Rapid Antimicrobial Susceptibility Test of Helicobacter pylori to Metronidazole via Single-Cell Raman Spectrometry.

BACKGROUND: Metronidazole is a first-line antibiotic to treat Helicobacter pylori infections. However, the Clinical Laboratory Standards Institute guidelines recommend against using antimicrobial susceptibility test (AST) to test metronidazole resistance, due to the unreliable predictive power which can result in treatment failure. OBJECTIVES: The aim of this study was to establish an 8-h, metabolic-phenotype based AST for H. pylori metronidazole susceptibility using D2O-probed Raman microspectroscopy. METHODS: Minimal inhibitory concentration (MIC) measured by conventional AST (E-test) were compared with expedited MIC via metabolic activity (eMIC-MA) for 10 H. pylori isolates. Raman barcodes of cellular-response to stress (RBCS) incorporating protein and carbohydrate Raman bands, were utilized to identify a biomarker to distinguish metronidazole susceptibility. RESULTS: Specifically, eMIC-MA produces metronidazole susceptibility results showing 100% agreement with E-test, and determines the bactericidal dosage for both high- and low-level resistant H. pylori strains. In addition, RBCS not just reliably distinguish between metronidazole-susceptible and -resistant strains, but reveal their distinct mechanisms in bacterial responses to metronidazole. CONCLUSION: The speed, accuracy, low cost, and rich information content that reveals the mode-of-action of drugs suggest the method's value in guiding metronidazole prescriptions for H. pylori eradication and in rapid screening based on drug-resistance mechanism.

A comprehensive performance evaluation, comparison, and integration of computational methods for detecting and estimating cross-contamination of human samples in cancer next-generation sequencing analysis.

Cross-sample contamination is one of the major issues in next-generation sequencing (NGS)-based molecular assays. This type of contamination, even at very low levels, can significantly impact the results of an analysis, especially in the detection of somatic alterations in tumor samples. Several contamination identification tools have been developed and implemented as a crucial quality-control step in the routine NGS bioinformatic pipeline. However, no study has been published to comprehensively and systematically investigate, evaluate, and compare these computational methods in the cancer NGS analysis. In this study, we comprehensively investigated nine state-of-the-art computational methods for detecting cross-sample contamination. To explore their application in cancer NGS analysis, we further compared the performance of five representative tools by qualitative and quantitative analyses using in silico and simulated experimental NGS data. The results showed that Conpair achieved the best performance for identifying contamination and predicting the level of contamination in solid tumors NGS analysis. Moreover, based on Conpair, we developed a Python script, Contamination Source Predictor (ConSPr), to identify the source of contamination. We anticipate that this comprehensive survey and the proposed tool for predicting the source of contamination will assist researchers in selecting appropriate cross-contamination detection tools in cancer NGS analysis and inspire the development of computational methods for detecting sample cross-contamination and identifying its source in the future.

An Additional L451G452N453 in the RpoB Protein Suppressed the Synthetic Lethality in Escherichia coli at 37 Degrees Caused by Depletion of DnaK/J and Trigger Factor.

Escherichia coli depletion of chaperone trigger factor and DnaK/J were not viable at 37°C, but viable below 30°C. Among the engineered E. coli depleted of trigger factor and DnaK/J, one strain Z625, exhibited survival at 37°C, while another strain Z629 only survived below 30°C. Comparative analysis of fatty acid profiles of Z625 and Z629 revealed absence of numerous saturated fatty acids in Z625 as compared to the wild-type E. coli BW25113. In addition, increased unsaturated fatty acids were present in Z625, whereas the fatty acids profile of Z629 closely resembled that of BW25113. Whole genome sequencing revealed a 9-bp insertion in rpoB of Z625. Combined structural analysis of simulated RpoB protein bearing the amino acid sequence L451G452N453 insertion and susceptibility analysis to rifampicin suggested that the insertion did not disturb the individual RpoB structure as beta subunit of RNA polymerase. Comparative transcriptomic analysis of Z625 and Z629 suggested that this insertion impacted transcription of the overall RNA polymerase in Z625, leading to potential repression of some genes whose overexpression was toxic to E. coli. Additionally, Z625 exhibited distinctive metabolic adaptations, likely contributing to its survival at 37°C. In summary, our study elucidated one LGN insertion in rpoB that impacts transcriptional regulation in E. coli, thereby explaining the survival of E. coli depletion of trigger factor and DnaK/J at 37°C, and these founding suggested that some simple mutations in critical genes like rpoB might play an important role in driving adaptive evolution.

