The genetic basis of the kakapo structural color polymorphism suggests balancing selection by an extinct apex predator.

The information contained in population genomic data can tell us much about the past ecology and evolution of species. We leveraged detailed phenotypic and genomic data of nearly all living kakapo to understand the evolution of its feather color polymorphism. The kakapo is an endangered and culturally significant parrot endemic to Aotearoa New Zealand, and the green and olive feather colorations are present at similar frequencies in the population. The presence of such a neatly balanced color polymorphism is remarkable because the entire population currently numbers less than 250 birds, which means it has been exposed to severe genetic drift. We dissected the color phenotype, demonstrating that the two colors differ in their light reflectance patterns due to differential feather structure. We used quantitative genomics methods to identify two genetic variants whose epistatic interaction can fully explain the species' color phenotype. Our genomic forward simulations show that balancing selection might have been pivotal to establish the polymorphism in the ancestrally large population, and to maintain it during population declines that involved a severe bottleneck. We hypothesize that an extinct apex predator was the likely agent of balancing selection, making the color polymorphism in the kakapo a "ghost of selection past."

Creating cell-specific computational models of stem cell-derived cardiomyocytes using optical experiments.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have gained traction as a powerful model in cardiac disease and therapeutics research, since iPSCs are self-renewing and can be derived from healthy and diseased patients without invasive surgery. However, current iPSC-CM differentiation methods produce cardiomyocytes with immature, fetal-like electrophysiological phenotypes, and the variety of maturation protocols in the literature results in phenotypic differences between labs. Heterogeneity of iPSC donor genetic backgrounds contributes to additional phenotypic variability. Several mathematical models of iPSC-CM electrophysiology have been developed to help to predict cell responses, but these models individually do not capture the phenotypic variability observed in iPSC-CMs. Here, we tackle these limitations by developing a computational pipeline to calibrate cell preparation-specific iPSC-CM electrophysiological parameters. We used the genetic algorithm (GA), a heuristic parameter calibration method, to tune ion channel parameters in a mathematical model of iPSC-CM physiology. To systematically optimize an experimental protocol that generates sufficient data for parameter calibration, we created in silico datasets by simulating various protocols applied to a population of models with known conductance variations, and then fitted parameters to those datasets. We found that calibrating to voltage and calcium transient data under 3 varied experimental conditions, including electrical pacing combined with ion channel blockade and changing buffer ion concentrations, improved model parameter estimates and model predictions of unseen channel block responses. This observation also held when the fitted data were normalized, suggesting that normalized fluorescence recordings, which are more accessible and higher throughput than patch clamp recordings, could sufficiently inform conductance parameters. Therefore, this computational pipeline can be applied to different iPSC-CM preparations to determine cell line-specific ion channel properties and understand the mechanisms behind variability in perturbation responses.

Electronic Spectrum of α-Hydrofulvenyl Radical (C6H7), and a Simple and Accurate Recipe for Predicting Adiabatic Ionization Energies of Resonance-Stabilized Hydrocarbon Radicals.

Using a combination of resonant two-photon two-color ionization (R2C2PI) and laser-induced fluorescence/dispersed fluorescence spectroscopy, we have examined the A~  2A″ ← X~ 2A″ transition of the resonance-stabilized α-hydrofulvenyl radical, produced from methylcyclopentadiene dimer in a jet-cooled discharge. Like the related 1,4-pentadienyl and cyclohexadienyl radicals, the α-hydrofulvenyl Ã-state lifetime is orders of magnitude shorter than the predicted f-value implies, indicative of rapid nonradiative decay. The transition is fully allowed by symmetry but considerably weakened by transition moment interference. Intensity borrowing among a' modes brings about static (i.e., Condon) and vibronic (i.e., Herzberg-Teller) moments of similar size, the result being a spectrum substantially less origin-dominated than is usually observed for extensively delocalized radicals. Twenty A~-state modes and twelve X~-state modes are identified with high confidence and assignments for several others are suggested. In addition, from a series of two-color appearance potential scans with the A~-state zero-point level serving as an intermediate, we obtain a field-free adiabatic ionization energy (AIE) of 7.012(1) eV. For a set of 21 resonance-stabilized radicals bearing 5 to 11 carbon atoms, it emerges that the field-free AIE obtained by R2C2PI methods under jet-cooled conditions lies very close to the average of B3LYP/6-311G++(d,p) (with harmonic zero-point energy) and CBS-QB3 0 K calculations, with a mean absolute deviation of only 0.010(7) eV (approximately 1 kJ/mol). On average, this represents a nearly 10-fold improvement in accuracy over CBS-QB3 predictions for the same set of radicals.

