Improving the accuracy of 31P NMR chemical shift calculations by use of scaling methods.

Calculation of 31P NMR chemical shifts for a series of tri- and tetracoordinate phosphorus compounds using several basis sets and density functional theory (DFT) functionals gave a modest fit to experimental chemical shifts, but an excellent linear fit when plotted against the experimental values. The resultant scaling methods were then applied to a variety of "large" compounds previously selected by Latypov et al. and a set of stereoisomeric and unusual compounds selected here. No one method was best for all structural types. For compounds that contain P-P bonds and P-C multiple bonds, the Latypov et al. method using the PBE0 functional was best (mean absolute deviation/root mean square deviation (MAD/RMSD) = 6.9/8.5 ppm and 6.6/8.2 ppm, respectively), but for the full set of compounds gave higher deviations (MAD/RMSD = 8.2/12.3 ppm), and failed by over 60 ppm for a three-membered phosphorus heterocycle. Use of the M06-2X functional for both the structural optimization and NMR chemical shift calculation was best overall for the compounds without P-C multiple bonds (MAD/RMSD = 5.4/7.1 ppm), but failed by 30-49 ppm for compounds having any P-C multiple-bond character. Failures of these magnitudes have not been reported previously for these widely used functionals. These failures were then used to screen a variety of recommended functionals, leading to better overall methods for calculation of these chemical shifts: optimization with the M06-2X functional and NMR calculation with the PBE0 or ωB97x-D functionals gave values for MAD/RMSD = 6.9/8.5 ppm and 6.8/9.1 ppm, respectively, over an experimental chemical shift range of -181 to 356 ppm. Due to the unexplained failures observed, we recommend use of more than one method when looking at novel structures.

A comparative analysis of system features used in the TREC-COVID information retrieval challenge.

The COVID-19 pandemic has resulted in a rapidly growing quantity of scientific publications from journal articles, preprints, and other sources. The TREC-COVID Challenge was created to evaluate information retrieval (IR) methods and systems for this quickly expanding corpus. Using the COVID-19 Open Research Dataset (CORD-19), several dozen research teams participated in over 5 rounds of the TREC-COVID Challenge. While previous work has compared IR techniques used on other test collections, there are no studies that have analyzed the methods used by participants in the TREC-COVID Challenge. We manually reviewed team run reports from Rounds 2 and 5, extracted features from the documented methodologies, and used a univariate and multivariate regression-based analysis to identify features associated with higher retrieval performance. We observed that fine-tuning datasets with relevance judgments, MS-MARCO, and CORD-19 document vectors was associated with improved performance in Round 2 but not in Round 5. Though the relatively decreased heterogeneity of runs in Round 5 may explain the lack of significance in that round, fine-tuning has been found to improve search performance in previous challenge evaluations by improving a system's ability to map relevant queries and phrases to documents. Furthermore, term expansion was associated with improvement in system performance, and the use of the narrative field in the TREC-COVID topics was associated with decreased system performance in both rounds. These findings emphasize the need for clear queries in search. While our study has some limitations in its generalizability and scope of techniques analyzed, we identified some IR techniques that may be useful in building search systems for COVID-19 using the TREC-COVID test collections.

Searching for scientific evidence in a pandemic: An overview of TREC-COVID.

We present an overview of the TREC-COVID Challenge, an information retrieval (IR) shared task to evaluate search on scientific literature related to COVID-19. The goals of TREC-COVID include the construction of a pandemic search test collection and the evaluation of IR methods for COVID-19. The challenge was conducted over five rounds from April to July 2020, with participation from 92 unique teams and 556 individual submissions. A total of 50 topics (sets of related queries) were used in the evaluation, starting at 30 topics for Round 1 and adding 5 new topics per round to target emerging topics at that state of the still-emerging pandemic. This paper provides a comprehensive overview of the structure and results of TREC-COVID. Specifically, the paper provides details on the background, task structure, topic structure, corpus, participation, pooling, assessment, judgments, results, top-performing systems, lessons learned, and benchmark datasets.

Maltol- and Allomaltol-Derived Oxidopyrylium Ylides: Methyl Substitution Pattern Kinetically Influences [5 + 3] Dimerization versus [5 + 2] Cycloaddition Reactions.

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.

