Enhancing reproducibility of gene expression analysis with known protein functional relationships: The concept of well-associated protein.

Identification of differentially expressed genes (DEGs) is well recognized to be variable across independent replications of genome-wide transcriptional studies. These are often employed to characterize disease state early in the process of discovery and prioritize novel targets aimed at addressing unmet medical need. Increasing reproducibility of biological findings from these studies could potentially positively impact the success rate of new clinical interventions. This work demonstrates that statistically sound combination of gene expression data with prior knowledge about biology in the form of large protein interaction networks can yield quantitatively more reproducible observations from studies characterizing human disease. The novel concept of Well-Associated Proteins (WAPs) introduced herein-gene products significantly associated on protein interaction networks with the differences in transcript levels between control and disease-does not require choosing a differential expression threshold and can be computed efficiently enough to enable false discovery rate estimation via permutation. Reproducibility of WAPs is shown to be on average superior to that of DEGs under easily-quantifiable conditions suggesting that they can yield a significantly more robust description of disease. Enhanced reproducibility of WAPs versus DEGs is first demonstrated with four independent data sets focused on systemic sclerosis. This finding is then validated over thousands of pairs of data sets obtained by random partitions of large studies in several other diseases. Conditions that individual data sets must satisfy to yield robust WAP scores are examined. Reproducible identification of WAPs can potentially benefit drug target selection and precision medicine studies.

M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model.

BACKGROUND: The transfer of pathogenic immunoglobulin G antibodies from mother to fetus is a critical step in the pathophysiology of alloimmune and autoimmune diseases of the fetus and neonate. Immunoglobulin G transfer across the human placenta to the fetus is mediated by the neonatal Fc receptor, and blockade of the neonatal Fc receptor may provide a therapeutic strategy to prevent or minimize pathological events associated with immune-mediated diseases of pregnancy. M281 is a fully human, aglycosylated monoclonal immunoglobulin G1 antineonatal Fc receptor antibody that has been shown to block the neonatal Fc receptor with high affinity in nonclinical studies and in a phase 1 study in healthy volunteers. OBJECTIVE: The objective of the study was to determine the transplacental transfer of M281 and its potential to inhibit transfer of immunoglobulin G from maternal to fetal circulation. STUDY DESIGN: To determine the concentration of M281 required for rapid cellular uptake and complete saturation of the neonatal Fc receptor in placental trophoblasts, primary human villous trophoblasts were incubated with various concentrations of M281 in a receptor occupancy assay. The placental transfer of M281, immunoglobulin G, and immunoglobulin G in the presence of M281 was studied using the dually perfused human placental lobule model. Immunoglobulin G transfer was established using a representative immunoglobulin G molecule, adalimumab, a human immunoglobulin G1 monoclonal antibody, at a concentration of 270 µg/mL. Inhibition of immunoglobulin G transfer by M281 was determined by cotransfusing 270 µg/mL of adalimumab with 10 µg/mL or 300 µg/mL of M281. Concentrations of adalimumab and M281 in sample aliquots from maternal and fetal circuits were analyzed using a sandwich enzyme-linked immunosorbent assay and Meso Scale Discovery assay, respectively. RESULTS: In primary human villous trophoblasts, the saturation of the neonatal Fc receptor by M281 was observed within 30-60 minutes at 0.15-5.0 µg/mL, suggesting rapid blockade of neonatal Fc receptor in placental cells. The transfer rate of adalimumab (0.23% ± 0.21%) across dually perfused human placental lobule was significantly decreased by 10 µg/mL and 300 µg/mL of M281 to 0.07 ± 0.01% and 0.06 ± 0.01%, respectively. Furthermore, the transfer rate of M281 was 0.002% ± 0.02%, approximately 100-fold lower than that of adalimumab. CONCLUSION: The significant inhibition of immunoglobulin G transfer across the human placental lobule by M281 and the minimal transfer of M281 supports the development of M281 as a novel agent for the treatment of fetal and neonatal diseases caused by transplacental transfer of alloimmune and autoimmune pathogenic immunoglobulin G antibodies.

Detection of Delirium in Hospitalized Older General Medicine Patients: A Comparison of the 3D-CAM and CAM-ICU.

