Abstract
Objective
Developing algorithms to extract phenotypes from electronic health records (EHRs) can be challenging and time-consuming. We developed PheMap, a high-throughput phenotyping approach ...that leverages multiple independent, online resources to streamline the phenotyping process within EHRs.
Materials and Methods
PheMap is a knowledge base of medical concepts with quantified relationships to phenotypes that have been extracted by natural language processing from publicly available resources. PheMap searches EHRs for each phenotype’s quantified concepts and uses them to calculate an individual’s probability of having this phenotype. We compared PheMap to clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network for type 2 diabetes mellitus (T2DM), dementia, and hypothyroidism using 84 821 individuals from Vanderbilt Univeresity Medical Center's BioVU DNA Biobank. We implemented PheMap-based phenotypes for genome-wide association studies (GWAS) for T2DM, dementia, and hypothyroidism, and phenome-wide association studies (PheWAS) for variants in FTO, HLA-DRB1, and TCF7L2.
Results
In this initial iteration, the PheMap knowledge base contains quantified concepts for 841 disease phenotypes. For T2DM, dementia, and hypothyroidism, the accuracy of the PheMap phenotypes were >97% using a 50% threshold and eMERGE case-control status as a reference standard. In the GWAS analyses, PheMap-derived phenotype probabilities replicated 43 of 51 previously reported disease-associated variants for the 3 phenotypes. For 9 of the 11 top associations, PheMap provided an equivalent or more significant P value than eMERGE-based phenotypes. The PheMap-based PheWAS showed comparable or better performance to a traditional phecode-based PheWAS. PheMap is publicly available online.
Conclusions
PheMap significantly streamlines the process of extracting research-quality phenotype information from EHRs, with comparable or better performance to current phenotyping approaches.
Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their ...hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01, and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.
Objectives
Sepsis has been called a “disease of the elderly,” and as in‐hospital mortality has decreased, more sepsis survivors are progressing into poorly characterized long‐term outcomes. The ...purpose of this study was to describe the current epidemiology of sepsis in older adults compared with middle‐aged and young adults.
Design
Prospective longitudinal study with young (≤45 years), middle‐aged (46‐64 years), and older (≥65 years) patient groups.
Setting
University tertiary medical center.
Participants
A total of 328 adult surgical intensive care unit (ICU) sepsis patients.
Measurements
Patients were characterized by (1) baseline demographics and predisposition, (2) septic event, (3) hospital outcomes and discharge disposition, (4) 12‐month mortality, and (5) Zubrod Performance Status, physical function (Short Physical Performance Battery and handgrip strength), and cognitive function (Hopkins Verbal Learning Test, Controlled Oral Word Association, and Mini‐Mental Status Examination) at 3‐, 6‐, and 12‐month follow‐up. Loss to follow‐up was due to death (in 68), consent withdrawal (in 32), and illness and scheduling difficulties: month 3 (in 51), month 6 (in 29), and month 12 (in 20).
Results
Compared with young and middle‐aged patients, older patients had (1) significantly more comorbidities at presentation (eg, chronic renal disease 6% vs 12% vs 21%), intra‐abdominal infections (14% vs 25% vs 37%), septic shock (12% vs 25% vs 36%), and organ dysfunctions; (2) higher 30‐day mortality (6% vs 4% vs 17%) and fewer ICU‐free days (median = 25 vs 23 vs 20); (3) more progression into chronic critical illness (22% vs 34% vs 42%) with higher poor disposition discharge to non‐home destinations (19% vs 40% vs 62%); (4) worse 12‐month mortality (11% vs 14% vs 33%); and (5) poorer Zubrod Performance Status and objectively measured physical and cognitive functions with only slight improvement over 12‐month follow‐up.
Conclusion
Compared with younger patients, older sepsis survivors suffer both a higher persistent disability burden and 12‐month mortality.
