ATAC-Me Captures Prolonged DNA Methylation of Dynamic Chromatin Accessibility Loci during Cell Fate Transitions.

DNA methylation of enhancers is dynamic, cell-type specific, and vital for cell fate progression. However, current models inadequately define its role within the hierarchy of gene regulation. Analysis of independent datasets shows an unanticipated overlap between DNA methylation and chromatin accessibility at enhancers of steady-state stem cells, suggesting that these two opposing features might exist concurrently. To define their temporal relationship, we developed ATAC-Me, which probes accessibility and methylation from single DNA library preparations. We identified waves of accessibility occurring rapidly across thousands of myeloid enhancers in a monocyte-to-macrophage cell fate model. Prolonged methylation states were observed at a majority of these sites, while transcription of nearby genes tracked closely with accessibility. ATAC-Me uncovers a significant disconnect between chromatin accessibility, DNA methylation status, and gene activity. This unexpected observation highlights the value of ATAC-Me in constructing precise molecular timelines for understanding the role of DNA methylation in gene regulation.

Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates.

During germ cell and preimplantation development, mammalian cells undergo nearly complete reprogramming of DNA methylation patterns. We profiled the methylomes of human and chimp sperm as a basis for comparison to methylation patterns of ESCs. Although the majority of promoters escape methylation in both ESCs and sperm, the corresponding hypomethylated regions show substantial structural differences. Repeat elements are heavily methylated in both germ and somatic cells; however, retrotransposons from several subfamilies evade methylation more effectively during male germ cell development, whereas other subfamilies show the opposite trend. Comparing methylomes of human and chimp sperm revealed a subset of differentially methylated promoters and strikingly divergent methylation in retrotransposon subfamilies, with an evolutionary impact that is apparent in the underlying genomic sequence. Thus, the features that determine DNA methylation patterns differ between male germ cells and somatic cells, and elements of these features have diverged between humans and chimpanzees.

Socioeconomic changes predict genome-wide DNA methylation in childhood.

Childhood socioeconomic position (SEP) is a major determinant of health and well-being across the entire life course. To effectively prevent and reduce health risks related to SEP, it is critical to better understand when and under what circumstances socioeconomic adversity shapes biological processes. DNA methylation (DNAm) is one such mechanism for how early life adversity 'gets under the skin'. In this study, we evaluated the dynamic relationship between SEP and DNAm across childhood using data from 946 mother-child pairs in the Avon Longitudinal Study of Parents and Children. We assessed six SEP indicators spanning financial, occupational and residential domains during very early childhood (ages 0-2), early childhood (ages 3-5) and middle childhood (ages 6-7). Epigenome-wide DNAm was measured at 412 956 cytosine-guanines (CpGs) from peripheral blood at age 7. Using an innovative two-stage structured life-course modeling approach, we tested three life-course hypotheses for how SEP shapes DNAm profiles-accumulation, sensitive period and mobility. We showed that changes in the socioeconomic environment were associated with the greatest differences in DNAm, and that middle childhood may be a potential sensitive period when socioeconomic instability is especially important in shaping DNAm. Top SEP-related DNAm CpGs were overrepresented in genes involved in pathways important for neural development, immune function and metabolic processes. Our findings highlight the importance of socioeconomic stability during childhood and if replicated, may emphasize the need for public programs to help children and families experiencing socioeconomic instability and other forms of socioeconomic adversity.

Diagnostic Accuracy of CT for the Detection of Hepatic Steatosis: A Systematic Review and Meta-Analysis.