Health Literacy and Treatment Satisfaction Among Patients with Venous Thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) treatment requires complex management, and patients with limited health literacy (HL) may perceive higher burden and lower benefits associated with their treatment. OBJECTIVE: To examine the association of HL with treatment satisfaction among patients with VTE. DESIGN: Retrospective cohort study PARTICIPANTS: Kaiser Permanente Southern and Northern California members who were taking oral anticoagulants (OAC) for incident VTE between 2015 and 2018 were surveyed. Main Measures HL was assessed using a 3-item HL assessment and dichotomized as having adequate or limited HL. High treatment burden and low treatment benefit were defined as Anti-Clot Treatment Scale (ACTS) scores below the 25th percentile of the distributions for ACTS Burdens and Benefits survey components, respectively. Using Poisson regression, multivariable adjusted risk ratios (RR) and 95% confidence intervals (CI) were calculated for the association of HL with high treatment burden and low treatment benefits. RESULTS: Among 2154 respondents, 397 (18.4%) had limited HL. Patients with limited vs adequate HL were older (47.9% vs 27.5% aged ≥ 75 years, p<0.001), more likely to use a non-English language when discussing their health (10.8% vs 1.7%, p<0.001), to have less than high school education (10.1% vs 1.7%, p<0.001), and to self-rate their health as fair or poor (47.6% vs 25.5%, p<0.001). After multivariable adjustment, patients with limited HL were more likely to have higher perceived treatment burden (RR 1.24, 95% CI 1.07, 1.45) and lower perceived treatment benefits (RR 1.21, 95% CI 1.08, 1.37). CONCLUSIONS: Limited HL was associated with lower OAC treatment satisfaction, though absolute differences in satisfaction scores were small. Further examination of the intersection of HL with VTE treatment satisfaction and compliance among older and non-English speaking patients is warranted.

Management of Adults with Newly Diagnosed Atrial Fibrillation with and without CKD.

BACKGROUND: Atrial fibrillation (AF) is highly prevalent in CKD and is associated with worse cardiovascular and kidney outcomes. Limited data exist on use of AF pharmacotherapies and AF-related procedures by CKD status. We examined a large "real-world" contemporary population with incident AF to study the association of CKD with management of AF. METHODS: We identified patients with newly diagnosed AF between 2010 and 2017 from two large, integrated health care delivery systems. eGFR (≥60, 45-59, 30-44, 15-29, <15 ml/min per 1.73 m2) was calculated from a minimum of two ambulatory serum creatinine measures separated by ≥90 days. AF medications and procedures were identified from electronic health records. We performed multivariable Fine-Gray subdistribution hazards regression to test the association of CKD severity with receipt of targeted AF therapies. RESULTS: Among 115,564 patients with incident AF, 34% had baseline CKD. In multivariable models, compared with those with eGFR >60 ml/min per 1.73 m2, patients with eGFR 30-44 (adjusted hazard ratio [aHR] 0.91; 95% CI, 0.99 to 0.93), 15-29 (aHR, 0.78; 95% CI, 0.75 to 0.82), and <15 ml/min per 1.73 m2 (aHR, 0.64; 95% CI, 0.58-0.70) had lower use of any AF therapy. Patients with eGFR 15-29 ml/min per 1.73 m2 had lower adjusted use of rate control agents (aHR, 0.61; 95% CI, 0.56 to 0.67), warfarin (aHR, 0.89; 95% CI, 0.84 to 0.94), and DOACs (aHR, 0.23; 95% CI, 0.19 to 0.27) compared with patients with eGFR >60 ml/min per 1.73 m2. These associations were even stronger for eGFR <15 ml/min per 1.73 m2. There was also a graded association between CKD severity and receipt of AF-related procedures (vs eGFR >60 ml/min per 1.73 m2): eGFR 30-44 ml/min per 1.73 (aHR, 0.78; 95% CI, 0.70 to 0.87), eGFR 15-29 ml/min per 1.73 m2 (aHR, 0.73; 95% CI, 0.61 to 0.88), and eGFR <15 ml/min per 1.73 m2 (aHR, 0.48; 95% CI, 0.31 to 0.74). CONCLUSIONS: In adults with newly diagnosed AF, CKD severity was associated with lower receipt of rate control agents, anticoagulation, and AF procedures. Additional data on efficacy and safety of AF therapies in CKD populations are needed to inform management strategies.