IgG4-related disease in the nervous system.

IgG4-related disease (IgG4-RD) is a recently described multisystemic disorder with a spectrum of manifestations that continue to be described. Nonetheless, there are recognised distinct patterns of disease. Neurological involvement is rare, particularly in isolation, but IgG4-RD may present with orbital disease, hypophysitis or pachymeningitis. Typically, it is highly responsive to treatment. This review highlights neurological manifestations of IgG4-RD and emphasises the importance of a high index of clinical suspicion to facilitate investigation and appropriate management, avoiding irreversible tissue damage and neurological dysfunction. We present a treatment algorithm for suggested management of IgG4-RD affecting the nervous system.

Surgical practices in emergency umbilical hernia repair and implications for trial design.

INTRODUCTION: There is variation in the investigation, management, and surgical technique of acutely symptomatic umbilical hernias and optimal strategies remain to be established. This survey aimed to identify key variables influencing decision-making and preferred surgical techniques in emergency umbilical hernia care to help inform trial design and understand potential challenges to trial delivery. METHODS: A survey was distributed to surgeons through social media, personal contacts, and ASGBI lists. It comprised five sections: (i) performer of repair, (ii) repair preferences, (iii) important outcomes, (iv) perioperative antibiotic use, and (v) potential future trial design. RESULTS: There were 105 respondents, of which 49 (46.6%) were consultants. The median largest defect surgeons would attempt to repair with sutures alone was 2 cm (IQR 2-4 cm). In the acute setting, the most common mesh preferences are preperitoneal plane placement (n = 61, 58.1%), with synthetic non-absorbable mesh (n = 72, 68.6%), in clean (n = 41, 39.0%) or clean-contaminated (n = 52, 49.5%) wounds. Respondents believed suture repair to be associated with better short-term outcomes, and mesh repair with better long-term outcomes. Pre-/intra-operative antibiotics were very frequently given (n = 48, 45.7%) whilst post-operative antibiotics were rarely (n = 41, 39%) or very rarely (n = 28, 26.7%) given. The trial design felt to most likely influence practice is comparing mesh and suture repair, and post-operative antibiotics versus no post-operative antibiotics. Respondents indicated that to change their practice, the median difference in surgical site infection rate and recurrence rate would both need to be 5%. CONCLUSION: This survey provides insight into surgical preferences in emergency umbilical hernia management, offering guidance for the design of future trials.

Collateral assessment on magnetic resonance imaging/angiography up to 30 hours after stroke onset.

PURPOSE: We aimed to validate hyperintense vessel sign (HVS) on FLAIR imaging or posterior cerebral artery (PCA) laterality on MR angiography beyond 4.5 hours after stroke onset. MATERIALS AND METHODS: Data from acute ischemic stroke patients with internal carotid or middle cerebral artery occlusion who underwent CT perfusion imaging at baseline, follow-up MR perfusion imaging and angiography within 30 hours after stroke, without effective recanalization on follow-up imaging, were analysed retrospectively. Patients were separately classified as high or low HVS (>5 or ≤5 slices of HVS), and PCA laterality positive or negative group. We compared core and penumbra volumes at follow-up imaging and neurological outcomes between high or low HVS group, and between PCA laterality positive or negative group. RESULTS: Of 49 patients analyzed, four patients with artifacts were excluded and 45 were classified into high (n = 23) or low (n = 22) HVS group. High group had a smaller core volume (median 32 ml versus 109 ml, p = 0.004), larger penumbra volume at follow-up (68 ml versus 0 ml, p = 0.001), and better outcomes (modified Rankin Scale at three months, 3 versus 5, p = 0.03). For PCA laterality analysis, 1 patient with previously occluded PCA was excluded and 48 patients were classified as positive (n = 22) or negative (n = 26). Positive group had larger core volume (116 ml versus 37 ml), and no significant differences in penumbral volumes or outcomes. CONCLUSION: Prominent HVS in later time was associated with small core volume, persistent penumbra volume and favorable outcomes.

