Electronic medical records are emerging as a major source of data for clinical and translational research studies, although phenotypes of interest need to be accurately defined first. This article ...provides an overview of how to develop a phenotype algorithm from electronic medical records, incorporating modern informatics and biostatistics methods.
Electronic medical records (EMR) provide a unique opportunity for efficient, large-scale clinical investigation in psychiatry. However, such studies will require development of tools to define ...treatment outcome.
Natural language processing (NLP) was applied to classify notes from 127 504 patients with a billing diagnosis of major depressive disorder, drawn from out-patient psychiatry practices affiliated with multiple, large New England hospitals. Classifications were compared with results using billing data (ICD-9 codes) alone and to a clinical gold standard based on chart review by a panel of senior clinicians. These cross-sectional classifications were then used to define longitudinal treatment outcomes, which were compared with a clinician-rated gold standard.
Models incorporating NLP were superior to those relying on billing data alone for classifying current mood state (area under receiver operating characteristic curve of 0.85-0.88 v. 0.54-0.55). When these cross-sectional visits were integrated to define longitudinal outcomes and incorporate treatment data, 15% of the cohort remitted with a single antidepressant treatment, while 13% were identified as failing to remit despite at least two antidepressant trials. Non-remitting patients were more likely to be non-Caucasian (p<0.001).
The application of bioinformatics tools such as NLP should enable accurate and efficient determination of longitudinal outcomes, enabling existing EMR data to be applied to clinical research, including biomarker investigations. Continued development will be required to better address moderators of outcome such as adherence and co-morbidity.
Summary
Background
Psychiatric co‐morbidity, in particular major depression and anxiety, is common in patients with Crohn's disease (CD) and ulcerative colitis (UC). Prior studies examining this may ...be confounded by the co‐existence of functional bowel symptoms. Limited data exist examining an association between depression or anxiety and disease‐specific endpoints such as bowel surgery.
Aims
To examine the frequency of depression and anxiety (prior to surgery or hospitalisation) in a large multi‐institution electronic medical record (EMR)‐based cohort of CD and UC patients; to define the independent effect of psychiatric co‐morbidity on risk of subsequent surgery or hospitalisation in CD and UC, and to identify the effects of depression and anxiety on healthcare utilisation in our cohort.
Methods
Using a multi‐institution cohort of patients with CD and UC, we identified those who also had co‐existing psychiatric co‐morbidity (major depressive disorder or generalised anxiety). After excluding those diagnosed with such co‐morbidity for the first time following surgery, we used multivariate logistic regression to examine the independent effect of psychiatric co‐morbidity on IBD‐related surgery and hospitalisation. To account for confounding by disease severity, we adjusted for a propensity score estimating likelihood of psychiatric co‐morbidity influenced by severity of disease in our models.
Results
A total of 5405 CD and 5429 UC patients were included in this study; one‐fifth had either major depressive disorder or generalised anxiety. In multivariate analysis, adjusting for potential confounders and the propensity score, presence of mood or anxiety co‐morbidity was associated with a 28% increase in risk of surgery in CD (OR: 1.28, 95% CI: 1.03–1.57), but not UC (OR: 1.01, 95% CI: 0.80–1.28). Psychiatric co‐morbidity was associated with increased healthcare utilisation.
Conclusions
Depressive disorder or generalised anxiety is associated with a modestly increased risk of surgery in patients with Crohn's disease. Interventions addressing this may improve patient outcomes.
Summary
Background
Patients with inflammatory bowel diseases (IBD) have an increased risk of clostridium difficile infection (CDI). Cathelicidins are anti‐microbial peptides that attenuate colitis ...and inhibit the effect of clostridial toxins. Plasma calcifediol 25(OH)D stimulates production of cathelicidins.
Aim
To examine the association between plasma 25(OH)D and CDI in patients with IBD.
Methods
From a multi‐institutional IBD cohort, we identified patients with at least one measured plasma 25(OH)D. Our primary outcome was development of CDI. Multivariate logistic regression models adjusting for potential confounders were used to identify independent effect of plasma 25(OH)D on risk of CDI.
Results
We studied 3188 IBD patients of whom 35 patients developed CDI. Patients with CDI‐IBD were older and had greater co‐morbidity. The mean plasma 25(OH)D level was significantly lower in patients who developed CDI (20.4 ng/mL) compared to non‐CDI‐IBD patients (27.1 ng/mL) (P = 0.002). On multivariate analysis, each 1 ng/mL increase in plasma 25(OH)D was associated with a 4% reduction in risk of CDI (OR 0.96, 95% CI 0.93–0.99, P = 0.046). Compared to individuals with vitamin D >20 ng/mL, patients with levels <20 ng/mL were more likely to develop CDI (OR 2.27, 95% CI 1.16–4.44). The mean plasma 25(OH)D in patients with CDI who subsequently died was significantly lower (12.8 ± 8.1 ng/mL) compared to those who were alive at the end of follow‐up (24.3 ± 13.2 ng/mL) (P = 0.01).
Conclusions
Higher plasma calcifediol 25(OH)D is associated with reduced risk of C. difficile infection in patients with IBD. Further studies of therapeutic supplementation of vitamin D in patients with inflammatory bowel disease and C. difficile infection may be warranted.
