Using Artificial Intelligence With Natural Language Processing to Combine Electronic Health Record's Structured and Free Text Data to Identify Nonvalvular Atrial Fibrillation to Decrease Strokes and Death: Evaluation and Case-Control Study.

BACKGROUND: Nonvalvular atrial fibrillation (NVAF) affects almost 6 million Americans and is a major contributor to stroke but is significantly undiagnosed and undertreated despite explicit guidelines for oral anticoagulation. OBJECTIVE: The aim of this study is to investigate whether the use of semisupervised natural language processing (NLP) of electronic health record's (EHR) free-text information combined with structured EHR data improves NVAF discovery and treatment and perhaps offers a method to prevent thousands of deaths and save billions of dollars. METHODS: We abstracted 96,681 participants from the University of Buffalo faculty practice's EHR. NLP was used to index the notes and compare the ability to identify NVAF, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, sex category (CHA2DS2-VASc), and Hypertension, Abnormal liver/renal function, Stroke history, Bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage (HAS-BLED) scores using unstructured data (International Classification of Diseases codes) versus structured and unstructured data from clinical notes. In addition, we analyzed data from 63,296,120 participants in the Optum and Truven databases to determine the NVAF frequency, rates of CHA2DS2­VASc ≥2, and no contraindications to oral anticoagulants, rates of stroke and death in the untreated population, and first year's costs after stroke. RESULTS: The structured-plus-unstructured method would have identified 3,976,056 additional true NVAF cases (P<.001) and improved sensitivity for CHA2DS2-VASc and HAS-BLED scores compared with the structured data alone (P=.002 and P<.001, respectively), causing a 32.1% improvement. For the United States, this method would prevent an estimated 176,537 strokes, save 10,575 lives, and save >US $13.5 billion. CONCLUSIONS: Artificial intelligence-informed bio-surveillance combining NLP of free-text information with structured EHR data improves data completeness, prevents thousands of strokes, and saves lives and funds. This method is applicable to many disorders with profound public health consequences.

National Physician Survey for Nonvalvular Atrial Fibrillation (NVAF) Anticoagulation Comparing Knowledge, Attitudes and Practice of Cardiologist to PCPs.

INTRODUCTION: NVAF is estimated to affect between 6.4 and 7.4 million Americans in 2018, and increases the risk of stroke 5-fold. To mitigate this risk, guidelines recommend anticoagulating AF patients unless their stroke risk is very low. Despite these recommendations, 30.0-60.0% of NVAF patients do not receive indicated anticoagulation. To better understand why this may be, we surveyed PCPs and cardiologists nationwide on their attitudes, knowledge and practices toward managing NVAF with warfarin and direct-acting oral anticoagulants (DOACs). METHODS: We surveyed 1,000 PCPs and 500 cardiologists selected randomly from a master list of the American Medical Association, using a paper based, anonymous, self-administered, mailed scannable survey. The survey contained questions on key demographics and data concerning attitudes, knowledge and practices related to prescribing DOACs. The surveys went out in the fall/winter of 2017-8 with a $10 incentive gift card. Survey responses were scanned into an Excel database and analyzed using SAS 9.3 (Cary, NC) for descriptive and inferential statistics. RESULTS: Two hundred and forty-nine providers (167 PCPs, 82 cardiologists) participated in the study with a response rate of 18.8% (249/1320). Respondent mean years ±SD of experience since completing residency was 23.2 ± 13.8. Relative to cardiologists, less PCPs use CHADsVASC (36.8% vs. 74.4%) (p < 0.0001); more have never used HAS-BLED, HEMORR2HAGES, or ATRIA (38.5% vs. 9.8%) (p < .0001); more felt that their lack of knowledge/experience with DOACs was a barrier to prescribing the agents (p = 0.005); and more reported that they could use additional education on DOACs (87.0% vs. 47.0%) (p < 0.0001). Overall, cardiologists were more concerned about ischemic stroke outcomes, while PCPs were more concerned with GI bleeding. Cardiologists also felt that clinical trial data were most helpful in choosing the most appropriate DOAC for their patients, while PCPs felt that Real World Data was most useful. CONCLUSIONS: Cardiologists were more concerned with ischemic stroke while anticoagulating patients and utilized screening instruments like CHADsVASC in a majority of their patients. PCPs were concerned with GI bleeds when anticoagulating but nearly 40.0% utilized no screening tools to assess bleeding risk. Our findings show that future education about DOACs would be warranted especially with PCPs.