Background
Microglia are a primary mediator of the neuroinflammatory response to neurologic injury, such as that in traumatic brain injury. Their response includes changes to their cytokine ...expression, metabolic profile, and immunophenotype. Dexmedetomidine (DEX) is an α
2
adrenergic agonist used as a sedative in critically ill patients, such as those with traumatic brain injury. Given its pharmacologic properties, DEX may alter the phenotype of inflammatory microglia.
Methods
Primary microglia were isolated from Sprague–Dawley rats and cultured. Microglia were activated using multiple mediators: lipopolysaccharide (LPS), polyinosinic-polycytidylic acid (Poly I:C), and traumatic brain injury damage-associated molecular patterns (DAMP) from a rat that sustained a prior controlled cortical impact injury. After activation, cultures were treated with DEX. At the 24-h interval, the cell supernatant and cells were collected for the following studies: cytokine expression (tumor necrosis factor-α TNFα, interleukin-10 IL-10) via enzyme-linked immunosorbent assay, 6-phosphofructokinase enzyme activity assay, and immunophenotype profiling with flow cytometry. Cytokine expression and metabolic enzyme activity data were analyzed using two-way analysis of variance. Cell surface marker expression was analyzed using FlowJo software.
Results
In LPS-treated cultures, DEX treatment decreased the expression of TNFα from microglia (mean difference = 121.5 ± 15.96 pg/mL;
p
< 0.0001). Overall, DEX-treated cultures had a lower expression of IL-10 than nontreated cultures (mean difference = 39.33 ± 14.50 pg/mL,
p
< 0.0001). DEX decreased IL-10 expression in LPS-stimulated microglia (mean difference = 74.93 ± 12.50 pg/mL,
p
= 0.0039) and Poly I:C-stimulated microglia (mean difference = 23.27 ± 6.405 pg/mL,
p
= 0.0221). In DAMP-stimulated microglia, DEX decreased the activity of 6-phosphofructokinase (mean difference = 18.79 ± 6.508 units/mL;
p
= 0.0421). The microglial immunophenotype was altered to varying degrees with different inflammatory stimuli and DEX treatment.
Conclusions
DEX may alter the neuroinflammatory response of microglia. By altering the microglial profile, DEX may affect the progression of neurologic injury.
Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With ...the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology.
In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer.
Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs.
It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.
Endometrial cancer survivors are at an increased risk of poor quality of life outcomes. Physical activity is positively associated with general quality of life in this population, however, little is ...known about how changes in physical activity may be associated with changes in specific aspects of quality of life. The aim of this secondary data analysis was to explore the relationships between change in physical activity and change in physical, mental, social, and other aspects of quality of life in endometrial cancer survivors receiving a physical activity intervention.
Endometrial cancer survivors (N = 100) participated in a telephone-based physical activity intervention for six months. At baseline and post-intervention we measured physical activity via accelerometry and ecological momentary assessment, and quality of life via the Short Form Health Survey (SF-36), the Quality of Life of Adult Cancer Survivors instrument, the Brief Symptom Inventory, the Pittsburgh Sleep Quality Index, and the Perceived Stress Scale. We conducted structural equation modeling path analyses to investigate how physical activity post-intervention was associated with the quality of life measures' subscales post-intervention, adjusting for baseline levels and potentially confounding covariates.
Increasing physical activity was positively associated with improvements in general health (p = .044), role limitation due to physical health (p = .005), pain (p = .041), and somatic distress (p = .023). There was no evidence to indicate that change in physical activity was associated with change in other aspects of quality of life.
Endometrial cancer survivors are at higher risk for suffering from challenges to physical quality of life, and findings from this study suggest that increasing physical activity may alleviate some of these problems. Further research is needed to determine whether other aspects of quality of life are linked to change in physical activity.
Trial registration number: NCT00501761 Name of registry: clinicaltrials.gov Date of registration: July 16, 2007. Date of enrollment: June 16, 2005.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:Increased circulating myeloid-derived suppressor cells (MDSCs) are independently associated with poor long-term clinical outcomes in sepsis. Studies implicate subsets of MDSCs having ...unique roles in lymphocyte suppression; however, characterization of these cells after sepsis remains incomplete. We performed a pilot study to determine the transcriptomic landscape in MDSC subsets in sepsis using single-cell RNAseq (scRNA-seq).