BACKGROUND: Delirium is common in older hospitalized patients and is associated with poor outcomes, yet most cases go undetected. The best approach for systematic delirium identification outside the intensive care unit remains unknown. OBJECTIVE: To conduct a comparative effectiveness study of the Confusion Assessment Method for the ICU (CAM-ICU) and the newly developed 3-minute diagnostic assessment for delirium using the Confusion Assessment Method (3D-CAM) in general medicine inpatients. DESIGN: Cross-sectional comparative effectiveness study. SETTING: Two non-intensive care general medicine units at a single academic medical center. PARTICIPANTS: Hospitalized general medicine patients aged ≥75 years. MEASUREMENTS: Clinicians performed a reference standard assessment for delirium that included patient interviews, family interviews, and review of the medical record. An expert panel determined the presence or absence of delirium using DSM-IV criteria. Two blinded research assistants administered the CAM-ICU and the 3D-CAM in random order, and we determined their diagnostic test characteristics compared to the reference standard. RESULTS: Among the 101 participants (mean age 84 ± 5.5 years, 61 % women, 25 % with dementia), 19 % were classified as delirious based on the reference standard. Evaluation times for the 3D-CAM and CAM-ICU were similar. The sensitivity [95 % confidence interval (CI)] of delirium detection for the 3D-CAM was 95 % [74 %, 100 %] and for the CAM-ICU was 53 % [29 %, 76 %], while specificity was >90 % for both instruments. Subgroup analyses showed that the CAM-ICU had sensitivity of 30 % in patients with mild delirium vs. 100 % for the 3D-CAM. CONCLUSIONS: In this comparative effectiveness study, we found that the 3D-CAM had substantially higher sensitivity than the CAM-ICU in hospitalized older general medicine patients, and similar administration time. Therefore, the 3D-CAM may be a superior screening tool for delirium in this patient population.

Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions.

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

Plasma proteomics reveals tissue-specific cell death and mediators of cell-cell interactions in severe COVID-19 patients.

COVID-19 has caused over 1 million deaths globally, yet the cellular mechanisms underlying severe disease remain poorly understood. By analyzing several thousand plasma proteins in 306 COVID-19 patients and 78 symptomatic controls over serial timepoints using two complementary approaches, we uncover COVID-19 host immune and non-immune proteins not previously linked to this disease. Integration of plasma proteomics with nine published scRNAseq datasets shows that SARS-CoV-2 infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins. By comparing patients who died to severely ill patients who survived, we identify dynamic immunomodulatory and tissue-associated proteins associated with survival, providing insights into which host responses are beneficial and which are detrimental to survival. We identify intracellular death signatures from specific tissues and cell types, and by associating these with angiotensin converting enzyme 2 (ACE2) expression, we map tissue damage associated with severe disease and propose which damage results from direct viral infection rather than from indirect effects of illness. We find that disease severity in lung tissue is driven by myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells. Based on these results, we propose a model of immune and epithelial cell interactions that drive cell-type specific and tissue-specific damage in severe COVID-19.

Necuparanib, A Multitargeting Heparan Sulfate Mimetic, Targets Tumor and Stromal Compartments in Pancreatic Cancer.

Pancreatic cancer has an abysmal 5-year survival rate of 8%, making it a deadly disease with a need for novel therapies. Here we describe a multitargeting heparin-based mimetic, necuparanib, and its antitumor activity in both in vitro and in vivo models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a three-dimensional (3D) culture model; in vivo, it extended survival and reduced metastasis. Furthermore, proteomic analysis demonstrated that necuparanib altered the expression levels of multiple proteins involved in cancer-driving pathways including organ development, angiogenesis, proliferation, genomic stability, cellular energetics, and invasion and metastasis. One protein family known to be involved in invasion and metastasis and altered by necuparanib treatment was the matrix metalloprotease (MMP) family. Necuparanib reduced metalloproteinase 1 (MMP1) and increased tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels and was found to increase RNA expression of TIMP3. MMP enzymatic activity was also found to be reduced in the 3D model. Finally, we confirmed necuparanib's in vivo activity by analyzing plasma samples of patients enrolled in a phase I/II study in patients with metastatic pancreatic cancer; treatment with necuparanib plus standard of care significantly increased TIMP3 plasma protein levels. Together, these results demonstrate necuparanib acts as a broad multitargeting therapeutic with in vitro and in vivo anti-invasive and antimetastatic activity.

Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor.

BACKGROUND: The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA). METHODS: Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database. RESULTS: A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p < 0.01) between the two cohorts. A baseline, response signature of increased innate cell types in responders compared to increased adaptive cell types in non-responders was identified in both cohorts. This result was further assessed by applying the cell type-specific analysis to five other publicly available RA datasets. Evaluation of the neutrophil-to-lymphocyte ratio at baseline in the remaining patients (n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03-1.41, p = 0.02]). CONCLUSION: Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

Circulating Markers of Inflammation Persist in Children and Adults With Giant Aneurysms After Kawasaki Disease.

BACKGROUND: The sequelae of Kawasaki disease (KD) vary widely with the greatest risk for future cardiovascular events among those who develop giant coronary artery aneurysms (CAA). We sought to define the molecular signature associated with different outcomes in pediatric and adult KD patients. METHODS: Molecular profiling was conducted using mass spectrometry-based shotgun proteomics, transcriptomics, and glycomics methods on 8 pediatric KD patients at the acute, subacute, and convalescent time points. Shotgun proteomics was performed on 9 KD adults with giant CAA and matched healthy controls. Plasma calprotectin was measured by ELISA in 28 pediatric KD patients 1 year post-KD, 70 adult KD patients, and 86 healthy adult volunteers. RESULTS: A characteristic molecular profile was seen in pediatric patients during the acute disease, which resolved at the subacute and convalescent periods in patients with no coronary artery sequelae but persisted in 2 patients who developed giant CAA. We, therefore, investigated persistence of inflammation in KD adults with giant CAA by shotgun proteomics that revealed a signature of active inflammation, immune regulation, and cell trafficking. Correlating results obtained using shotgun proteomics in the pediatric and adult KD cohorts identified elevated calprotectin levels in the plasma of patients with CAA. Investigation of expanded pediatric and adult KD cohorts revealed elevated levels of calprotectin in pediatric patients with giant CAA 1 year post-KD and in adult KD patients who developed giant CAA in childhood. CONCLUSIONS: Complex patterns of biomarkers of inflammation and cell trafficking can persist long after the acute phase of KD in patients with giant CAA. Elevated levels of plasma calprotectin months to decades after acute KD and infiltration of cells expressing S100A8 and A9 in vascular tissues suggest ongoing, subclinical inflammation. Calprotectin may serve as a biomarker to inform the management of KD patients following the acute illness.

Antipsychotic medication utilization in nonpsychiatric hospitalizations.

BACKGROUND: Although antipsychotics are used for treatment of delirium/agitation in hospitalized patients, their scope of use has not been investigated in a large, multicenter cohort. OBJECTIVE: To determine rates of use and hospital variation in use of antipsychotics in nonpsychiatric admissions. DESIGN, SETTING, PATIENTS: Cohort study of adult, nonpsychiatric admissions to 300 US hospitals contributing data to the Premier database, from July 1, 2009 to June 30, 2010. MEASUREMENTS: Antipsychotic exposure defined using pharmacy charges. Potentially excessive dosing defined using guidelines for long-term care facilities. RESULTS: Our cohort included 2,695,081 admissions (median age, 63 years; 56% female). Antipsychotic exposure occurred in 160,773 (6%) admissions; 102,148 (64%) received atypical antipsychotics, 76,979 (48%) received typical, and 18,354 (11%) received both. Among exposed admissions, 47% received ≥1 potentially excessive daily dose. Among the variables we analyzed, the strongest predictors of antipsychotic receipt were delirium (relative risk [RR]: 2.93, 95% CI: 2.88-2.98) and dementia (RR: 2.78, 95% CI: 2.72-2.83). After adjustment for patient characteristics, patients admitted to hospitals in the highest antipsychotic prescribing quintile were more than twice as likely to be exposed compared to patients admitted to hospitals in the lowest prescribing quintile (RR: 2.56, 95% CI: 2.50-2.61). This relationship was similar across subgroups of admissions with delirium and dementia. CONCLUSIONS: Antipsychotic medication exposure is common in nonpsychiatric admissions to US hospitals. The observed variation in antipsychotic prescribing was not fully explained by measured patient characteristics, suggesting the possibility of differing hospital prescribing cultures. Additional research and guidelines are necessary to define appropriate use of these potentially harmful medications in the hospital setting. Journal of Hospital Medicine 2016;11:543-549. © 2016 Society of Hospital Medicine.

