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The separation and identification of lipids in complex mixtures are critical to deciphering their cellular functions. Failure to resolve isobaric compounds (e.g., via high mass resolution or tandem mass spectrometry) can result in incorrect identifications in mass spectrometry experiments. In imaging mass spectrometry, unresolved peaks can also result in composite images of multiple compounds, giving inaccurate depictions of molecular distributions. Gas-phase ion/ion reactions can be used to selectively react with specific chemical functional groups on a target analyte, thereby extracting it from a complex mixture and shifting its m/z value to an unobstructed region of the mass range. Herein, we use selective Schiff base formation via a novel charge inversion ion/ion reaction to purify phosphatidylserines from other isobaric (i.e., same nominal mass) lipids and reveal their singular distributions in imaging mass spectrometry. The selective Schiff base formation between singly deprotonated phosphatidylserine (PS) lipid anions and doubly charged N,N,N′,N′-tetramethyl-N,N′-bis(6-oxohexyl)hexane-1,6-diaminium (TMODA) cations is performed using a modified commercial dual source hybrid Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. This process is demonstrated using the isobaric lipids [PS 40:6 - H] − ( m/z 834.528) and [SHexCer d38:1 - H] − ( m/z 834.576), which produces [PS 40:6 + TMODA - H - H 2 O] + ( m/z 1186.879), and [SHexCer d38:1 + TMODA - H] + ( m/z 1204.938) product ions following the gas-phase charge inversion reaction. These product ions differ by roughly 18 Da in mass and are easily separated by low mass resolution analysis, while the isobaric precursor ions require roughly 45,000 mass resolving power (full-width at half maximum) to separate. Imaging mass spectrometry using targeted gas-phase ion/ion reactions shows distinct spatial distributions for the separated lipid product ions relative to the composite images of the unseparated precursor ions. Graphical abstract

Since the early 2000’s, digital reading applications have enhanced the language and literacy skills of typically hearing young children; however, no digital storybook intervention currently exists to scaffold the early language and literacy skills of their peers who are deaf or hard of hearing. To address this gap, our research team developed a novel digital storybook intervention called Hear Me Read with the aim of enhancing the therapeutic, language, and literacy benefits of speech-language therapy. This prospective clinical trial (registered at clinicaltrials.gov, NCT#: 05245799) aims to determine the efficacy of adding Hear Me Read to in-person speech-language therapy for children aged three to five years who are deaf or hard of hearing. Fifty caregivers, their child, and their child’s treating speech-language pathologist participate in the trial for 12 months. In the first six months, children attend standard-of-care speech-language therapy sessions. In the second six months, children continue to attend standard-of-care speech-language therapy sessions and use the Hear Me Read application, via a study supplied iPad. The primary outcome of this trial is that, compared to in-person speech-language therapy alone, in-person speech-language therapy with Hear Me Read will improve vocabulary , speech , and language outcomes in children aged three to five years who are deaf or hard of hearing. The secondary outcome is that, compared to in-person speech-language therapy alone, in-person speech-language therapy with Hear Me Read will improve literacy outcomes in children aged three to five years who are deaf or hard of hearing. The goal of this intervention is to help children who are deaf or hard of hearing achieve their vocabulary, speech, language, and literacy goals through interactive digital storybook reading.

One of the most challenging problems in clinical dermatology is the early detection of melanoma. Reflectance confocal microscopy (RCM) is an added tool to dermoscopy improving considerably diagnostic accuracy. However, diagnosis strongly depends on the experience of physicians. High-definition optical coherence tomography (HD-OCT) appears to offer additional structural and cellular information on melanocytic lesions complementary to that of RCM. However, the diagnostic potential of HD-OCT seems to be not high enough for ruling out the diagnosis of melanoma if based on morphology analysis. The aim of this paper is first to quantify in vivo optical properties such as light attenuation in melanocytic lesions by HD-OCT. The second objective is to determine the best critical value of these optical properties for melanoma diagnosis. The technique of semi-log plot whereby an exponential function becomes a straight line has been implemented on HD-OCT signals coming from four successive skin layers (epidermis, upper papillary dermis, deeper papillary dermis and superficial reticular dermis). This permitted the HD-OCT in vivo measurement of skin entrance signal (SES), relative attenuation factor normalized for the skin entrance signal ( µ raf1 ) and half value layer ( z 1/2 ). The diagnostic accuracy of HD-OCT for melanoma detection based on the optical properties, µ raf1 , SES and z 1/2 was high (95.6, 82.2 and 88.9 %, respectively). High negative predictive values could be found for these optical properties (96.7, 89.3 and 96.3 %, respectively) compared to morphologic assessment alone (89.9 %), reducing the risk of mistreating a malignant lesion to a more acceptable level (3.3 % instead of 11.1 %). HD-OCT seems to enable the combination of in vivo morphological analysis of cellular and 3-D micro-architectural structures with in vivo analysis of optical properties of tissue scatterers in melanocytic lesions. In vivo HD-OCT analysis of optical properties permits melanoma diagnosis with higher accuracy than in vivo HD-OCT analysis of morphology alone.

Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) allows for the visualization of molecular distributions within tissue sections. While providing excellent molecular specificity and spatial information, absolute quantification by MALDI IMS remains challenging. Especially in the low molecular weight region of the spectrum, analysis is complicated by matrix interferences and ionization suppression. Though tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity and improve sensitivity by eliminating chemical noise, typical MALDI MS/MS modalities only scan for a single MS/MS event per laser shot. Herein, we describe TOF/TOF instrumentation that enables multiple fragmentation events to be performed in a single laser shot, allowing the intensity of the analyte to be referenced to the intensity of the internal standard in each laser shot while maintaining the benefits of MS/MS. This approach is illustrated by the quantitative analyses of rifampicin (RIF), an antibiotic used to treat tuberculosis, in pooled human plasma using rifapentine (RPT) as an internal standard. The results show greater than 4-fold improvements in relative standard deviation as well as improved coefficients of determination (R 2 ) and accuracy (>93% quality controls, <9% relative errors). This technology is used as an imaging modality to measure absolute RIF concentrations in liver tissue from an animal dosed in vivo. Each microspot in the quantitative image measures the local RIF concentration in the tissue section, providing absolute pixel-to-pixel quantification from different tissue microenvironments. The average concentration determined by IMS is in agreement with the concentration determined by HPLC-MS/MS, showing a percent difference of 10.6%. Graphical Abstract ᅟ

Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract 1 . This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens 2 . Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut—the enterococci—enhances the fitness and pathogenesis of Clostridioides difficile . Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic-perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile . These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection. Enterococci enhance the fitness and pathogenesis of Clostridioides difficile in the gut by altering the amino acid composition and providing signals that increase its virulence towards the host.

Microorganisms form biofilms containing differentiated cell populations. To determine factors driving differentiation, we herein visualize protein and metal distributions within Pseudomonas aeruginosa biofilms using imaging mass spectrometry. These in vitro experiments reveal correlations between differential protein distribution and metal abundance. Notably, zinc- and manganese-depleted portions of the biofilm repress the production of anti-staphylococcal molecules. Exposure to calprotectin (a host protein known to sequester metal ions at infectious foci) recapitulates responses occurring within metal-deplete portions of the biofilm and promotes interaction between P. aeruginosa and Staphylococcus aureus. Consistent with these results, the presence of calprotectin promotes co-colonization of the murine lung, and polymicrobial communities are found to co-exist in calprotectin-enriched airspaces of a cystic fibrosis lung explant. These findings, which demonstrate that metal fluctuations are a driving force of microbial community structure, have clinical implications because of the frequent occurrence of P. aeruginosa and S. aureus co-infections. Co-infections with Pseudomonas aeruginosa and Staphylococcus aureus are common in cystic fibrosis patients. Here, the authors show that metal depletion induced by a host protein, calprotectin, promotes co-existence of both pathogens by inhibiting production of anti-staphylococcal molecules by P. aeruginosa .

Ungulate neonates — individuals less than four weeks old — typically experience the greatest predation rates, and variation in their survival can influence ungulate population dynamics. Typical methods to measure neonate survival involve capture and radio-tracking of adults and neonates to discover mortality events. This type of fieldwork is invasive and expensive, can bias results if it leads to neonate abandonment, and may still have high uncertainty about the predator species involved. Here we explore the potential for a non-invasive approach to estimate an index for neonate survival using camera traps paired with decoys that mimic white-tailed deer ( Odocoileus virginianus ) neonates in the first month of life. We monitored sites with camera traps for two weeks before and after the placement of the neonate decoy and urine scent lure. Predator response to the decoy was classified into three categories: did not approach, approached within 2.5 m but did not touch the decoy, or physically touched the decoy; when conducting survival analyses, we considered these second two categories as dead neonates. The majority (76.3%) of the predators approached the decoy, with 51.1% initiating physical contact. Decoy probability of survival was 0.31 (95% CI = 0.22, 0.35) for a 30-day period. Decoys within the geographic range of American black bear ( Ursus americanus ) were primarily (75%) attacked by bears. Overall, neonate survival probability decreased as predator abundance increased. The camera-decoy protocol required about ½ the effort and 1/3 the budget of traditional capture-track approaches. We conclude that the camera-decoy approach is a cost-effective method to estimate a neonate survival probability index based on depredation probability and identify which predators are most important.

