Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.

Irish national real-world analysis of the clinical and economic impact of 21-gene oncotype DX® testing in early-stage, 1-3 lymph node-positive, oestrogen receptor-positive, HER2-negative, breast cancer.

PURPOSE: The treatment landscape of Oestrogen receptor-positive (ER-positive) breast cancer is evolving, with declining chemotherapy use as a result of Oncotype DX Breast Recurrence Score® testing. Results from the SWOG S1007 RxPONDER trial suggest that adjuvant chemotherapy may benefit some premenopausal women with ER-positive, HER2-negative disease with 1-3 positive lymph nodes (N1), and a Recurrence Score® (RS) of ≤ 25. Postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. We examine the clinical and economic impact of Oncotype DX® testing on treatment decisions in patients with N1 disease in Ireland using real world data. METHODS: From March 2011 to October 2022, a retrospective, cross-sectional observational study was performed of patients with ER-positive, HER2-negative N1 breast cancer, who had Oncotype DX testing across 5 of Ireland's largest cancer centres. Patients were classified into low risk (RS 0-13), intermediate risk (RS 14-25) and high risk (RS > 25). Data were collected via electronic patient records. Information regarding costing was provided primarily by pre-published sources. RESULTS: A total of 828 N1 patients were included in this study. Post Oncotype DX testing, 480 patients (58%) were spared chemotherapy. Of the patients who had a change in chemotherapy recommendation based on Oncotype DX testing, 271 (56%), 205 (43%), 4 (1%) had a RS result of 0-13, 14-25 and > 25 respectively. Use of Oncotype DX testing was associated with a 58% reduction in chemotherapy administration overall. This resulted in estimated savings of over €6 million in treatment costs. Deducting the assay cost, estimated net savings of over €3.3 million were achieved. Changes in the ordering demographics of Oncotype DX tests were identified after RxPONDER data were presented, with increased testing in women ≥ 50 years and a reduction in proportion of tests ordered for women < 50 years. CONCLUSION: Between 2011 and 2022, assay use resulted in a 58% reduction in chemotherapy administration and net savings of over €3.3 million.

Interprofessional communication in the hospital setting : a systematic review of the qualitative literature.

Communication plays a key role in the provision of safe patient care, and miscommunication in healthcare can lead to avoidable patient harm or mortality. Interprofessional communication (IPCom) can be challenging due to differences in training, education and roles between healthcare professions. The aim of this systematic review was to synthesize the qualitative evidence regarding healthcare providers' perceptions of interprofessional communication in the hospital setting. Four databases (PubMed, CINAHL, Web of Science, and Embase) were searched for studies that met the inclusion criteria. Eighteen studies were identified as suitable for inclusion in the review and were examined using thematic synthesis. Thematic synthesis led to the development of five descriptive themes: 1) 'Hierarchy", 2) "Interprofessional Ethos," 3) "Healthcare Environment," 4) "Personal Factors" and 5) "Methods of Communication," and two overarching analytical themes: "Barriers to Communication" and "Facilitators to Communication." Personal factors, such as strong interprofessional relationships, were found to be important facilitators to IPCom, while organizational factors, such as challenging and hierarchical working environments, were found to pose barriers to IPCom.

Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome.

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with acute respiratory distress syndrome (ARDS), and that these variants would alter MAP3K1-mediated changes in inflammation and transcriptional regulation. To test this hypothesis, we genotyped single-nucleotide polymorphisms covering linkage disequilibrium bins in MAP3K1 in 306 subjects with ARDS from the ARDSNet FACTT (Fluid and Catheter Treatment Trial) study, and tested for associations between MAP3K1 single-nucleotide polymorphisms and ventilator-free days (VFDs) and mortality. We then validated these associations in a separate cohort of 241 patients with ARDS from Harborview Medical Center (Seattle, WA). We found the variant allele of rs832582 (MAP3K1906Val) was significantly associated with decreased VFDs using multivariate linear regression (-6.1 d, false discovery rate = 0.06) in the FACTT cohort. In the Harborview Medical Center cohort, subjects homozygous for MAP3K1906Val also had decreased VFDs (-15.1 d, false discovery rate < 0.01), and increased 28-day mortality (all subjects homozygous for the rare allele died). In whole blood stimulated with various innate immune agonists ex vivo, MAP3K1906Val was associated with increased IL-1ß, IL-6, IL-8, monocyte chemoattractant protein 1, and TNF-α production. Transcriptome analysis of whole blood stimulated with Toll-like receptor 4 agonist ex vivo demonstrated enrichment of inflammatory gene sets in subjects homozygous for MAP3K1906Val. Our findings show a robust association between the variant allele of rs832582 (MAP3K1906Val) and decreased VFDs in patients with ARDS and suggest that this variant may predispose individuals to a greater inflammatory response.