Summary
Background
Infections are an important concern in patients using immunosuppressive therapy for their inflammatory bowel disease (IBD). Diabetes affects nearly 10% of Americans. Whether it ...confers an additional risk with immunosuppression in IBD has not been examined previously.
Aim
To examine the association between diabetes and infections with immunomodulator use in IBD
Methods
Using a validated, multi‐institutional IBD cohort, we identified all patients who received at least one prescription for immunomodulators (thiopurines, methotrexate). Our primary outcome was infection within 1 year of the prescription of the immunomodulator. Multivariable logistic regression adjusting for relevant confounders was used to estimate the independent association with diabetes.
Results
Our study included 2766 patients receiving at least one prescription for immunomodulators among whom 210 (8%) developed an infection within 1 year. Patients who developed an infection were likely to be older, have more comorbidities, more likely to have received a prescription for steroids but similar in initiation of anti‐TNF therapy within that year. Only 8% of those without an infection had diabetes compared to 19% of those who developed an infection within 1 year odds ratio (OR) 2.74, 95% confidence interval (CI) 1.88–3.98, P < 0.001. On multivariate analysis, diabetes was independently associated with a nearly two‐fold increase in risk of infections (OR: 1.80, 95% CI: 1.20–2.68). There was no increase in risk of infections with addition of anti‐TNF therapy (OR: 1.14, 95% CI: 0.80–1.63).
Conclusion
Diabetes is an independent risk factor for infection in IBD patients using immunomodulator therapy.
Objective To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse ...clinical population.Design A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity. Setting A large New England healthcare system comprising two academic medical centres and outpatient clinics.Participants 38 397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011.Main outcome measures Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined.Results Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01).Conclusions This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments.
The primary objective of this cross-sectional study was to examine the association between time spent treating patients with Coronavirus disease 2019 (COVID-19) and levels of depression, anxiety, and ...posttraumatic stress disorder (PTSD) in US physicians.
The authors conducted an anonymous online survey of US physicians. Linear regression was used to test the association between proportion of day treating COVID-19 and symptoms of depression, anxiety, and PTSD.
In a sample of 1724 US physicians, proportion of day treating COVID-19 was positively and significantly associated with depression, anxiety, and PTSD scores (P < 0.001 for each).
Mental health resources should be provided to physicians who treat COVID-19 because the proportion of day treating COVID-19 is associated with depression, anxiety, and PTSD outcomes.
Angiotensin-converting-enzyme (ACE) inhibitors not only decrease the production of angiotensin II but also decrease the degradation of bradykinin. In this study, a specific bradykinin-receptor ...antagonist, icatibant acetate (HOE 140), was used to determine the contribution of bradykinin to the short-term effects of ACE inhibition on blood pressure and plasma renin activity in both normotensive and hypertensive subjects.
We compared the hemodynamic, renal, and endocrine effects of captopril alone (25 mg), captopril plus icatibant (100 microg per kilogram of body weight), the angiotensin II subtype 1-receptor antagonist losartan (75 mg), and placebo in 20 subjects with normal blood pressure and 7 subjects with hypertension. The subjects were studied while they were salt depleted (i.e., in balance on a diet in which they were allowed 10 mmol of sodium per day). The drugs were administered on four separate study days in a single-blind, randomized fashion.
The coadministration of icatibant significantly attenuated the hypotensive effect of captopril (maximal decrease in mean arterial pressure for all subjects combined, 10.5+/-1.0 mm Hg, as compared with 14.0+/-1.0 mm Hg for captopril alone; P=0.001), in such a way that the decrease in blood pressure after the administration of captopril plus icatibant was similar to that after the administration of losartan (maximal decrease in mean arterial pressure, 11.0+/-1.7 mm Hg). Icatibant did not alter the renal hemodynamic response to captopril, but it significantly altered the change in plasma renin activity in response to ACE inhibition (-0.4+/-0.4 ng of angiotensin I per milliliter per hour, as compared with 2.0+/-0.7 ng per milliliter per hour for captopril alone; P=0.007). The magnitude of these effects was similar in both the normotensive and the hypertensive subjects, as well as in both the black subjects and the white subjects.
These data confirm that bradykinin contributes to the short-term effects of ACE inhibition on blood pressure in normotensive and hypertensive persons and suggest that bradykinin also contributes to the short-term effects of ACE inhibition on the renin-angiotensin system.
Informatics for Integrating Biology and the Bedside (i2b2) is one of seven projects sponsored by the NIH Roadmap National Centers for Biomedical Computing (http://www.ncbcs.org). Its mission is to ...provide clinical investigators with the tools necessary to integrate medical record and clinical research data in the genomics age, a software suite to construct and integrate the modern clinical research chart. i2b2 software may be used by an enterprise's research community to find sets of interesting patients from electronic patient medical record data, while preserving patient privacy through a query tool interface. Project-specific mini-databases ("data marts") can be created from these sets to make highly detailed data available on these specific patients to the investigators on the i2b2 platform, as reviewed and restricted by the Institutional Review Board. The current version of this software has been released into the public domain and is available at the URL: http://www.i2b2.org/software.
The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of ...anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1
activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1
T cells versus PD-1
T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4
. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1
T cells. SIGNIFICANCE: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1
T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.
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