Mobile App Usage Patterns of Patients Prescribed a Smoking Cessation Medicine: Prospective Observational Study.

BACKGROUND: Cigarette smoking is the leading preventable cause of death and is responsible for more than 480,000 deaths per year in the United States. Smoking cessation is challenging for many patients. Regardless of available treatment options, most quit attempts are unaided, and it takes multiple attempts before a patient is successful. With the ever-increasing use of smartphones, mobile apps hold promise in supporting cessation efforts. This study evaluates the ease of use and user satisfaction with the Pfizer Meds app to support smoking cessation among patients prescribed varenicline (Chantix). OBJECTIVE: Study participants included varenicline users who downloaded and used the app on their personal smartphone. The main objectives were to report mobile app download frequency and usage details and to describe the participant-reported satisfaction with and usefulness of the app over the 14-week follow-up study period. METHODS: Adults aged 18 years or older who had been prescribed varenicline were identified from the Express Scripts Incorporated pharmacy claims database. After meeting privacy restrictions, subjects were sent an invitation letter and second reminder letter with instructions on how to download the Pfizer Meds mobile app. Participants received a push notification to complete a smartphone-enabled survey regarding the utility of the app 12 weeks after downloading the app. Descriptive statistics summarized sociodemographics, use of varenicline, and details of use and satisfaction with the mobile app. RESULTS: Of the 38,129 varenicline users who were sent invitation letters, 1281 participants (3.35%) downloaded the Pfizer Meds app. Of the 1032 users with demographic and other data, 585 (56.68%) were females, and 446 (43.22%) were males; mean age was 46.4 years (SD 10.8). The mean number of app sessions per participant was 4.0 (SD 6.8). The end-of-study survey was completed by 131 survey respondents (10.23%, 131/1281); a large number of participants (117/131, 89.3%) reported being extremely, very, or moderately satisfied with the app. A total of 97 survey respondents (97/131, 74.0%) reported setting up a quit date in the app. Of those, 74 (74/97, 76%) reported quitting on their quit date. CONCLUSIONS: Positive patient engagement was observed in this study based on app download and usage. This study quantified how the Pfizer Meds app performed in an observational real-world data setting. The findings demonstrate the willingness of participants to set a quit date and use the app for support in medication adherence, refill reminders, and information regarding how to take the medication. This study provides real-world evidence of the contribution apps can make to the continued encouragement of smokers to improve their health by smoking cessation.

Rapid assessment of tetanus vaccine-induced immunity in Bangladesh and the Gambia.

We have developed recombinant fragment C based rapid point of care dipstick devices to assess tetanus immunization status using plasma or whole blood. The devices demonstrated specificity of 0.90 and sensitivity of 0.90 (whole blood)/0.94 (plasma) at field sites in Bangladesh and The Gambia when compared to a commercial ELISA with the immune cut-off titer set as ≥0.1IU/mL.

Tracking low back problems in a major self-insured workforce: toward improvement in the patient's journey.

OBJECTIVE: To assess the cost outcomes of treatment approaches to care for back problems in a major self-insured workforce, using published guidelines to focus on low back pain. METHODS: Longitudinally tracked episodes of three types of International Classification of Diseases, Ninth Revision diagnosis code-identified back problems (n=14,787) during 2001 to 2009. Identified five patterns of care on the basis of the first 6 weeks of claims and compared their total costs per episode with tests that included splits by episode type and duration, use of guidelines, and propensity-derived adjustments. RESULTS: Care congruent with 10 of 11 guidelines was linked to lower total costs. Of the five patterns, complex medical management and chiropractic reported the highest and lowest rates, respectively, of guideline-incongruent use of imaging, surgeries, and medications, and the highest and lowest total costs. CONCLUSIONS: Approaches marked by higher resource utilization and lower guideline congruence are linked to greater low back pain total costs. Total cost is a needed input for guideline development.

Cell membranes and apoptosis: role of cardiolipin, phosphatidylcholine, and anticancer lipid analogues.