Iron-Catalyzed Transfer Hydrogenation in Aged N-Methyl-2-pyrrolidone: Reductive Ring-Opening of 3,5-Disubstituted Isoxazoles and Isoxazolines.

3,5-Disubstituted isoxazoles and isoxazolines undergo an iron-catalyzed reductive ring-opening in aged N-methyl-2-pyrrolidone (NMP). 5-Hydroxy-N-methyl-2-pyrrolidone generated in situ via a simple activation of commercial NMP acts as the hydrogen donor in the iron-catalyzed transfer hydrogenation reaction. It is the first example employing a combination of an iron catalyst and 5-hydroxy-N-methyl-2-pyrrolidone as reducing agents in a transfer hydrogenation reaction. The protocol is highly efficient for the synthesis of ß-enaminones and 1,3-diketones, providing a versatile route for the preparation of these 1,3-difunctional compounds bearing diversified substitution patterns.

Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization.

The reaction of the diamidite, (iPr2N)2PH, with acyl chlorides proceeds with the loss of HCl to give the corresponding acyl diamidites, RC(O)P(N(iPr)2)2 (R = Me (7), Ph (9)), without the intervention of sodium to give a phosphorus anion. The structure of 9 was confirmed by single-crystal X-ray diffraction. The coupling of the diamidites 7 and 9 with 5'-O-DMTr-thymidine was carried out with N-methylimidazolium triflate as the activator to give the monoamidites 3'-O-(P(N(iPr)2)C(O)R)-5'-O-DMTr-thymidine, and further coupling with 3'-O-(tert-butyldimethylsilyl)thymidine was carried out with activation by pyridinium trifluoroacetate/N-methylimidazole. The new dinucleoside acylphosphonites could be further oxidized, hydrolyzed to the H-phosphonates, and sulfurized to give the known mixture of diastereomeric phosphorothioates. The goal of this work was the measurement of the barrier to inversion of the acylphosphonites, which was expected to be low by analogy to the low barrier found in acylphosphines. However, the barrier was found to be high as no epimerization was detected up to 150 °C, and consistent with this, density functional theory calculations give an inversion barrier of over 40 kcal/mol.

Synthesis of dibenzocyclohepten-5-ones by electrophilic iodocyclization of 1-([1,1'-biphenyl]-2-yl)alkynones.

A synthesis of iodo-substituted dibenzocyclohepten-5-ones by the iodine monochloride (or iodine)-induced intramolecular 7-endo-dig cyclization of 1-([1,1'-biphenyl]-2-yl)alkynones is reported. Detailed investigations on the substituent effects during the electrophilic iodocyclization of the alkynones show that they play a crucial role in determining the reaction pathways of the cyclization. By modifying the substitution pattern on the alkynone substrates, the cyclization takes place regioselectively, leading to either dibenzocyclohepten-5-ones, via a 7-endo-dig cyclization, or spiroconjugated compounds, via a 6-endo-dig cyclization.

Participation in EHR based simulation improves recognition of patient safety issues.

BACKGROUND: Electronic health records (EHR) are becoming increasingly integrated into the clinical environment. With the rapid proliferation of EHRs, a number of studies document an increase in adverse patient safety issues due to the EHR-user interface. Because of these issues, greater attention has been placed on novel educational activities which incorporate use of the EHR. The ICU environment presents many challenges to integrating an EHR given the vast amounts of data recorded each day, which must be interpreted to deliver safe and effective care. We have used a novel EHR based simulation exercise to demonstrate that everyday users fail to recognize a majority of patient safety issues in the ICU. We now sought to determine whether participation in the simulation improves recognition of said issues. METHODS: Two ICU cases were created in our EHR simulation environment. Each case contained 14 safety issues, which differed in content but shared common themes. Residents were given 10 minutes to review a case followed by a presentation of management changes. Participants were given an immediate debriefing regarding missed issues and strategies for data gathering in the EHR. Repeated testing was performed in a cohort of subjects with the other case at least 1 week later. RESULTS: 116 subjects have been enrolled with 25 subjects undergoing repeat testing. There was no difference between cases in recognition of patient safety issues (39.5% vs. 39.4%). Baseline performance for subjects who participated in repeat testing was no different than the cohort as a whole. For both cases, recognition of safety issues was significantly higher among repeat participants compared to first time participants. Further, individual performance improved from 39.9% to 63.6% (p = 0.0002), a result independent of the order in which the cases were employed. The degree of improvement was inversely related to baseline performance. Further, repeat participants demonstrated a higher rate of recognition of changes in vitals, misdosing of antibiotics and oversedation compared to first time participants. CONCLUSION: Participation in EHR simulation improves EHR use and identification of patient safety issues.