Transcriptional analysis of the dimorphic fungus Umbilicaria muehlenbergii reveals the molecular mechanism of phenotypic transition.

The lichen-forming fungus Umbilicaria muehlenbergii undergoes a phenotypic transition from a yeast-like to a pseudohyphal form. However, it remains unknown if a common mechanism is involved in the phenotypic switch of U. muehlenbergii at the transcriptional level. Further, investigation of the phenotype switch molecular mechanism in U. muehlenbergii has been hindered by incomplete genomic sequencing data. Here, the phenotypic characteristics of U. muehlenbergii were investigated after cultivation on several carbon sources, revealing that oligotrophic conditions due to nutrient stress (reduced strength PDA (potato dextrose agar) media) exacerbated the pseudohyphal growth of U. muehlenbergii. Further, the addition of sorbitol, ribitol, and mannitol exacerbated the pseudohyphal growth of U. muehlenbergii regardless of PDA medium strength. Transcriptome analysis of U. muehlenbergii grown in normal and nutrient-stress conditions revealed the presence of several biological pathways with altered expression levels during nutrient stress and related to carbohydrate, protein, DNA/RNA and lipid metabolism. Further, the results demonstrated that altered biological pathways can cooperate during pseudohyphal growth, including pathways involved in the production of protectants, acquisition of other carbon sources, or adjustment of energy metabolism. Synergistic changes in the functioning of these pathways likely help U. muehlenbergii cope with dynamic stimuli. These results provide insights into the transcriptional response of U. muehlenbergii during pseudohyphal growth under oligotrophic conditions. Specifically, the transcriptomic analysis indicated that pseudohyphal growth is an adaptive mechanism of U. muehlenbergii that facilitates its use of alternative carbon sources to maintain survival.

Comparative transcriptome analysis to investigate the mechanism of anti-Helicobacter pylori activity of zinc.

As a potential anti-Helicobacter pylori agent, zinc causes impairment of Helicobacter pylori growth, and this property of zinc is of broad interest to biological investigators. However, little is known about the molecular mechanisms by which zinc inhibits the growth of Helicobacter pylori. Here, an in vitro experiment revealed that zinc at specific concentrations inhibits Helicobacter pylori growth. Furthermore, an RNA sequencing-based investigation of the global regulatory response to zinc revealed that exposure to zinc altered the Helicobacter pylori transcriptional profile in numerous ways. A high concentration of zinc induced the upregulation of genes related to ribosomal subunit, ribosome biosynthesis, chaperone and adhesins. However, flagellar assembly genes and some type IV secretion system genes were repressed. In addition, the expression levels of some genes that encode transporters of metal ions and that play key roles in Helicobacter pylori pathogenicity were altered under conditions of zinc-induced stress. In summary, high concentrations of zinc initiated antimicrobial activity to Helicobacter pylori under the combined effect of multiple repressed or altered pathogenetic genes and metabolic pathways associated with bacteria growth. This result has significant implications for understanding not only the antimicrobial activity mechanism of zinc but also the role of zinc-mediated homeostasis in Helicobacter pylori.

Primary Nephrotic Syndrome and Risks of ESKD, Cardiovascular Events, and Death: The Kaiser Permanente Nephrotic Syndrome Study.

BACKGROUND: Little population-based data exist about adults with primary nephrotic syndrome. METHODS: To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996 and 2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of ESKD, cardiovascular outcomes, and death through 2014, using multivariable Cox regression. RESULTS: We confirmed 907 patients with primary nephrotic syndrome (655 definite and 252 presumed patients with FSGS [40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR, 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR, 3.01; 95% CI, 2.16 to 4.19), ischemic stroke (aHR, 1.80; 95% CI, 1.06 to 3.05), venous thromboembolism (aHR, 2.56; 95% CI, 1.35 to 4.85), and death (aHR, 1.34; 95% CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death. CONCLUSIONS: Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in the risk for developing ESKD.

Anticoagulant treatment satisfaction with warfarin and direct oral anticoagulants for venous thromboembolism.

