Search

Purpose: To develop and evaluate a novel method for computationally efficient reconstruction from noisy MR spectroscopic imaging (MRSI) data., Methods: The proposed method features (a) a novel strategy that jointly learns a nonlinear low-dimensional representation of high-dimensional spectroscopic signals and a neural-network-based projector to recover the low-dimensional embeddings from noisy/limited data; (b) a formulation that integrates the forward encoding model, a regularizer exploiting the learned representation, and a complementary spatial constraint; and (c) a highly efficient algorithm enabled by the learned projector within an alternating direction method of multipliers (ADMM) framework, circumventing the computationally expensive network inversion subproblem., Results: The proposed method has been evaluated using simulations as well as in vivo   1 $$ {}^1 $$ H and   31 $$ {}^{31} $$ P MRSI data, demonstrating improved performance over state-of-the-art methods, with about 6 × $$ \times $$ fewer averages needed than standard Fourier reconstruction for similar metabolite estimation variances and up to 100 × $$ \times $$ reduction in processing time compared to a prior neural network constrained reconstruction method. Computational and theoretical analyses were performed to offer further insights into the effectiveness of the proposed method., Conclusion: A novel method was developed for fast, high-SNR spatiospectral reconstruction from noisy MRSI data. We expect our method to be useful for enhancing the quality of MRSI or other high-dimensional spatiospectral imaging data., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live cells is an effective strategy for discovering cell-targeting ligands. The DNA-encoded chemical library (DEL or DECL) technology has emerged as a robust tool in drug discovery and has been successfully utilized in identifying ligands for biological targets. However, nearly all DEL selections have predefined targets, while target-agnostic DEL selections interrogating the entire cell surface remain underexplored. Herein, we systematically optimized a cell-based DEL selection method against cancer cells without predefined targets. A 104.96-million-member DEL was selected against MDA-MB-231 and MCF-7 breast cancer cells, representing high and low metastatic properties, respectively, which led to the identification of cell-specific small molecules. We further demonstrated cell-targeting applications of these ligands in cancer photodynamic therapy and targeted drug delivery. Finally, leveraging the DNA tag of DEL compounds, we identified α-enolase (ENO1) as the cell surface receptor of one of the ligands targeting the more aggressive MDA-MB-231 cells. Overall, this work offers an efficient approach for discovering cell-targeting small molecule ligands by using DELs and demonstrates that DELs can be a useful tool to identify specific surface receptors on cancer cells., (© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control. The highly conserved and ubiquitously expressed SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex plays a central role in cell type- and context-dependent gene expression. Despite the absence of a defined DNA recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open chromatin state. It does so while retaining the ability to respond dynamically to cellular signals. However, the mechanisms that guide SWI/SNF to specific genomic targets have remained elusive. Here we demonstrate that trans-acting long non-coding RNAs (lncRNAs) direct the SWI/SNF complex to cell type-specific enhancers. SWI/SNF preferentially binds lncRNAs and these predominantly bind DNA targets in trans. Together they localize to enhancers, many of which are cell type-specific. Knockdown of SWI/SNF- and enhancer-bound lncRNAs causes the genome-wide redistribution of SWI/SNF away from enhancers and a concomitant differential expression of spatially connected target genes. These lncRNA-SWI/SNF-enhancer networks support an enhancer hub model of SWI/SNF genomic targeting. Our findings reveal that lncRNAs competitively recruit SWI/SNF, providing a specific and dynamic layer of control over chromatin accessibility, and reinforcing their role in mediating enhancer activity and gene expression., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

A major event in vertebrate evolution was the separation of the skull from the pectoral girdle and the acquisition of a functional neck, transitions that required profound developmental rearrangements of the musculoskeletal system. The neck is a hallmark of the tetrapod body plan and allows for complex head movements on land. While head and trunk muscles arise from distinct embryonic mesoderm populations, the origins of neck muscles remain elusive. Here, we combine comparative embryology and anatomy to reconstruct the mesodermal contribution to neck evolution. We demonstrate that head/trunk-connecting muscle groups have conserved mesodermal origins in fishes and tetrapods and that the neck evolved from muscle groups present in fishes. We propose that expansions of mesodermal populations into head and trunk domains during embryonic development underpinned the emergence and adaptation of the tetrapod neck. Our results provide evidence for the exaptation of archetypal muscle groups in ancestral fishes, which were co-opted to acquire novel functions adapted to a terrestrial lifestyle., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Achieving high-resolution and high signal-to-noise ratio (SNR) in vivo metabolic imaging via fast magnetic resonance spectroscopic imaging (MRSI) has been a longstanding challenge. This study combines the methods of relaxation enhancement (RE) and subspace imaging for the first time, enabling high-resolution and high-SNR in vivo MRSI of rodent brains at 9.4 T. Specifically, an RE-based chemical shift imaging sequence, which combines a frequency-selective pulse to excite only the metabolite frequencies with minimum perturbation of the water spins and a pair of adiabatic pulses to spatially localize the slice of interest, is designed and evaluated in vivo. This strategy effectively shortens the apparent T 1 of metabolites, thereby increasing the SNR during relatively short repetition time ((T R ) compared with acquisitions with only spatially selective wideband excitations, and does not require water suppression. The SNR was further enhanced via a state-of-the-art subspace reconstruction method. A novel subspace learning strategy tailored for 9.4 T and RE acquisitions is developed. In vivo, high-resolution (e.g., voxel size of 0.6 × 0.6 × 1.5 mm 3 ) MRSI of both healthy mouse brains and a glioma-bearing mouse brain in 12.5 min has been demonstrated., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

The functional role of long noncoding RNAs in the endothelium is highly diverse. Among their many functions, regulation of transcription factor activity and abundance is one of the most relevant. This review summarizes the recent progress in the research on the lncRNA-transcription factor axes and their implications for the vascular endothelium under physiological and pathological conditions. The focus is on transcription factors critical for the endothelial response to external stressors, such as hypoxia, inflammation, and shear stress, and their lncRNA interactors. These regulatory interactions will be exemplified by a selected number of lncRNAs that have been identified in the endothelium under physiological and pathological conditions that are influencing the activity or protein stability of important transcription factors. Thus, lncRNAs can add a layer of cell type-specific function to transcription factors. Understanding the interaction of lncRNAs with transcription factors will contribute to elucidating cardiovascular disease pathologies and the development of novel therapeutic approaches.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Cardiac involvement in systemic light chain amyloidosis (AL) leads to chronic heart failure and is a major prognosis factor. Severe cellular defects are provoked in cardiac cells by tissue-deposited amyloid fibrils of misfolded free immunoglobulin light chains (LCs) and their prefibrillar oligomeric precursors., Objective: Understanding the molecular mechanisms behind cardiac cell cytotoxicity is necessary to progress in therapy and to improve patient management. One key question is how extracellularly deposited molecules exert their toxic action inside cardiac cells. Here we searched for direct evidence of amyloid LC uptake by cardiomyocytes in patient biopsies., Methods: We immunolocalized LCs in cardiac biopsies from four AL cardiac amyloidosis patients and analysed histopathological images by high resolution confocal microscopy and 3D image reconstruction., Results: We show, for the first time directly in patient tissue, the presence of LCs inside cardiomyocytes, and report their proximity to nuclei and to caveolin-3-rich areas. Our observations point to macropinocytosis as a probable mechanism of LC uptake., Conclusions: Internalisation of LCs occurs in patient cardiomyocytes. This event could have important consequences for the pathogenesis of the cardiac disease by enabling interactions between amyloid molecules and cellular organelles inducing specific signalling pathways, and might bring new insight regarding treatment.