Real-world learnings for digital health industry-NHS collaboration: Life sciences vision in action.

Several publications have indicated potential benefit from collaboration with industry regarding wider use of anonymised routine NHS healthcare data. However, there is limited guidance regarding exactly how such collaborations between NHS hospitals and industry partners should best be carried out, and specific issues that need to be addressed at an individual project or collaboration level to achieve desired benefit. Specifically, routine health data are complex, not collected in a format optimised for secondary use, and often require interpretation based on clinical understanding of the medical conditions or patients. In order to address these issues, a formal partnership collaboration was established between an NHS organisation (Great Ormond Street Hospital for Children) and a pharmaceutical company (Roche Products Limited), to jointly understand the problems that require solving in order to maximise such use of NHS data to support improved patient outcomes and other patient/NHS benefit in a more sustainable way. We present the learnings from the first 2 years of the 5-year collaboration addressing aspects such as complexities of NHS Electronic Patient Record (EPR), data engineering and use of modern technology to optimise such data. Plus, the development of appropriate technology and data infrastructure within the NHS to support interoperability and prepare the NHS for wider application of artificial intelligence. We also highlight the staff skills and training needed to support such systems in the NHS, governance structures and processes needed to ensure appropriate use of tools and data and how best to co-design with patients, their families, and clinical teams. It is hoped that this review may provide useful information for both healthcare organisations and industry partners working towards the future of optimal use of data and technology for healthcare benefit.

PIK-III exerts anti-fibrotic effects in activated fibroblasts by regulating p38 activation.

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-driven connective tissue disorder that results in fibrosis of the skin and internal organs such as the lung. Fibroblasts are known as the main effector cells involved in the progression of SSc through the induction of extracellular matrix (ECM) proteins and myofibroblast differentiation. Here, we demonstrate that 4'-(cyclopropylmethyl)-N2-4-pyridinyl-[4,5'-bipyrimidine]-2,2'-diamine (PIK-III), known as class III phosphatidylinositol 3-kinase (PIK3C3/VPS34) inhibitor, exerts potent antifibrotic effects in human dermal fibroblasts (HDFs) by attenuating transforming growth factor-beta 1 (TGF-ß1)-induced ECM expression, cell contraction and myofibroblast differentiation. Unexpectedly, neither genetic silencing of PIK3C3 nor other PIK3C3 inhibitors (e.g., SAR405 and Autophinib) were able to mimic PIK-III-mediated antifibrotic effect in dermal fibroblasts, suggesting that PIK-III inhibits fibroblast activation through another signaling pathway. We identified that PIK-III effectively inhibits p38 activation in TGF-ß1-stimulated dermal fibroblasts. Finally, PIK-III administration significantly attenuated dermal and lung fibrosis in bleomycin-injured mice.

Incidence of Psoriatic Arthritis in a Primary Care Psoriasis Population in the United Kingdom.

OBJECTIVE: To determine the annual incidence of psoriatic arthritis (PsA) in a United Kingdom primary care population with preexisting psoriasis (PsO) followed prospectively over 2 years after excluding baseline prevalence of existing disease. METHODS: Total Burden of Psoriasis (TUDOR; ISRCTN registry: ISRCTN38877516) was a multicenter, prospective, 2-arm parallel-group cluster randomized controlled trial of the early identification of PsA by annual rheumatological assessment (termed "Enhanced Surveillance") vs standard care in people with PsO identified in primary care. Incidence of PsA is reported at 12 months and 24 months using patients from the Enhanced Surveillance arm, which allows for the exclusion of patients with prevalent PsA at baseline. RESULTS: Fourteen of 511 participants attending a 12-month screen developed PsA over that interval, giving an incidence of 2.74/100 patient-years (PYs; 95% CI 1.32-4.16). Another 7/444 participants attending the 24-month visit developed PsA, giving an incidence of 1.58/100 PYs (95% CI 0.42-2.74). The combined incidence over 2 years was 2.20/100 PYs (95% CI 1.27-3.13). CONCLUSION: The estimated annual incidence of PsA over a 2-year period was 2.20/100 PYs, which is in keeping with studies including clinical assessment rather than relying on health records alone. Extended follow-up of the TUDOR cohort with accrual of larger numbers of incident cases will allow risk factors for PsA to be explored in more depth.

Pulmonary Vein Systolic Flow Reversal and Outcomes in Patients From the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) Trial.