Treatment options for patients with venous thromboembolism (VTE) include warfarin and direct oral anticoagulants (DOACs). Although DOACs are easier to administer than warfarin and do not require routine laboratory monitoring, few studies have directly assessed whether patients are more satisfied with DOACs. We surveyed adults from two large integrated health systems taking DOACs or warfarin for incident VTE occurring between January 1, 2015 and June 30, 2018. Treatment satisfaction was assessed using the validated Anti-Clot Treatment Scale (ACTS), divided into the ACTS Burdens and ACTS Benefits scores; higher scores indicate greater satisfaction. Mean treatment satisfaction was compared using multivariable linear regression, adjusting for patient demographic and clinical characteristics. The effect size of the difference in means was calculated using a Cohen's d (0.20 is considered a small effect and ≥ 0.80 is considered large). We surveyed 2217 patients, 969 taking DOACs and 1248 taking warfarin at the time of survey. Thirty-one point five percent of the cohort was aged ≥ 75 years and 43.1% were women. DOAC users were on average more satisfied with anticoagulant treatment, with higher adjusted mean ACTS Burdens (50.18 v. 48.01, p < 0.0001) and ACTS Benefits scores (10.21 v. 9.84, p = 0.046) for DOACs vs. warfarin, respectively. The magnitude of the difference was small (Cohen's d of 0.29 for ACTS Burdens and 0.12 for ACTS Benefits). Patients taking DOACs for venous thromboembolism were on average more satisfied with anticoagulant treatment than were warfarin users, although the magnitude of the difference was small.

Exploring the roles of substrate-binding surface of the chaperone site in the chaperone activity of trigger factor.

Trigger factor (TF) is a key component of the prokaryotic chaperone network, which is involved in many basic cellular processes, such as protein folding, protein trafficking, and ribosome assembly. The major chaperone site of TF has a cradle-like structure in which protein substrate may fold without interference from other proteins. Here, we investigated in vivo and in vitro the roles of hydrophobic and charged patches on the edge and interior of cradle during TF-assisted protein folding. Our results showed that most of the surface of the cradle was involved in TF-assisted protein folding, which was larger than found in early studies. Although the inner surface of cradle was mostly hydrophobic, both hydrophobic and electrostatic patches were indispensable for TF to facilitate correct protein folding. However, hydrophobic patches were more important for the antiaggregation activity of TF. Furthermore, it was found that the patches on the surface of cradle were involved in TF-assisted protein folding in a spatial and temporal order. These results suggest that the folding-favorable interface between the cradle and substrate was dynamic during TF-assisted protein folding, which enabled TF to be involved in the folding of substrate in an aggressive manner rather than acting as a classic holdase.-Fan, D., Cao, S., Zhou, Q., Zhang, Y., Yue, L., Han, C., Yang, B., Wang, Y., Ma, Z., Zhu, L., Liu, C. Exploring the roles of substrate-binding surface of chaperone site in the chaperone activity of trigger factor.

Global Analysis of the Impact of Deleting Trigger Factor on the Transcriptome Profile of Escherichia coli.

Trigger factor (TF) is a key component of prokaryotic chaperone network, which is involved various basic cellular processes such as nascent peptide folding, protein trafficking, ribosome assembly. To better understanding the physiological roles of TF, global transcriptome profiles of a variety of TF deletion mutant strains of Escherichia coli were determined. We found that deletion of the tig gene, encoding TF, led to a dramatic alteration of transcriptome profile, not only affecting the gene expression of members of the chaperone network, but also changing the levels of quite a few RNAs related to metabolism and other cellular processes. Further studies showed that this alteration was only partially recovered by knockin of TF domain-deletion mutants into the endogenous tig locus, indicating that structural integrity is crucial for the biological function of TF. Finally, by combining the transcriptome and phenotype results, a physiological mechanism underlying the impact of TF deletion on the transcriptome profile was proposed. J. Cell. Biochem. 118: 141-153, 2017. © 2016 Wiley Periodicals, Inc.

Contemporary rates and correlates of statin use and adherence in nondiabetic adults with cardiovascular risk factors: The KP CHAMP study.

BACKGROUND: Statin therapy is highly efficacious in the prevention of fatal and nonfatal atherosclerotic events in persons at increased cardiovascular risk. However, its long-term effectiveness in practice depends on a high level of medication adherence by patients. METHODS: We identified nondiabetic adults with cardiovascular risk factors between 2008 and 2010 within a large integrated health care delivery system in Northern California. Through 2013, we examined the use and adherence of newly initiated statin therapy based on data from dispensed prescriptions from outpatient pharmacy databases. RESULTS: Among 209,704 eligible adults, 68,085 (32.5%) initiated statin therapy during the follow-up period, with 90.4% receiving low-potency statins. At 12 and 24 months after initiating statins, 84.3% and 80.2%, respectively, were actively receiving statin therapy, but only 42% and 30%, respectively, had no gaps in treatment during those time periods. There was also minimal switching between statins or use of other lipid-lowering therapies for augmentation during follow-up. Age≥50 years, Asian/Pacific Islander race, Hispanic ethnicity, prior myocardial infarction, prior ischemic stroke, hypertension, and baseline low-density lipoprotein cholesterol>100 mg/dL were associated with higher adjusted odds, whereas female gender, black race, current smoking, dementia were associated with lower adjusted odds, of active statin treatment at 12 months after initiation. CONCLUSIONS: There remain opportunities for improving prevention in patients at risk for cardiovascular events. Our study identified certain patient subgroups that may benefit from interventions to enhance medication adherence, particularly by minimizing treatment gaps and discontinuation of statin therapy within the first year of treatment.