Background: Medical oxygen services are essential for the care of acutely unwell patients. We aimed to assess the effects of a multilevel, multicomponent health-system intervention on hypoxaemia detection, oxygen therapy, and mortality among neonates and children attending level IV health centres and hospitals in Uganda., Methods: For this before-after intervention study, we included children who attended paediatric or neonatal wards of 24 level IV health centres and seven general or regional referral hospitals in the Busoga and North Buganda regions of Uganda between June 1, 2020, and June 30, 2022. All neonates younger than 1 month and children aged 1 month to 14 years were eligible for inclusion. We excluded neonates who were not sick but stayed in the maternity ward for routine postnatal care. The intervention involved clinical training, mentorship, and supportive supervision; provision of pulse oximeters and cylinder-based oxygen sources; biomedical-capacity support; and support to develop and disseminate oxygen supply strategies, oxygen therapy guidelines, and lists of essential oxygen supplies. Trained research assistants extracted individual patient data from case notes using a standardised electronic data collection form. Data were collected on health-facility details, age, sex, clinical signs and symptoms, admission diagnoses, pulse oximetry readings, oxygen therapy details, and final patient outcome. The primary outcome was the proportion of admitted neonates and children with a pulse oximetry oxygen saturation reading documented in their patient case notes on day 1 of health-facility admission (ie, pulse oximetry coverage). We used mixed-effects logistic regression to evaluate the effect of the intervention., Findings: We obtained data on 71 997 eligible neonates and children admitted to 31 participating health facilities; the primary analysis included 10 001 patients in the pre-intervention period (ie, June 1 to Oct 30, 2020) and 51 329 patients in the post-intervention period (ie, March 1, 2021, to June 30, 2022). Because 1356 patients had missing data for sex, 4365 (46·7%) of 9347 in the pre-intervention group and 22 831 (46·2%) of 49 410 in the post-intervention group were female; 4982 (53·3%) in the pre-intervention group and 26 579 (53·8%) in the post-intervention group were male. The proportion of neonates and children with pulse oximetry at admission increased from 2365 (23·7%) of 10 001 in the pre-intervention period to 45 029 (87·7%) of 51 328 in the post-intervention period. Adjusted analysis indicated greater likelihood of a patient receiving pulse oximetry during the post-intervention period compared with the pre-intervention period (adjusted odds ratio 40·10, 95% CI 37·38-42·93; p<0·0001)., Interpretation: Large-scale improvements in hospital oxygen services are achievable and have the potential to improve clinical outcomes. Governments should be encouraged to develop national oxygen plans and focus investment on interventions that have been shown to be effective, including the introduction of pulse oximetry into routine hospital care and clinical and biomedical mentoring and support., Funding: Bill & Melinda Gates Foundation and ELMA Philanthropies., Translations: For the Luganda and Lusoga translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests HRG is an adviser to the Lifebox Foundation and Unitaid and receives a salary from the University of Melbourne. YK, JM, BK, SE, DK, AZ, LNK, and FL were employed by Clinton Health Access Initiative during implementation of the oxygen programme in Uganda. YK, BK, SE, AZ, DK, and LNK received a salary from Clinton Health Access Initiative Uganda. CO is employed by the Ugandan Ministry of Health. FEK and FS receive a salary from Makerere University. HA declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Diarrhoea kills 500,000 children every year despite availability of cheap and effective treatment. In addition, a large number are inappropriately treated with antibiotics, which do not benefit the patient but can contribute to the development of antibiotic resistance. We investigated whether the prevalence of antibiotic use among children under the age of five with diarrhoea in Uganda changed following a national intervention to increase the use of oral rehydration salts (ORS), and whether any socioeconomic characteristics were associated with antibiotic use., Methods: A cross-sectional survey was conducted among caregivers of children under the age of five and among private health care providers and drug sellers in Uganda in 2014. This was compared to a similar survey among private health care providers, and the national demographic and health survey in Uganda in 2016. Logistic regression was used to find associations between antibiotic use and socioeconomic characteristics, and chi-square test and independent sample t-test were used to find significant differences between groups., Results: The prevalence of antibiotic use among children under the age of five with diarrhoea in Uganda decreased from 30.5% in 2014 to 20.0% (p < 0.001) in 2016. No associations between socioeconomic characteristics and the use of antibiotics were significant in both 2014 and 2016., Conclusions: The use of antibiotics in children with diarrhoeal disease decreased significantly in Uganda between 2014 and 2016. However, the extent of the contribution of the ORS scale-up programme to this decrease cannot be determined from this study., (© 2024. The Author(s).)

Fluorescence lifetime imaging microscopy (FLIM) opens new dimensions for highly multiplexed imaging in live cells and organisms using differences in fluorescence lifetime to distinguish spectrally identical fluorescent probes. Here, a set of fluorescence-activating and absorption-shifting tags (FASTs) capable of modulating the fluorescence lifetime of embedded fluorogenic 4-hydroxybenzylidene rhodanine (HBR) derivatives is described. It is shown that changes in the FAST protein sequence can vary the local environment of the chromophore and lead to significant changes in fluorescence lifetime. These fluorescence lifetime-modulating tags enable multiplexed imaging of up to three targets in one spectral channel using a single HBR derivative in live cells and live zebrafish larvae. The combination of fluorescence lifetime multiplexing with spectral multiplexing allows to successfully image six targets in live cells, opening great prospects for multicolor fluorescence lifetime multiplexing., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer's disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures., Competing Interests: M.L. Gordon has received compensation for participating in Advisory Board meetings for Corium and Labcorp. He has been a clinical trial site Principal Investigator for AbbVie, Alector, Bristol Myers Squibb, Eisai, and Novo Nordisk (payments made to institution). J. Koppel has received grant support from NIA, NIMH, and Alzheimer’s Foundation of America, and has been a clinical trial site Principal Investigator for Karuna and Otsuka (payments made to institution). J. Gomar has received grant support from NIA and Alzheimer’s Association (payments made to institution). E. Christen, L. Keehlisen, M. Gong, F. Lam, and L. Giliberto have no disclosures., (© 2024 – The authors. Published by IOS Press.)

Objective: To develop a novel multi-TE MR spectroscopic imaging (MRSI) approach to enable label-free, simultaneous, high-resolution mapping of several molecules and their biophysical parameters in the brain., Methods: The proposed method uniquely integrated an augmented molecular-component-specific subspace model for multi-TE 1 H-MRSI signals, an estimation-theoretic experiment optimization (nonuniform TE selection) for molecule separation and parameter estimation, a physics-driven subspace learning strategy for spatiospectral reconstruction and molecular quantification, and a new accelerated multi-TE MRSI acquisition for generating high-resolution data in clinically relevant times. Numerical studies, phantom and in vivo experiments were conducted to validate the optimized experiment design and demonstrate the imaging capability offered by the proposed method., Results: The proposed TE optimization improved estimation of metabolites, neurotransmitters and their T 2 's over conventional TE choices, e.g., reducing variances of neurotransmitter concentration by  ∼  40% and metabolite T 2 by  ∼  60%. Simultaneous metabolite and neurotransmitter mapping of the brain can be achieved at a nominal resolution of 3.4 × 3.4 × 6.4 mm 3 . High-resolution, 3D metabolite T 2 mapping was made possible for the first time. The translational potential of the proposed method was demonstrated by mapping biochemical abnormality in a post-traumatic epilepsy (PTE) patient., Conclusion: The feasibility for high-resolution mapping of metabolites/neurotransmitters and metabolite T 2 's within clinically relevant time was demonstrated. We expect our method to offer richer information for revealing and understanding metabolic alterations in neurological diseases., Significance: A novel multi-TE MRSI approach was presented that enhanced the technological capability of multi-parametric molecular imaging of the brain. The proposed method presents new technology development and application opportunities for providing richer molecular level information to uncover and comprehend metabolic changes relevant in various neurological applications.