Search still matters: information retrieval in the era of generative AI.

OBJECTIVE: Information retrieval (IR, also known as search) systems are ubiquitous in modern times. How does the emergence of generative artificial intelligence (AI), based on large language models (LLMs), fit into the IR process? PROCESS: This perspective explores the use of generative AI in the context of the motivations, considerations, and outcomes of the IR process with a focus on the academic use of such systems. CONCLUSIONS: There are many information needs, from simple to complex, that motivate use of IR. Users of such systems, particularly academics, have concerns for authoritativeness, timeliness, and contextualization of search. While LLMs may provide functionality that aids the IR process, the continued need for search systems, and research into their improvement, remains essential.

Automatically pre-screening patients for the rare disease aromatic l-amino acid decarboxylase deficiency using knowledge engineering, natural language processing, and machine learning on a large EHR population.

OBJECTIVES: Electronic health record (EHR) data may facilitate the identification of rare diseases in patients, such as aromatic l-amino acid decarboxylase deficiency (AADCd), an autosomal recessive disease caused by pathogenic variants in the dopa decarboxylase gene. Deficiency of the AADC enzyme results in combined severe reductions in monoamine neurotransmitters: dopamine, serotonin, epinephrine, and norepinephrine. This leads to widespread neurological complications affecting motor, behavioral, and autonomic function. The goal of this study was to use EHR data to identify previously undiagnosed patients who may have AADCd without available training cases for the disease. MATERIALS AND METHODS: A multiple symptom and related disease annotated dataset was created and used to train individual concept classifiers on annotated sentence data. A multistep algorithm was then used to combine concept predictions into a single patient rank value. RESULTS: Using an 8000-patient dataset that the algorithms had not seen before ranking, the top and bottom 200 ranked patients were manually reviewed for clinical indications of performing an AADCd diagnostic screening test. The top-ranked patients were 22.5% positively assessed for diagnostic screening, with 0% for the bottom-ranked patients. This result is statistically significant at P < .0001. CONCLUSION: This work validates the approach that large-scale rare-disease screening can be accomplished by combining predictions for relevant individual symptoms and related conditions which are much more common and for which training data is easier to create.

C(sp2)-H selenylation of substituted benzo[4,5]imidazo[2,1-b]thiazoles using phenyliodine(iii)bis(trifluoroacetate) as a mediator.

Herein, an expeditious metal-free regioselective C-H selenylation of substituted benzo[4,5]imidazo[2,1-b]thiazole derivatives was devised to synthesize structurally orchestrated selenoethers with good to excellent yields. This PIFA [bis(trifluoroacetoxy)iodobenzene]-mediated protocol operates under mild conditions and offers broad functional group tolerance. In-depth mechanistic investigation supports the involvement of radical pathways. Furthermore, the synthetic utility of this methodology is portrayed through gram-scale synthesis.

Clinical Information Retrieval: A Literature Review.

Clinical information retrieval (IR) plays a vital role in modern healthcare by facilitating efficient access and analysis of medical literature for clinicians and researchers. This scoping review aims to offer a comprehensive overview of the current state of clinical IR research and identify gaps and potential opportunities for future studies in this field. The main objective was to assess and analyze the existing literature on clinical IR, focusing on the methods, techniques, and tools employed for effective retrieval and analysis of medical information. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted an extensive search across databases such as Ovid Embase, Ovid Medline, Scopus, ACM Digital Library, IEEE Xplore, and Web of Science, covering publications from January 1, 2010, to January 4, 2023. The rigorous screening process led to the inclusion of 184 papers in our review. Our findings provide a detailed analysis of the clinical IR research landscape, covering aspects like publication trends, data sources, methodologies, evaluation metrics, and applications. The review identifies key research gaps in clinical IR methods such as indexing, ranking, and query expansion, offering insights and opportunities for future studies in clinical IR, thus serving as a guiding framework for upcoming research efforts in this rapidly evolving field. The study also underscores an imperative for innovative research on advanced clinical IR systems capable of fast semantic vector search and adoption of neural IR techniques for effective retrieval of information from unstructured electronic health records (EHRs). Supplementary Information: The online version contains supplementary material available at 10.1007/s41666-024-00159-4.