Antipsychotic Use in Hospitalized Adults: Rates, Indications, and Predictors.

OBJECTIVES: To investigate patterns and predictors of use of antipsychotics in hospitalized adults. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PARTICIPANTS: Individuals aged 18 and older hospitalized from August 2012 to August 2013, excluding those admitted to obstetrics and gynecology or psychiatry or with a psychotic disorder. MEASUREMENTS: Use was ascertained from pharmacy charges. Potentially excessive dosing was defined using guidelines for long-term care facilities. A review of 100 records was performed to determine reasons for use. RESULTS: The cohort included 17,775 admissions with a median age 64; individuals could have been admitted more than once during the study period. Antipsychotics were used in 9%, 55% of which were initiations. The most common reasons for initiation were delirium (53%) and probable delirium (12%). Potentially excessive dosing occurred in 16% of admissions exposed to an antipsychotic. Of admissions with antipsychotic initiation, 26% were discharged on these medications. Characteristics associated with initiation included age 75 and older (relative risk (RR) = 1.4, 95% confidence interval (CI) = 1.2-1.7), male sex (RR = 1.2, 95% CI = 1.1-1.4), black race (RR = 0.8, 95% CI = 0.6-0.96), delirium (RR = 4.8, 95% CI = 4.2-5.7), dementia (RR = 2.1, 95% CI = 1.7-2.6), admission to a medical service (RR = 1.2, 95% CI = 1.1-1.4), intensive care unit stay (RR = 2.1, 95% CI = 1.8-2.4), and mechanical ventilation (RR = 2.0, 95% CI = 1.7-2.4). In individuals who were initiated on an antipsychotic, characteristics associated with discharge on antipsychotics were age 75 and older (RR = 0.6, 95% CI = 0.4-0.7), discharge to any location other than home (RR = 2.5, 95% CI = 1.8-3.3), and class of in-hospital antipsychotic exposure (RR = 1.6, 95% CI = 1.1-2.3 for atypical vs typical; RR = 2.7, 95% CI = 1.9-3.8 for both vs typical). CONCLUSION: Antipsychotic initiation and use were common during hospitalization, most often for delirium, and individuals were frequently discharged on these medications. Several predictors of use on discharge were identified, suggesting potential targets for decision support tools that would be used to prompt consideration of ongoing necessity.

Derivation and Validation of a Severity Scoring Method for the 3-Minute Diagnostic Interview for Confusion Assessment Method--Defined Delirium.

OBJECTIVES: To derive and validate a method for scoring delirium severity using a recently validated, brief, structured diagnostic interview for Confusion Assessment Method (CAM)-defined delirium (3D-CAM) and to demonstrate its agreement with the CAM Severity short form (CAM-S SF) as the reference standard. DESIGN: Derivation and validation analysis in a prospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Individuals aged 70 and older enrolled in the Successful Aging after Elective Surgery Study undergoing major elective noncardiac surgery (N = 566). MEASUREMENTS: The sample was randomly divided into a derivation dataset (n = 377) and an independent validation dataset (n = 189). These datasets were used to develop a severity scoring method using the 3D-CAM based on the four-item CAM-S SF (3D-CAM-S) and evaluate agreement between the 3D-CAM-S and the traditional CAM-S SF using weighted kappa statistics. RESULTS: A method for scoring severity using 3D-CAM items was developed that achieved good agreement with the CAM-S SF in the derivation dataset (κ = 0.94, 95% confidence interval (CI) = 0.93-0.95). The 3D-CAM-S achieved nearly identical agreement in the independent validation dataset (κ = 0.93, 95% CI = 0.92-0.95), and 100% of 3D-CAM-S scores were within 1 point of the CAM-S SF score in both datasets. The 3D-CAM-S also strongly predicts clinical outcomes. CONCLUSION: A newly developed method for scoring delirium severity using the 3D-CAM (the 3D-CAM-S) has excellent agreement with the CAM-S SF. This new methodology enables clinicians and researchers using the 3D-CAM for surveillance to measure delirium severity and monitor its course simultaneously by tracking changes over time. The 3D-CAM-S expands the utility of the 3D-CAM as an important tool for delirium recognition and management.