Objective: To develop a new method that integrates subspace and generative image models for high-dimensional MR image reconstruction., Methods: We proposed a formulation that synergizes a low-dimensional subspace model of high-dimensional images, an adaptive generative image prior serving as spatial constraints on the sequence of "contrast-weighted" images or spatial coefficients of the subspace model, and a conventional sparsity regularization. A special pretraining plus subject-specific network adaptation strategy was proposed to construct an accurate generative-network-based representation for images with varying contrasts. An iterative algorithm was introduced to jointly update the subspace coefficients and the multi-resolution latent space of the generative image model that leveraged an recently proposed intermediate layer optimization technique for network inversion., Results: We evaluated the utility of the proposed method for two high-dimensional imaging applications: accelerated MR parameter mapping and high-resolution MR spectroscopic imaging. Improved performance over state-of-the-art subspace-based methods was demonstrated in both cases., Conclusion: The proposed method provided a new way to address high-dimensional MR image reconstruction problems by incorporating an adaptive generative model as a data-driven spatial prior for constraining subspace reconstruction., Significance: Our work demonstrated the potential of integrating data-driven and adaptive generative priors with canonical low-dimensional modeling for high-dimensional imaging problems.

Identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C∧N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high-affinity targets. Upon iridium complex treatment, the folding activity of Heat Shock Protein HSP90 was inhibited in vitro and major cytoskeleton disorganization was observed. A wide array of imaging and biochemical methods validated selected targets and provided a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity. The proposed methodological workflow can open innovative avenues in metallodrug discovery.

Spatial omics technologies can reveal the molecular intricacy of the brain. While mass spectrometry imaging (MSI) provides spatial localization of compounds, comprehensive biochemical profiling at a brain-wide scale in three dimensions by MSI with single-cell resolution has not been achieved. We demonstrate complementary brain-wide and single-cell biochemical mapping using MEISTER, an integrative experimental and computational mass spectrometry (MS) framework. Our framework integrates a deep-learning-based reconstruction that accelerates high-mass-resolving MS by 15-fold, multimodal registration creating three-dimensional (3D) molecular distributions and a data integration method fitting cell-specific mass spectra to 3D datasets. We imaged detailed lipid profiles in tissues with millions of pixels and in large single-cell populations acquired from the rat brain. We identified region-specific lipid contents and cell-specific localizations of lipids depending on both cell subpopulations and anatomical origins of the cells. Our workflow establishes a blueprint for future development of multiscale technologies for biochemical characterization of the brain., (© 2024. The Author(s).)

Background: An estimated 50% of suspected malaria cases in sub-Saharan Africa first seek care in the private sector, especially in private medicine retail outlets. Quality of care in these outlets is generally unknown but considered poor with many patients not receiving a confirmatory diagnosis or the recommended first-line artemisinin-based combination therapy (ACT). In 2010, a subsidy pilot scheme, the Affordable Medicines Facility malaria, was introduced to crowd out the use of monotherapies in favour of WHO-pre-qualified artemisinin-based combinations (WHO-PQ-ACTs) in the private health sector. The scheme improved the availability, market share, and cost of WHO-PQ-ACTs in countries like Nigeria and Uganda, but in 2018, the subsidies were halted in Nigeria and significantly reduced in Uganda. This paper presents findings from six retail audit surveys conducted from 2014 to 2021 in Nigeria and Uganda to assess whether the impact of subsidies on the price, availability, and market share of artemisinin-based combinations has been sustained after the subsidies were reduced or discontinued., Methods: Six independent retail audits were conducted in private medicine retail outlets, including pharmacies, drug shops, and clinics in Nigeria (2016, 2018, 2021), and Uganda (2014, 2019, 2020) to assess the availability, price, and market share of anti-malarials, including WHO-PQ-ACTs and non-WHO-PQ-ACTs, and malaria rapid diagnostic tests (RDTs)., Results: Between 2016 and 2021, there was a 57% decrease in WHO-PQ-ACT availability in Nigeria and a 9% decrease in Uganda. During the same period, non-WHO-PQ-ACT availability increased in Nigeria by 41% and by 34% in Uganda. The price of WHO-PQ-ACTs increased by 42% in Nigeria to $0.68 and increased in Uganda by 24% to $0.95. The price of non-WHO-PQ-ACTs decreased in Nigeria by 26% to $1.08 and decreased in Uganda by 64% to $1.23. There was a 76% decrease in the market share of WHO-PQ-ACTs in Nigeria and a 17% decrease in Uganda. Malaria RDT availability remained low throughout., Conclusion: With the reduction or termination of subsidies for WHO-PQ-ACTs in Uganda and Nigeria, retail prices have increased, and retail prices of non-WHO-PQ-ACTs decreased, likely contributing to a shift of higher availability and increased use of non-WHO-PQ-ACTs., (© 2024. The Author(s).)

Background: Pneumonia remains the leading cause of mortality in under-five children outside the neonatal period. Progress has slowed down in the last decade, necessitating increased efforts to scale up effective pneumonia interventions., Methods: We used the Lives Saved Tool (LiST), a modelling software for child mortality in low- and middle-income settings, to prospectively analyse the potential impact of upscaling pneumonia interventions in Bangladesh, Chad, and Ethiopia from 2023 to 2030. We included Haemophilus influenzae type B (Hib) vaccination, pneumococcal conjugate vaccine (PCV), oral antibiotics, pulse oximetry, and oxygen as pneumonia interventions in our analysis. Outcomes of interest were the number of pneumonia deaths averted, the proportion of deaths averted by intervention, and changes in the under-five mortality rate., Findings: We found that 19 775 lives of children under-five could be saved in Bangladesh, 76 470 in Chad, and 97 343 in Ethiopia by scaling intervention coverages to ≥90% by 2030. Our estimated reductions in pneumonia deaths among children under five range from 44.61% to 57.91% in the respective countries. Increased coverage of oral antibiotics, pulse oximetry, and oxygen show similar effects in all three countries, averting between 18.80% and 23.65% of expected pneumonia deaths. Scaling-up PCV has a prominent effect, especially in Chad, where it could avert 14.04% of expected pneumonia deaths. Under-five mortality could be reduced by 1.42 per 1000 live births in Bangladesh, 22.52 per 1000 live births in Chad, and 5.48 per 1000 live births in Ethiopia., Conclusions: This analysis shows the high impact of upscaling pneumonia interventions. The lack of data regarding coverage indicators is a barrier for further research, policy, and implementation, all requiring increased attention., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: FL is employed by CHAI and implementing oxygen strengthening programmes across low-resource settings. RS and SR (Rashed and Shohel) have been working for Fighting Against Childhood Pneumonia projects in Save the Children., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

5-hydroxyindole acetic acid, a metabolite of serotonin, is used in the diagnosis and monitoring of patients with neuroendocrine tumours, in particular patients with small intestinal neuroendocrine tumours associated with the carcinoid syndrome. Analysis of 5-hydroxyindole acetic acid was commonly performed in urine, but blood-based assays are now becoming available. The objective of this study was to assess how 5-hydroxyindole acetic acid compares in plasma and serum as a biochemical marker of neuroendocrine tumours. Twenty-four-hour urine, plasma and serum samples were obtained from 80 patients with neuroendocrine tumours and 30 healthy volunteers. We developed a liquid chromatography tandem mass spectrometry assay for plasma and serum 5-hydroxyindole acetic acid. Comparison was made between them, and their cut-off was determined using a receiver-operating characteristic curve. A close correlation was shown between plasma and serum 5-hydroxyindole acetic acid. At a cut-off of 135 nmol/l, a sensitivity of 91.2% with a specificity of 61.9% was obtained for both compared to the urinary assay. A statistically significant agreement was shown when plasma and serum 5-hydroxyindole acetic acid were compared with the currently used urine assay in patients with neuroendocrine tumours; κ = 0.675 (95% CI 0.49 to 0.86), p  < 0.001 and healthy volunteers; 0.967 (95% CI 0.828 to 0.999), p = <0.001. In conclusion, 5-hydroxyindole acetic acid in plasma and serum were comparable, hence either sample type can be used interchangeably.

