Pathways Linking Post-Traumatic Stress Disorder to Incident Ischemic Heart Disease in Women: Call to Action.

Background: Post-traumatic stress disorder (PTSD) is associated with increased rates of incident ischemic heart disease (IHD) in women. Objectives: The purpose of this study was to determine mechanisms of the PTSD-IHD association in women. Methods: In this retrospective longitudinal cohort study, data were obtained from electronic health records of all U.S. women veterans who were enrolled in Veterans Health Administration care from January 1, 2000 to December 31, 2017. Propensity score matching was used to match women with PTSD to women without PTSD on age, number of prior Veterans Health Administration visits, and presence of various traditional and nontraditional cardiovascular risk factors at index visit. Cox regression was used to model time until incident IHD diagnosis (ie, coronary artery disease, angina, or myocardial infarction) as a function of PTSD and potential mediating risk factors. Diagnoses of IHD, PTSD, and risk factors were defined by International Classification of Diseases-9th or -10th Revision, and/or Current Procedural Terminology codes. Results: PTSD was associated with elevated rates of developing each risk factor. Traditional risk factors (hypertension, hyperlipidemia, smoking, diabetes) accounted for 24.2% of the PTSD-IHD association, psychiatric risk factors (eg, depression, anxiety, substance use disorders) accounted for 33.8% of the association, and all 13 risk factors accounted for 48.5% of the association. Conclusions: Traditional IHD risk factors explained a quarter of the PTSD-IHD association in women veterans, and over half of the risk of IHD associated with PTSD remained unexplained even when adjusting for a wide range of risk factors. To be actionable, factors underlying the remaining PTSD-IHD association warrant timely investigation.

Interplay Between the Histone Variant H2A.Z and the Epigenome in Pancreatic Cancer.

BACKGROUND: The oncogenic process is orchestrated by a complex network of chromatin remodeling elements that shape the cancer epigenome. Histone variant H2A.Z regulates DNA control elements such as promoters and enhancers in different types of cancer; however, the interplay between H2A.Z and the pancreatic cancer epigenome is unknown. OBJECTIVE: This study analyzed the role of H2A.Z in different DNA regulatory elements. METHODS: We performed Chromatin Immunoprecipitation Sequencing assays (ChiP-seq) with total H2A.Z and acetylated H2A.Z (acH2A.Z) antibodies and analyzed published data from ChIP-seq, RNA-seq, bromouridine labeling-UV and sequencing (BruUV-seq), Hi-C and ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) in the pancreatic cancer cell line PANC-1. RESULTS: The results indicate that total H2A.Z facilitates the recruitment of RNA polymerase II and transcription factors at promoters and enhancers allowing the expression of pro-oncogenic genes. Interestingly, we demonstrated that H2A.Z is enriched in super-enhancers (SEs) contributing to the transcriptional activation of key genes implicated in tumor development. Importantly, we established that H2A.Z contributes to the three-dimensional (3D) genome organization of pancreatic cancer and that it is a component of the Topological Associated Domains (TADs) boundaries in PANC-1 and that total H2A.Z and acH2A.Z are associated with A and B compartments, respectively. CONCLUSIONS: H2A.Z participates in the biology and development of pancreatic cancer by generating a pro-oncogenic transcriptome through its posttranslational modifications, interactions with different partners, and regulatory elements, contributing to the oncogenic 3D genome organization. These data allow us to understand the molecular mechanisms that promote an oncogenic transcriptome in pancreatic cancer mediated by H2A.Z.

Cytokines secretion from human mesenchymal stem cells induced by bovine bone matrix.

BACKGROUND: Bovine bone matrix is a natural material that has been used in the treatment of bone lesions. In this study, bovine bone matrix Nukbone® (NKB) was investigated due its osteoconductive and osteoinductive properties. This biomaterial induces CBFA-1 activation and osteogenic differentiation, although the cytokines involved in these processes is still unknown. OBJECTIVE: The aim of this work was to determine the influence of NKB on the pro-osteoblastic and anti-osteoblastic cytokines secretion from human mesenchymal stem cells (hMSCs). METHODS: The hMSCs were cultured onto NKB and cytokines IL-2, IL-4, IL-6, IL-10, IL-12, IFN-γ and TNF-α were analized at 0-14 days by immunoassay. In addition, hemocompatibility of NKB and characterization of hMSCs were evaluated. RESULTS: NKB induces an increase on pro-osteoblastic cytokine secretion IL-4 and a decrease on anti-osteoblastic cytokine IL-6 secretion, at days 7 and 14 of cell culture. Interestingly, there was no statistical difference between secretion profiles of others cytokines analized. CONCLUSIONS: The up-regulation of IL-4 and down-regulation of IL-6, and the secretion profiles of other cytokines examined in this work, are findings that will contribute to the understanding of the role of NKB, and similar biomaterials, in bone homeostasis and in the osteoblastic differentiation of hMSCs.

Prevalence and Significance of Potential Pharmacokinetic Drug-Drug Interactions Among Patients with Lung Cancer: Implications for Clinical Trials.