Drug consumption and futile medication prescribing in the last year of life: an observational study.

Background: the last year of life for many older people is associated with high symptom burden and frequent hospitalizations. Hospital physicians have an opportunity to prioritize essential medications and deprescribe potentially futile medications. Objective: to measure medication consumption during hospitalization in the last year of life and the prevalence of potentially inappropriate medications (PIMs) at hospital discharge. Design: retrospective chart review. Setting: acute hospital. Subjects: ≥65 years, hospitalized in the last year of life. Methods: medication consumption was determined by examining hospital Medication Administration Records. PIMs were defined using STOPPFrail deprescribing criteria. Results: the study included 410 patients. The mean age of participants was 80.8, 49.3% were female, and 63.7% were severely frail. The median number of days spent in hospital in the last year of life was 32 (interquartile range 15-59). During all hospitalizations, the mean number of individual medications consumed was 23.8 (standard deviation 10.1). One-in-six patients consumed 35 or more medications in their last year. Over 80% of patients were prescribed at least one PIM at discharge and 33% had ≥3 PIMs. Lipid-lowering medications, proton pump inhibitors, anti-psychotics and calcium supplements accounted for 59% of all PIMs. Full implementation of STOPPFrail recommendations would have resulted in one-in-four long-term medications being discontinued. Conclusion: high levels of medication consumption in the last year of life not only reflect high symptom burden experienced by patients but also continued prescribing of futile medications. Physicians assisted by the STOPPFrail tool can reduce medication burden for older people approaching end of life.

A Two-Biomarker Model Predicts Mortality in the Critically Ill with Sepsis.

RATIONALE: Improving the prospective identification of patients with systemic inflammatory response syndrome (SIRS) and sepsis at low risk for organ dysfunction and death is a major clinical challenge. OBJECTIVES: To develop and validate a multibiomarker-based prediction model for 28-day mortality in critically ill patients with SIRS and sepsis. METHODS: A derivation cohort (n = 888) and internal test cohort (n = 278) were taken from a prospective study of critically ill intensive care unit (ICU) patients meeting two of four SIRS criteria at an academic medical center for whom plasma was obtained within 24 hours. The validation cohort (n = 759) was taken from a prospective cohort enrolled at another academic medical center ICU for whom plasma was obtained within 48 hours. We measured concentrations of angiopoietin-1, angiopoietin-2, IL-6, IL-8, soluble tumor necrosis factor receptor-1, soluble vascular cell adhesion molecule-1, granulocyte colony-stimulating factor, and soluble Fas. MEASUREMENTS AND MAIN RESULTS: We identified a two-biomarker model in the derivation cohort that predicted mortality (area under the receiver operator characteristic curve [AUC], 0.79; 95% confidence interval [CI], 0.74-0.83). It performed well in the internal test cohort (AUC, 0.75; 95% CI, 0.65-0.85) and the external validation cohort (AUC, 0.77; 95% CI, 0.72-0.83). We determined a model score threshold demonstrating high negative predictive value (0.95) for death. In addition to a low risk of death, patients below this threshold had shorter ICU length of stay, lower incidence of acute kidney injury, acute respiratory distress syndrome, and need for vasopressors. CONCLUSIONS: We have developed a simple, robust biomarker-based model that identifies patients with SIRS/sepsis at low risk for death and organ dysfunction.