Elucidating the spatial-biochemical organization of the brain across different scales produces invaluable insight into the molecular intricacy of the brain. While mass spectrometry imaging (MSI) provides spatial localization of compounds, comprehensive chemical profiling at a brain-wide scale in three dimensions by MSI with single-cell resolution has not been achieved. We demonstrate complementary brain-wide and single-cell biochemical mapping via MEISTER, an integrative experimental and computational mass spectrometry framework. MEISTER integrates a deep-learning-based reconstruction that accelerates high-mass-resolving MS by 15-fold, multimodal registration creating 3D molecular distributions, and a data integration method fitting cell-specific mass spectra to 3D data sets. We imaged detailed lipid profiles in tissues with data sets containing millions of pixels, and in large single-cell populations acquired from the rat brain. We identified region-specific lipid contents, and cell-specific localizations of lipids depending on both cell subpopulations and anatomical origins of the cells. Our workflow establishes a blueprint for future developments of multiscale technologies for biochemical characterization of the brain., Competing Interests: Competing interests The authors declare no competing interests.

Three-dimensional stroma engineered models would enable fundamental and applicative studies of human tissues interaction and remodeling in both physiological and pathological conditions. In this work, we propose a 3D vascularized stroma model to be used as in vitro platform for drug testing. A pullulan/dextran-based porous scaffold containing pre-patterned microchannels of 100 μm diameter is used for co-culturing of fibroblasts within the matrix pores and endothelial cells to form the lumen. Optical clearing of the constructs by hyperhydration allows for in-depth imaging of the model up to 1 mm by lightsheet and confocal microscopy. Our 3D vascularized stroma model allows for higher viability, metabolism and cytokines expression compared to a monocultured vascular model. Stroma-endothelium cross-talk is then investigated by exposing the system to pro and anti-angiogenic molecules. The results highlight the protective role played by fibroblasts on the vasculature, as demonstrated by decreased cytotoxicity, restoration of nitric oxide levels upon challenge, and sustained expression of endothelial markers CD31, vWF and VEGF. Our tissue model provides a 3D engineered platform for in vitro studies of stroma remodeling in angiogenesis-driven events, known to be a leading mechanism in diseased conditions, such as metastatic cancers, retinopathies and ischemia, and to investigate related potential therapies., Competing Interests: Declaration of competing interest The authors declare no competing financial interests nor personal relationships that could have influenced the work reported here., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Mildly delignified wood showed a well-preserved wood cell wall framework, and its derived compressed materials demonstrate excellent mechanical properties and advanced functional material potential. Here, we proposed a simple yet effective approach for making strong, tough, and fire-retardant wooden laminate by a three-step process of mild delignification, infiltrating potassium nonafluoro-1-butanesulfonate (PFBS), and hot-pressing to densify the material. PFBS can be infiltrated into the micro/nano-structures of the mildly delignified wood to achieve a good flame-resistant protective barrier. Flame retardant tests showed that this strong, tough, and fire-retardant wooden laminate has a superior flame-retardant performance to natural wood. Additionally, the wooden laminate also exhibits a simultaneously enhanced tensile strength (175.6 MPa vs. 89.9 MPa for natural wood) and toughness (22.9 MJ m -3 vs. 10.9 MJ m -3 for natural wood). Given these attributes, the resulting wooden laminates are identified as promising candidates for high-performance structural applications, fulfilling stringent requirements for both mechanical resilience and flame-retardant efficacy.

Objectives: Up to 20% of individuals who die by suicide have visited an emergency department (ED) within 4 weeks of their death. Limited guidance is available regarding the modification of clinical outcomes following a psychosocial intervention in the ED for pediatric and adult populations., Methods: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted to identify studies focused on single-session psychosocial interventions for pediatric and adult patients experiencing suicide-related thoughts or behaviors (SRTB) in the ED. Two reviewers independently screened articles identified using the key terms suicide/self-harm, emergency department, and interview. Medline, PubMed, Embase, PsycINFO, CINAHL, and CENTRAL were searched from inception to August 2018., Results: After screening 3234 abstracts, 29 articles were selected for full-text review and 14 articles, representing 8 distinct studies (N=782), were included. A high level of heterogeneity was present in the included articles, with 7 randomized-controlled trials, 2 nonrandomized-controlled trials, 2 cohort studies, 2 observational studies, and 1 feasibility study. Most of the included studies focused on adolescents (6 articles) or military veterans (7 articles). Strong statistical evidence of ED interventions improving outpatient service linkage was supported (χ2: 81.80, P<0.0001, 7 studies)., Conclusions: The findings of this study suggested promising outcomes for patients presenting to the ED with SRTB who receive a single-session psychosocial intervention. All of the studies that measured such outcomes found significantly increased follow-up care in the intervention arm. Further research is needed to strengthen the evidence base, provide better patient representation, and improve our understanding of the mechanisms by which the psychosocial intervention for SRTB in the ED ameliorates patient outcomes (CRD42020156496)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The influence of recent influenza infection on perioperative outcomes is not completely understood., Method: Using Taiwan's National Health Insurance Research Data from 2008 to 2013, we conducted a surgical cohort study, which included 20,544 matched patients with a recent history of influenza and 10,272 matched patients without. The main outcomes were postoperative complications and mortality. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the complications and for mortality in patients with a history of influenza within 1-14 days or 15-30 days compared with non-influenza controls., Results: Compared with patients who had no influenza, patients with influenza within preoperative days 1-7 had increased risks of postoperative pneumonia (OR 2.22, 95% CI 1.81-2.73), septicemia (OR 1.98, 95% CI 1.70-2.31), acute renal failure (OR 2.10, 95% CI 1.47-3.00), and urinary tract infection (OR 1.45, 95% CI 1.23-1.70). An increased risk of intensive care admission, prolonged length of stay, and higher medical expenditure was noted in patients with history of influenza within 1-14 days., Conclusion: We found that there was an association between influenza within 14 days preoperatively and the increased risk of postoperative complications, particularly with the occurrence of influenza within 7 days prior to surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lam, Liao, Chen, Huang, Lee and Chiou.)

