Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort.

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid ß-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

An Extensively Hydrolyzed Formula Supplemented with Two Human Milk Oligosaccharides Modifies the Fecal Microbiome and Metabolome in Infants with Cow's Milk Protein Allergy.

Cow's milk protein allergy (CMPA) is a prevalent food allergy among infants and young children. We conducted a randomized, multicenter intervention study involving 194 non-breastfed infants with CMPA until 12 months of age (clinical trial registration: NCT03085134). One exploratory objective was to assess the effects of a whey-based extensively hydrolyzed formula (EHF) supplemented with 2'-fucosyllactose (2'-FL) and lacto-N-neotetraose (LNnT) on the fecal microbiome and metabolome in this population. Thus, fecal samples were collected at baseline, 1 and 3 months from enrollment, as well as at 12 months of age. Human milk oligosaccharides (HMO) supplementation led to the enrichment of bifidobacteria in the gut microbiome and delayed the shift of the microbiome composition toward an adult-like pattern. We identified specific HMO-mediated changes in fecal amino acid degradation and bile acid conjugation, particularly in infants commencing the HMO-supplemented formula before the age of three months. Thus, HMO supplementation partially corrected the dysbiosis commonly observed in infants with CMPA. Further investigation is necessary to determine the clinical significance of these findings in terms of a reduced incidence of respiratory infections and other potential health benefits.

Standardizing and Improving Care for Pediatric Agitation Management in the Emergency Department.

BACKGROUND AND OBJECTIVES: Pediatric mental health emergency department (ED) visits are rising in the United States, with more visits involving medication for acute agitation. Timely, standardized implementation of behavioral strategies and medications may reduce the need for physical restraint. Our objective was to standardize agitation management in a pediatric ED and reduce time in physical restraints. METHODS: A multidisciplinary team conducted a quality improvement initiative from September 2020 to August 2021, followed by a 6-month maintenance period. A barrier assessment revealed that agitation triggers were inadequately recognized, few activities were offered during long ED visits, staff lacked confidence in verbal deescalation techniques, medication choices were inconsistent, and medications were slow to take effect. Sequential interventions included development of an agitation care pathway and order set, optimization of child life and psychiatry workflows, implementation of personalized deescalation plans, and adding droperidol to the formulary. Measures include standardization of medication choice for severe agitation and time in physical restraints. RESULTS: During the intervention and maintenance periods, there were 129 ED visits with medication given for severe agitation and 10 ED visits with physical restraint use. Among ED visits with medication given for severe agitation, standardized medication choice (olanzapine or droperidol) increased from 8% to 88%. Mean minutes in physical restraints decreased from 173 to 71. CONCLUSIONS: Implementing an agitation care pathway standardized and improved care for a vulnerable and high-priority population. Future studies are needed to translate interventions to community ED settings and to evaluate optimal management strategies for pediatric acute agitation.

An online atlas of human plasma metabolite signatures of gut microbiome composition.

Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 58% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas ( https://gutsyatlas.serve.scilifelab.se/ ). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition.

Host-microbial co-metabolites modulated by human milk oligosaccharides relate to reduced risk of respiratory tract infections.

Human milk oligosaccharides (HMOs) are structurally diverse oligosaccharides present in breast milk, supporting the development of the gut microbiota and immune system. Previously, 2-HMO (2'fucosyllactose, lacto-N-neotetraose) compared to control formula feeding was associated with reduced risk of lower respiratory tract infections (LRTIs), in part linked to lower acetate and higher bifidobacteria proportions. Here, our objective was to gain further insight into additional molecular pathways linking the 2-HMO formula feeding and LRTI mitigation. From the same trial, we measured the microbiota composition and 743 known biochemical species in infant stool at 3 months of age using shotgun metagenomic sequencing and untargeted mass spectrometry metabolomics. We used multivariate analysis to identify biochemicals associated to 2-HMO formula feeding and LRTI and integrated those findings with the microbiota compositional data. Three molecular pathways stood out: increased gamma-glutamylation and N-acetylation of amino acids and decreased inflammatory signaling lipids. Integration of stool metagenomic data revealed some Bifidobacterium and Bacteroides species to be implicated. These findings deepen our understanding of the infant gut/microbiome co-metabolism in early life and provide evidence for how such metabolic changes may influence immune competence at distant mucosal sites such as the airways.