Background CT plays an important role in the opportunistic identification of hepatic steatosis. CT performance for steatosis detection has been inconsistent across various studies, and no clear guidelines on optimum thresholds have been established. Purpose To conduct a systematic review and meta-analysis to assess CT diagnostic accuracy in hepatic steatosis detection and to determine reliable cutoffs for the commonly mentioned measures in the literature. Materials and Methods A systematic search of the PubMed, Embase, and Scopus databases (English-language studies published from September 1977 to January 2024) was performed. Studies evaluating the diagnostic accuracy of noncontrast CT (NCCT), contrast-enhanced (CECT), and dual-energy CT (DECT) for hepatic steatosis detection were included. Reference standards included biopsy, MRI proton density fat fraction (PDFF), or NCCT. In several CECT and DECT studies, NCCT was used as the reference standard, necessitating subgroup analysis. Statistical analysis included a random-effects meta-analysis, assessment of heterogeneity with use of the I2 statistic, and meta-regression to explore potential sources of heterogeneity. When available, mean liver attenuation, liver-spleen attenuation difference, liver to spleen attenuation ratio, and the DECT-derived fat fraction for hepatic steatosis diagnosis were assessed. Results Forty-two studies (14 186 participants) were included. NCCT had a sensitivity and specificity of 72% and 88%, respectively, for steatosis (>5% fat at biopsy) detection and 82% and 94% for at least moderate steatosis (over 20%-33% fat at biopsy) detection. CECT had a sensitivity and specificity of 66% and 90% for steatosis detection and 68% and 93% for at least moderate steatosis detection. DECT had a sensitivity and specificity of 85% and 88% for steatosis detection. In the subgroup analysis, the sensitivity and specificity for detecting steatosis were 80% and 99% for CECT and 84% and 93% for DECT. There was heterogeneity among studies focusing on CECT and DECT. Liver attenuation less than 40-45 HU, liver-spleen attenuation difference less than -5 to 0 HU, and liver to spleen attenuation ratio less than 0.9-1 achieved high specificity for detection of at least moderate steatosis. Conclusion NCCT showed high performance for detection of at least moderate steatosis. © RSNA, 2024 Supplemental material is available for this article.

Depressive symptoms in adolescence and adult educational and employment outcomes: a structured life course analysis.

BACKGROUND: Depression is a common mental health disorder that often starts during adolescence, with potentially important future consequences including 'Not in Education, Employment or Training' (NEET) status. METHODS: We took a structured life course modeling approach to examine how depressive symptoms during adolescence might be associated with later NEET status, using a high-quality longitudinal data resource. We considered four plausible life course models: (1) an early adolescent sensitive period model where depressive symptoms in early adolescence are more associated with later NEET status relative to exposure at other stages; (2) a mid adolescent sensitive period model where depressive symptoms during the transition from compulsory education to adult life might be more deleterious regarding NEET status; (3) a late adolescent sensitive period model, meaning that depressive symptoms around the time when most adults have completed their education and started their careers are the most strongly associated with NEET status; and (4) an accumulation of risk model which highlights the importance of chronicity of symptoms. RESULTS: Our analysis sample included participants with full information on NEET status (N = 3951), and the results supported the accumulation of risk model, showing that the odds of NEET increase by 1.015 (95% CI 1.012-1.019) for an increase of 1 unit in depression at any age between 11 and 24 years. CONCLUSIONS: Given the adverse implications of NEET status, our results emphasize the importance of supporting mental health during adolescence and early adulthood, as well as considering specific needs of young people with re-occurring depressed mood.

The relationship between type, timing and duration of exposure to adverse childhood experiences and adolescent self-harm and depression: findings from three UK prospective population-based cohorts.