Sepsis-induced coagulopathy leading to disseminated microvascular thrombosis is associated with high mortality and has no existing therapy. Despite the high prevalence of Gram-positive bacterial sepsis, especially methicillin-resistant Staphylococcus aureus (MRSA), there is a paucity of published Gram-positive pediatric sepsis models. Large animal models replicating sepsis-induced coagulopathy are needed to test new therapeutics before human clinical trials., Hypothesis: Our objective is to develop a pediatric sepsis-induced coagulopathy swine model that last 70 hours., Methods and Models: Ten 3 weeks old piglets, implanted with telemetry devices for continuous hemodynamic monitoring, were IV injected with MRSA ( n = 6) (USA300, Texas Children's Hospital 1516 strain) at 1 × 10 9 colony forming units/kg or saline ( n = 4). Fluid resuscitation was given for heart rate greater than 50% or mean arterial blood pressure less than 30% from baseline. Acetaminophen and dextrose were provided as indicated. Point-of-care complete blood count, prothrombin time (PT), activated thromboplastin time, d-dimer, fibrinogen, and specialized coagulation assays were performed at pre- and post-injection, at 0, 24, 48, 60, and 70 hours. Piglets were euthanized and necropsies performed., Results: Compared with the saline treated piglets (control), the septic piglets within 24 hours had significantly lower neurologic and respiratory scores. Over time, PT, d-dimer, and fibrinogen increased, while platelet counts and activities of factors V, VII, protein C, antithrombin, and a disintegrin and metalloproteinase with thrombospondin-1 motifs (13th member of the family) (ADAMTS-13) decreased significantly in septic piglets compared with control. Histopathologic examination showed minor focal organ injuries including microvascular thrombi and necrosis in the kidney and liver of septic piglets., Interpretations and Conclusions: We established a 70-hour swine model of MRSA sepsis-induced coagulopathy with signs of consumptive coagulopathy, disseminated microvascular thrombosis, and early organ injuries with histological minor focal organ injuries. This model is clinically relevant to pediatric sepsis and can be used to study dysregulated host immune response and coagulopathy to infection, identify potential early biomarkers, and to test new therapeutics., Competing Interests: Drs. Nguyen, Vijayan, and Cruz received funding from National Institute of General Medical Sciences (NIGMS; R01GM112806). Dr. Marini received funding from NIGMS (R01GM108940). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood., Methods: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5., Results: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry., Conclusion: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Recurrent respiratory papillomatosis (RRP), a rare chronic disease caused primarily by human papillomavirus types 6 and 11, consists of repeated growth of premalignant papillomas in the airway. RRP is characterized by multiple abnormalities in innate and adaptive immunity. Natural killer (NK) cells play important roles in immune surveillance and are part of the innate immune responses that help prevent tumor growth. We identified that papillomas lack classical class I MHC and retain nonclassical class I MHC expression. Moreover, in this study, we have identified and characterized the mechanism that blocks NK cell targeting of papilloma cells. Here, we show for the first time that the PGE 2 secreted by papilloma cells directly inhibits NK cells activation/degranulation principally through the PGE 2 receptor EP2, and to a lesser extent through EP4 signaling. Thus, papilloma cells have a potent mechanism to block NK cell function that likely supports papilloma cell growth., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

As a key partner of Ministry of Health (MOH) Ethiopia, The Clinton Health Access Initiative (CHAI) had been implementing the Child Survival Project (CSP) since October 2015. Strengthening DTC was one of its focuses to improve overall supply chain management (SCM). The objective of this study are to review the evolution of DTCs in Ethiopia from their early years to current practice and identify the major driving and hindering factors for their functionality. A descriptive mixed study design was employed. The study made use of qualitative data supplemented with quantitative data, generated from both primary and secondary sources through key informant interviews and desk review methods. DTCs were introduced in Ethiopia in the early 1980s. The mandate of DTCs has been given to four different government organizations during that time. As a result, due to a lack of coordination among these organizations, its implementation was lagging. Recently, the government and its partners have given attention to DTCs. More than 5847 professionals underwent DTC training from 2016 onwards. DTC establishment in health facilities improved from 85% to 98% between 2015 and 2019 during baseline and end-line assessments carried out by CHAI/CSP. Similarly, DTC functionality in HFs improved from 20% to 63%. The CHAI/CSP regular supervision data analysis revealed that DTC establishment improved from 83% to 100% of HFs, while its functionality improved from 5% to 72% between 2016 and 2019, respectively. A chi-square test of independence examining the relationship between facility and pharmacy head training on DTCs and functionality of DTC in the same facility revealed a significant association between the two variables at p<0.0001. Conclusions: Providing consistent capacity building and availing strong monitoring and evaluation system improves functionality of DTCs. Moreover, national coordinating bodies for DTCs and similar structures at Regional Health Bureaus and woreda health offices should be established., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Seyoum H et al.)

Magnetic resonance spectroscopic imaging (MRSI) offers a unique molecular window into the physiological and pathological processes in the human body. However, the applications of MRSI have been limited by a number of long-standing technical challenges due to high dimensionality and low signal-to-noise ratio (SNR). Recent technological developments integrating physics-based modeling and data-driven machine learning that exploit unique physical and mathematical properties of MRSI signals have demonstrated impressive performance in addressing these challenges for rapid, high-resolution, quantitative MRSI. This paper provides a systematic review of these progresses in the context of MRSI physics and offers perspectives on promising future directions.

Objective: Organ dysfunction (OD) after lung transplantation can reflect preoperative organ failure, intraoperative acute organ damage and post-operative complications. We assessed two OD scoring systems, both the PEdiatric Logistic Organ Dysfunction (PELOD) and the pediatric Sequential Organ Failure Assessment (pSOFA) scores, in recognizing risk factors for morbidity as well as recipients with prolonged post-transplant morbidity., Design: Medical records of recipients from January 2009 to March 2016 were reviewed. PELOD and pSOFA scores were calculated on post-transplant days 1-3. Risk factors assessed included cystic fibrosis (CF), prolonged surgical time and worst primary graft dysfunction (PGD) score amongst others. Patients were classified into three groups based on their initial scores (group A) and subsequent trends either uptrending (group B) or downtrending (group C). Morbidity outcomes were compared between these groups., Results: Total 98 patients were enrolled aged 0-20 years. Risk factors for higher pSOFA scores ≥ 5 on day 1 included non-CF diagnosis and worst PGD scores (p = .0006 and p = .03, respectively). Kruskal Wallis analysis comparing pSOFA group A versus B versus C scores showed significantly prolonged ventilatory days (median 1 vs. 4 vs. 2, p = .0028) and ICU days (median 4 vs. 10 vs. 6, p = .007). Similarly, PELOD group A versus B versus C scores showed significantly prolonged ventilatory days (1 vs. 5 vs. 2, p = < .0001)., Conclusion: Implementing pSOFA scores bedside is a more effective tool compared to PELOD in identifying risk factors for worsened OD post-lung transplant and can be valuable in providing direction on morbidity outcomes in the ICU., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the "premetastatic" or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-G/SPAG9/STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive and/or more efficacious BM therapies.

Objective: The school setting can provide an environment that supports healthy behaviours, including the provision of food. School food activities, that is, school feeding, are commonplace globally, but not well understood in the Pacific Islands region. The aim of this research is to explore learnings associated within existing school food programmes (SFP), and adoption resistors in those Pacific Island Countries and Territories (PICT) without SFP, with the intent of improving current and future SFP interventions., Design: This observational cross-sectional study utilised four facilitated workshop sessions to explore SFP within an existing framework., Setting: Pacific Islands region., Participants: Fourteen participants representing the education and health sectors from eleven PICT, and two participants representing regional organisations., Results: Most countries reported some form of related policy, but key critical constraints to the use of SFP included local food environments, strategic alignment to organisational priorities, advocacy and organisational leadership, and community and cultural connections and collaboration. There are opportunities for integration of SFP into existing frameworks (i.e. Health Promoting Schools), increased collaboration, greater professional development and awareness activities, improved monitoring and evaluation, improved awareness of SFP and promotion of healthy eating for the wider school community., Conclusions: Given the current health, social and economic challenges faced by countries and territories in the Pacific Islands region, SFP should be considered as an opportunity for food provision and associated nutrition education for students and their wider community. Further research is needed to understand the critical constraints of SFP in this region and how to support stakeholders to advocate for, develop and sustain SFP that are contextually and culturally appropriate.