Infant Formula With a Specific Blend of Five Human Milk Oligosaccharides Drives the Gut Microbiota Development and Improves Gut Maturation Markers: A Randomized Controlled Trial.

Background: Human milk oligosaccharides (HMOs) have important biological functions for a healthy development in early life. Objective: This study aimed to investigate gut maturation effects of an infant formula containing five HMOs (2'-fucosyllactose, 2',3-di-fucosyllactose, lacto-N-tetraose, 3'-sialyllactose, and 6'-sialyllactose). Methods: In a multicenter study, healthy infants (7-21 days old) were randomly assigned to a standard cow's milk-based infant formula (control group, CG); the same formula with 1.5 g/L HMOs (test group 1, TG1); or with 2.5 g/L HMOs (test group 2, TG2). A human milk-fed group (HMG) was enrolled as a reference. Fecal samples collected at baseline (n∼150/formula group; HMG n = 60), age 3 (n∼140/formula group; HMG n = 65) and 6 (n∼115/formula group; HMG n = 60) months were analyzed for microbiome (shotgun metagenomics), metabolism, and biomarkers. Results: At both post-baseline visits, weighted UniFrac analysis indicated different microbiota compositions in the two test groups (TGs) compared to CG (P < 0.01) with coordinates closer to that of HMG. The relative abundance of Bifidobacterium longum subsp. infantis (B. infantis) was higher in TGs vs. CG (P < 0.05; except at 6 months: TG2 vs. CG P = 0.083). Bifidobacterium abundance was higher by ∼45% in TGs vs. CG at 6-month approaching HMG. At both post-baseline visits, toxigenic Clostridioides difficile abundance was 75-85% lower in TGs vs. CG (P < 0.05) and comparable with HMG. Fecal pH was significantly lower in TGs vs. CG, and the overall organic acid profile was different in TGs vs. CG, approaching HMG. At 3 months, TGs (vs. CG) had higher secretory immunoglobulin A (sIgA) and lower alpha-1-antitrypsin (P < 0.05). At 6 months, sIgA in TG2 vs. CG remained higher (P < 0.05), and calprotectin was lower in TG1 (P < 0.05) vs. CG. Conclusion: Infant formula with a specific blend of five HMOs supports the development of the intestinal immune system and gut barrier function and shifts the gut microbiome closer to that of breastfed infants with higher bifidobacteria, particularly B. infantis, and lower toxigenic Clostridioides difficile. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/], identifier [NCT03722550].

A systematic review of the effectiveness and safety of droperidol for pediatric agitation in acute care settings.

OBJECTIVE: Agitation in children in acute care settings poses significant patient and staff safety concerns. While behavioral approaches are central to reducing agitation and oral medications are preferred, parenteral medications are used when necessary to promote safety. The goal of this systematic review was to evaluate the effectiveness and safety of an ultra-short-acting parenteral medication, droperidol, for the management of acute, severe agitation in children in acute care settings. METHODS: A systematic review of randomized controlled trials, observational studies, and case series/reports examined the effectiveness and safety of parenteral droperidol for management of acute agitation in patients ≤21 years old in acute care settings. Effectiveness outcomes included time to sedation and need for a subsequent dose of medication. Safety outcomes were adverse effects such as QTc prolongation, hypotension, respiratory depression, and dystonic reactions. RESULTS: A total of 431 unique articles were identified. Six articles met inclusion criteria: two in the prehospital setting, one in the emergency department, and three in the inpatient hospital setting. The articles included a prospective observational study, three retrospective observational studies, and two case reports. The largest study reported a median time to sedation of 14 min (interquartile range 10-20 min); other studies reported a time to sedation of 15 min or less. Across studies, 8%-22% of patients required a second dose of medication for ongoing agitation. The most frequent adverse effects were dystonic reactions and transient hypotension. One patient had QTc prolongation and another developed respiratory depression, but both had significant comorbidities that may have contributed. The risk of bias in included studies ranged from moderate to critical. CONCLUSIONS: Existing data on droperidol for management of acute agitation in children suggest that droperidol is both effective and safe for acute, severe agitation in children. Data are limited by study designs that may introduce bias.

