initial White Paper From the Informatics Technology for Cancer Research Sustainability and Industry Partnership Working Group.

BACKGROUND: The National Cancer Institute Informatics Technology for Cancer Research (ITCR) program provides a series of funding mechanisms to create an ecosystem of open-source software (OSS) that serves the needs of cancer research. As the ITCR ecosystem substantially grows, it faces the challenge of the long-term sustainability of the software being developed by ITCR grantees. To address this challenge, the ITCR sustainability and industry partnership working group (SIP-WG) was convened in 2019. OBJECTIVE: The charter of the SIP-WG is to investigate options to enhance the long-term sustainability of the OSS being developed by ITCR, in part by developing a collection of business model archetypes that can serve as sustainability plans for ITCR OSS development initiatives. The working group assembled models from the ITCR program, from other studies, and from the engagement of its extensive network of relationships with other organizations (eg, Chan Zuckerberg Initiative, Open Source Initiative, and Software Sustainability Institute) in support of this objective. METHODS: This paper reviews the existing sustainability models and describes 10 OSS use cases disseminated by the SIP-WG and others, including 3D Slicer, Bioconductor, Cytoscape, Globus, i2b2 (Informatics for Integrating Biology and the Bedside) and tranSMART, Insight Toolkit, Linux, Observational Health Data Sciences and Informatics tools, R, and REDCap (Research Electronic Data Capture), in 10 sustainability aspects: governance, documentation, code quality, support, ecosystem collaboration, security, legal, finance, marketing, and dependency hygiene. RESULTS: Information available to the public reveals that all 10 OSS have effective governance, comprehensive documentation, high code quality, reliable dependency hygiene, strong user and developer support, and active marketing. These OSS include a variety of licensing models (eg, general public license version 2, general public license version 3, Berkeley Software Distribution, and Apache 3) and financial models (eg, federal research funding, industry and membership support, and commercial support). However, detailed information on ecosystem collaboration and security is not publicly provided by most OSS. CONCLUSIONS: We recommend 6 essential attributes for research software: alignment with unmet scientific needs, a dedicated development team, a vibrant user community, a feasible licensing model, a sustainable financial model, and effective product management. We also stress important actions to be considered in future ITCR activities that involve the discussion of the sustainability and licensing models for ITCR OSS, the establishment of a central library, the allocation of consulting resources to code quality control, ecosystem collaboration, security, and dependency hygiene.

NO Coupling by Nonclassical Dinuclear Dinitrosyliron Complexes to Form N2O Dictated by Hemilability.

Selective coupling of NO by a nonclassical dinuclear dinitrosyliron complex (D-DNIC) to form N2O is reported. The coupling is facilitated by the pyridinediimine (PDI) ligand scaffold, which enables the necessary denticity changes to produce mixed-valent, electron-deficient tethered DNICs. One-electron oxidation of the [{Fe(NO)2}]210/10 complex Fe2(PyrrPDI)(NO)4 (4) results in NO coupling to form N2O via the mixed-valent {[Fe(NO)2]2}9/10 species, which possesses an electron-deficient four-coordinate {Fe(NO)2}10 site, crucial in N-N bond formation. The hemilability of the PDI scaffold dictates the selectivity in N-N bond formation because stabilization of the five-coordinate {Fe(NO)2}9 site in the mixed-valent [{Fe(NO)2}]29/10 species, [Fe2(Pyr2PDI)(NO)4][PF6] (6), does not result in an electron-deficient, four-coordinate {Fe(NO)2}10 site, and hence no N-N coupling is observed.

Introduction to Artificial Intelligence and Machine Learning for Pathology.

CONTEXT.­: Recent developments in machine learning have stimulated intense interest in software that may augment or replace human experts. Machine learning may impact pathology practice by offering new capabilities in analysis, interpretation, and outcomes prediction using images and other data. The principles of operation and management of machine learning systems are unfamiliar to pathologists, who anticipate a need for additional education to be effective as expert users and managers of the new tools. OBJECTIVE.­: To provide a background on machine learning for practicing pathologists, including an overview of algorithms, model development, and performance evaluation; to examine the current status of machine learning in pathology and consider possible roles and requirements for pathologists in local deployment and management of machine learning systems; and to highlight existing challenges and gaps in deployment methodology and regulation. DATA SOURCES.­: Sources include the biomedical and engineering literature, white papers from professional organizations, government reports, electronic resources, and authors' experience in machine learning. References were chosen when possible for accessibility to practicing pathologists without specialized training in mathematics, statistics, or software development. CONCLUSIONS.­: Machine learning offers an array of techniques that in recent published results show substantial promise. Data suggest that human experts working with machine learning tools outperform humans or machines separately, but the optimal form for this combination in pathology has not been established. Significant questions related to the generalizability of machine learning systems, local site verification, and performance monitoring remain to be resolved before a consensus on best practices and a regulatory environment can be established.