BACKGROUND: Adverse childhood experiences (ACEs) are well-established risk factors for self-harm and depression. However, despite their high comorbidity, there has been little focus on the impact of developmental timing and the duration of exposure to ACEs on co-occurring self-harm and depression. METHODS: Data were utilised from over 22,000 children and adolescents participating in three UK cohorts, followed up longitudinally for 14-18 years: the Avon Longitudinal Study of Parents and Children (ALSPAC), the Millennium Cohort Study (MCS) and the Environmental Risk (E-Risk) Longitudinal Twin Study. Multinomial logistic regression models estimated associations between each ACE type and a four-category outcome: no self-harm or depression, self-harm alone, depression alone and self-harm with co-occurring depression. A structured life course modelling approach was used to examine whether the accumulation (duration) of exposure to each ACE, or a critical period (timing of ACEs) had the strongest effects on self-harm and depression in adolescence. RESULTS: The majority of ACEs were associated with co-occurring self-harm and depression, with consistent findings across cohorts. The importance of timing and duration of ACEs differed across ACEs and across cohorts. For parental mental health problems, longer duration of exposure was strongly associated with co-occurring self-harm and depression in both ALSPAC (adjusted OR: 1.18, 95% CI: 1.10-1.25) and MCS (1.18, 1.11-1.26) cohorts. For other ACEs in ALSPAC, exposure in middle childhood was most strongly associated with co-occurring self-harm and depression, and ACE occurrence in early childhood and adolescence was more important in the MCS. CONCLUSIONS: Efforts to mitigate the impact of ACEs should start in early life with continued support throughout childhood, to prevent long-term exposure to ACEs contributing to risk of self-harm and depression in adolescence.

Prospective Evaluation of Artificial Intelligence Triage of Incidental Pulmonary Emboli on Contrast-Enhanced CT Examinations of the Chest or Abdomen.

BACKGROUND. Artificial intelligence (AI) algorithms improved detection of incidental pulmonary embolism (IPE) on contrast-enhanced CT (CECT) examinations in retrospective studies; however, prospective validation studies are lacking. OBJECTIVE. The purpose of this study was to assess the effect on radiologists' real-world diagnostic performance and report turnaround times of a radiology department's clinical implementation of an AI triage system for detecting IPE on CECT examinations of the chest or abdomen. METHODS. This prospective single-center study included consecutive adult patients who underwent CECT of the chest or abdomen for reasons other than pulmonary embolism (PE) detection from May 12, 2021, to June 30, 2021 (phase 1), or from September 30, 2021, to December 4, 2021 (phase 2). Before phase 1, the radiology department installed a commercially available AI triage algorithm for IPE detection that automatically processed CT examinations and notified radiologists of positive results through an interactive floating widget. In phase 1, the widget was inactive, and radiologists interpreted examinations without AI assistance. In phase 2, the widget was activated, and radiologists interpreted examinations with AI assistance. A review process involving a panel of radiologists was implemented to establish the reference standard for the presence of IPE. Diagnostic performance and report turnaround times were compared using the Pearson chi-square test and Wilcoxon rank sum test, respectively. RESULTS. Phase 1 included 1467 examinations in 1434 patients (mean age, 53.8 ± 18.5 [SD] years; 753 men, 681 women); phase 2 included 3182 examinations in 2886 patients (mean age, 55.4 ± 18.2 years; 1520 men, 1366 women). The frequency of IPE was 1.4% (20/1467) in phase 1 and 1.6% (52/3182) in phase 2. Radiologists without AI, in comparison to radiologists with AI, showed significantly lower sensitivity (80.0% vs 96.2%, respectively; p = .03), without a significant difference in specificity (99.9% vs 99.9%, p = .58), for the detection of IPE. The mean report turnaround time for IPE-positive examinations was not significantly different between radiologists without AI and radiologists with AI (78.3 vs 74.6 minutes, p = .26). CONCLUSION. An AI triage system improved radiologists' sensitivity for IPE detection on CECT examinations of the chest or abdomen without significant change in report turnaround times. CLINICAL IMPACT. This prospective real-world study supports the use of AI assistance for maximizing IPE detection.

Prospective Evaluation of Artificial Intelligence Triage of Intracranial Hemorrhage on Noncontrast Head CT Examinations.