Background: The implications of pulmonary vein (PV) flow patterns in patients with heart failure (HF) and mitral regurgitation (MR) are uncertain. We examined PV flow patterns in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial (NCT01626079), in which patients with HF and moderate-to-severe or severe functional MR were randomized to transcatheter edge-to-edge repair (TEER) with the MitraClip device plus guideline-directed medical therapy (GDMT) vs. GDMT alone. We sought to evaluate the prognostic utility of baseline PV systolic flow reversal (PVSFR) in HF patients with severe MR and to determine whether the presence of PVSFR can discriminate patients most likely to benefit from TEER in COAPT trial patients. Methods: Patients were categorized by the echocardiographic core laboratory-assessed baseline presence of PVSFR. Two-year outcomes were examined according to PVSFR and treatment. Results: Baseline PV flow patterns were evaluable in 526/614(85.7%) patients, 48.9% of whom had PVSFR. Patients with PVSFR had more severe MR, reduced stroke volume and cardiac output, greater right ventricular dysfunction, and worse hemodynamics. By multivariable analysis, PVSFR was not an independent predictor of 2-year all-cause death, or heart failure hospitalization (HFH). The reductions in the 2-year rates of all-cause death and HFH with TEER compared with GDMT alone were similar in patients with and without PVSFR (Pinteraction = 0.40 and 0.12, respectively). The effect of TEER on improving Kansas City Cardiomyopathy Questionnaire scores and 6-minute walk distance were also independent of PVSFR. Conclusions: In the COAPT trial, PVSFR identified HF patients with severe MR and more advanced heart disease. Patients with and without PVSFR had consistent reductions in mortality, HFH, and improved quality-of-life and functional capacity after TEER. Clinical Trial Registration: ClinicalTrial.gov IdentifierNCT01626079.

Two new mouse alleles of Ocm and Slc26a5.

The genes Ocm (encoding oncomodulin) and Slc26a5 (encoding prestin) are expressed strongly in outer hair cells and both are involved in deafness in mice. However, it is not clear if they influence the expression of each other. In this study, we characterise the auditory phenotype resulting from two new mouse alleles, Ocmtm1e and Slc26a5tm1Cre. Each mutation leads to absence of detectable mRNA transcribed from the mutant allele, but there was no evidence that oncomodulin regulates expression of prestin or vice versa. The two mutants show distinctive patterns of auditory dysfunction. Ocmtm1e homozygotes have normal auditory brainstem response thresholds at 4 weeks old followed by progressive hearing loss starting at high frequencies, while heterozygotes show largely normal thresholds until 6 months of age, when signs of worse thresholds are detected. In contrast, Slc26a5tm1Cre homozygotes have stable but raised thresholds across all frequencies tested, 3 to 42 kHz, at least from 4 to 8 weeks old, while heterozygotes have raised thresholds at high frequencies. Distortion product otoacoustic emissions and cochlear microphonics show deficits similar to auditory brainstem responses in both mutants, suggesting that the origin of hearing impairment is in the outer hair cells. Endocochlear potentials are normal in the two mutants. Scanning electron microscopy revealed normal development of hair cells in Ocmtm1e homozygotes but scattered outer hair cell loss even at 4 weeks old when thresholds appeared normal, indicating that there is not a direct relationship between numbers of outer hair cells present and auditory thresholds.

The origins of mammal growth patterns during the Jurassic mammalian radiation.

We use synchrotron x-ray tomography of annual growth increments in the dental cementum of mammaliaforms (stem and crown fossil mammals) from three faunas across the Jurassic to map the origin of patterns of mammalian growth patterns, which are intrinsically related to mammalian endothermy. Although all fossils studied exhibited slower growth rates, longer life spans, and delayed sexual maturity relative to comparably sized extant mammals, the earliest crown mammals developed significantly faster growth rates in early life that reduced at sexual maturity, compared to stem mammaliaforms. Estimation of basal metabolic rates (BMRs) suggests that some fossil crown mammals had BMRs approaching the lowest rates of extant mammals. We suggest that mammalian growth patterns first evolved during their mid-Jurassic adaptive radiation, although growth remained slower than in extant mammals.

Comparison of Medical Research Abstracts Written by Surgical Trainees and Senior Surgeons or Generated by Large Language Models.