Caveats for the use of operational electronic health record data in comparative effectiveness research.

The growing amount of data in operational electronic health record systems provides unprecedented opportunity for its reuse for many tasks, including comparative effectiveness research. However, there are many caveats to the use of such data. Electronic health record data from clinical settings may be inaccurate, incomplete, transformed in ways that undermine their meaning, unrecoverable for research, of unknown provenance, of insufficient granularity, and incompatible with research protocols. However, the quantity and real-world nature of these data provide impetus for their use, and we develop a list of caveats to inform would-be users of such data as well as provide an informatics roadmap that aims to insure this opportunity to augment comparative effectiveness research can be best leveraged.

ICl-induced intramolecular electrophilic cyclization of 1-[4'-methoxy(1,1'-biphenyl)2-yl]alkynones--a facile approach to spiroconjugated molecules.

Spiro compounds: An iodine monochloride-induced intramolecular cyclization of 1-[4'-methoxy(1,1'-biphenyl)2-yl]alkynones has been developed (see scheme). An electrophilic iodocyclization selectively takes place at the ipso position (versus the ortho electrophilic aromatic substitution) to afford 4'H-spiro(cyclohexa[2,5]diene-1,1'-naphthalene)-4,4'-diones, a new group of spiroconjugated compounds.

Physicians perceptions of an educational support system integrated into an electronic health record.

The purpose of this study is to determine the perceptions by physicians of an educational system integrated into an electronic health record (EHR). Traditional approaches to continuous medical education (CME) have not shown improvement in patient health care outcomes. Hospital Italiano de Buenos Aires (HIBA) has implemented a system that embeds information pearls into the EHR, providing learning opportunities that are integrated into the patient care process. This study explores the acceptability and general perceptions of the system by physicians when they are in the consulting room. We interviewed 12 physicians after one or two weeks of using this CME system and we performed a thematic analysis of these interviews. The themes that emerged were use and ease of use of the system; value physicians gave to the system; educational impact on physicians; respect for the individual learning styles; content available in the system; and barriers that were present or absent for using the CME system. We found that the integrated CME system developed at HIBA was well accepted and perceived as useful and easy to use. Future work will involve modifications to the system interface, expansion of the content offered and further evaluation.

Beyond mathematics, statistics, and programming: data science, machine learning, and artificial intelligence competencies and curricula for clinicians, informaticians, science journalists, and researchers.

Data science, machine learning and artificial intelligence applications impact clinicians, informaticians, science journalists, and researchers. Most biomedical data science training focuses on learning a programming language in addition to higher mathematics and advanced statistics. This approach is appropriate for graduate students but greatly reduces the number of individuals in healthcare who can be involved in data science. To serve these four stakeholder audiences, we describe several curricular strategies focusing on solving real problems of interest to these audiences. Relevant competencies for these audiences include using intuitive programming tools that facilitate data exploration with minimal programming background, creating data models, evaluating results of data analyses, and assessing data science research reports, among others. Offering the curricula described here more broadly could broaden the stakeholder groups knowledgeable about and engaged in data science.

The IMPACT framework and implementation for accessible in silico clinical phenotyping in the digital era.

Clinical phenotyping is often a foundational requirement for obtaining datasets necessary for the development of digital health applications. Traditionally done via manual abstraction, this task is often a bottleneck in development due to time and cost requirements, therefore raising significant interest in accomplishing this task via in-silico means. Nevertheless, current in-silico phenotyping development tends to be focused on a single phenotyping task resulting in a dearth of reusable tools supporting cross-task generalizable in-silico phenotyping. In addition, in-silico phenotyping remains largely inaccessible for a substantial portion of potentially interested users. Here, we highlight the barriers to the usage of in-silico phenotyping and potential solutions in the form of a framework of several desiderata as observed during our implementation of such tasks. In addition, we introduce an example implementation of said framework as a software application, with a focus on ease of adoption, cross-task reusability, and facilitating the clinical phenotyping algorithm development process.

Recommendations of the International Medical Informatics Association (IMIA) on Education in Biomedical and Health Informatics: Second Revision.