Cigarette smoking is associated with surgical complications, including wound healing and surgical site infection. However, the association between smoking status and postoperative wound complications is not completely understood. Our objective was to investigate the effect of smoking on postoperative wound complications for major surgeries. Data were collected from the 2013 to 2018 participant use files of the American College of Surgeons National Surgical Quality Improvement Program database. A propensity score matching procedure was used to create the balanced smoker and nonsmoker groups. Multivariable logistic regression was used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs) for postoperative wound complications, pulmonary complications, and in-hospital mortality associated with smokers. A total of 1 156 002 patients (578 001 smokers and 578 001 nonsmokers) were included in the propensity score matching analysis. Smoking was associated with a significantly increased risk of postoperative wound disruption (OR 1.65, 95% CI 1.56-1.75), surgical site infection (OR 1.31, 95% CI 1.28-1.34), reintubation (OR 1.47, 95% CI 1.40-1.54), and in-hospital mortality (OR 1.13, 95% CI 1.07-1.19) compared with nonsmoking. The length of hospital stay was significantly increased in smokers compared with nonsmokers. Our analysis indicates that smoking is associated with an increased risk of surgical site infection, wound disruption, and postoperative pulmonary complications. The results may drive the clinicians to encourage patients to quit smoking before surgery., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Oropharyngeal squamous cell cancer (OPC) accounts for 3% of all cancers and greater than 1.5% of all cancer deaths in the United States, with marked treatment-associated morbidity in survivors. More than 80% of OPC is caused by HPV16. Tumors induced by HPV have been linked to impaired immune functions, with most studies focused on the local tumor microenvironment. Fewer studies have characterized the effects of these tumors on systemic responses in OPC, especially innate responses that drive subsequent adaptive responses, potentially creating feed-back loops favorable to the tumor. Here we report that elevated plasma levels of PGE 2 are expressed in half of patients with OPC secondary to overexpression of COX-2 by peripheral blood monocytes, and this expression is driven by IL-1α secreted by the tumors. Monocytes from patients are much more sensitive to the stimulation than monocytes from controls, suggesting the possibility of enhanced immune-modulating feed-back loops. Furthermore, control monocytes pre-exposed to PGE 2 overexpress COX-2 in response to IL-1α, simulating responses made by monocytes from some OPC patients. Disrupting the PGE 2 /IL-1α feed-back loop can have potential impact on targeted medical therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 DeVoti, Israr, Lam, Papayannakos, Frank, Kamdar, Pereira, Abramson, Steinberg and Bonagura.)

We present a novel method to enhance the SNR for multi-TE MR spectroscopic imaging (MRSI) data by integrating learned nonlinear low-dimensional model and spatial constraints. A deep complex convolutional autoencoder (DCCAE) was developed to learn a nonlinear low-dimensional representation of the high-dimensional multi-TE 1 H spectroscopy signals. The learned model significantly reduces the data dimension thus serving as an effective constraint for noise reduction. A reconstruction formulation was proposed to integrate the spatiospectral encoding model, the learned model, and a spatial constraint for an SNR-enhancing reconstruction from multi-TE data. The proposed method has been evaluated using both numerical simulations and in vivo brain MRSI experiments. The superior denoising performance of the proposed over alternative methods was demonstrated, both qualitatively and quantitatively. In vivo multi-TE data was used to assess the improved metabolite quantification reproducibility and accuracy achieved by the proposed method. We expect the proposed SNR-enhancing reconstruction to enable faster and/or higher-resolution multi-TE 1 H-MRSI of the brain, potentially useful for various clinical applications.

The COVID-19 pandemic is often accompanied by severe respiratory illness and thrombotic complications. Von Willebrand Factor (VWF) levels are highly elevated in this condition. However, limited data are available on the qualitative activity of VWF in COVID-19. We measured plasma VWF levels quantitatively (VWF antigen) and qualitatively (ristocetin-induced platelet agglutination, glycoprotein IbM (GPIbM) binding, and collagen binding). Consistent with prior reports, VWF antigen levels were significantly elevated in hospitalized patients with or without COVID-19. The GPIbM and collagen binding activity-to-antigen ratios were significantly reduced, consistent with qualitative changes in VWF in COVID-19. Of note, critically ill hospitalized patients without COVID-19 had similar reductions in VWF activity-to-antigen ratios as patients with COVID-19. Our data suggest that qualitative changes in VWF in COVID-19 may not be specific to COVID-19. Future studies are warranted to determine the mechanisms responsible for qualitative changes in VWF in COVID-19 and other critical illnesses.• VWF levels were increased in COVID-19 compared to healthy controls.• VWF activity-to-antigen ratios were decreased in COVID-19 compared to healthy controls.• There were no differences in VWF activity-to-antigen ratios between hospitalized patients with or without COVID-19.• These findings are consistent with qualitative changes in VWF in systemic inflammation which are not specific to COVID-19.• Future studies are needed to define possible roles of changes in conformation or multimer length in the qualitative changes in VWF in systemic inflammation., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background An aesthetic smile displays a symmetrical 2 mm or less of gingival tissue. A smile with over 3 mm of gingival display can be deemed socially unaesthetic, impacting on a patient's psychosocial status. This literature review aimed to explore the role of botulinum toxin A as a treatment modality for different types of excessive gingival display (EGD) and appropriate treatment protocols.Methods A systematic search of the literature dating from 1980 onwards was conducted using electronic databases (Medline, Scopus and Web of Science). The Fowkes and Fulton quality assessment was undertaken to review the level of bias.Results Nine prospective studies were assessed for the number and site of injections, the unit dosage, the reconstitution and the improvement of EGD. Guidelines for treatment of EGD were constructed for operator consideration.Conclusions The data from this study elucidated that botulinum toxin is an effective treatment for all types of EGD caused by hyperfunctional smile muscles. It can be regarded as a safe treatment that reversibly improves facial aesthetics in patients suffering from gummy smile due to hyperactive musculature. Botulinum toxin was confirmed to be useful as a diagnostic tool and palliative treatment, as well as an adjunctive therapy in the treatment of a gummy smile., (© 2022. The Author(s), under exclusive licence to the British Dental Association.)

Application of a kurtosis correction to frequency-weighted sound exposure level (SEL) improved predictions of risk of hearing damage in humans and terrestrial mammals for sound exposures with different degrees of impulsiveness. To assess whether kurtosis corrections may lead to improved predictions for marine mammals, corrections were applied to temporary threshold shift (TTS) growth measurements for harbor porpoises (Phocoena phocoena) exposed to different sounds. Kurtosis-corrected frequency-weighted SEL predicted accurately the growth of low levels of TTS (TTS 1-4 < 10 dB) for intermittent sounds with short (1-13 s) silence intervals but was not consistent with frequency-weighted SEL data for continuous sound exposures.

Background: Pneumonia is the leading infectious cause of death in children worldwide, accounting for 15% of all deaths in children under the age of five. Hypoxemia is a major cause of death in patients suffering from pneumonia. There is strong evidence that using pulse oximetry and having reliable oxygen sources in health care facilities can reduce deaths due to pneumonia by one-third. Despite its importance, hypoxemia is frequently overlooked in resource-constrained settings. Aside from the limited availability of pulse oximetry, evidence showed that healthcare workers did not use it as frequently to generate evidence-based decisions on the need for oxygen therapy. As a result, the goal of this study was to assess the availability of medical oxygen devices, operating manuals, guidelines, healthcare workers' knowledge, and skills in the practice of hypoxemia diagnosis and oxygen therapy in piloted health centers of Ethiopia., Methods: A pre-post non-experimental study design was employed. An interviewer-administered questionnaire was used to collect primary data and review medical record charts. A chi-square test with a statistical significance level of P < 0.05 was used as a cut-off point for claiming statistical significance., Results: Eighty one percent of healthcare workers received oxygen therapy training, up from 6% at baseline. As a result of the interventions, knowledge of pulse oximetry use and oxygen therapy provision, skills such as oxygen saturation and practices of oxygen therapy have significantly improved among healthcare workers in the piloted Health Centers. In terms of availability of oxygen devices (e.g. cylinders, concentrators, and pulse oximeters) in the facilities, seven (58%) facilities did not have any at baseline, but due to the interventions, all facilities were equipped with the oxygen devices., Conclusions: Given the prevalence of pneumonia and hypoxemia, a lack of access to oxygen delivery devices, as well as a lack of knowledge and skills among healthcare workers in the administration of oxygen therapy, may represent an important and reversible barrier to improving child survival. Therefore, scaling up clinician training, technical support, availability of oxygen devices, guidelines, manuals, strengthening maintenance schemes, and close monitoring of healthcare workers and health facilities is strongly advised., (© 2022. The Author(s).)