Background: Retrospective studies evaluating artificial intelligence (AI) algorithms for intracranial hemorrhage (ICH) detection on noncontrast CT (NCCT) have shown promising results but lack prospective validation. Objective: To evaluate the impact on radiologists' real-world aggregate performance for ICH detection and report turnaround times for ICH-positive examinations of a radiology department's implementation of an AI triage and notification system for ICH detection on head NCCT examinations. Methods: This prospective single-center study included adult patients who underwent head NCCT examinations from May 12, 2021 to June 30, 2021 (phase 1) or September 30, 2021 to December 4, 2021 (phase 2). Before phase 1, the radiology department implemented a commercial AI triage system for ICH detection that processed head NCCT examinations and notified radiologists of positive results through a widget with a floating pop-up display. Examinations were interpreted by neuroradiologists or emergency radiologists, who evaluated examinations without and with AI assistance in phase 1 and phase 2, respectively. A panel of radiologists conducted a review process for all examinations with discordance between the radiology report and AI and a subset of remaining examinations, to establish the reference standard. Diagnostic performance and report turnaround times were compared using Pearson chi-square test and Wilcoxon rank-sum test, respectively. Bonferroni correction was used to account for five diagnostic performance metrics (adjusted significance threshold, .01 [α=.05/5]). Results: A total of 9954 examinations from 7371 patients (mean age, 54.8±19.8 years; 3773 female, 3598 male) were included. In phases 1 and 2, 19.8% (735/3716) and 21.9% (1368/6238) of examinations, respectively, were positive for ICH (P=.01). Radiologists without versus with AI showed no significant difference in accuracy (99.5% vs 99.2%), sensitivity (98.6% vs 98.9%), PPV (99.0% vs 99.7%), or NPV (99.7% vs 99.7%) (all P>.01); specificity was higher for radiologists without than with AI (99.8% vs 99.3%, respectively, P=.004). Mean report turnaround time for ICH-positive examinations was 147.1 minutes without AI versus 149.9 minutes with AI (P=.11). Conclusion: An AI triage system for ICH detection did not improve radiologists' diagnostic performance or report turnaround times. Clinical Impact: This large prospective real-world study does not support use of AI assistance for ICH detection.

Developing emotional preparedness and mental resilience through high-fidelity simulation: a 'bridge too far' for institutions teaching major trauma management and mass-casualty medicine?

BACKGROUND: Clinical acumen represents only part of being adequately equipped to attend a major incident. The emotive sights, sounds and smells of these dynamic environments are all-encompassing experiences, and responders must also be armed with the emotional preparedness to perform their clinical or managerial duties effectively, as well as the mental resilience to facilitate professional continuance. Despite this, limited training and a sparsity of evidence exists to guide developments within this domain. Historically, major incident training has focused on clinical theory acquisition, but irrespective of how comprehensive the learning materials, they are of little consequence if tandem steps to cultivate mental resilience and emotional preparedness are absent. High-Fidelity Simulation (HFS) has a growing reputation as an effective means of bridging important gaps between theory and practice. This pilot study aimed to measure student's self-reported perception of their readiness to respond to a major incident following a large-scale HFS. METHODS: Quantitative data was obtained from a sample of 108 students undertaking paramedic science, physician associate studies and adult nursing degree programmes. A bespoke questionnaire was developed to measure self-reported clinical acumen, mental and emotional preparedness. RESULTS: 91% of students agreed the combination of theoretical training and HFS provided made them feel clinically prepared to attend a real major incident; 86% agreed this experience had developed their mental resilience and 90% agreed that they felt emotionally prepared to attend a major incident. CONCLUSION: Within this pilot study, the blend of theoretical training and HFS contributed to self-reported clinical acumen, mental and emotional preparation, in learners training to work in disaster environments or emergency medicine settings.

Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols.

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O⋅⋅⋅isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Synthesis of Tetra-Substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution.

A general and highly enantioselective method for the preparation of tetra-substituted 3-hydroxyphthalide esters via isothiourea-catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)-HyperBTM (5 mol %) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99 %, 99 : 1 er). Substitution of the aromatic core within the 3-hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3), is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computationally, with a key substrate heteroatom donor O⋅⋅⋅acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Isothiourea-Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols.