Functional characterization of polymorphisms in the peptidase inhibitor 3 (elafin) gene and validation of their contribution to risk of acute respiratory distress syndrome.

Elafin (peptidase inhibitor 3 [PI3]) and its biologically active precursor, pre-elafin, are neutrophil serine proteinase inhibitors with an important role in preventing excessive tissue injury during inflammatory events. Recently, we reported an association between single-nucleotide polymorphism (SNP) rs2664581 in the PI3 gene, increased risk of acute respiratory distress syndrome (ARDS) and pre-elafin circulating levels. This study aims to validate the legitimacy of this association by using a cohort of patients who met the criteria for systemic inflammatory response syndrome and were at risk of developing ARDS (n = 840). A comprehensive functional study of SNPs in PI3 gene was also performed. Luciferase assays and electrophoretic mobility shift assays were conducted to determine the functional relevance of promoter region variants. The effect of the coding SNP rs2664581 on the neutrophil elastase inhibitory activity and transglutaminase binding properties of pre-elafin was also investigated. The variant allele of rs2664581 (C) was significantly associated with increased ARDS risk, mainly among subjects with sepsis (odds ratio = 1.44; 95% confidence interval = 1.04-1.99; P = 0.0276, adjusted by age, sex, and Acute Physiology and Chronic Health Evaluation III). Pre-elafin recombinant protein carrying the amino acid change associated with rs2664581 (Thr34Pro, mutant protein [MT]) had greater capacity to undergo transglutaminase-mediated cross-linking to immobilized fibronectin than wild-type protein in vitro (P < 0.003). No differences were observed in the neutrophil elastase inhibitory activities of wild-type versus MT proteins. In addition, the risk allele-promoter construct had significantly lower cytokine-induced transcriptional activity. Electrophoretic mobility shift assay results indicated a differential binding of nuclear proteins to the G and A alleles of SNP -338G > A. Our results confirm the association between SNP rs2664581 and enhanced risk of ARDS, further supporting the role of PI3 in ARDS development. SNPs in the PI3 locus may act synergistically by regulating PI3 gene expression and pre-elafin biological functions.

Antipsychotic prescribing and drug-related readmissions in multimorbid older inpatients: a post-hoc analysis of the OPERAM population.

BACKGROUND: Limited data are available on characteristics associated with antipsychotic use in multimorbid older adults. AIM: Primary: to identify patient characteristics associated with antipsychotic prescribing in a multimorbid population of older inpatients with polypharmacy. Secondary: (1) to observe if antipsychotics use during an index hospitalisation was associated with a drug related admission (DRA) within one year, and (2) to describe these cases of antipsychotic-related readmissions. METHOD: This was a secondary analysis of the OPERAM randomized controlled trial. Multivariate analysis assessed the association between characteristics and comorbidities with antipsychotic use. An expert team assessed DRA occurring during the one-year follow-up. RESULTS: Antipsychotics were prescribed to 5.5% (n = 110) patients upon admission while 7.7% (n = 154) inpatients received antipsychotics at any time (i.e. upon admission, during hospitalisation, and/or at discharge). The most frequently prescribed antipsychotics were quetiapine (n = 152), haloperidol (n = 48) and risperidone (n = 22). Antipsychotic prescribing was associated with dementia (OR = 3.7 95%CI[2.2;6.2]), psychosis (OR = 26.2 [7.4;92.8]), delirium (OR = 6.4 [3.8;10.8]), mood disorders (OR = 2.6 [1.6;4.1]),  ≥ 15 drugs a day (OR = 1.7 [1.1;2.6]), functional dependency (Activities of Daily Living score < 50/100) (OR = 3.9 [2.5;6.1]) and < 2 units of alcohol per week (OR = 2.2 [1.4;3.6]). DRA occurred in 458 patients (22.8%) within one year. Antipsychotic prescribing at any time was not associated with DRA (OR = 1.0 [0.3;3.9]) however contributed to 8 DRAs, including 3 falls. CONCLUSION: In this European multimorbid polymedicated older inpatients, antipsychotics were infrequently prescribed, most often at low dosage. Besides neuro-psychiatric symptoms, risk factors for inhospital antipsychotic prescribing were lower functional status and polymedication.