Complete denitrification of nitrate and nitrite to N2 gas by samarium(II) iodide.

The reduction of nitrogen oxides (NxOyn-) to dinitrogen gas by samarium(ii) iodide is reported. The polyoxoanions nitrate (NO3-) and nitrite (NO2-), as well as nitrous oxide (N2O) and nitric oxide (NO) were all shown to react with stoichiometric amounts of SmI2 in THF for the complete denitrification to N2.

Harnessing the active site triad: merging hemilability, proton responsivity, and ligand-based redox-activity.

Metalloenzymes catalyze many important reactions by managing the proton and electron flux at the enzyme active site. The motifs utilized to facilitate these transformations include hemilabile, redox-active, and so called proton responsive sites. Given the importance of incorporating and understanding these motifs in the area of coordination chemistry and catalysis, we highlight recent milestones in the field. Work incorporating the triad of hemilability, redox-activity, and proton responsivity into single ligand scaffolds will be described.

Hemilabile Proton Relays and Redox Activity Lead to {FeNO} x and Significant Rate Enhancements in NO2- Reduction.

Incorporation of the triad of redox activity, hemilability, and proton responsivity into a single ligand scaffold is reported. Due to this triad, the complexes Fe(PyrrPDI)(CO)2 (3) and Fe(MorPDI)(CO)2 (4) display 40-fold enhancements in the initial rate of NO2- reduction, with respect to Fe(MeOPDI)(CO)2 (7). Utilizing the proper sterics and p Ka of the pendant base(s) to introduce hemilability into our ligand scaffolds, we report unusual {FeNO} x mononitrosyl iron complexes (MNICs) as intermediates in the NO2- reduction reaction. The {FeNO} x species behave spectroscopically and computationally similar to {FeNO}7, an unusual intermediate-spin Fe(III) coupled to triplet NO- and a singly reduced PDI ligand. These {FeNO} x MNICs facilitate enhancements in the initial rate.

Career Paths of Pathology Informatics Fellowship Alumni.

BACKGROUND: The alumni of today's Pathology Informatics and Clinical Informatics fellowships fill diverse roles in academia, large health systems, and industry. The evolving training tracks and curriculum of Pathology Informatics fellowships have been well documented. However, less attention has been given to the posttraining experiences of graduates from informatics training programs. Here, we examine the career paths of subspecialty fellowship-trained pathology informaticians. METHODS: Alumni from four Pathology Informatics fellowship training programs were contacted for their voluntary participation in the study. We analyzed various components of training, and the subsequent career paths of Pathology Informatics fellowship alumni using data extracted from alumni provided curriculum vitae. RESULTS: Twenty-three out of twenty-seven alumni contacted contributed to the study. A majority had completed undergraduate study in science, technology, engineering, and math fields and combined track training in anatomic and clinical pathology. Approximately 30% (7/23) completed residency in a program with an in-house Pathology Informatics fellowship. Most completed additional fellowships (15/23) and many also completed advanced degrees (10/23). Common primary posttraining appointments included chief medical informatics officer (3/23), director of Pathology Informatics (10/23), informatics program director (2/23), and various roles in industry (3/23). Many alumni also provide clinical care in addition to their informatics roles (14/23). Pathology Informatics alumni serve on a variety of institutional committees, participate in national informatics organizations, contribute widely to scientific literature, and more than half (13/23) have obtained subspecialty certification in Clinical Informatics to date. CONCLUSIONS: Our analysis highlights several interesting phenomena related to the training and career trajectory of Pathology Informatics fellowship alumni. We note the long training track alumni complete in preparation for their careers. We believe flexible training pathways combining informatics and clinical training may help to alleviate the burden. We highlight the importance of in-house Pathology Informatics fellowships in promoting interest in informatics among residents. We also observe the many important leadership roles in academia, large community health systems, and industry available to early career alumni and believe this reflects a strong market for formally trained informaticians. We hope this analysis will be useful as we continue to develop the informatics fellowships to meet the future needs of our trainees and discipline.

Uncoupled Redox-Inactive Lewis Acids in the Secondary Coordination Sphere Entice Ligand-Based Nitrite Reduction.