The apoptotic program utilizes cellular membranes to transduce and generate operative signals. Lipids are major components of cellular membranes and have the potential to control the effectiveness of the signal by directing it to the proper location, being a source of new signals or as mediators in the response. These possible lipid functions are illustrated in the present review, focussing on the role that two different phospholipids, cardiolipin and phosphatidyl choline, play in apoptosis. Mitochondria have a central role in apoptosis, and many important aspects of the process mediated by this organelle converge through its distinctive lipid cardiolipin. Specifically, changes in cardiolipin metabolism have been detected in early steps of the death program and it is postulated (i) to mediate recruitment of pro apoptotic proteins like Bid to the mitochondria surface and (ii) to actively participate in the release of proteins relevant for the execution phase of apoptosis, like cytochrome c. Unlike the organelle specific distribution of cardiolipin, phosphatidylcholine is widely distributed among all organelles of the cell. The importance of phosphatidylcholine in apoptosis has been approached mainly through the study of the mode of action of (i) phosphatidylcholine anticancer analogues such as edelfosine and (ii) molecules that alter phosphatidylcholine metabolism, such as farnesol. The contribution of phosphatidylcholine metabolism to the apoptotic program is discussed, analyzing the experimental evidence available and pointing out some controversies in the proposed mechanisms of action.

Factors associated with medication-related problems in ambulatory hemodialysis patients.

BACKGROUND: Hemodialysis (HD) patients are at risk for medication-related problems. Patient characteristics associated with the number of medication-related problems in HD patients have not been investigated. METHODS: Patient records were reviewed to identify medical problems, prescribed medications, medication indication(s), and medication-related problems. Medication classes and medication-related problems were compared between patients with and without diabetes mellitus (DM). Correlations were performed to determine whether associations exist between medication-related problems, number of medications, number of medication doses per day, number of comorbid conditions, patient age, and duration of end-stage renal disease while controlling for DM status. RESULTS: Medical records of 133 patients were evaluated. Patients were 60.5 +/- 15.2 years old, prescribed 11.0 +/- 4.2 medications, and had 6.0 +/- 2.3 comorbidities. Medication-related problems were identified in 97.7% of patients. Four hundred seventy-five medication-related problems were identified, averaging 3.6 +/- 1.8 medication-related problems per patient. Patients with DM had more medication-related problems identified than those without DM (303 versus 172 medication-related problems, respectively; P < 0.05). Medication-related problems correlated positively with number of patient comorbidities (P < 0.001). CONCLUSION: Medication-related problems are prevalent in virtually all HD patients. The number of medication-related problems in an individual patient increases as the number of comorbid conditions increases. The most frequent medication-related problems were drug without indication (30.9%), laboratory (27.6%), indication without drug use (17.5%), and dosing errors (15.4%). Patients with DM are at increased risk for medication-related problems. Health care providers taking care of HD patients should be aware of this problem, and efforts to avoid or resolve medication-related problems should be undertaken at all HD clinics.

Phospholipid synthesis, diacylglycerol compartmentation, and apoptosis.

Apoptosis is a means by which organisms dispose of unwanted cells without inducing an inflammatory response. Alterations in apoptosis is a common process by which cells become cancerous. Paradoxically, many cancer chemotherapeutics preferentially kill cancer cells by inducing apoptosis. Diacylglycerol is a lipid second messenger that regulates cell growth and apoptosis and is produced during signal transduction by hydrolysis of membrane phospholipids. Protein kinase Cs are a family of diacyglycerol responsive enzymes that are recruited to cellular membranes as a consequence of diacylglycerol production where they phosphorylate specific target proteins responsible for regulating cell growth. In this review, we will first summarize our current understanding of the role of specific proteins kinase C isoforms in the induction of cell growth/apoptosis. Subsequently, we will discuss how insights gained in lipid-mediated regulation of protein kinase Cs promotes our understanding of the role specific family members play in regulating cell growth. Finally, other diacylglycerol binding proteins involved in regulating apoptosis will be discussed.

PC and PE synthesis: mixed micellar analysis of the cholinephosphotransferase and ethanolaminephosphotransferase activities of human choline/ethanolamine phosphotransferase 1 (CEPT1).