Hypoxaemia (low blood oxygen) is common among hospitalised patients, increasing the odds of death five-fold and requiring prompt detection and treatment. However, we know little about hypoxaemia prevalence in primary care and the role for pulse oximetry and oxygen therapy. This study assessed the prevalence and management of hypoxaemia at primary care facilities in Uganda. We conducted a cross sectional prevalence study and prospective cohort study of children with hypoxaemia in 30 primary care facilities in Uganda, Feb-Apr 2021. Clinical data collectors used handheld pulse oximeters to measure blood oxygen level (SpO2) of all acutely unwell children, adolescents, and adults. We followed up a cohort of children aged under 15 years with SpO2<93% by phone after 7 days to determine if the patient had attended another health facility, been admitted, or recovered. Primary outcome: proportion of children under 5 years of age with severe hypoxaemia (SpO2<90%). Secondary outcomes: severe (SpO2<90%) and moderate hypoxaemia (SpO2 90-93%) prevalence by age/sex/complaint; number of children with hypoxaemia referred, admitted and recovered. We included 1561 children U5, 935 children 5-14 years, and 3284 adolescents/adults 15+ years. Among children U5, the prevalence of severe hypoxaemia was 1.3% (95% CI 0.9 to 2.1); an additional 4.9% (3.9 to 6.1) had moderate hypoxaemia. Performing pulse oximetry according to World Health Organization guidelines exclusively on children with respiratory complaints would have missed 14% (3/21) of severe hypoxaemia and 11% (6/55) of moderate hypoxaemia. Hypoxaemia prevalence was low among children 5-14 years (0.3% severe, 1.1% moderate) and adolescents/adults 15+ years (0.1% severe, 0.5% moderate). A minority (12/27, 44%) of severely hypoxaemic patients were referred; 3 (12%) received oxygen. We followed 87 children aged under 15 years with SpO2<93%, with complete data for 61 (70%), finding low rates of referral (6/61, 10%), hospital attendance (10/61, 16%), and admission (6/61, 10%) with most (44/61, 72%) fully recovered at day 7. Barriers to referral included caregiver belief it was unnecessary (42/51, 82%), cost (8/51, 16%), and distance or lack of transport (3/51, 6%). Hypoxaemia is common among acutely unwell children under five years of age presenting to Ugandan primary care facilities. Routine pulse oximetry has potential to improve referral, management and clinical outcomes. Effectiveness, acceptability, and feasibility of pulse oximetry and oxygen therapy for primary care should be investigated in implementation trials, including economic analysis from health system and societal perspectives., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: HG is an advisor to the Lifebox Foundation, UNICEF, and Unitaid on pulse oximetry; YK, JM, BK, SE, LK, FL are employed by CHAI who are implementing the oxygen program in Uganda; CO works for the Ministry of Health which provides funding and oversight for health facilities., (Copyright: © 2022 Graham et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mass spectrometry imaging (MSI) allows for untargeted mapping of the chemical composition of tissues with attomole detection limits. MSI using Fourier transform (FT)-based mass spectrometers, such as FT-ion cyclotron resonance (FT-ICR), grants the ability to examine the chemical space with unmatched mass resolution and mass accuracy. However, direct imaging of large tissue samples using FT-ICR is slow. In this work, we present an approach that combines the subspace modeling of ICR temporal signals with compressed sensing to accelerate high-resolution FT-ICR MSI. A joint subspace and spatial sparsity constrained model computationally reconstructs high-resolution MSI data from the sparsely sampled transients with reduced duration, allowing a significant reduction in imaging time. Simulation studies and experimental implementation of the proposed method in investigation of brain tissues demonstrate a 10-fold enhancement in throughput of FT-ICR MSI, without the need for instrumental or hardware modifications.

Importance: Gliomas, tumors of the central nervous system, are classically diagnosed through invasive surgical biopsy and subsequent histopathological study. Innovations in ultra-high field (UHF) imaging, namely 7-Tesla magnetic resonance imaging (7T MRI) are advancing preoperative tumor grading, visualization of intratumoral structures, and appreciation of small brain structures and lesions., Objective: Summarize current innovative uses of UHF imaging techniques in glioma diagnostics and treatment., Methods: A systematic review in accordance with PRISMA guidelines was performed utilizing PubMed. Case reports and series, observational clinical trials, and randomized clinical trials written in English were included. After removing unrelated studies and those with non-human subjects, only those related to 7T MRI were independently reviewed and summarized for data extraction. Some preclinical animal models are briefly described to demonstrate future usages of ultra-high-field imaging., Results: We reviewed 46 studies (43 human and 3 animal models) which reported clinical usages of UHF MRI in the diagnosis and management of gliomas. Current literature generally supports greater resolution imaging from 7T compared to 1.5T or 3T MRI, improving visualization of cerebral microbleeds and white and gray matter, and providing more precise localization for radiotherapy targeting. Additionally, studies found that diffusion or susceptibility-weighted imaging techniques applied to 7T MRI, may be used to predict tumor grade, reveal intratumoral structures such as neovasculature and microstructures like axons, and indicate isocitrate dehydrogenase 1 mutation status in preoperative imaging. Similarly, newer imaging techniques such as magnetic resonance spectroscopy and chemical exchange saturation transfer imaging can be performed on 7T MRI to predict tumor grading and treatment efficacy. Geometrical distortion, a known challenge of 7T MRI, was at a tolerable level in all included studies., Conclusion: UHF imaging has the potential to preoperatively and non-invasively grade gliomas, provide precise therapy target areas, and visualize lesions not seen on conventional MRI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shaffer, Kwok, Naik, Anderson, Lam, Wszalek, Arnold and Hassaneen.)

Purpose: To improve the estimation of coil sensitivity functions from limited auto-calibration signals (ACS) in SENSE-based reconstruction for brain imaging., Methods: We propose to use deep learning to estimate coil sensitivity functions by leveraging information from previous scans obtained using the same RF receiver system. Specifically, deep convolutional neural networks were designed to learn an end-to-end mapping from the initial sensitivity to the high-resolution counterpart. Sensitivity alignment was further proposed to reduce the geometric variation caused by different subject positions and imaging FOVs. Cross-validation with a small set of datasets was performed to validate the learned neural network. Iterative SENSE reconstruction was adopted to evaluate the utility of the sensitivity functions from the proposed and conventional methods., Results: The proposed method produced improved sensitivity estimates and SENSE reconstructions compared to the conventional methods in terms of aliasing and noise suppression with very limited ACS data. Cross-validation with a small set of data demonstrated the feasibility of learning coil sensitivity functions for brain imaging. The network learned on the spoiled GRE data can be applied to predict sensitivity functions for spin-echo and MPRAGE datasets., Conclusion: A deep learning-based method has been proposed for improving the estimation of coil sensitivity functions. Experimental results have demonstrated the feasibility and potential of the proposed method for improving SENSE-based reconstructions especially when the ACS data are limited., (© 2021 International Society for Magnetic Resonance in Medicine.)