Bifidobacterium infantis suppression of Peyer's patch MIP-1α and MIP-1ß secretion during Salmonella infection correlates with increased local CD4+CD25+ T cell numbers.

The outcome following infection depends on the generation of an immune response that results in control of the pathogenic microorganism, while limiting inflammatory collateral damage to the host. Bifidobacterium infantis 35624 was shown to be protective against Salmonella associated host injury via a Treg-dependent mechanism. In this study, we further examined the mechanisms by which B. infantis-induced Tregs protect against Salmonella-associated inflammation. B. infantis 35624 feeding to Salmonella-infected mice significantly reduced Peyer's patch MIP-1α and MIP-1ß secretion. Chemokine secretion was significantly inversely correlated with Peyer's patch CD4+CD25+ cell numbers. In vitro, CD25+ T cells, but not CD25- T cells, specifically inhibited TNF-α and IFN-γ secretion. However, both CD25+ and CD25- T cells suppressed MIP-1α and MIP-1ß secretion to the same extent. This study suggests that although B. infantis 35624-induced Tregs correlate with inhibition of chemokine secretion within the mucosa of pathogen infected animals, indirect cellular mechanisms may play a role.

Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin.

BACKGROUND: The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been specifically investigated. The aim of this study was to identify genetic variants contributing to ALI/ARDS from pulmonary or extrapulmonary causes. METHODS: We conducted a multistage genetic association study. We first performed a large-scale genotyping (50K ITMAT-Broad_CARe Chip) in 1717 critically ill Caucasian patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p≤0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n=765) and pneumonia/pulmonary sepsis (Population II; n=838), as causes for ALI/ARDS. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n=224, Stage III). RESULTS: In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p<0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p<0.006, Stage II; p<0.05, Stage III). Meta-analysis confirmed these associations. CONCLUSIONS: Different genetic variants may influence ARDS susceptibility depending on direct versus indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI/ARDS, respectively.

Healthcare provider perceptions of safety culture: A multi-site study using the safety attitudes questionnaire.

Introduction: Patient safety culture, the way in which members of a healthcare organisation think about and prioritise safety, has been linked to positive patient outcomes. The aim of this study was to use the Safety Attitudes Questionnaire (SAQ) to measure the safety culture in a variety of healthcare settings located in the province of Munster of Ireland. Methods: The SAQ was applied in six healthcare settings in the Munster province of Ireland between December 2017 and November 2019. The attitudes of healthcare staff towards six domains of safety culture were assessed over 32 Likert-scaled items. The mean, median, interquartile range and percent positive scores for each domain were calculated for the study population, and subgroup analyses were carried out between study sites and professions. Results for each setting were compared to international benchmarking data. Chi-Squared tests were used to determine whether study site or profession were related to domain scores. Reliability analysis was carried out using Cronbach's alpha. Results: Study participants (n = 1749) comprising doctors, pharmacists, nurses, and healthcare assistants, were found to have positive attitudes towards patient safety culture but scored poorly in the domains Working Conditions and Perceptions of Management. Perceptions of safety culture were more positive in smaller healthcare settings, and amongst nurses and HCAs. The survey had acceptable internal consistency. Conclusions: In this study investigating the safety culture of healthcare organisations in Ireland, study participants had generally positive attitudes towards the safety culture in their organisation, however working conditions, perceptions of management, and medication incident reporting were identified as key areas for improvement.

Order Set Usage is Associated With Lower Hospital Mortality in Patients With Sepsis.