Several non-invasive two-dimensional techniques with different lateral resolution and measurable depth range have proved to be useful in assessing and quantifying morphological changes in skin ageing. Among these, only in vivo microscopy techniques permit histometric measurements in vivo. Qualitative and quantitative assessment of chronological (intrinsic) age-related (IAR) morphological changes of epidermis, dermo-epidermal junction (DEJ), papillary dermis (PD), papillary-reticular dermis junction and reticular dermis (RD) have been performed by high-definition optical coherence tomography in real time 3-D. HD-OCT images were taken at the internal site of the right upper arm. Qualitative HD-OCT IAR descriptors were reported at skin surface, at epidermal layer, DEJ, PD and upper RD. Quantitative evaluation of age-related compaction and backscattered intensity or brightness of different skin layers was performed by using the plugin plot z -axis profile of ImageJ ® software permitting intensity assessment of HD-OCT (DICOM) images (3-D images). Analysis was in blind from all clinical information. Sixty, fair-skinned (Fitzpatrick types I–III) healthy females were analysed retrospectively in this study. The subjects belonged to three age groups: twenty in group I aged 20–39, twenty in group II aged 40–59 and twenty in group III aged 60–79. Only intrinsic ageing in women has been studied. Significant age-related qualitative and quantitative differences could be noticed. IAR changes in dermal matrix fibers morphology/organisation and in microvasculature were observed. The brightness and compaction of the different skin layers increased significantly with intrinsic skin ageing. The depth of visibility of fibers in RD increased significantly in the older age group. In conclusion, HD-OCT allows 3-D in vivo and real time qualitative and quantitative assessment of chronological (intrinsic) age-related morphological skin changes at high resolution from skin surface to a depth of the superficial reticular dermis.

Metabolites, lipids, and glycans are fundamental but interconnected classes of biomolecules that form the basis of the metabolic network. These molecules are dynamically channeled through multiple pathways that govern cellular physiology and pathology. Here, we present a framework for the simultaneous spatial analysis of the metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. This workflow integrates a computational platform, the Spatial Augmented Multiomics Interface (Sami), which enables multiomics integration, high-dimensional clustering, spatial anatomical mapping of matched molecular features, and metabolic pathway enrichment. To demonstrate the utility of this approach, we applied Sami to evaluate metabolic diversity across distinct brain regions and to compare wild-type and Ps19 Alzheimer’s disease (AD) mouse models. Our findings reveal region-specific metabolic demands in the normal brain and highlight metabolic dysregulation in the Ps19 model, providing insights into the biochemical alterations associated with neurodegeneration. Clarke et al. presents a framework for spatial analysis of the metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. Applying this approach, they revealed region-specific metabolic diversity and dysregulation in both normal and diseased mouse brains.

Postoperative neurocognitive disorders (PNDs) after surgical procedures are common and may be associated with increased health care expenditures. To quantify the economic burden associated with a PND diagnosis in 1 year following surgical treatment among older patients in the United States. This retrospective cohort study used claims data from the Bundled Payments for Care Improvement Advanced Model from 4285 hospitals that submitted Medicare Fee-for-service (FFS) claims between January 2013 and December 2016. All Medicare patients aged 65 years or older who underwent an inpatient hospital admission associated with a surgical procedure, did not experience a PND before index admission, and were not undergoing dialysis or concurrently enrolled in Medicaid were included. Data were analyzed from October 2019 and May 2020. PND, defined as an International Classification of Diseases, Ninth or Tenth Revision, diagnosis of delirium, mild cognitive impairment, or dementia within 1 year of discharge from the index surgical admission. The primary outcome was total inflation-adjusted Medicare postacute care payments within 1 year after the index surgical procedure. A total of 2 380 473 patients (mean [SD] age, 75.36 (7.31) years; 1 336 736 [56.1%] women) who underwent surgical procedures were included, of whom 44 974 patients (1.9%) were diagnosed with a PND. Among all patients, most were White (2 142 157 patients [90.0%]), presenting for orthopedic surgery (1 523 782 patients [64.0%]) in urban medical centers (2 179 893 patients [91.6%]) that were private nonprofits (1 798 749 patients [75.6%]). Patients with a PND, compared with those without a PND, experienced a significantly longer hospital length of stay (mean [SD], 5.91 [6.01] days vs 4.29 [4.18] days; P < .001), were less likely to be discharged home (9947 patients [22.1%] vs 914 925 patients [39.2%]; P < .001), and had a higher incidence of mortality at 1 year after treatment (4580 patients [10.2%] vs 103 767 patients [4.4%]; P < .001). After adjusting for patient and hospital characteristics, the presence of a PND within 1 year of the index procedure was associated with an increase of $17 275 (95% CI, $17 058-$17 491) in cost in the 1-year postadmission period (P < .001). The findings of this cohort study suggest that among older Medicare patients undergoing surgical treatment, a diagnosis of a PND was associated with an increase in health care costs for up to 1 year following the surgical procedure. Given the magnitude of this cost burden, PNDs represent an appealing target for risk mitigation and improvement in value-based health care.