Both neuronal and genetic mechanisms regulate brain function. While there are excellent methods to study neuronal activity in vivo, there are no nondestructive methods to measure global gene expression in living brains. Here, we present a method, epigenetic MRI (eMRI), that overcomes this limitation via direct imaging of DNA methylation, a major gene-expression regulator. eMRI exploits the methionine metabolic pathways for DNA methylation to label genomic DNA through 13 C-enriched diets. A 13 C magnetic resonance spectroscopic imaging method then maps the spatial distribution of labeled DNA. We validated eMRI using pigs, whose brains have stronger similarity to humans in volume and anatomy than rodents, and confirmed efficient 13 C-labeling of brain DNA. We also discovered strong regional differences in global DNA methylation. Just as functional MRI measurements of regional neuronal activity have had a transformational effect on neuroscience, we expect that the eMRI signal, both as a measure of regional epigenetic activity and as a possible surrogate for regional gene expression, will enable many new investigations of human brain function, behavior, and disease.

Purpose: To develop a novel method to achieve fast, high-resolution, 3D multi-TE 1 H-MRSI of the brain., Methods: A new multi-TE MRSI acquisition strategy was developed that integrates slab selective excitation with adiabatic refocusing for better volume coverage, rapid spatiospectral encoding, sparse multi-TE sampling, and interleaved water navigators for field mapping and calibration. Special data processing strategies were developed to interpolate the sparsely sampled data, remove nuisance signals, and reconstruct multi-TE spatiospectral distributions with high SNR. Phantom and in vivo experiments have been carried out to demonstrate the capability of the proposed method., Results: The proposed acquisition can produce multi-TE 1 H-MRSI data with three TEs at a nominal spatial resolution of 3.4 × 3.4 × 5.3 mm 3 in around 20 min. High-SNR brain metabolite spatiospectral reconstructions can be obtained from both a metabolite phantom and in vivo experiments by the proposed method., Conclusion: High-resolution, 3D multi-TE 1 H-MRSI of the brain can be achieved within clinically feasible time. This capability, with further optimizations, could be translated to clinical applications and neuroscience studies where simultaneously mapping metabolites and neurotransmitters and TE-dependent molecular spectral changes are of interest., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background: Children with end-stage liver disease and multi-organ failure, previously considered as poor surgical candidates, can now benefit from liver transplantation (LT). They often need prolonged mechanical ventilation (MV) post-LT and may need tracheostomy to advance care. Data on tracheostomy after pediatric LT are lacking., Method: Retrospective chart review of children who required tracheostomy in the peri-LT period in a large, freestanding quaternary children's hospital from 2014 to 2019., Results: Out of 205 total orthotopic LTs performed in 200 children, 18 (9%) required tracheostomy in the peri-transplant period: 4 (2%) pre-LT and 14 (7%) post-LT. Among those 14 needing tracheostomy post-LT, median age was 9 months [IQR = 7, 14] at LT and 10 months [9, 17] at tracheostomy. Nine (64%) were infants and 12 (85%) were cirrhotic at the time of LT. Seven (50%) were intubated before LT. Median MV days prior to LT was 23 [7, 36]. Eight (57%) patients received perioperative continuous renal replacement therapy (CRRT). The median MV days from LT to tracheostomy was 46 [33, 56]; total MV days from initial intubation to tracheostomy was 57 [37, 66]. Four (28%) children died, of which 3 (21%) died within 1 year of transplant. Total ICU and hospital length of stay were 92 days [I72, 126] and 177 days [115, 212] respectively. Among survivors, 3/10 (30%) required MV at home and 8/10 (80%) were successfully decannulated at 400 median days [283, 584]., Conclusion: Tracheostomy though rare after LT remains a feasible option to support and rehabilitate critically ill children who need prolonged MV in the peri-LT period., (© 2021 Wiley Periodicals LLC.)

Background: The aim of this study was to validate our previous finding that frailty predicts early mortality in patients with advanced heart failure (AHF) and that including cognition in the frailty assessment enhances the prediction of mortality., Methods: Patients with AHF referred to our Transplant Unit between November 2015 and April 2020 underwent physical frailty assessment using the modified Fried physical frailty (PF) phenotype as well as cognitive assessment using the Montreal Cognitive Assessment to identify patients who were cognitively frail (CogF). We assessed the predictive value of the 2 frailty measures (PF ≥ 3 of 5 = frail; CogF ≥ 3 of 6 = frail) for pretransplant mortality., Results: Three hundred thirteen patients (233 male and 80 female; age 53 ± 13 y) were assessed. Of these, 224 patients (72%) were nonfrail and 89 (28%) were frail using the PF. The CogF assessment identified an additional 30 patients as frail: 119 (38%). Frail patients had significantly increased mortality as compared to nonfrail patients. Ventricular assist device and heart transplant-censored survival at 12 mo was 92 ± 2 % for nonfrail and 69 ± 5% for frail patients (P < 0.0001) using the CogF instrument., Conclusions: This study validates our previously published findings that frailty is prevalent in patients with AHF referred for heart transplantation. PF predicts early mortality. The addition of cognitive assessment to the physical assessment of frailty identifies an additional cohort of patients with a similarly poor prognosis., Competing Interests: E.K. has received personal fees from Actelion, GSK, and Novartis for participation in the advisory boards and speaker fees; A.M.K. has received clinical trial funding from Acceleron, Arena, Bayer, Bellarophon, Gilead, GSK, Janssen, Pfizer, Respira, and United Therapeutics, and personal fees from Respira outside the submitted work. C.H. has received grants from Medtronic PLC, other from Novartis, personal fees from Novartis, personal fees from Abbott-St Jude, personal fees from Medtronic PLC, other from Medtronic, outside the submitted work; P.S.M. has received grants from Novartis, personal fees from Novartis, personal fees from Astra-Zeneca, personal fees from Actelion, outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Increasing access to oxygen services may improve outcomes among children with pneumonia living in low-resource settings. We conducted a systematic review to estimate the impact and cost-effectiveness of strengthening oxygen services in low-income and middle-income countries with the objective of including oxygen as an intervention in the Lives Saved Tool., Design: We searched EMBASE and PubMed on 31 March 2021 using keywords and MeSH terms related to 'oxygen', 'pneumonia' and 'child' without restrictions on language or date. The risk of bias was assessed for all included studies using the quality assessment tool for quantitative studies, and we assessed the overall certainty of the evidence using Grading of Recommendations, Assessment, Development and Evaluations. Meta-analysis methods using random effects with inverse-variance weights was used to calculate a pooled OR and 95% CIs. Programme cost data were extracted from full study reports and correspondence with study authors, and we estimated cost-effectiveness in US dollar per disability-adjusted life-year (DALY) averted., Results: Our search identified 665 studies. Four studies were included in the review involving 75 hospitals and 34 485 study participants. We calculated a pooled OR of 0.52 (95% CI 0.39 to 0.70) in favour of oxygen systems reducing childhood pneumonia mortality. The median cost-effectiveness of oxygen systems strengthening was $US62 per DALY averted (range: US$44-US$225). We graded the risk of bias as moderate and the overall certainty of the evidence as low due to the non-randomised design of the studies., Conclusion: Our findings suggest that strengthening oxygen systems is likely to reduce hospital-based pneumonia mortality and may be cost-effective in low-resource settings. Additional implementation trials using more rigorous designs are needed to strengthen the certainty in the effect estimate., Competing Interests: Competing interests: FL is employed by CHAI is who implementing oxygen strengthening programmes across low-resource settings. HRG is a lead investigator for one of the studies included in the review (Graham 2019), coinvestigator for one other study (Duke 2020) and advisor to the Lifebox Foundation, UNICEF and Unitaid on pulse oximetry. AS and VBC declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)