The Surviving Sepsis Campaign recommends standard operating procedures for patients with sepsis. Real-world evidence about sepsis order set implementation is limited. OBJECTIVES: To estimate the effect of sepsis order set usage on hospital mortality. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Fifty-four acute care hospitals in the United States from December 1, 2020 to November 30, 2022 involving 104,662 patients hospitalized for sepsis. MAIN OUTCOMES AND MEASURES: Hospital mortality. RESULTS: The sepsis order set was used in 58,091 (55.5%) patients with sepsis. Initial mean sequential organ failure assessment score was 0.3 lower in patients for whom the order set was used than in those for whom it was not used (2.9 sd [2.8] vs 3.2 [3.1], p < 0.01). In bivariate analysis, hospital mortality was 6.3% lower in patients for whom the sepsis order set was used (9.7% vs 16.0%, p < 0.01), median time from emergency department triage to antibiotics was 54 minutes less (125 interquartile range [IQR, 68-221] vs 179 [98-379], p < 0.01), and median total time hypotensive was 2.1 hours less (5.5 IQR [2.0-15.0] vs 7.6 [2.5-21.8], p < 0.01) and septic shock was 3.2% less common (22.0% vs 25.4%, p < 0.01). Order set use was associated with 1.1 fewer median days of hospitalization (4.9 [2.8-9.0] vs 6.0 [3.2-12.1], p < 0.01), and 6.6% more patients discharged to home (61.4% vs 54.8%, p < 0.01). In the multivariable model, sepsis order set use was independently associated with lower hospital mortality (odds ratio 0.70; 95% CI, 0.66-0.73). CONCLUSIONS AND RELEVANCE: In a cohort of patients hospitalized with sepsis, order set use was independently associated with lower hospital mortality. Order sets can impact large-scale quality improvement efforts.

Phase 2, randomized, double-blind, placebo-controlled multi-center trial of the clinical and biological effects of anti-CD14 treatment in hospitalized patients with COVID-19 pneumonia.

BACKGROUND: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target. METHODS: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo. All participants received remdesivir. The primary outcome was time-to-resolution of illness, defined as improvement on the 8-point NIH-Ordinal COVID-19 Scale to category ≤3. Secondary endpoints were safety and exploratory endpoints were pro-inflammatory and antiviral mediators in serum on days 0-5 & 7. The trial was stopped after 40 patients were randomized and treated due to slow enrollment. FINDINGS: 40 participants were randomized and treated with IC14 (n = 20) or placebo (n = 20). The median time-to-recovery was 6 days (95% CI, 5-11) in the IC14 group vs. 5 days (95% CI, 4-10) in the Placebo group (recovery rate ratio: 0.77 (95% CI, 0.40, 1.48) (log-rank p = 0.435). The number of adverse events was similar in each group, and no IC14-attributable secondary infections occurred. In repeated-measures mixed-effects analyses, IC14 treatment increased serum sCD14 concentrations, an expected pharmacodynamic effect. Pre-planned, exploratory analyses suggested that IC14 treatment decreased the trajectories of circulating MIP-1ß and TNF-α. INTERPRETATION: IC14 treatment did not improve time-to-resolution of illness in hypoxemic patients with COVID-19 in this small trial. Results of exploratory analyses suggested IC14 had biologic effects that warrant future clinical investigation. FUNDING: National Institute of Allergy and Infectious Diseases.

Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. Methods: We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31st of December 2018. A retrospective electronic chart review was performed. Results: The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, P = .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (P = 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, P = 0.02). Conclusions: ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.

Hospital physicians' and older patients' agreement with individualised STOPP/START-based medication optimisation recommendations in a clinical trial setting.

OBJECTIVE: To evaluate the agreement of hospital physicians and older patients with individualised STOPP/START-based medication optimisation recommendations from a pharmacotherapy team. METHODS: This study was embedded within a large European, multicentre, cluster randomised controlled trial examining the effect of a structured medication review on drug-related hospital admissions in multimorbid (≥ 3 chronic conditions) older people (≥ 70 years) with polypharmacy (≥ 5 chronic medications), called OPERAM. Data from the Dutch intervention arm of this trial were used for this study. Medication review was performed jointly by a physician and pharmacist (i.e. pharmacotherapy team) supported by a Clinical Decision Support System with integrated STOPP/START criteria. Individualised STOPP/START-based medication optimisation recommendations were discussed with patients and attending hospital physicians. RESULTS: 139 patients were included, mean (SD) age 78.3 (5.1) years, 47% male and median (IQR) number of medications at admission 11 (9-14). In total, 371 recommendations were discussed with patients and physicians, overall agreement was 61.6% for STOPP and 60.7% for START recommendations. Highest agreement was found for initiation of osteoporosis agents and discontinuation of proton pump inhibitors (both 74%). Factors associated with higher agreement in multivariate analysis were: female gender (+ 17.1% [3.7; 30.4]), ≥ 1 falls in the past year (+ 15.0% [1.5; 28.5]) and renal impairment i.e. eGFR 30-50 ml/min/1.73 m2; (+ 18.0% [2.0; 34.0]). The main reason for disagreement (40%) was patients' reluctance to discontinue or initiate medication. CONCLUSION: Better patient and physician education regarding the benefit/risk balance of pharmacotherapy, in addition to more precise and up-to-date medical records to avoid irrelevant recommendations, will likely result in higher adherence with future pharmacotherapy optimisation recommendations. CLINICAL TRIAL REGISTRATION: Trial Registration Number NCT02986425.