Importance: Artificial intelligence (AI) has permeated academia, especially OpenAI Chat Generative Pretrained Transformer (ChatGPT), a large language model. However, little has been reported on its use in medical research. Objective: To assess a chatbot's capability to generate and grade medical research abstracts. Design, Setting, and Participants: In this cross-sectional study, ChatGPT versions 3.5 and 4.0 (referred to as chatbot 1 and chatbot 2) were coached to generate 10 abstracts by providing background literature, prompts, analyzed data for each topic, and 10 previously presented, unassociated abstracts to serve as models. The study was conducted between August 2023 and February 2024 (including data analysis). Exposure: Abstract versions utilizing the same topic and data were written by a surgical trainee or a senior physician or generated by chatbot 1 and chatbot 2 for comparison. The 10 training abstracts were written by 8 surgical residents or fellows, edited by the same senior surgeon, at a high-volume hospital in the Southeastern US with an emphasis on outcomes-based research. Abstract comparison was then based on 10 abstracts written by 5 surgical trainees within the first 6 months of their research year, edited by the same senior author. Main Outcomes and Measures: The primary outcome measurements were the abstract grades using 10- and 20-point scales and ranks (first to fourth). Abstract versions by chatbot 1, chatbot 2, junior residents, and the senior author were compared and judged by blinded surgeon-reviewers as well as both chatbot models. Five academic attending surgeons from Denmark, the UK, and the US, with extensive experience in surgical organizations, research, and abstract evaluation served as reviewers. Results: Surgeon-reviewers were unable to differentiate between abstract versions. Each reviewer ranked an AI-generated version first at least once. Abstracts demonstrated no difference in their median (IQR) 10-point scores (resident, 7.0 [6.0-8.0]; senior author, 7.0 [6.0-8.0]; chatbot 1, 7.0 [6.0-8.0]; chatbot 2, 7.0 [6.0-8.0]; P = .61), 20-point scores (resident, 14.0 [12.0-7.0]; senior author, 15.0 [13.0-17.0]; chatbot 1, 14.0 [12.0-16.0]; chatbot 2, 14.0 [13.0-16.0]; P = .50), or rank (resident, 3.0 [1.0-4.0]; senior author, 2.0 [1.0-4.0]; chatbot 1, 3.0 [2.0-4.0]; chatbot 2, 2.0 [1.0-3.0]; P = .14). The abstract grades given by chatbot 1 were comparable to the surgeon-reviewers' grades. However, chatbot 2 graded more favorably than the surgeon-reviewers and chatbot 1. Median (IQR) chatbot 2-reviewer grades were higher than surgeon-reviewer grades of all 4 abstract versions (resident, 14.0 [12.0-17.0] vs 16.9 [16.0-17.5]; P = .02; senior author, 15.0 [13.0-17.0] vs 17.0 [16.5-18.0]; P = .03; chatbot 1, 14.0 [12.0-16.0] vs 17.8 [17.5-18.5]; P = .002; chatbot 2, 14.0 [13.0-16.0] vs 16.8 [14.5-18.0]; P = .04). When comparing the grades of the 2 chatbots, chatbot 2 gave higher median (IQR) grades for abstracts than chatbot 1 (resident, 14.0 [13.0-15.0] vs 16.9 [16.0-17.5]; P = .003; senior author, 13.5 [13.0-15.5] vs 17.0 [16.5-18.0]; P = .004; chatbot 1, 14.5 [13.0-15.0] vs 17.8 [17.5-18.5]; P = .003; chatbot 2, 14.0 [13.0-15.0] vs 16.8 [14.5-18.0]; P = .01). Conclusions and Relevance: In this cross-sectional study, trained chatbots generated convincing medical abstracts, undifferentiable from resident or senior author drafts. Chatbot 1 graded abstracts similarly to surgeon-reviewers, while chatbot 2 was less stringent. These findings may assist surgeon-scientists in successfully implementing AI in medical research.

Correlative three-dimensional X-ray histology (3D-XRH) as a tool for quantifying mammalian placental structure.