The development of methods for the selective acylative kinetic resolution (KR) of tertiary alcohols is a recognised synthetic challenge with relatively few successful substrate classes reported to date. In this manuscript, a highly enantioselective isothiourea-catalysed acylative KR of tertiary pyrazolone alcohols is reported. The scope and limitations of this methodology have been developed, with high selectivity observed across a broad range of substrate derivatives incorporating varying substitution at N(2)-, C(4)- and C(5)-, as well as bicyclic constraints within the pyrazolone scaffold (30 examples, selectivity factors (s) typically >100) at generally low catalyst loadings (1 mol %). The application of this KR method to tertiary alcohols derived directly from a natural product (geraniol), alongside pharmaceutically relevant drug compounds (indomethacin, gemfibrozil and probenecid), with high efficiency (s >100) is also described. The KR process is readily amenable to scale up using bench grade solvents and reagents, with effective resolution on a 50 g (0.22 mol) scale demonstrated. The key structural motif leading to excellent selectivity in this KR process has been probed through computation, with an NC=O⋅⋅⋅isothiouronium interaction from substrate to acylated catalyst observed within the favoured transition state. Similarly, the effect of C(5)-aryl substitution that leads to reduced experimental selectivity is probed, with a competitive π-isothiouronium interaction identified as leading to reduced selectivity.

Prospective Evaluation of AI Triage of Pulmonary Emboli on CT Pulmonary Angiograms.

Background Artificial intelligence (AI) algorithms have shown high accuracy for detection of pulmonary embolism (PE) on CT pulmonary angiography (CTPA) studies in academic studies. Purpose To determine whether use of an AI triage system to detect PE on CTPA studies improves radiologist performance or examination and report turnaround times in a clinical setting. Materials and Methods This prospective single-center study included adult participants who underwent CTPA for suspected PE in a clinical practice setting. Consecutive CTPA studies were evaluated in two phases, first by radiologists alone (n = 31) (May 2021 to June 2021) and then by radiologists aided by a commercially available AI triage system (n = 37) (September 2021 to December 2021). Sixty-two percent of radiologists (26 of 42 radiologists) interpreted studies in both phases. The reference standard was determined by an independent re-review of studies by thoracic radiologists and was used to calculate performance metrics. Diagnostic accuracy and turnaround times were compared using Pearson χ2 and Wilcoxon rank sum tests. Results Phases 1 and 2 included 503 studies (participant mean age, 54.0 years ± 17.8 [SD]; 275 female, 228 male) and 1023 studies (participant mean age, 55.1 years ± 17.5; 583 female, 440 male), respectively. In phases 1 and 2, 14.5% (73 of 503) and 15.9% (163 of 1023) of CTPA studies were positive for PE (P = .47). Mean wait time for positive PE studies decreased from 21.5 minutes without AI to 11.3 minutes with AI (P < .001). The accuracy and miss rate, respectively, for radiologist detection of any PE on CTPA studies was 97.6% and 12.3% without AI and 98.6% and 6.1% with AI, which was not significantly different (P = .15 and P = .11, respectively). Conclusion The use of an AI triage system to detect any PE on CTPA studies improved wait times but did not improve radiologist accuracy, miss rate, or examination and report turnaround times. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Murphy and Tee in this issue.

Is time a healer? How quality of life changes over time reported by parents of children and young people with juvenile idiopathic arthritis.