Validity of Using Inpatient and Outpatient Administrative Codes to Identify Acute Venous Thromboembolism: The CVRN VTE Study.

BACKGROUND: Administrative data are frequently used to identify venous thromboembolism (VTE) for research and quality reporting. However, the validity of these codes, particularly in outpatients, has not been well-established. OBJECTIVE: To determine how well International Classification of Diseases, Ninth Revision (ICD-9) codes for VTE predict chart-confirmed acute VTE in inpatient and outpatients. PATIENTS AND METHODS: We selected 4642 adults with an incident ICD-9 diagnosis of VTE between years 2004 and 2010 from the Cardiovascular Research Network Venous Thromboembolism cohort study. Medical charts were reviewed to determine validity of events. Positive predictive values (PPVs) of ICD-9 codes were calculated as the number of chart-validated VTE events divided by the number with specific VTE codes. Analyses were stratified by VTE type [pulmonary embolism (PE), deep venous thrombosis (DVT)], code position (primary, secondary), and setting [hospital/emergency department (ED), outpatient]. RESULTS: The PPV for any diagnosis of VTE was 64.6% for hospital/ED patients and 30.9% for outpatients. Primary diagnosis codes from hospital/ED patients were more likely to represent acute VTE than secondary diagnosis codes (78.9% vs. 44.4%, P<0.001). Primary hospital/ED codes for PE and lower extremity DVT had higher PPV than for upper extremity DVT (89.1%, 74.9%, and 58.1%, respectively). Outpatient codes were poorly predictive of acute VTE: 28.0% for PE and 53.6% for lower extremity DVT. CONCLUSIONS: ICD-9 codes for VTE obtained from outpatient encounters or from secondary diagnosis codes do not reliably reflect acute VTE. More accurate ways of identifying VTE in outpatients are needed before these codes can be adopted for research or policy purposes.

Incident atrial fibrillation and risk of end-stage renal disease in adults with chronic kidney disease.

BACKGROUND: Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD). However, the long-term impact of development of AF on the risk of adverse renal outcomes in patients with CKD is unknown. In this study, we determined the association between incident AF and risk of end-stage renal disease (ESRD) among adults with CKD. METHODS AND RESULTS: We studied adults with CKD (defined as estimated glomerular filtration rate eGFR <60 mL/min per 1.73 m(2) by the Chronic Kidney Disease Epidemiology Collaboration equation) enrolled in Kaiser Permanente Northern California who were identified between 2002 and 2010 and who did not have previous ESRD or previously documented AF. Incident AF was identified by using primary hospital discharge diagnoses or 2 or more outpatient visits for AF. Incident ESRD was ascertained from a comprehensive health plan registry for dialysis and renal transplant. Among 206 229 adults with CKD, 16 463 developed incident AF. During a mean follow-up of 5.1±2.5 years, there were 345 cases of ESRD that occurred after development of incident AF (74 per 1000 person-years) in comparison with 6505 cases of ESRD during periods without AF (64 per 1000 person-years, P<0.001). After adjustment for potential confounders, incident AF was associated with a 67% increase in the rate of ESRD (hazard ratio, 1.67; 95% confidence interval, 1.46-1.91). CONCLUSIONS: Incident AF is independently associated with increased risk of developing ESRD in adults with CKD. Further study is needed to identify potentially modifiable pathways through which AF leads to a higher risk of progression to ESRD.

The biochemistry of melanogenesis: an insight into the function and mechanism of melanogenesis-related proteins.