Mammalian placentas exhibit unparalleled structural diversity, despite sharing a common ancestor and principal functions. The bulk of structural studies in placental research has used two-dimensional (2D) histology sectioning, allowing significant advances in our understanding of mammalian placental structure. However, 2D histology sectioning may be limited if it does not provide accurate information of three-dimensional (3D) tissue architecture. Here, we propose correlative 3D X-ray histology (3D-XRH) as a tool with great potential for resolving mammalian placental structures. 3D-XRH involves scanning a formaldehyde-fixed, paraffin embedded (FFPE) tissue block with 3D X-ray microscopy (microCT) prior to histological sectioning to generate a 3D image volume of the embedded tissue piece. The subsequent 2D histology sections can then be correlated back into the microCT image volume to couple histology staining (or immunolabelling) with 3D tissue architecture. 3D-XRH is non-destructive and requires no additional sample preparation than standard FFPE histology sectioning, however the image volume provides 3D morphometric data and can be used to guide microtomy. As such, 3D-XRH introduces additional information to standard histological workflows with minimal effort or disruption. Using primary examples from porcine, bovine, equine, and canine placental samples, we demonstrate the application of 3D-XRH to quantifying placental structure as well as discussing the limitations and future directions of the methodology. The wealth of information derived from 2D histological sectioning in the biomedical, veterinary, and comparative reproductive sciences provides a rich foundation from which 3D-XRH can build on to advance the study of placental structure and function.

Causes of sudden unexpected death in infants with and without pre-existing conditions: a retrospective autopsy study.

OBJECTIVE: We investigated sudden unexpected death in infancy (SUDI) autopsy data from 1996 to 2015 inclusive, comparing findings from infants with and without pre-existing medical conditions. DESIGN: Large, retrospective single-centre autopsy series. SETTING: Tertiary paediatric hospital, London, UK. METHODS: Non-identifiable autopsy findings were extracted from an existing research database for infants older than 7 days up to and including 365 days old who died suddenly and unexpectedly (SUDI; n=1739). Cases were classified into SUDI with pre-existing condition (SUDI-PEC) (n=233) versus SUDI without PEC (SUDI non-PEC) (n=929), where PEC indicates a potentially life-limiting pre-existing medical condition. Findings were compared between groups including evaluation of type of PEC and whether the deaths were medically explained (infectious or non-infectious) or apparently unexplained. RESULTS: Median age of death was greater in SUDI-PEC compared with SUDI non-PEC (129 days vs 67 days) with similar male to female ratio (1.4:1). A greater proportion of deaths were classified as medically explained in SUDI-PEC versus SUDI non-PEC (73% vs 30%). Of the explained SUDI, a greater proportion of deaths were non-infectious for SUDI-PEC than SUDI non-PEC (66% vs 32%). SUDI-PEC (infectious) infants were most likely to have respiratory infection (64%), with susceptible PEC, including neurological, prematurity with a PEC, and syndromes or other anomalies. CONCLUSION: SUDI-PEC deaths occur later in infancy and are likely to have their death attributed to their PEC, even in the absence of specific positive autopsy findings. Future research should aim to further define this cohort to help inform SUDI postmortem guidelines, paediatric clinical practice to reduce infant death, and to reduce the risk of overattribution of deaths in the context of a PEC.

An Automated Machine Learning-Based Quantitative Multiparametric Approach for Mitral Regurgitation Severity Grading.

BACKGROUND: Considering the high prevalence of mitral regurgitation (MR) and the highly subjective, variable MR severity reporting, an automated tool that could screen patients for clinically significant MR (≥ moderate) would streamline the diagnostic/therapeutic pathways and ultimately improve patient outcomes. OBJECTIVES: The authors aimed to develop and validate a fully automated machine learning (ML)-based echocardiography workflow for grading MR severity. METHODS: ML algorithms were trained on echocardiograms from 2 observational cohorts and validated in patients from 2 additional independent studies. Multiparametric echocardiography core laboratory MR assessment served as ground truth. The machine was trained to measure 16 MR-related parameters. Multiple ML models were developed to find the optimal parameters and preferred ML model for MR severity grading. RESULTS: The preferred ML model used 9 parameters. Image analysis was feasible in 99.3% of cases and took 80 ± 5 seconds per case. The accuracy for grading MR severity (none to severe) was 0.80, and for significant (moderate or severe) vs nonsignificant MR was 0.97 with a sensitivity of 0.96 and specificity of 0.98. The model performed similarly in cases of eccentric and central MR. Patients graded as having severe MR had higher 1-year mortality (adjusted HR: 5.20 [95% CI: 1.24-21.9]; P = 0.025 compared with mild). CONCLUSIONS: An automated multiparametric ML model for grading MR severity is feasible, fast, highly accurate, and predicts 1-year mortality. Its implementation in clinical practice could improve patient care by facilitating referral to specialized clinics and access to evidence-based therapies while improving quality and efficiency in the echocardiography laboratory.