OBJECTIVE: To investigate changes in health-related quality of life (HRQoL) in children and young people with JIA (Juvenile Idiopathic Arthritis) over 3 years following diagnosis. METHODS: Data on children and young people recruited to the Childhood Arthritis Prospective Study (CAPS) were selected if >5 years of age at diagnosis. HRQoL was assessed at diagnosis (baseline), 1 year and 3 years using the proxy-reported Child Health Questionnaire (CHQ) completed by a parent or guardian. The CHQ measures aspects of HRQoL including physical functioning and mental health. Analyses included descriptive statistics, comparison with a US reference population and analysis of CHQ scores longitudinally and by gender and age of onset. RESULTS: Using CHQ data from parents/guardians of 182 CAPS study participants [median age 9.6 years (interquartile range 7.2-12.2)], all HRQoL domains significantly improved over the 3 year follow-up, except general health perceptions. Physical health domains showed greater improvement than psychosocial domains, although psychosocial scores were generally higher than physical scores throughout. Although similar at diagnosis, at 1 year females had significantly worse HRQoL than males in physical functioning (P = 0.03), bodily pain (P = 0.03), mental health (P = 0.00), social-emotional (P = 0.02) and social-physical (P < 0.001). Differences largely remained at 3 years. Age at onset was not significantly associated with HRQoL. CONCLUSION: Children and young people with JIA have low HRQoL across domains compared with the reference population. This improves within 3 years of diagnosis, with the greatest improvement within the first year. Early developmentally appropriate clinical intervention is recommended to reduce both psychosocial and physical impact of JIA. The lower HRQoL scores of females require further investigation.

Multi-Resonant Thermally Activated Delayed Fluorescent (MR-TADF) Compounds as Photocatalysts.

Donor-acceptor (D-A) thermally activated delayed fluorescent (TADF) compounds, such as 4CzIPN, have become a widely used sub-class of organic photocatalysts for a plethora of photocatalytic reactions. Multi-resonant TADF (MR-TADF) compounds, a subclass of TADF emitters that are rigid nanographene derivatives, such as DiKTa and Mes3 DiKTa, have to date not been explored as photocatalysts. In this study both DiKTa and Mes3 DiKTa were found to give comparable or better product yield than 4CzIPN in a range of photocatalytic processes that rely upon reductive quenching, oxidative quenching, energy transfer and dual photocatalytic processes. In a model oxidative quench process, DiKTa and Mes3 DiKTa gave increased reaction rates in comparison to 4CzIPN, with DiKTa being of particular interest due to the lower material cost (£0.94/mmol) compared to that of 4CzIPN (£3.26/mmol). These results suggest that DiKTa and Mes3 DiKTa would be excellent additions to any chemist's collection of photocatalysts.

Testing lifecourse theories characterising associations between maternal depression and offspring depression in emerging adulthood: the Avon Longitudinal Study of Parents and Children.

BACKGROUND: Maternal depression is a major determinant of offspring mental health. Yet, little is understood about how the duration and timing of maternal depression shapes youth risk for depressive symptoms, which if understood could inform when best to intervene. This study aimed to determine how the timing and duration of maternal depression was related to offspring depression in emerging adulthood, and if these associations varied by sex. METHODS: We analysed data from the Avon Longitudinal Study of Parents and Children (a prenatal cohort in the Avon area of England, 1991-2003), n = 3,301. We applied the structured lifecourse modelling approach to maternal depression (assessed at 13 points from prenatal period to adolescence) and emerging adult depressive symptoms (age 21). Lifecourse models assessed were accumulation (sum of timepoints when maternal depression was reported), sensitive periods (each period assessed as one during which maternal depression has a stronger effect) and instability (frequent fluctuations in maternal depression). RESULTS: Female adolescents (n = 2,132) had higher SMFQ scores (mean = 6.15, SD = 5.90) than males (n = 1,169, mean = 4.87, SD = 4.82). Maternal depression was most common in the infancy period (21.2% males; 21.4% females). For males, accumulation was the most appropriate lifecourse model; for each additional period of maternal depression, depressive symptoms in emerging adulthood increased by 0.11 (95% CI: 0.07, 0.15, one-sided p value ≤ .001). For females, exposure to maternal depression was associated with increasing depressive symptoms in emerging adulthood, with the largest effect in mid-childhood (increase of 0.27 units, 95% CI 0.03-0.50, p = .015 for difference between mid-childhood and other time-periods) and a smaller, equal effect at all other time-periods (increase of 0.07 units per time-period, 95% CI: 0.03-0.12, p = .002). CONCLUSIONS: This study highlights the importance of ongoing maternal depression for the development of depression in offspring through to emerging adulthood. Because long-term exposure to maternal depression was particularly important, early interventions are warranted.