Melanin is an amino acid derivative produced by melanocyte through a series of enzymatic reactions using tyrosinase as substrate. Human skin and hair color is also closely related to melanin, so understanding the mechanisms and proteins that produce melanin is very important. There are many proteins involved in the process of melanin expression, For example, proteins involved in melanin formation such as p53, HNF-1α (Hepatocyte nuclear factor 1α), SOX10 (Sry-related HMg-Box gene 10) and pax3 (paired box gene 3), MC1R(Melanocortin 1 Receptor), MITF (Microphthalmia-associated transcription factor), TYR (tyrosinase), TYRP1 (tyrosinase-related protein-1), TYRP2 (tyrosinase-related protein-2), and can be regulated by changing their content to control the production rate of melanin. Others, such as OA1 (ocular albinism type 1), Par-2 (protease-activated receptor 2) and Mlph (Melanophilin), have been found to control the transfer rate of melanosomes from melanocytes to keratinocytes, and regulate the amount of human epidermal melanin to control the depth of human skin color. In addition to the above proteins, there are other protein families also involved in the process of melanin expression, such as BLOC, Rab and Rho. This article reviews the origin of melanocytes, the related proteins affecting melanin and the basic causes of related gene mutations. In addition, we also summarized the active ingredients of 5 popular whitening cosmetics and their mechanisms of action.

Identification of recurrent atrial fibrillation using natural language processing applied to electronic health records.

AIMS: This study aimed to develop and apply natural language processing (NLP) algorithms to identify recurrent atrial fibrillation (AF) episodes following rhythm control therapy initiation using electronic health records (EHRs). METHODS AND RESULTS: We included adults with new-onset AF who initiated rhythm control therapies (ablation, cardioversion, or antiarrhythmic medication) within two US integrated healthcare delivery systems. A code-based algorithm identified potential AF recurrence using diagnosis and procedure codes. An automated NLP algorithm was developed and validated to capture AF recurrence from electrocardiograms, cardiac monitor reports, and clinical notes. Compared with the reference standard cases confirmed by physicians' adjudication, the F-scores, sensitivity, and specificity were all above 0.90 for the NLP algorithms at both sites. We applied the NLP and code-based algorithms to patients with incident AF (n = 22 970) during the 12 months after initiating rhythm control therapy. Applying the NLP algorithms, the percentages of patients with AF recurrence for sites 1 and 2 were 60.7% and 69.9% (ablation), 64.5% and 73.7% (cardioversion), and 49.6% and 55.5% (antiarrhythmic medication), respectively. In comparison, the percentages of patients with code-identified AF recurrence for sites 1 and 2 were 20.2% and 23.7% for ablation, 25.6% and 28.4% for cardioversion, and 20.0% and 27.5% for antiarrhythmic medication, respectively. CONCLUSION: When compared with a code-based approach alone, this study's high-performing automated NLP method identified significantly more patients with recurrent AF. The NLP algorithms could enable efficient evaluation of treatment effectiveness of AF therapies in large populations and help develop tailored interventions.

Clinical Outcomes of Direct Oral Anticoagulants vs Warfarin for Extended Treatment of Venous Thromboembolism.

Importance: Extending the duration of oral anticoagulation for venous thromboembolism (VTE) beyond the initial 3 to 6 months of treatment is often recommended, but it is not clear whether clinical outcomes differ when using direct oral anticoagulants (DOACs) or warfarin. Objective: To compare rates of recurrent VTE, hospitalizations for hemorrhage, and all-cause death among adults prescribed DOACs or warfarin whose anticoagulant treatment was extended beyond 6 months after acute VTE. Design, Setting, and Participants: This cohort study was conducted in 2 integrated health care delivery systems in California with adults aged 18 years or older who received a diagnosis of incident VTE between 2010 and 2018 and completed at least 6 months of oral anticoagulant treatment with DOACs or warfarin. Patients were followed from the end of the initial 6-month treatment period until discontinuation of anticoagulation, occurrence of an outcome event, health plan disenrollment, or end of the study follow-up period (December 31, 2019). Data were obtained from the Kaiser Permanente Virtual Data Warehouse and electronic health records. Data analysis was conducted from March 2022 to January 2023. Exposure: Dispensed prescriptions of DOACs or warfarin after a 6-month initial treatment for VTE. Main Outcomes and Measures: The primary outcomes were rates per 100 person-years of recurrent VTE, hospitalizations for hemorrhage, and all-cause death. Comparison of DOAC and warfarin outcomes were performed using multivariable Cox proportional hazards regression. Results: A total of 18 495 patients (5477 [29.6%] aged ≥75 years; 8973 women [48.5%]) with VTE who were treated with at least 6 months of anticoagulation were identified, of whom 2134 (11.5%) were receiving DOAC therapy and 16 361 (88.5%) were receiving warfarin therapy. Unadjusted event rates were lower for patients receiving DOAC therapy than warfarin therapy for recurrent VTE (event rate per 100 person-years, 2.92 [95% CI, 2.29-3.54] vs 4.14 [95% CI, 3.90-4.38]), hospitalizations for hemorrhage (event rate per 100 person-years, 1.02 [95% CI, 0.66-1.39] vs 1.81 [95% CI, 1.66-1.97]), and all-cause death (event rate per 100 person-years, 3.79 [95% CI, 3.09-4.49] vs 5.40 [95% CI, 5.13-5.66]). After multivariable adjustment, DOAC treatment was associated with a lower risk of recurrent VTE (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.52-0.82). For patients prescribed DOAC treatment, the risks of hospitalization for hemorrhage (aHR, 0.79; 95% CI, 0.54-1.17) and all-cause death (aHR, 0.96; 95% CI, 0.78-1.19) were not significantly different than those for patients prescribed warfarin treatment. Conclusions and Relevance: In this cohort study of patients with VTE who continued warfarin or DOAC anticoagulation beyond 6 months, DOAC treatment was associated with a lower risk of recurrent VTE, supporting the use of DOACs for the extended treatment of VTE in terms of clinical outcomes.

