A global metagenomic map of urban microbiomes and antimicrobial resistance.

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.

The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.

Spaceflight induces molecular, cellular, and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet, current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools, and protocols. Here, we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular, and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, plus Axiom and Polaris. The SOMA resource represents a >10-fold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome data sets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation, and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific murine data sets. Leveraging the datasets, tools, and resources in SOMA can help accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation, and countermeasures data for upcoming lunar, Mars, and exploration-class missions.

Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.

Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.

PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

Haplotype diversity and sequence heterogeneity of human telomeres.

Telomeres are regions of repetitive nucleotide sequences capping the ends of eukaryotic chromosomes that protect against deterioration, and whose lengths can be correlated with age and adverse health risk factors. Yet, given their length and repetitive nature, telomeric regions are not easily reconstructed from short-read sequencing, thus making telomere sequencing, mapping, and variant resolution challenging problems. Recently, long-read sequencing, with read lengths measuring in hundreds of kilobase pairs, has made it possible to routinely read into telomeric regions and inspect their sequence structure. Here, we describe a framework for extracting telomeric reads from whole-genome single-molecule sequencing experiments, including de novo identification of telomere repeat motifs and repeat types, and also describe their sequence variation. We find that long, complex telomeric stretches and repeats can be accurately captured with long-read sequencing, observe extensive sequence heterogeneity of human telomeres, discover and localize noncanonical telomere sequence motifs (both previously reported, as well as novel), and validate them in short-read sequence data. These data reveal extensive intra- and inter-population diversity of repeats in telomeric haplotypes, reveal higher paternal inheritance of telomeric variants, and represent the first motif composition maps of multi-kilobase-pair human telomeric haplotypes across three distinct ancestries (Ashkenazi, Chinese, and Utah), which can aid in future studies of genetic variation, aging, and genome biology.

Topical Calcineurin Inhibitors in the Management of Chronic Pruritus in Older Adults: A Research Letter.

In this study, we aimed to analyze the literature to date on the utilization of topical calcineurin inhibitors in the management of pruritus among older adults, ages 65 and older. The 16 studies included in the final analysis demonstrated that topical calcineurin inhibitors are well tolerated across ages and are effective in treating a wide variety of chronic pruritic conditions. Collectively, these findings support that topical calcineurin inhibitors should be considered a safe, plausible option for managing age-associated itch. J Drugs Dermatol. 2024;23(2): doi:10.36849/JDD.7190e.

Chronic Pruritus: A Review.

Importance: Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Approximately 1% of physician visits are for the chief concern of chronic pruritus. Chronic pruritus is associated with adverse outcomes, including impaired sleep and reduced quality of life. Observations: Chronic pruritus can be categorized by etiology into inflammatory, neuropathic, or a combination of inflammatory and neuropathic pruritus. Chronic pruritus is due to inflammation in approximately 60% of patients and may be caused by eczema, psoriasis, or seborrheic dermatitis. Chronic pruritus is due to a neuropathic or mixed etiology in approximately 25% of patients. Neuropathic causes of chronic pruritus include postherpetic neuralgia and notalgia paresthetica and are typically due to localized or generalized nerve dysregulation. Approximately 15% of people with chronic pruritus have other causes including systemic diseases with secondary itch, such as uremic pruritus and cholestatic pruritus, medication-induced pruritus such as pruritus due to immunotherapy, and infectious etiologies such as tinea corporis and scabies. When few primary changes are present, a thorough history, review of symptoms, and laboratory evaluation should be performed, particularly for people with chronic pruritus lasting less than 1 year. Clinicians should consider the following tests: complete blood cell count, complete metabolic panel, and thyroid function testing to evaluate for hematologic malignancy, liver disease, kidney disease, or thyroid disease. First-line treatment for inflammatory chronic pruritus includes topical anti-inflammatory therapies such as hydrocortisone (2.5%), triamcinolone (0.1%), or tacrolimus ointment. Approximately 10% of patients do not respond to topical therapies. In these patients, referral to dermatology and systemic oral or injectable treatments such as dupilumab or methotrexate may be considered. When no underlying systemic disease associated with pruritus is identified, patients are likely to have neuropathic chronic pruritus or mixed etiology such as chronic pruritus of unknown origin. In these patients, neuropathic topical treatments such as menthol, pramoxine, or lidocaine can be used either alone or in combination with immunomodulatory agents such as topical steroids. Other effective therapies for neuropathic pruritus include gabapentin, antidepressants such as sertraline or doxepin, or opioid receptor agonist/antagonists such as naltrexone or butorphanol. Conclusions and Relevance: Chronic pruritus can adversely affect quality of life and can be categorized into inflammatory, neuropathic, or a combined etiology. First-line therapies are topical steroids for inflammatory causes, such as hydrocortisone (2.5%) or triamcinolone (0.1%); topical neuropathic agents for neuropathic causes, such as menthol or pramoxine; and combinations of these therapies for mixed etiologies of chronic pruritus.