Probing Regio- and Enantioselectivity in the Formal [2 + 2] Cycloaddition of C(1)-Alkyl Ammonium Enolates with ß- and α,ß-Substituted Trifluoromethylenones.

The isothiourea-catalyzed regio- and enantioselective formal [2 + 2] cycloaddition of C(1)-alkyl and C(1)-unsubstituted ammonium enolates with ß- and α,ß-substituted trifluoromethylenones has been developed. In all cases, preferential [2 + 2]-cycloaddition over the alternative [4 + 2]-cycloaddition is observed, giving ß-lactones with excellent diastereo- and enantioselectivity (34 examples, up to >95:5 dr, >99:1 er). The regioselectivity of the process was dictated by the nature of the substituents on both reaction components. Solely [2 + 2] cycloaddition products are observed when using α,ß-substituted trifluoromethylenones or α-trialkylsilyl acetic acid derivatives; both [2 + 2] and [4 + 2] cycloaddition products are observed when using ß-substituted trifluoromethylenones and α-alkyl-α-trialkylsilyl acetic acids as reactants, with the [2 + 2] cycloaddition as the major reaction product. The beneficial role of the α-silyl substituent within the acid component in this protocol has been demonstrated by control experiments.

Potential Use Cases for ChatGPT in Radiology Reporting.

Large language models (LLMs) such as ChatGPT are advanced artificial intelligence models that are designed to process and understand human language. LLMs have the potential to improve radiology reporting and patient engagement by automating generation of the clinical history and impression of a radiology report, creating layperson reports, and providing patients with pertinent questions and answers about findings in radiology reports. However, LLMs are error prone, and human oversight is needed to reduce the risk of patient harm.

Benzophenone as a cheap and effective photosensitizer for the photocatalytic synthesis of dimethyl cubane-1,4-dicarboxylate.

The key intramolecular [2 + 2] photochemical cycloaddition step in the synthesis of dimethyl cubane-1,4-dicarboxylate is performed with substoichiometric amounts of the photosensitizer benzophenone. The reaction proceeds via a Dexter energy transfer process between the triplet excited state benzophenone and a well-known cubane precursor diene. The use of the cheap and widely available benzophenone as the photosensitizer enables lower energy light to be used than the traditional photochemical process.

Pulmonary Surface Irregularity Score as a New Quantitative CT Marker for Idiopathic Pulmonary Fibrosis-a Pilot Study.

The purpose of this study is to evaluate the accuracy and inter-observer agreement of a quantitative pulmonary surface irregularity (PSI) score on high-resolution chest CT (HRCT) for predicting transplant-free survival in patients with IPF. For this IRB-approved HIPAA-compliant retrospective single-center study, adult patients with IPF and HRCT imaging (N = 50) and an age- and gender-matched negative control group with normal HRCT imaging (N = 50) were identified. Four independent readers measured the PSI score in the midlungs on HRCT images using dedicated software while blinded to clinical data. A t-test was used to compare the PSI scores between negative control and IPF cohorts. In the IPF cohort, multivariate cox regression analysis was used to associate PSI score and clinical parameters with transplant-free survival. Inter-observer agreement for the PSI score was assessed by intraclass correlation coefficient (ICC). The technical failure rate of the midlung PSI score was 0% (0/100). The mean PSI score of 5.38 in the IPF cohort was significantly higher than 3.14 in the negative control cohort (p < .001). In the IPF cohort, patients with a high PSI score (≥ median) were 8 times more likely to die than patients with a low PSI score (HR: 8.36; 95%CI: 2.91-24.03; p < .001). In a multivariate model including age, gender, FVC, DLCO, and PSI score, only the PSI score was associated with transplant-free survival (HR:2.11 per unit increase; 95%CI: 0.26-3.51; p = .004). Inter-observer agreement for the PSI score among 4 readers was good (ICC: 0.88; 95%CI: 0.84-0.91). The PSI score had high accuracy and good inter-observer agreement on HRCT for predicting transplant-free survival in patients with IPF.