Association of Kidney Function With Risk of Adverse Effects of Therapies for Atrial Fibrillation.

Introduction: Atrial fibrillation (AF) is common in chronic kidney disease (CKD) and is treated with rate control medications, antiarrhythmic medications, as well as anticoagulation and procedures, each of which have associated risks. We aimed to evaluate the association of CKD status with the risks of adverse effects after initiation of AF therapies. Methods: This was a cohort study of community-based adults who newly initiated rate control medications, antiarrhythmic medications, warfarin, direct oral anticoagulants (DOACs) or received AF procedures in the 1 year after diagnosis of AF. Baseline estimated glomerular filtration rate (eGFR) was calculated using outpatient serum creatinine measures. Adverse effects within 1 year related to each AF therapy or within 1 month of an AF procedure were ascertained from vital sign databases, electrocardiograms (ECGs), and administrative codes. Fine-Gray hazard models were used to study the association of eGFR categories with risk of adverse effects for each AF therapy. Results: Among 115,564 patients with incident AF, lower eGFR (vs. eGFR ≥60 ml/min per 1.73 m2) was significantly associated with higher adjusted risk of adverse effects after initiation of rate control therapies (most commonly hypotension and bradycardia) as follows: eGFR 45-59 (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.07-1.22), 30-44 (HR 1.15, 95% CI 1.06-1.25), and 15-29 (HR 1.29, 95% CI: 1.12-1.47) ml/min per 1.73 m2. Lower eGFR was associated with higher adjusted risk of adverse effects (most commonly prolonged QRS and QTc intervals) after initiation of an antiarrhythmic medication (vs. eGFR >60 ml/min per 1.73 m2) as follows: eGFR 45-59 (HR 1.12, 95% CI 1.01-1.23) and eGFR<15 (HR 1.43, 95% CI 1.01-2.01) ml/min per 1.73 m2. Conclusion: There was a graded association between lower eGFR and risk of major bleeding with warfarin use, with the greatest risk among those with eGFR <15 ml/min per 1.73 m2 (HR of 2.93, 95% CI 1.99-4.30). There was no association of eGFR with major bleeding in patients receiving DOACs. Rates of adverse effects within 1 month of an AF procedure were low among patients with (n = 18) and without (n = 41) CKD and was underpowered for further analyses. In conclusion, lower eGFR was associated with significantly higher risks of adverse effects after initiation of commonly used therapies to treat AF. These data may help inform the complex therapeutic decisions in patients with CKD and AF.

Incident Atrial Fibrillation and Risk of Dementia in a Diverse, Community-Based Population.