The Influence of FUT2 and FUT3 Polymorphisms and Nasopharyngeal Microbiome on Respiratory Infections in Breastfed Bangladeshi Infants from the Microbiota and Health Study.

Acute respiratory infections (ARIs) are one of the most common causes of morbidity and mortality in young children. The aim of our study was to examine whether variation in maternal FUT2 (α1,2-fucosyltransferase 2) and FUT3 (α1,3/4-fucosyltransferase 3) genes, which shape fucosylated human milk oligosaccharides (HMOs) in breast milk, are associated with the occurrence of ARIs in breastfed infants as well as the influence of the nasopharyngeal microbiome on ARI risk. Occurrences of ARIs were prospectively recorded in a cohort of 240 breastfed Bangladeshi infants from birth to 2 years. Secretor and Lewis status was established by sequencing of FUT2/3 genes. The nasopharyngeal microbiome was characterized by shotgun metagenomics, complemented by specific detection of respiratory pathogens; 88.6% of mothers and 91% of infants were identified as secretors. Maternal secretor status was associated with reduced ARI incidence among these infants in the period from birth to 6 months (incidence rate ratio [IRR], 0.66; 95% confidence interval [CI], 0.47 to 0.94; P = 0.020), but not at later time periods. The nasopharyngeal microbiome, despite precise characterization to the species level, was not predictive of subsequent ARIs. The observed risk reduction of ARIs among infants of secretor mothers during the predominant breastfeeding period is consistent with the hypothesis that fucosylated oligosaccharides in human milk contribute to protection against respiratory infections. However, we found no evidence that modulation of the nasopharyngeal microbiome influenced ARI risk. IMPORTANCE The observed risk reduction of acute respiratory infections (ARIs) among infants of secretor mothers during the predominant breastfeeding period is consistent with the hypothesis that fucosylated oligosaccharides in human milk contribute to protection against respiratory infections. Respiratory pathogens were only weak modulators of risk, and the nasopharyngeal microbiome did not influence ARI risk, suggesting that the associated protective effects of human milk oligosaccharides (HMOs) are not conveyed via changes in the nasopharyngeal microbiome. Our observations add to the evidence for a role of fucosylated HMOs in protection against respiratory infections in exclusively or predominantly breastfed infants in low-resource settings. There is no indication that the nasopharyngeal microbiome substantially modulates the risk of subsequent mild ARIs. Larger studies are needed to provide mechanistic insights on links between secretor status, HMOs, and risk of respiratory infections.

Strand Orientation Bias Detector to determine the probability of FFPE sequencing artifacts.

Formalin-fixed paraffin-embedded tissue, the most common tissue specimen stored in clinical practice, presents challenges in the analysis due to formalin-induced artifacts. Here, we present Strand Orientation Bias Detector (SOBDetector), a flexible computational platform compatible with all the common somatic SNV-calling pipelines, designed to assess the probability whether a given detected mutation is an artifact. The underlying predictor mechanism is based on the posterior distribution of a Bayesian logistic regression model trained on The Cancer Genome Atlas whole exomes. SOBDetector is a freely available cross-platform program, implemented in Java 1.8.

Acute poisoning with gamma-hydroxybutyrate. / Akutt forgiftning med gammahydroksybutyrat.

BACKGROUND: Many patients with gamma-hydroxybutyrate (GHB) poisoning are treated at the emergency primary health care (A&E clinic) level in Oslo. We describe the clinical picture of GHB poisoning and compare hospitalised patients with patients who were discharged from the main A&E clinic in Oslo. MATERIAL AND METHOD: We registered retrospectively all patients with the clinical diagnosis GHB poisoning at the Oslo Accident and Emergency Outpatient Clinic from 1 October 2013 to 30 September 2015. We only included cases where GHB was taken as an intoxicant. RESULTS: We found 329 cases of GHB poisoning in the period. The median age was 30 years (interquartile range 25-36 years, range 15-56 years), and 228 (69 %) of the cases were men. GHB was taken as the only intoxicant in 128 cases (39 %), combined with alcohol in 96 (29 %) and with amphetamine in 65 (20 %). Reduced level of consciousness was observed in 218 cases (69 %), coma (Glasgow Coma Scale score ≤ 7) in 43 (14 %) and agitation in 117 (36 %). Compared with patients who were discharged from the A&E clinic, the 159 hospitalised patients (48 % of the total number) were more often comatose (23 % vs 5 %, p < 0.001) and agitated (43 % vs 28 %, p = 0.008). The median observation time at the A&E clinic prior to hospitalisation was 42 minutes (interquartile range 26 min - 1 h 23 min, range 2 min - 20 h 10 min) vs 3 h 1 min (interquartile range 1 h 32 min - 4 h 42 min, range 14 min - 15 h 37 min) for those who were discharged from the A&E clinic (p < 0.001). INTERPRETATION: Half of the patients with GHB poisoning were only treated at A&E clinic level. Many of those who were hospitalised had severe symptoms that quickly called for hospitalisation.