Phytotherapy (BNO 1045) of Acute Lower Uncomplicated Urinary Tract Infection in Women Normalizes Local Host Responses.

INTRODUCTION: Acute lower uncomplicated urinary tract infection (uUTI) affects a large proportion of women. Increased antimicrobial resistance has created an urgent need for novel therapeutics and the phytotherapeutic drug BNO 1045 (Canephron® N) has previously been shown to be noninferior to standard antimicrobial stewardship. This sub-analysis from a randomized, double-blind, controlled phase III noninferiority clinical trial using BNO 1045 versus fosfomycin to treat uUTI aimed to determine how urine cytokine levels are altered by the two different treatments. METHODS: Urine samples from a predefined subset of women diagnosed with uUTI (18-70 years) and treated with BNO 1045 (n = 58) or fosfomycin (n = 69) were analyzed for urine levels of IL-6 and IL-8, using analyte-to-creatinine ratios. RESULTS: BNO 1045 treatment showed similar effects to fosfomycin treatment in reducing both urine IL-6 and IL-8 levels. Mean IL-6 and IL-8 levels were markedly reduced in all patients regardless of treatment. BNO 1045 treatment decreased urine IL-8 significantly (p = 0.0142) and showed a trend toward reduction of urine IL-6 (p = 0.0551). Fosfomycin treatment reduced both IL-6 and IL-8 levels significantly (p = 0.0038, <0.0001 respectively). CONCLUSION: BNO 1045 is, in addition to reducing symptoms, comparable to fosfomycin treatment in reducing the local inflammatory response associated with uUTI.

Betacoronavirus-specific alternate splicing.

Viruses can subvert a number of cellular processes including splicing in order to block innate antiviral responses, and many viruses interact with cellular splicing machinery. SARS-CoV-2 infection was shown to suppress global mRNA splicing, and at least 10 SARS-CoV-2 proteins bind specifically to one or more human RNAs. Here, we investigate 17 published experimental and clinical datasets related to SARS-CoV-2 infection, datasets from the betacoronaviruses SARS-CoV and MERS, as well as Streptococcus pneumonia, HCV, Zika virus, Dengue virus, influenza H3N2, and RSV. We show that genes showing differential alternative splicing in SARS-CoV-2 have a similar functional profile to those of SARS-CoV and MERS and affect a diverse set of genes and biological functions, including many closely related to virus biology. Additionally, the differentially spliced transcripts of cells infected by coronaviruses were more likely to undergo intron-retention, contain a pseudouridine modification, and have a smaller number of exons as compared with differentially spliced transcripts in the control groups. Viral load in clinical COVID-19 samples was correlated with isoform distribution of differentially spliced genes. A significantly higher number of ribosomal genes are affected by differential alternative splicing and gene expression in betacoronavirus samples, and the betacoronavirus differentially spliced genes are depleted for binding sites of RNA-binding proteins. Our results demonstrate characteristic patterns of differential splicing in cells infected by SARS-CoV-2, SARS-CoV, and MERS. The alternative splicing changes observed in betacoronaviruses infection potentially modify a broad range of cellular functions, via changes in the functions of the products of a diverse set of genes involved in different biological processes.

Antihistamine safety in older adult dermatologic patients.

Twenty percent of Americans will be older than 65 years by 2030, and without a dedicated geriatrics curriculum in many residency trainings programs, dermatologists may be less familiar with age-associated adverse effects of common dermatologic medications. Herein, we provide a practical guide and clinical safety pearls for the use of antihistamines in older adults. This Review aims to address the risks of antihistamines, anticholinergic burden and polypharmacy, pertinent preexisting medical conditions, and safe alternatives for aging adult patients.

Do undergraduate general practice placements propagate the 'inverse care law'?

INTRODUCTION: Fifty years since Dr Tudor-Hart's publication of the 'Inverse Care Law', all-cause mortality rates and COVID-19 mortality rates are higher in more deprived areas. Part of the solution is to increase access and availability to healthcare in underserved and deprived areas. This paper examined how socio-economically representative the undergraduate general practice placements are in Northern Ireland (NI). METHODS: A quantitative study of general practices involved in undergraduate medical placements through Queen's University Belfast, comparing practice lists by deprivation indices, examining both blanket deprivation and deprivation quintile trends for teaching and non-teaching practices. RESULTS: Deprivation data for 135 teaching practices were compared against the 323 NI practices. Teaching practices had fewer patients living in the most deprived quintiles compared with non-teaching practices. Fewer practices with blanket deprivation were involved in undergraduate medical education, 32% compared with 42% without blanket deprivation. Practices in areas of blanket deprivation were under-represented as teaching practices, 10%, compared to 14% of NI general practices that met this criterion. CONCLUSION: Practices with blanket deprivation were under-represented as teaching practices. Exposure to general practice in deprived areas is an essential step to improving future workforce recruitment and ultimately to closing the health inequalities gap. Ensuring practices in high-need areas are proportionately represented in undergraduate placements is one way to direct action in addressing the 'Inverse Care Law'. This study is limited to NI and further work is required to compare institutions across the UK and Ireland.