BACKGROUND: The overall prevalence of potential drug-drug interactions (DDIs) among patients with lung cancer is unknown. OBJECTIVE: The objective of this study was to determine the prevalence of potential DDIs and major DDIs among individuals newly diagnosed with lung cancer in a national cohort. PATIENTS AND METHODS: We performed a retrospective cross-sectional study of adult patients in the United States Veterans' Affairs (VA) medical system diagnosed with lung cancer between 2003 and 2016. The primary endpoint was the prevalence of prescriptions for medications associated with any potential DDIs during the 3 months leading up to and including the date of lung cancer diagnosis. The secondary endpoint was the prevalence of prescriptions associated with major DDIs during the same time period. RESULTS: Overall, 280,068 patients were included in the study; 55.9% of patients were prescribed medications associated with potential DDIs, while 5.3% received prescriptions for medications associated with major DDIs. Among the 20 most commonly prescribed drugs associated with potential DDIs, only two were associated with major DDIs. CONCLUSION: Medications with potential DDIs are prescribed to the majority of patients with lung cancer; however, only about 5% of patients are prescribed medications with major DDIs that might be prohibited in certain clinical trials.

Características clínicas y epidemiológicas de casos de enfermedad de Chagas aguda en la cuenca amazónica peruana, 2009-2016 / Clinical and epidemiological characteristics of cases of acute Chagas disease in the Peruvian Amazon basin, 2009-2016

RESUMEN Los casos de la enfermedad de Chagas aguda (ECA) se reportan en forma esporádica en el Perú. En este artículo se describe las características clínicas y epidemiológicas de ocho nuevos casos de ECA detectados por el sistema de vigilancia en la cuenca amazónica, entre 2009 y 2016. La media de la edad fue 12,7 ± 13,7 años, rango de 1 a 44 años y 4/8 casos fueron varones. Un caso se asoció a enfermedad diarreica aguda, otro a leptospirosis y dos a infección del tracto urinario. La tasa de letalidad global fue 12,5% (1/8). La detección tardía es una característica frecuente relacionada a una escasa sospecha diagnóstica en pacientes con historial de fiebre. Se identificó el linaje TcI y TcIV del agente etiológico de la enfermedad de Chagas. Se reporta ocho nuevos casos de ECA, de los cuales siete fueron menores de edad.

ABSTRACT Acute Chagas disease (ACD) cases are reported sporadically in Peru. In this report we describe the clinical and epidemiological characteristics of eight new ACD cases detected by the surveillance system in the Amazon basin, between 2009 and 2016. The average age was 12,7 ±13.7 years, range between 1 to 44 years and 4/8 cases were men. One case was associated with acute diarrheal disease, another with Leptospirosis, and two with urinary tract infection. The global case fatality-rate was 12.5% ​​(1/8). Late detection is a frequent characteristic related with low diagnostic suspicion in patients with a history of fever. The TcI and TcIV lineage was identified as the etiological agent of Chagas disease. Eight new cases of ACDs are reported, of which seven were children.

Características clínicas y epidemiológicas de casos de enfermedad de Chagas aguda en la cuenca amazónica peruana, 2009-2016 / Clinical and epidemiological characteristics of cases of acute Chagas disease in the Peruvian Amazon basin, 2009-2016

RESUMEN Los casos de la enfermedad de Chagas aguda (ECA) se reportan en forma esporádica en el Perú. En este artículo se describe las características clínicas y epidemiológicas de ocho nuevos casos de ECA detectados por el sistema de vigilancia en la cuenca amazónica, entre 2009 y 2016. La media de la edad fue 12,7 ± 13,7 años, rango de 1 a 44 años y 4/8 casos fueron varones. Un caso se asoció a enfermedad diarreica aguda, otro a leptospirosis y dos a infección del tracto urinario. La tasa de letalidad global fue 12,5% (1/8). La detección tardía es una característica frecuente relacionada a una escasa sospecha diagnóstica en pacientes con historial de fiebre. Se identificó el linaje TcI y TcIV del agente etiológico de la enfermedad de Chagas. Se reporta ocho nuevos casos de ECA, de los cuales siete fueron menores de edad.

ABSTRACT Acute Chagas disease (ACD) cases are reported sporadically in Peru. In this report we describe the clinical and epidemiological characteristics of eight new ACD cases detected by the surveillance system in the Amazon basin, between 2009 and 2016. The average age was 12,7 ±13.7 years, range between 1 to 44 years and 4/8 cases were men. One case was associated with acute diarrheal disease, another with Leptospirosis, and two with urinary tract infection. The global case fatality-rate was 12.5% ​​(1/8). Late detection is a frequent characteristic related with low diagnostic suspicion in patients with a history of fever. The TcI and TcIV lineage was identified as the etiological agent of Chagas disease. Eight new cases of ACDs are reported, of which seven were children.

Characterization of Polysaccharide A Response Reveals Interferon Responsive Gene Signature and Immunomodulatory Marker Expression.