Ambulatory Risk Models for the Long-Term Prevention of Sepsis: Retrospective Study.

BACKGROUND: Sepsis is a life-threatening condition that can rapidly lead to organ damage and death. Existing risk scores predict outcomes for patients who have already become acutely ill. OBJECTIVE: We aimed to develop a model for identifying patients at risk of getting sepsis within 2 years in order to support the reduction of sepsis morbidity and mortality. METHODS: Machine learning was applied to 2,683,049 electronic health records (EHRs) with over 64 million encounters across five states to develop models for predicting a patient's risk of getting sepsis within 2 years. Features were selected to be easily obtainable from a patient's chart in real time during ambulatory encounters. RESULTS: The models showed consistent prediction scores, with the highest area under the receiver operating characteristic curve of 0.82 and a positive likelihood ratio of 2.9 achieved with gradient boosting on all features combined. Predictive features included age, sex, ethnicity, average ambulatory heart rate, standard deviation of BMI, and the number of prior medical conditions and procedures. The findings identified both known and potential new risk factors for long-term sepsis. Model variations also illustrated trade-offs between incrementally higher accuracy, implementability, and interpretability. CONCLUSIONS: Accurate implementable models were developed to predict the 2-year risk of sepsis, using EHR data that is easy to obtain from ambulatory encounters. These results help advance the understanding of sepsis and provide a foundation for future trials of risk-informed preventive care.

Bacterial strain-specific induction of Foxp3+ T regulatory cells is protective in murine allergy models.

BACKGROUND: The incidence of atopic disease has increased dramatically during recent decades and the potential immunoregulatory influence of the microbiota in these individuals is under investigation. OBJECTIVE: The aim of our study was to identify a bacterial strain that is protective in murine allergy models and to determine if microbial induction of T regulatory cells was associated with protection from allergic inflammation. METHODS: Three microbes (Bifidobacterium breve AH1205, B. longum AH1206 and Lactobacillus salivarius AH102) of human origin were fed to newborn, adult and germ-free animals. Induction of Foxp3(+) T regulatory cells was assessed by flow cytometry. Gene array analysis was performed on Peyer's patches. Strains were also examined for their protective effects in the ovalbumin (OVA) respiratory allergy model and the OVA-cholera toxin dietary allergy model. RESULTS: Bifidobacterium longum AH1206 consumption resulted in increased numbers of Foxp3(+) T regulatory cells in infant, adult and germ-free animals. B. breve AH1205 induced Foxp3(+) T regulatory cell expansion only in infant mice while L. salivarius AH102 did not alter T regulatory cell numbers in any animal model tested. B. longum AH1206 reduced the Peyer's patch gene expression associated with antigen presentation, TLR signalling and cytokine production while increasing the expression of genes associated with retinoic acid metabolism. B. longum AH1206 protected against airway inflammation in OVA-sensitized animals and B. longum AH1206 blocked the induction of IgE to orally administered OVA. Neither B. breve AH1205 nor L. salivarius AH102 had a protective effect in either model. CONCLUSION: Bacterial strain-specific induction of Foxp3(+) T regulatory cells in vivo is associated with protection from respiratory and oral allergy.