Fimbriae reprogram host gene expression - Divergent effects of P and type 1 fimbriae.

Pathogens rely on a complex virulence gene repertoire to successfully attack their hosts. We were therefore surprised to find that a single fimbrial gene reconstitution can return the virulence-attenuated commensal strain Escherichia coli 83972 to virulence, defined by a disease phenotype in human hosts. E. coli 83972pap stably reprogrammed host gene expression, by activating an acute pyelonephritis-associated, IRF7-dependent gene network. The PapG protein was internalized by human kidney cells and served as a transcriptional agonist of IRF-7, IFN-ß and MYC, suggesting direct involvement of the fimbrial adhesin in this process. IRF-7 was further identified as a potent upstream regulator (-log (p-value) = 61), consistent with the effects in inoculated patients. In contrast, E. coli 83972fim transiently attenuated overall gene expression in human hosts, enhancing the effects of E. coli 83972. The inhibition of RNA processing and ribosomal assembly indicated a homeostatic rather than a pathogenic end-point. In parallel, the expression of specific ion channels and neuropeptide gene networks was transiently enhanced, in a FimH-dependent manner. The studies were performed to establish protective asymptomatic bacteriuria in human hosts and the reconstituted E. coli 83972 variants were developed to improve bacterial fitness for the human urinary tract. Unexpectedly, P fimbriae were able to drive a disease response, suggesting that like oncogene addiction in cancer, pathogens may be addicted to single super-virulence factors.

Efficacy of Daily Intake of Dried Cranberry 500 mg in Women with Overactive Bladder: A Randomized, Double-Blind, Placebo Controlled Study.

PURPOSE: We sought to determine the efficacy of dried cranberry on reducing symptoms of overactive bladder in women. MATERIALS AND METHODS: Eligible women aged 18 or older with overactive bladder were randomized to either daily dried cranberry powder (500 mg) or placebo (500 mg) and followed for 24 weeks. Efficacy was measured by 3-day voiding diaries and Overactive Bladder Questionnaire Short Form, Patient Perception of Bladder Condition, Sexual Quality of Life-Female and Pelvic Floor Distress Inventory surveys. Statistical analyses were performed by BIOFORTIS using SAS® software version 9.4. RESULTS: Of the 98 women who were randomized 77 completed all the visits and 60 were included in the per protocol analysis. Compared to placebo using per protocol analysis the cranberry group showed a significant reduction of daily micturitions (-1.91, 95% CI -3.74--0.88, p=0.0406), urgency episodes (-2.81, 95% CI -4.82--0.80, p=0.0069), and Patient Perception of Bladder Condition scores (-0.66, 95% CI -1.23-0.08, p=0.0258) at 24 weeks of followup. Mean volume per micturition, nocturia and the remaining survey outcomes did not differ significantly between the groups (p >0.05). CONCLUSIONS: Daily intake of dried cranberry powder reduced daily micturition by 16.4%, urgency episodes by 57.3% and patient perception of bladder condition by 39.7%. However, an intent-to-treat analysis showed no statistically significant difference between the groups for these measurements (p >0.05). Future larger studies with longer followup periods are needed to further determine the long-term effect of cranberry on overactive bladder.

Revisiting the Direct Brow Lift in Patients With Facial Palsy: 4 Key Modifications.

PURPOSE: The direct brow lift is a simple and popular technique, particularly in patients with brow ptosis secondary to facial palsy. It provides a high degree of control in determining the degree of brow elevation and shape achieved. However, it is arguably the least debated in terms of addressing some of its sequelae, namely the risks of a visible or indrawn scar and forehead paraesthesia. In this article, we report outcomes using four alternative principles to those outlined in current published literature. METHODS: All patients undergoing a primary direct brow lift for brow ptosis secondary to facial palsy between January 2015 and December 2019 under a single surgeon (R.M.) were included in the study. The technical refinements of the procedure included a W-plasty type stealth skin incision, counter-bevelling of the upper and lower incision lines, skin excision in the subcutaneous plane only with minimal excision of fat and browpexy to the frontal periosteum through small linear puncture incisions in the frontalis. RESULTS: A total of 23 patients undergoing 24 direct brow lifts were included in the study. The mean follow-up was 1.3 years (range 0.5-3 years). No patients reported postoperative forehead paraesthesia or brow alopecia. One patient required a further temporal browlift 15 months later. Brow height was rated excellent (0-1.5 mm difference) in 71% of brows and good (1.6-4.9 mm difference) in 14% of brows. The average Manchester scar scale was 8.6/28. CONCLUSION: The technical modifications presented substantially reduce the rates of postoperative paraesthesia, whilst achieving satisfactory aesthetic outcomes.