Background Atrial fibrillation (AF) is the most common, clinically relevant arrhythmia in adults and associated with ischemic stroke and premature death. However, data are conflicting on whether AF is independently associated with risk of dementia, particularly in diverse populations. Methods and Results We identified all adults from 2 large integrated health care delivery systems between 2010 and 2017 and performed a 1:1 match of incident AF: no AF by age at index date, sex, estimated glomerular filtration rate category, and study site. Subsequent dementia was identified through previously validated diagnosis codes. Fine-Gray subdistribution hazard models were used to examine the association of incident AF (versus no AF) with risk of incident dementia, adjusting for sociodemographics and comorbidity and accounting for competing risk of death. Subgroup analyses by age, sex, race, ethnicity, and chronic kidney disease status were also performed. Among 196 968 matched adults, mean (SD) age was 73.6 (11.3) years, with 44.8% women, and 72.3% White. Incidence rates (per 100 person-years) for dementia over a median follow-up of 3.3 (interquartile range, 1.7-5.4) years were 2.79 (95% CI, 2.72-2.85) and 2.04 (95% CI, 1.99-2.08) per 100 person-years in persons with versus without incident AF, respectively. In adjusted models, incident AF was associated with a significantly greater risk of diagnosed dementia (subdistribution hazard ratio [sHR], 1.13 [95% CI, 1.09-1.16]). With additional adjustment for interim stroke events, the association of incident AF with dementia remained statistically significant (sHR, 1.10 [95% CI, 1.07-1.15]). Associations were stronger for age <65 (sHR, 1.65 [95% CI, 1.29-2.12]) versus ≥65 (sHR, 1.07 [95% CI, 1.03-1.10]) years (interaction P<0.001); and those without (sHR, 1.20 [95% CI, 1.14-1.26]) versus with chronic kidney disease (sHR, 1.06 [95% CI, 1.01-1.11]; interaction P<0.001). No meaningful differences were seen by sex, race, or ethnicity. Conclusions In a large, diverse community-based cohort, incident AF was associated with a modestly increased risk of dementia that was more prominent in younger patients and those without chronic kidney disease but did not substantially vary across sex, race, or ethnicity. Further studies should delineate mechanisms underpinning these findings, which may inform use of AF therapies.

Assessment of the Risk of Venous Thromboembolism in Nonhospitalized Patients With COVID-19.

Importance: Patients hospitalized with COVID-19 have higher rates of venous thromboembolism (VTE), but the risk and predictors of VTE among individuals with less severe COVID-19 managed in outpatient settings are less well understood. Objectives: To assess the risk of VTE among outpatients with COVID-19 and identify independent predictors of VTE. Design, Setting, and Participants: A retrospective cohort study was conducted at 2 integrated health care delivery systems in Northern and Southern California. Data for this study were obtained from the Kaiser Permanente Virtual Data Warehouse and electronic health records. Participants included nonhospitalized adults aged 18 years or older with COVID-19 diagnosed between January 1, 2020, and January 31, 2021, with follow-up through February 28, 2021. Exposures: Patient demographic and clinical characteristics identified from integrated electronic health records. Main Outcomes and Measures: The primary outcome was the rate per 100 person-years of diagnosed VTE, which was identified using an algorithm based on encounter diagnosis codes and natural language processing. Multivariable regression using a Fine-Gray subdistribution hazard model was used to identify variables independently associated with VTE risk. Multiple imputation was used to address missing data. Results: A total of 398 530 outpatients with COVID-19 were identified. The mean (SD) age was 43.8 (15.8) years, 53.7% were women, and 54.3% were of self-reported Hispanic ethnicity. There were 292 (0.1%) VTE events identified over the follow-up period, for an overall rate of 0.26 (95% CI, 0.24-0.30) per 100 person-years. The sharpest increase in VTE risk was observed during the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% CI, 0.51-0.67 per 100 person-years vs 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days). In multivariable models, the following variables were associated with a higher risk for VTE in the setting of nonhospitalized COVID-19: age 55 to 64 years (HR 1.85 [95% CI, 1.26-2.72]), 65 to 74 years (3.43 [95% CI, 2.18-5.39]), 75 to 84 years (5.46 [95% CI, 3.20-9.34]), greater than or equal to 85 years (6.51 [95% CI, 3.05-13.86]), male gender (1.49 [95% CI, 1.15-1.96]), prior VTE (7.49 [95% CI, 4.29-13.07]), thrombophilia (2.52 [95% CI, 1.04-6.14]), inflammatory bowel disease (2.43 [95% CI, 1.02-5.80]), body mass index 30.0-39.9 (1.57 [95% CI, 1.06-2.34]), and body mass index greater than or equal to 40.0 (3.07 [1.95-4.83]). Conclusions and Relevance: In this cohort study of outpatients with COVID-19, the absolute risk of VTE was low. Several patient-level factors were associated with higher VTE risk; these findings may help identify subsets of patients with COVID-19 who may benefit from more intensive surveillance or VTE preventive strategies.