Metal complexes composed of redox-active pyridinediimine (PDI) ligands are capable of forming ligand-centered radicals. In this Forum article, we demonstrate that integration of these types of redox-active sites with bioinspired secondary coordination sphere motifs produce direduced complexes, where the reduction potential of the ligand-based redox sites is uncoupled from the secondary coordination sphere. The utility of such ligand design was explored by encapsulating redox-inactive Lewis acidic cations via installation of a pendant benzo-15-crown-5 in the secondary coordination sphere of a series of Fe(PDI) complexes. Fe(15bz5PDI)(CO)2 was shown to encapsulate the redox-inactive alkali ion, Na+, causing only modest (31 mV) anodic shifts in the ligand-based redox-active sites. By uncoupling the Lewis acidic sites from the ligand-based redox sites, the pendant redox-inactive ion, Na+, can entice the corresponding counterion, NO2-, for reduction to NO. The subsequent initial rate analysis reveals an acceleration in anion reduction, confirming this hypothesis.

Ligand-based reduction of nitrate to nitric oxide utilizing a proton-responsive secondary coordination sphere.

Utilizing the proton-responsive pyridinediimine ligand [(2,6-iPrC6H3)(N[double bond, length as m-dash]CMe)(N(iPr)2C2H4)(N[double bond, length as m-dash]CMe)C5H3N] (didpa), the ligand-based reduction of nitrate (NO3-) to nitric oxide (NO) was achieved. The bioinspired [Fe(Hdidpa)(CO)2]+ was shown to react with tetrabutylammonium nitrate to form the dinitrosyl iron complex [Fe(didpa)(NO)2]+. The didpa scaffold was shown to provide two electrons for the net reduction of NO3- to NO in 43% yield.

The feasibility and effectiveness of Catch It, an innovative CBT smartphone app.

BACKGROUND: The widespread use of smartphones makes effective therapies such as cognitive-behavioural therapy (CBT) potentially accessible to large numbers of people. AIMS: This paper reports the usage data of the first trial of Catch It, a new CBT smartphone app. METHOD: Uptake and usage rates, fidelity of user responses to CBT principles, and impact on reported negative and positive moods were assessed. RESULTS: A relatively modest proportion of people chose to download the app. Once used, the app tended to be used more than once, and 84% of the user-generated content was consistent with the basic concepts of CBT. There were statistically significant reductions in negative mood intensity and increases in positive mood intensity. CONCLUSIONS: Smartphone apps have potential beneficial effects in mental health through the application of basic CBT principles. More research with randomised controlled trial designs should be conducted. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Nitrite reduction by a pyridinediimine complex with a proton-responsive secondary coordination sphere.

The proton-responsive pyridinediimine ligand, (DEA)PDI (where (DEA)PDI = [(2,6-(i)PrC6H3)(N[double bond, length as m-dash]CMe)(N(Et)2C2H4)(N[double bond, length as m-dash]CMe)C5H3N]) was utilized for the reduction of NO2(-) to NO. Nitrite reduction is facilitated by the protonated secondary coordination sphere coupled with the ligand-based redox-active sites of [Fe(H(DEA)PDI)(CO)2](+) and results in the formation of the {Fe(NO)2}(9) DNIC, [Fe((DEA)PDI)(NO)2](+).

Perceptions of pathology informatics by non-informaticist pathologists and trainees.

BACKGROUND: Although pathology informatics (PI) is essential to modern pathology practice, the field is often poorly understood. Pathologists who have received little to no exposure to informatics, either in training or in practice, may not recognize the roles that informatics serves in pathology. The purpose of this study was to characterize perceptions of PI by noninformatics-oriented pathologists and to do so at two large centers with differing informatics environments. METHODS: Pathology trainees and staff at Cleveland Clinic (CC) and Massachusetts General Hospital (MGH) were surveyed. At MGH, pathology department leadership has promoted a pervasive informatics presence through practice, training, and research. At CC, PI efforts focus on production systems that serve a multi-site integrated health system and a reference laboratory, and on the development of applications oriented to department operations. The survey assessed perceived definition of PI, interest in PI, and perceived utility of PI. RESULTS: The survey was completed by 107 noninformatics-oriented pathologists and trainees. A majority viewed informatics positively. Except among MGH trainees, confusion of PI with information technology (IT) and help desk services was prominent, even in those who indicated they understood informatics. Attendings and trainees indicated desire to learn more about PI. While most acknowledged that having some level of PI knowledge would be professionally useful and advantageous, only a minority plan to utilize it. CONCLUSIONS: Informatics is viewed positively by the majority of noninformatics pathologists at two large centers with differing informatics orientations. Differences in departmental informatics culture can be attributed to the varying perceptions of PI by different individuals. Incorrect perceptions exist, such as conflating PI with IT and help desk services, even among those who claim to understand PI. Further efforts by the PI community could address such misperceptions, which could help enable a better understanding of what PI is and is not, and potentially lead to increased acceptance by non-informaticist pathologists.

Stabilization of a Zn(ii) hydrosulfido complex utilizing a hydrogen-bond accepting ligand.