Direct Brow Lift and Skin Contraction in Facial Nerve Palsy: A Switch Technique.

The authors present a case series of 4 patients with facial nerve palsy who underwent a direct brow lift to correct brow ptosis, using the excised brow skin as a full-thickness skin graft to correct lower eyelid skin contracture, ectropion, and retraction. Functional outcomes were measured using the validated cornea, static asymmetry, dynamic function, synkinesis (CADS) grading system and by photographic assessment of lower eyelid height via margin reflex distance. Aesthetic outcomes were measured using a published grading scale specific to eyelid skin grafts.

Bladder cancer therapy without toxicity-A dose-escalation study of alpha1-oleate.

Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. Our study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17 mM) on days 3 to 11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor-bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model.

Glycogen Storage Disease Type IV Diagnosed at Fetal Autopsy.

Glycogen storage disease type IV (GSD IV; Andersen's disease) is a rare autosomal recessive disorder that results from defects in the GBE1 gene (3p12.2) and subsequent deficiencies of glycogen branching. We report a case of GSD IV diagnosed at autopsy in a 35 4/7 weeks gestational age female neonate that died shortly after birth. Multisystem blue, ground glass inclusions initially presumed artefactual were periodic acid-Schiff positive, diastase resistant. Chromosomal microarray analysis identified a deletion of exons 2 through 16 of the GBE1 gene and whole exome sequencing identified a nonsense mutation within exon 14, confirming the diagnosis of GSD IV. A strong index of suspicion was required determine GSD IV as the ultimate cause of death, illustrating the need for critical evaluation of postmortem artifact in the setting of fetal demise of unknown etiology and highlighting the role of postmortem molecular diagnostics in a subset of cases.

Microcrystalline Cellulose and Crospovidone Identified in Placentas With Vaginal Misoprostol Use.

Misoprostol is a prostaglandin analog commonly used to induce termination of pregnancy. Clandestine home terminations complicate forensic fetal autopsy when a history of misoprostol use is withheld and the gross and histologic findings are sparse, as is often the case. One hundred thirty-two placentas with no vaginal misoprostol use, low-dose misoprostol use, and high-dose misoprostol use were reviewed for the presence, volume, and locations of microcrystalline cellulose and crospovidone, common tablet fillers in misoprostol tablets. Microcrystalline cellulose and/or crospovidone was identified in 0 (0%) of 88 cases with no vaginal administration or low-dose vaginal administration and 29 (66%) of 44 placentas with high-dose vaginal administration. When identified, microcrystalline cellulose and/or crospovidone is most commonly present on the maternal surfaces of the extraplacental membranes. The presence of microcrystalline cellulose and/or crospovidone was associated with smaller placental weight (Mann-Whitney U, P = 0.019). These fillers have a reasonable sensitivity for high-dose vaginal tablet use and are very specific. Although they are not diagnostic for misoprostol administration, they provide a finding that may prompt additional investigation into the nature of the vaginal tablet administered and the circumstances surrounding birth.

LC-HRMS-Database Screening Metrics for Rapid Prioritization of Samples to Accelerate the Discovery of Structurally New Natural Products.

In order to accelerate the isolation and characterization of structurally new or novel secondary metabolites, it is crucial to develop efficient strategies that prioritize samples with greatest promise early in the workflow so that resources can be utilized in a more efficient and cost-effective manner. We have developed a metrics-based prioritization approach using exact LC-HRMS, which uses data for 24 618 marine natural products held in the PharmaSea database. Each sample was evaluated and allocated a metric score by a software algorithm based on the ratio of new masses over the total (sample novelty), ratio of known masses over the total (chemical novelty), number of peaks above a defined peak area threshold (sample complexity), and peak area (sample diversity). Samples were then ranked and prioritized based on these metric scores. To validate the approach, eight marine sponges and six tunicate samples collected from the Fiji Islands were analyzed, metric scores calculated, and samples targeted for isolation and characterization of new compounds. Structures of new compounds were elucidated by spectroscopic techniques, including 1D and 2D NMR, MS, and MS/MS. Structures were confirmed by computer-assisted structure elucidation methods (CASE) using the ACD/Structure Elucidator Suite.