Improving Xenon-129 lung ventilation image SNR with deep-learning based image reconstruction.

PURPOSE: To evaluate the feasibility and utility of a deep learning (DL)-based reconstruction for improving the SNR of hyperpolarized 129Xe lung ventilation MRI. METHODS: 129Xe lung ventilation MRI data acquired from patients with asthma and/or chronic obstructive pulmonary disease (COPD) were retrospectively reconstructed with a commercial DL reconstruction pipeline at five different denoising levels. Quantitative imaging metrics of lung ventilation including ventilation defect percentage (VDP) and ventilation heterogeneity index (VHI) were compared between each set of DL-reconstructed images and alternative denoising strategies including: filtering, total variation denoising and higher-order singular value decomposition. Structural similarity between the denoised and original images was assessed. In a prospective study, the feasibility of using SNR gains from DL reconstruction to allow natural-abundance xenon MRI was evaluated in healthy volunteers. RESULTS: 129Xe ventilation image SNR was improved with DL reconstruction when compared with conventionally reconstructed images. In patients with asthma and/or COPD, DL-reconstructed images exhibited a slight positive bias in ventilation defect percentage (1.3% at 75% denoising) and ventilation heterogeneity index (˜1.4) when compared with conventionally reconstructed images. Additionally, DL-reconstructed images preserved structural similarity more effectively than data denoised using alternative approaches. DL reconstruction greatly improved image SNR (greater than threefold), to a level that 129Xe ventilation imaging using natural-abundance xenon appears feasible. CONCLUSION: DL-based image reconstruction significantly improves 129Xe ventilation image SNR, preserves structural similarity, and leads to a minor bias in ventilation metrics that can be attributed to differences in the image sharpness. This tool should help facilitate cost-effective 129Xe ventilation imaging with natural-abundance xenon in the future.

An enantioselective and modular platform for C4'-modified nucleoside analogue synthesis enabled by intramolecular trans-acetalizations.

C4'-modified nucleoside analogues continue to attract global attention for their use in antiviral drug development and oligonucleotide-based therapeutics. However, current approaches to C4'-modified nucleoside analogues still involve lengthy (9-16 steps), non-modular routes that are unamenable to library synthesis. Towards addressing the challenges associated with their syntheses, we report a modular 5-step process to a diverse collection of C4'-modified nucleoside analogues through a sequence of intramolecular trans-acetalizations of readily assembled polyhydroxylated frameworks. Overall, the 2-3 fold reduction in step-count compares favorably to even recently reported biocatalytic approaches and should ultimately enable new opportunities in drug design around this popular chemotype.

A hydrophobic funnel governs monovalent cation selectivity in the ion channel TRPM5.

A key capability of ion channels is the facilitation of selective permeation of certain ionic species across cellular membranes at high rates. Due to their physiological significance, ion channels are of great pharmaceutical interest as drug targets. The polymodal signal-detecting transient receptor potential (TRP) superfamily of ion channels forms a particularly promising group of drug targets. While most members of this family permeate a broad range of cations including Ca2+, TRPM4 and TRPM5 are unique due to their strong monovalent selectivity and impermeability for divalent cations. Here, we investigated the mechanistic basis for their unique monovalent selectivity by in silico electrophysiology simulations of TRPM5. Our simulations reveal an unusual mechanism of cation selectivity, which is underpinned by the function of the central channel cavity alongside the selectivity filter. Our results suggest that a subtle hydrophobic barrier at the cavity entrance ("hydrophobic funnel") enables monovalent but not divalent cations to pass and occupy the cavity at physiologically relevant membrane voltages. Monovalent cations then permeate efficiently by a cooperative, distant knock-on mechanism between two binding regions in the extracellular pore vestibule and the central cavity. By contrast, divalent cations do not enter or interact favorably with the channel cavity due to its raised hydrophobicity. Hydrophilic mutations in the transition zone between the selectivity filter and the central channel cavity abolish the barrier for divalent cations, enabling both monovalent and divalent cations to traverse TRPM5.