Hydrogen sulfide (H2S) has gained recent attention as an important biological analyte that interacts with bioinorganic targets. Despite this importance, stable H2S or HS(-) adducts of bioinorganic metal complexes remain rare due to the redox activity of sulfide and its propensity to form insoluble metal sulfides. We report here reversible coordination of HS(-) to Zn(didpa)Cl2, which is enabled by an intramolecular hydrogen bond between the zinc hydrosulfido product and the pendant tertiary amine of the didpa ligand.

Square planar Cu(I) stabilized by a pyridinediimine ligand.

A set of distorted square planar Cu(I) complexes were synthesized and characterized utilizing the sterically encumbering pyridinediimine ligand, (iPr)PDI (where (iPr)PDI = 2,6-(2,6-(i)Pr2C6H3N=CMe)2C5H3N). The oxidation state of the Cu center(s) were elucidated to be Cu(I) with a neutral PDI ligand system based on structural, spectroscopic, and computational data.

Pyridinediimine Iron Complexes with Pendant Redox-Inactive Metals Located in the Secondary Coordination Sphere.

A series of pyridinediimine (PDI) iron complexes that contain a pendant 15-crown-5 located in the secondary coordination sphere were synthesized and characterized. The complex Fe((15c5)PDI)(CO)2 (2) was shown in both the solid state and solution to encapsulate redox-inactive metal ions. Modest shifts in the reduction potential of the metal-ligand scaffold were observed upon encapsulation of either Na(+) or Li(+).

Computational Pathology: A Path Ahead.

CONTEXT: We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. OBJECTIVE: To define the scope and needs of computational pathology. DATA SOURCES: A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. CONCLUSIONS: The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and nonpathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology.

Probing the Protonation State and the Redox-Active Sites of Pendant Base Iron(II) and Zinc(II) Pyridinediimine Complexes.

Utilizing the pyridinediimine ligand [(2,6-(i)PrC6H3)N═CMe)(N((i)Pr)2C2H4)N═CMe)C5H3N] (didpa), the zinc(II) and iron(II) complexes Zn(didpa)Cl2 (1), Fe(didpa)Cl2 (2), [Zn(Hdidpa)Cl2][PF6] (3), [Fe(Hdidpa)Cl2][PF6] (4), Zn(didpa)Br2 (5), and [Zn(Hdidpa)Br2][PF6] (6), Fe(didpa)(CO)2 (7), and [Fe(Hdidpa)(CO)2][PF6] (8) were synthesized and characterized. These complexes allowed for the study of the secondary coordination sphere pendant base and the redox-activity of the didpa ligand scaffold. The protonated didpa ligand is capable of forming metal halogen hydrogen bonds (MHHBs) in complexes 3, 4, and 6. The solution behavior of the MHHBs was probed via pKa measurements and (1)H NMR titrations of 3 and 6 with solvents of varying H-bond accepting strength. The H-bond strength in 3 and 6 was calculated in silico to be 5.9 and 4.9 kcal/mol, respectively. The relationship between the protonation state and the ligand-based redox activity was probed utilizing 7 and 8, where the reduction potential of the didpa scaffold was found to shift by 105 mV upon protonation of the reduced ligand in Fe(didpa)(CO)2.

Whole slide imaging for human epidermal growth factor receptor 2 immunohistochemistry interpretation: Accuracy, Precision, and reproducibility studies for digital manual and paired glass slide manual interpretation.

BACKGROUND: The use of digital whole slide imaging for human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) could create improvements in workflow and performance, allowing for central archiving of specimens, distributed and remote interpretation, and the potential for additional computerized automation. PROCEDURES: The accuracy, precision, and reproducibility of manual digital interpretation for HER2 IHC were determined by comparison to manual glass slide interpretation. Inter- and intra-pathologist reproducibility and precision between the glass slide and digital interpretations of HER2 IHC were determined in 5 studies using DAKO HercepTest-stained breast cancer slides with the Philips Digital Pathology System. In 2 inter-method studies, 3 pathologists interpreted glass and digital slides in sequence or in random order with a minimum of 7 days as a washout period. These studies also measured inter-observer reproducibility and precision. Another two studies measured intra-pathologist reproducibility on cases read 10 times by glass and digital methods. One additional study evaluated the effects of adding IHC control slides with each run, using 1 pathologist interpreting glass and digital slides randomized from the sets above along with appropriate controls for each slide in the set. RESULTS: The overall results show that there is no statistical difference between the variance of performance when comparing glass and digital HER2 interpretations; and there were no effects noted when control tissues were evaluated in conjunction with the test slides. CONCLUSIONS: The results show that there is an equivalence of result when interpreting HER2 IHC slides in breast cancer by either glass slides or digital images. Digital interpretation can therefore be safely and effectively used for this purpose.