Respiratory responses and rating of perceived exertion of severely obese adolescents during continuous and intermittent graded walking protocols: Application to cardiorespiratory field tests.

During 20 m shuttle tests, obese adolescents may have difficulty achieving maximum cardiorespiratory performance due to the presence of braking-relaunch phases (BRP). Nineteen obese adolescents aged 15.2 ± 1.5 years (body mass index [BMI] = 39.7 ± 5.9 kg.m-2) performed three graded walking exercises on a 50 m track at speeds between 3 and 6 km/h: a continuous-straight-line protocol (C), a continuous protocol that required turning back every 30 sec (C-BRP) and an intermittent protocol that consisted of successively walking then resting for 15 sec (15-15). Oxygen uptake (VO2), aerobic cost of walking (Cw), ventilation (VE) and rating of perceived exertion (RPE) were measured at each stage during the protocols. During C-BRP, the responses were not significantly higher compared with C (p > 0.30). During 15-15, the VO2, Cw and VE were ~ 15 to 25% lower than during C beginning at 4 km/h (p < 0.05). In obese adolescents, the respiratory impact of sudden directional changes during the 20 m shuttle-type test appeared to be minor at walking speeds. During the 15-15 test, the intensity increases more progressively, and this design may encourage obese adolescents to walk further than during a continuous test.

Using global positioning system methods to explore mobility patterns and exposure to high HIV prevalence neighbourhoods among transgender women in New York.

The aim of this study was to assess mobility patterns among a sample of transgender women (n=14) in New York City via survey and Global Positioning System (GPS) monitoring. We found varying levels of concordance between the residential neighbourhood and each of the non-residential contexts: 64.3% considered the neighbourhood that they socialised in most often to be different from their residential neighbourhood. While participants' residences represented 10 zone improvement plan code tabulation areas (ZCTAs), GPS data were recorded in 124 of 263 ZCTAs (47.1%). Overall, 58.2% (n=373,262) were recorded in ZCTAs in the highest quartile of human immunodeficiency virus (HIV) prevalence. The association between place, community HIV prevalence, mobility, and factors that increase the vulnerability of transgender women to HIV infection are worthy of future investigation in reducing the burden of the HIV epidemic in these communities.

Bifidobacteriumbreve Bif195 Protects Against Small-Intestinal Damage Caused by Acetylsalicylic Acid in Healthy Volunteers.

BACKGROUND & AIMS: Enteropathy and small-intestinal ulcers are common adverse effects of nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (ASA). Safe, cytoprotective strategies are needed to reduce this risk. Specific bifidobacteria might have cytoprotective activities, but little is known about these effects in humans. We used serial video capsule endoscopy (VCE) to assess the efficacy of a specific Bifidobacterium strain in healthy volunteers exposed to ASA. METHODS: We performed a single-site, double-blind, parallel-group, proof-of-concept analysis of 75 heathy volunteers given ASA (300 mg) daily for 6 weeks, from July 31 through October 24, 2017. The participants were randomly assigned (1:1) to groups given oral capsules of Bifidobacterium breve (Bif195) (≥5 × 1010 colony-forming units) or placebo daily for 8 weeks. Small-intestinal damage was analyzed by serial VCE at 6 visits. The area under the curve (AUC) for intestinal damage (Lewis score) and the AUC value for ulcers were the primary and first-ranked secondary end points of the trial, respectively. RESULTS: Efficacy data were obtained from 35 participants given Bif195 and 31 given placebo. The AUC for Lewis score was significantly lower in the Bif195 group (3040 ± 1340 arbitrary units) than the placebo group (4351 ± 3195) (P = .0376). The AUC for ulcer number was significantly lower in the Bif195 group (50.4 ± 53.1 arbitrary units) than in the placebo group (75.2 ± 85.3 arbitrary units) (P = .0258). Twelve adverse events were reported from the Bif195 group and 20 from the placebo group. None of the events was determined to be related to Bif195 intake. CONCLUSIONS: In a randomized, double-blind trial of healthy volunteers, we found oral Bif195 to safely reduce the risk of small-intestinal enteropathy caused by ASA. ClinicalTrials.gov no: NCT03228589.