Comparison of Frailty Measures as Predictors of Outcomes After Orthopedic Surgery.

OBJECTIVES: To apply the Frailty Phenotype (FP) and Frailty Index (FI) before major elective orthopedic surgery to categorize frailty status and assess associations with postoperative outcomes. DESIGN: Prospective cohort study. SETTING: Two tertiary hospitals in Boston, Massachusetts. PARTICIPANTS: Individuals aged 70 and older undergoing scheduled orthopedic surgery enrolled in the Successful Aging after Elective Surgery (SAGES) Study (N = 415). MEASUREMENTS: Preoperative evaluation included assessment of frailty using the FP and FI. The weighted kappa statistic was used to determine concordance between the two frailty measures and multivariable modeling to determine associations between each measure and postoperative complications, postoperative length of stay (LOS) of longer than 5 days, discharge to postacute institutional care (PAC), and 300 day readmission. RESULTS: Frailty was highly prevalent (FP, 35%; FI, 41%). There was moderate concordance between the FP and FI (κ = 0.42, 95% confidence interval (CI) 0.36-0.49). When using the FP, being prefrail predicted greater risk of complications (relative risk (RR) = 1.6, 95% CI = 1.1-2.1) and discharge to PAC (RR = 1.8, 95% CI = 1.2-2.9) than being robust, and being frail predicted more complications (RR = 1.7, 95% CI = 1.1-2.1), LOS longer than 5 days (RR = 3.1, 95% CI = 1.1-8.8), and discharge to PAC (RR = 2.3 95% CI = 1.4-3.7). When using FI, being prefrail predicted LOS longer than 5 days (RR = 2.1, 95% CI = 1.0-4.8) and discharge to PAC (RR = 1.5, 95% CI = 1.4-2.1), as did being frail (RR = 1.9, 95% CI = 1.4-2.5; RR = 3.1, 95% CI = 1.4-6.8, respectively). The other outcomes were not significantly associated with frailty status. CONCLUSION: FP and FI predict postoperative outcomes after major elective orthopedic surgery and should be considered for preoperative risk stratification.

The Montreal Cognitive Assessment: Creating a Crosswalk with the Mini-Mental State Examination.

OBJECTIVES: To establish Montreal Cognitive Assessment (MoCA) scores that correspond to well-established cut-points on the Mini-Mental State Examination (MMSE). DESIGN: Cross-sectional observational study. SETTING: General medical service of a large teaching hospital. PARTICIPANTS: Individuals aged 75 and older (N = 199; mean age 84, 63% female). MEASUREMENTS: The MoCA (range 0-30) and the MMSE (range 0-30) were administered within 2 hours of each other. The Abbreviated MoCA (A-MoCA; range 0-22) was calculated from the full MoCA. Scores from the three tests were analyzed using equipercentile equating, a statistical method for determining comparable scores on different tests of a similar construct by estimating percentile equivalents. RESULTS: MoCA scores were lower (mean 19.3 ± 5.8) than MMSE scored (mean 24.1 ± 6.6). Traditional MMSE cut-points of 27 for mild cognitive impairment and 23 for dementia corresponded to MoCA scores of 23 and 17, respectively. CONCLUSION: Scores on the full and abbreviated versions of the MoCA can be linked directly to the MMSE. The MoCA may be more sensitive to changes in cognitive performance at higher levels of functioning.

Preliminary development of an ultrabrief two-item bedside test for delirium.