METHODS:A mixture of whole blood myeloid-enriched and Ficoll-enriched PBMCʼs from two late septic patients on post-sepsis day 21 and two control subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq).
RESULTS:We successfully identified the three MDSC subset clusters – granulocytic (G-), monocytic (M-), and early (E-) MDSCs. Sepsis was associated with a greater relative expansion of G-MDSCs versus M-MDSCs at 21 days as compared to control subjects. Genomic analysis between septic patients and control subjects revealed cell-specific and common differential expression of genes in both G-MDSC and M-MDSC subsets. Many of the common genes have previously been associated with MDSC proliferation and immunosuppressive function. Interestingly, there was no differential expression of several genes demonstrated in the literature to be vital to immunosuppression in cancer-induced MDSC.
CONCLUSION:This pilot study successfully demonstrated that MDSCs maintain a transcriptomic profile that is immunosuppressive in late sepsis. Interestingly, the landscape in chronic critical illness is partially dependent on the original septic insult. Preliminary data would also indicate immunosuppressive MDSCs from late sepsis patients appear to have a somewhat unique transcriptome from cancer and/or other inflammatory diseases.
Two risk variants in the apolipoprotein L1 gene (
) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether
high-risk genotypes are ...associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease.
A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of
high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis.
Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk
genotypes had a significantly increased risk of sepsis (odds ratio OR=1.29 95% CI, 1.00-1.67; p=0.047); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 95% CI, 0.88-1.48; p=0.33), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 95% CI, 0.70-1.39; p=0.95).
high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 95% CI, 1.21-2.22; p=0.001), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk
genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 95% CI, 1.00-1.86; p=0.05) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 95% CI, 0.74-1.81; p=0.52).
high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease.
This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
BACKGROUND:Older adults have worse outcomes after sepsis than young adults. Additionally, alterations of the gut microbiota have been demonstrated to contribute to sepsis-related mortality. We sought ...to determine if there were alterations in the gut microbiota with a novel sepsis model in old adult mice, which enter a state of persistent inflammation, immunosuppression and catabolism (PICS), as compared to young adult mice, which recover with the sepsis model.
METHODS:Mixed sex old (∼20 mo) and young (∼4 mo) C57Bl/6J mice underwent cecal ligation and puncture with daily chronic stress (CLP+DCS) and were compared to naive age-matched controls. Mice were sacrificed at CLP+DCS day 7 and feces collected for bacterial DNA isolation. The V3-V4 hypervariable region was amplified, 16S rRNA gene sequencing performed, and cohorts compared. α-Diversity was assessed using Chao1 and Shannon indices using rarefied counts, and β-diversity was assessed using Bray-Curtis dissimilarity.
RESULTS:Naïve old adult mice had significantly different α and β-diversity compared to naïve adult young adult mice. After CLP+DCS, there was a significant shift in the α and β-diversity (FDR = 0.03 for both) of old adult mice (naïve vs. CLP+DCS). However, no significant shift was displayed in the microbiota of young mice that underwent CLP+DCS in regards to α-diversity (FDR = 0.052) and β-diversity (FDR = 0.12), demonstrating a greater overall stability of their microbiota at 7 days despite the septic insult. The taxonomic changes in old mice undergoing CLP+DCS were dominated by decreased abundance of the order Clostridiales and genera Oscillospira.
CONCLUSION:Young adult mice maintain an overall microbiome stability 7 days after CLP+DCS after compared to old adult mice. The lack of microbiome stability could contribute to PICS and worse long-term outcomes in older adult sepsis survivors. Further studies are warranted to elucidate mechanistic pathways and potential therapeutics.
Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the ...clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGS
) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGS
95%CI, 0.30-0.94, p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio HR = 0.78 0.69-0.88, p = 4.0 × 10
) or immunosuppressant (n = 354, HR = 0.61 0.38-0.99, p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 0.44-0.87, p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
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