The human choline/ethanolamine phosphotransferase 1 (CEPT1) gene codes for a dual-specificity enzyme that catalyzes the de novo synthesis of the two major phospholipids through the transfer of a phosphobase from CDP-choline or CDP-ethanolamine to DAG to form PC and PE. We used an expression system devoid of endogenous cholinephosphotransferase and ethanolaminephosphotransferase activities to assess the diradylglycerol specificity of CEPT1. A mixed micellar assay was used to ensure that the diradylglycerols delivered were not affecting the membrane environment in which CEPT1 resides. The CEPT1 enzyme displayed an apparent Km of 36 microM for CDP-choline and 4.2 mol% for di-18:1 DAG with a Vmax of 14.3 nmol min(-1) mg(-1). When CDP-ethanolamine was used as substrate, the apparent Km was 98 microM for CDP-ethanolamine and 4.3 mol% for di-18:1 DAG with a Vmax of 8.2 nmol min(-1) mg(-1). The preferred diradylglycerol substrates used by CEPT1 with CDP-choline as the phosphobase donor were di-18:1 DAG, di-16:1 DAG, and 16:0/18:1 DAG. A major difference between previous emulsion-based assay results and the mixed micelle results was a complete inability to use 16:0(O)/2:0 as a substrate for the de novo synthesis of platelet-activating factor when the mixed micelle assay was used. When CDP-ethanolamine was used as the phosphobase donor, 16:0/18:1 DAG, di-18:1 DAG, and di-16:1 DAG were the preferred substrates. The mixed micelle assay also allowed the lipid activation of CEPT to be measured, and both the cholinephosphotransferase and ethanolaminephosphotransferase activities displayed the unusual property of product activation at 5 mol%, implying that specific lipid activation binding sites exist on CEPT1. The protein kinase C inhibitor chelerythrine and the human DAG kinase inhibitor R59949 both inhibited CEPT1 activity with IC50 values of 40 microM.

The major sites of cellular phospholipid synthesis and molecular determinants of Fatty Acid and lipid head group specificity.

Phosphatidylcholine and phosphatidylethanolamine are the two main phospholipids in eukaryotic cells comprising ~50 and 25% of phospholipid mass, respectively. Phosphatidylcholine is synthesized almost exclusively through the CDP-choline pathway in essentially all mammalian cells. Phosphatidylethanolamine is synthesized through either the CDP-ethanolamine pathway or by the decarboxylation of phosphatidylserine, with the contribution of each pathway being cell type dependent. Two human genes, CEPT1 and CPT1, code for the total compliment of activities that directly synthesize phosphatidylcholine and phosphatidylethanolamine through the CDP-alcohol pathways. CEPT1 transfers a phosphobase from either CDP-choline or CDP-ethanolamine to diacylglycerol to synthesize both phosphatidylcholine and phosphatidylethanolamine, whereas CPT1 synthesizes phosphatidylcholine exclusively. We show through immunofluorescence that brefeldin A treatment relocalizes CPT1, but not CEPT1, implying CPT1 is found in the Golgi. A combination of coimmunofluorescence and subcellular fractionation experiments with various endoplasmic reticulum, Golgi, and nuclear markers confirmed that CPT1 was found in the Golgi and CEPT1 was found in both the endoplasmic reticulum and nuclear membranes. The rate-limiting step for phosphatidylcholine synthesis is catalyzed by the amphitropic CTP:phosphocholine cytidylyltransferase alpha, which is found in the nucleus in most cell types. CTP:phosphocholine cytidylyltransferase alpha is found immediately upstream cholinephosphotransferase, and it translocates from a soluble nuclear location to the nuclear membrane in response to activators of the CDP-choline pathway. Thus, substrate channeling of the CDP-choline produced by CTP:phosphocholine cytidylyltransferase alpha to nuclear located CEPT1 is the mechanism by which upregulation of the CDP-choline pathway increases de novo phosphatidylcholine biosynthesis. In addition, a series of CEPT1 site-directed mutants was generated that allowed for the assignment of specific amino acid residues as structural requirements that directly alter either phospholipid head group or fatty acyl composition. This pinpointed glycine 156 within the catalytic motif as being responsible for the dual CDP-alcohol specificity of CEPT1, whereas mutations within helix 214-228 allowed for the orientation of transmembrane helices surrounding the catalytic site to be definitively positioned.

Phospholipid synthesis, diacylglycerol compartmentation, and apoptosis

Apoptosis is a means by which organisms dispose of unwanted cells without inducing an inflammatory response. Alterations in apoptosis is a common process by which cells become cancerous. Paradoxically, many cancer chemotherapeutics preferentially kill cancer cells by inducing apoptosis. Diacylglycerol is a lipid second messenger that regulates cell growth and apoptosis and is produced during signal transduction by hydrolysis of membrane phospholipids. Protein kinase Cs are a family of diacyglycerol responsive enzymes that are recruited to cellular membranes as a consequence of diacylglycerol production where they phosphorylate specific target proteins responsible for regulating cell growth. In this review, we will first summarize our current understanding of the role of specific proteins kinase C isoforms in the induction of cell growth/apoptosis. Subsequently, we will discuss how insights gained in lipid-mediated regulation of protein kinase Cs promotes our understanding of the role specific family members play in regulating cell growth. Finally, other diacylglycerol binding proteins involved in regulating apoptosis will be discussed