Decoding the Apparent Horizon: Coarse-Grained Holographic Entropy.

When a black hole forms from collapse in a holographic theory, the information in the black hole interior remains encoded in the boundary. We prove that the area of the black hole's apparent horizon is precisely the entropy associated with coarse graining over the information in its interior, subject to knowing the exterior geometry. This is the maximum holographic entanglement entropy that is compatible with all classical measurements conducted outside of the apparent horizon. We identify the boundary dual to this entropy and explain why it obeys the second law of thermodynamics.

Migrating the SNP array-based homologous recombination deficiency measures to next generation sequencing data of breast cancer.

The first genomic scar-based homologous recombination deficiency (HRD) measures were produced using SNP arrays. As array-based technology has been largely replaced by next generation sequencing approaches, it has become important to develop algorithms that derive the same type of genomic scar scores from next generation sequencing (whole exome "WXS", whole genome "WGS") data. In order to perform this analysis, we introduce here the scarHRD R package and show that using this method the SNP array-based and next generation sequencing-based derivation of HRD scores show good correlation (Pearson correlation between 0.73 and 0.87 depending on the actual HRD measure) and that the NGS-based HRD scores distinguish similarly well between BRCA mutant and BRCA wild-type cases in a cohort of triple-negative breast cancer patients of the TCGA data set.

Acceptability and Feasibility of Using a Novel Geospatial Method to Measure Neighborhood Contexts and Mobility Among Transgender Women in New York City.

Purpose: To date, no studies utilizing global positioning system (GPS) technologies to measure mobility and environmental exposures have been conducted among a sample of transgender women despite the potential salient role neighborhood contexts may play in the health of this population. As such, the purpose of this study was to assess the acceptability and feasibility of a weeklong GPS protocol among a sample of transgender women in New York City. Methods: A sample of 14 transgender women residing in the New York City metropolitan area were recruited through community based methods to wear and charge a GPS device for 7 days to measure daily mobility. The acceptability of these methods was assessed using a pre- and postprotocol survey and their feasibility was measured using objective data derived from the GPS device. Pre- and postprotocol survey measures were compared using McNemar's test. Results: Participants reported high ratings of preprotocol acceptability, as well as few concerns regarding safety, appearance, and losing the device, all of which were maintained after completing the protocol. All 14 devices that were distributed were returned. In addition, all 14 participants had GPS data for at least 1 h on 1 day, and nine participants (64.3%) had at least 8 h of GPS data on all days. Conclusion: The findings of this pilot study demonstrate that the GPS methods are both acceptable and feasible among this sample of transgender women. GPS devices may be used in research among transgender women to understand neighborhood determinants of HIV and other STIs.

Lower Bound on the Energy Density in Classical and Quantum Field Theories.

A novel method for deriving energy conditions in stable field theories is described. In a local classical theory with one spatial dimension, a local energy condition always exists. For a relativistic field theory, one obtains the dominant energy condition. In a quantum field theory, there instead exists a quantum energy condition, i.e., a lower bound on the energy density that depends on information-theoretic quantities. Some extensions to higher dimensions are briefly discussed.

Reconstruction of Bulk Operators within the Entanglement Wedge in Gauge-Gravity Duality.

In this Letter we prove a simple theorem in quantum information theory, which implies that bulk operators in the anti-de Sitter/conformal field theory (AdS/CFT) correspondence can be reconstructed as CFT operators in a spatial subregion A, provided that they lie in its entanglement wedge. This is an improvement on existing reconstruction methods, which have at most succeeded in the smaller causal wedge. The proof is a combination of the recent work of Jafferis, Lewkowycz, Maldacena, and Suh on the quantum relative entropy of a CFT subregion with earlier ideas interpreting the correspondence as a quantum error correcting code.