BACKGROUND: The purpose of educational recommendations is to assist in establishing courses and programs in a discipline, to further develop existing educational activities in the various nations, and to support international initiatives for collaboration and sharing of courseware. The International Medical Informatics Association (IMIA) has published two versions of its international recommendations in biomedical and health informatics (BMHI) education, initially in 2000 and revised in 2010. Given the recent changes to the science, technology, the needs of the healthcare systems, and the workforce of BMHI, a revision of the recommendations is necessary. OBJECTIVE: The aim of these updated recommendations is to support educators in developing BMHI curricula at different education levels, to identify essential skills and competencies for certification of healthcare professionals and those working in the field of BMHI, to provide a tool for evaluators of academic BMHI programs to compare and accredit the quality of delivered programs, and to motivate universities, organizations, and health authorities to recognize the need for establishing and further developing BMHI educational programs. METHOD: An IMIA taskforce, established in 2017, updated the recommendations. The taskforce included representatives from all IMIA regions, with several having been involved in the development of the previous version. Workshops were held at different IMIA conferences, and an international Delphi study was performed to collect expert input on new and revised competencies. RESULTS: Recommendations are provided for courses/course tracks in BMHI as part of educational programs in biomedical and health sciences, health information management, and informatics/computer science, as well as for dedicated programs in BMHI (leading to bachelor's, master's, or doctoral degree). The educational needs are described for the roles of BMHI user, BMHI generalist, and BMHI specialist across six domain areas - BMHI core principles; health sciences and services; computer, data and information sciences; social and behavioral sciences; management science; and BMHI specialization. Furthermore, recommendations are provided for dedicated educational programs in BMHI at the level of bachelor's, master's, and doctoral degrees. These are the mainstream academic programs in BMHI. In addition, recommendations for continuing education, certification, and accreditation procedures are provided. CONCLUSION: The IMIA recommendations reflect societal changes related to globalization, digitalization, and digital transformation in general and in healthcare specifically, and center on educational needs for the healthcare workforce, computer scientists, and decision makers to acquire BMHI knowledge and skills at various levels. To support education in BMHI, IMIA offers accreditation of quality BMHI education programs. It supports information exchange on programs and courses in BMHI through its Working Group on Health and Medical Informatics Education.

Synthesis of trisubstituted isoxazoles by palladium(II)-catalyzed cascade cyclization-alkenylation of 2-alkyn-1-one O-methyl oximes.

A palladium-catalyzed, cascade 5-endo-dig cyclization-alkenylation synthesis of isoxazoles has been developed. The addition of 1 equiv of n-Bu(4)NBr significantly increases the yield of the desired 4-alkenyl-3,4,5-trisubstituted isoxazoles. A variety of trisubstituted isoxazoles are prepared in moderate to excellent yields. One example of the synthesis of a naphthoisoxazole is reported by a cascade cyclization-alkenylation-Heck reaction.

A non-Karplus effect: evidence from phosphorus heterocycles and DFT calculations of the dependence of vicinal phosphorus-hydrogen NMR coupling constants on lone-pair conformation.

In contrast to literature reports of a Karplus-type curve that correlates (3)J(PH) with phosphorus-hydrogen dihedral angle, a recently reported glycine-derived 1,3,2-oxazaphospholidine (7c) has two hydrogen atoms on the ring with identical PNCH dihedral angles but measured coupling constants of ∼6 and 1.5 Hz. DFT calculations were in accord with these values and suggested that the smaller coupling constant is negative. Experimental evidence of the opposite signs of these coupling constants was obtained by analysis of the ABX NMR spectrum of the new glycine-derived N-p-toluenesulfonyl phosphorus heterocycle 6c. DFT calculations on 6c and on Me(2)NPCl(2) and t-BuPCl(2) were also in accord with NMR data and allowed confirmation of unusual features including a lone pair effect on (3)J(PH), the negative coupling constant, temperature-dependent chemical shifts due to rotation about the sulfonamide S-N bond, and vicinal phosphorus-hydrogen coupling constants over 40 Hz. Calculation of phosphorus-hydrogen coupling constants both as a function of PYCH dihedral angle θ (Y = O, N, C) and lone pair-PYC dihedral angle ω shows similar θ,ω surfaces for (3)J(PH) with a range of (3)J(PH) from -4.4 to +51 Hz and demonstrates the large non-Karplus effect of lone-pair conformation on vicinal phosphorus-hydrogen coupling constants.