BACKGROUND: Delirium is common, morbid, and costly, yet is greatly under-recognized among hospitalized older adults. OBJECTIVE: To identify the best single and pair of mental status test items that predict the presence of delirium. DESIGN, SETTING: Diagnostic test evaluation study that enrolled medicine inpatients aged 75 years or older at an academic medical center. METHODS: Patients underwent a clinical reference standard assessment involving a patient interview, medical record review, and interviews with family members and nurses to determine the presence or absence of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition defined delirium. Participants also underwent the three-dimensional Confusion Assessment Method (3D-CAM), a brief, validated assessment for delirium. Individual items and pairs of items from the 3D-CAM were evaluated to determine sensitivity and specificity relative to the reference standard delirium diagnosis. RESULTS: Of the 201 participants (mean age 84 years, 62% female), 42 (21%) had delirium based on the clinical reference standard. The single item with the best test characteristics was "months of the year backwards" with a sensitivity of 83% (95% confidence interval [CI]: 69%-93%) and specificity of 69% (95% CI: 61%-76%). The best 2-item screen was the combination of "months of the year backwards" and "what is the day of the week?" with a sensitivity of 93% (95% CI: 81%-99%) and specificity of 64% (95% CI: 56%-70%). CONCLUSIONS: We identified a single item with >80% and pair of items with >90% sensitivity for delirium. If validated prospectively, these items will serve as an initial innovative screening step for delirium identification in hospitalized older adults.

Improving appropriateness of acid-suppressive medication use via computerized clinical decision support.

As part of the Choosing Wisely Campaign, the Society of Hospital Medicine identified reducing inappropriate use of acid-suppressive medication for stress ulcer prophylaxis as 1 of 5 key opportunities to improve the value of care for hospitalized patients. We designed a computerized clinical decision support intervention to reduce use of acid-suppressive medication for stress ulcer prophylaxis in hospitalized patients outside of the intensive care unit at an academic medical center. Using quasiexperimental interrupted time series analysis, we found that the decision support intervention resulted in a significant reduction in use of acid-suppressive medication with stress ulcer prophylaxis selected as the only indication, a nonsignificant reduction in overall use, and no change in use on discharge. We found low rates of use of acid-suppressive medication for the purpose of stress ulcer prophylaxis even before the intervention, and continuing preadmission medication was the most commonly selected indication throughout the study. Our results suggest that attention should be focused on both the inpatient and outpatient settings when designing future initiatives to improve the appropriateness of acid-suppressive medication use.

Cytokines and Postoperative Delirium in Older Patients Undergoing Major Elective Surgery.

BACKGROUND: A proinflammatory state has been associated with several age-associated conditions; however, the inflammatory mechanisms of delirium remain poorly characterized. METHODS: Using the Successful Aging after Elective Surgery Study of adults age ≥70 undergoing major noncardiac surgery, 12 cytokines were measured at four timepoints: preoperative, postanesthesia care unit, postoperative day 2 (POD2) and 30 days later (POD1M). We conducted a nested, longitudinal matched (on age, sex, surgery type, baseline cognition, vascular comorbidity, and Apolipoprotein E genotype) case-control study: delirium cases and no-delirium controls were selected from the overall cohort (N = 566; 24% delirium). Analyses were independently conducted in discovery, replication, and pooled cohorts (39, 36, 75 matched pairs, respectively). Nonparametric signed-rank tests evaluating differences in cytokine levels between matched pairs were used to identify delirium-associated cytokines. RESULTS: In the discovery and replication cohorts, matching variables were similar in cases and controls. Compared to controls, cases had (*p < .05, **p < .01) significantly higher interleukin-6 on POD2 in the discovery, replication, and pooled cohorts (median difference [pg/mL] 50.44**, 20.17*, 39.35**, respectively). In the pooled cohort, cases were higher than controls for interleukin-2 (0.99*, 0.77*, 1.07**, 0.73* at preoperative, postanesthesia care unit, POD2, POD1M, respectively), vascular endothelial growth factor (4.10* at POD2), and tumor necrosis factor-alpha (3.10* at POD1M), while cases had lower interleukin-12 at POD1M (-4.24*). CONCLUSIONS: In this large, well-characterized cohort assessed at multiple timepoints, we observed an inflammatory signature of delirium involving elevated interleukin-6 at POD2, which may be an important disease marker for delirium. We also observed preliminary evidence for involvement of other cytokines.