Polysaccharide A (PSA), a capsular carbohydrate from the commensal gut bacteria Bacteroides fragilis, has been shown to possess both potent T cell-dependent pro- and anti-inflammatory properties. PSA is able to induce abscess and adhesion formation in sepsis models, but can also inhibit asthma, inflammatory bowel disease (IBD) and experimental autoimmune encephalomyelitis (EAE) through MHCII-dependent activation of CD4+ T cells. Yet, despite decades of study, the ability of PSA to balance both these pro- and anti-inflammatory responses remains poorly understood. Here, we utilized an unbiased systems immunology approach consisting of RNAseq transcriptomics, high-throughput flow cytometry, and Luminex analysis to characterize the full impact of PSA-mediated stimulation of CD4+ T cells. We found that exposure to PSA resulted in the upregulation and secretion of IFNγ, TNFα, IL-6, and CXCL10, consistent with an interferon responsive gene (IRG) signature. Importantly, PSA stimulation also led to expression of immune checkpoint markers Lag3, Tim3, and, especially, PD1, which were also enriched and sustained in the gut associated lymphoid tissue of PSA-exposed mice. Taken together, PSA responding cells display an unusual mixture of pro-inflammatory cytokines and anti-inflammatory surface receptors, consistent with the ability to both cause and inhibit inflammatory disease.

The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases.

Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis (SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL, p < 0.01) and SSc (0.611 ± 0.296 ng/mL, p < 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target.

Rates of appropriate laxative prophylaxis for opioid-induced constipation in veterans with lung cancer: a retrospective cohort study.

PURPOSE: Opioid-induced constipation (OIC) is the most common side effect in patient-prescribed opioids for cancer pain treatment. Current guidelines recommend routine prescription of a laxative for preventing OIC in all patients prescribed an opioid unless a contraindication exists. We determined patterns of prescription of laxative agents in patients with lung cancer initiating opioids. METHODS: We performed a retrospective cohort study evaluating the prescription of laxatives for OIC to adult patients with incident lung cancer seen in the Veteran's Affairs (VA) system, between January 1, 2003, and December 31, 2016. Exposure to laxative agents was categorized as follows: none, docusate monotherapy, docusate plus another laxative, and other laxatives only. Prevalence of OIC prophylaxis was analyzed using descriptive statistics. Linear regression was performed to identify time trends in the prescription of OIC prophylaxis. RESULTS: Overall, 130,990 individuals were included in the analysis. Of these, 87% of patients received inadequate prophylaxis (75% no prophylaxis and 12% docusate alone), while 5% received OIC prophylaxis with the unnecessary addition of docusate to another laxative. Through the study period, laxative prescription significantly decreased, while all other categories of OIC prophylaxis were unchanged. We noted an inverse relationship with OIC prophylaxis and likelihood of a diagnosis of constipation at 3 and 6 months. CONCLUSIONS: In this study of veterans with lung cancer, almost 90% received inadequate or inappropriate OIC prophylaxis. Efforts to educate physicians and patients to promote appropriate OIC prophylaxis in combination with systems-level changes are warranted.

Triosephosphate isomerase, carbonic anhydrase, and creatinine kinase-brain isoform are possible antigen targets in patients with achalasia.

BACKGROUND: Idiopathic achalasia is an uncommon esophageal motor disorder. The disease involves interaction between inflammatory and autoimmune responses. However, the antigens related to the disease are still unknown. AIM: To identify the possible antigen targets in muscle biopsies from lower esophageal sphincter (LES) of achalasia patients. METHODS: Esophageal biopsies of patients with type I and type II achalasia and esophagogastric junction outflow obstruction (EGJOO) were analyzed. Lower esophageal sphincter muscle biopsy from a Healthy organ Donor (HD) was included as control for two-dimensional gel electrophoresis. Immunoblotting of muscle from LES lysate with sera of type I, type II achalasia, or type III achalasia, sera of EGJOO and sera of healthy subjects (HS) was performed. The target proteins of the serum were identified by mass spectrometry Matrix-assited laser desorption/ionization time-of-flight (MALDI-TOF). KEY RESULTS: The proteomic map of muscle from LES tissue lysates of type I, and type II achalasia, EGJOO, and HD were analyzed and divided into three important regions. We found a difference in the concentration of certain spots. Further, we observed the serum reactivity of type I achalasia and type II achalasia against 45 and 25 kDa bands of type I achalasia tissue. Serum of type III achalasia and EGJOO mainly recognized 25 kDa band. Bands correspond to triosephosphate isomerase (TPI) (25 kDa), carbonic anhydrase (CA) (25 kDa) and creatinine kinase-brain (CKB) isoform (45 kDa). CONCLUSIONS AND INFERENCES: We identify three antigen targets, TPI, CA, and CKB isoform, which are recognized by sera from patients with achalasia.

Impact of a Formulation Containing Unusual Polyunsaturated Fatty Acids, Trace Elements, Polyphenols and Plant Sterols on Insulin Resistance and Associated Disturbances.

INTRODUCTION: To evaluate the effect of a lipid-based formulation containing unusual polyunsaturated fatty acids, trace elements, polyphenols and plant sterols on insulin resistance and its associated disturbances among adults at risk of diabetes. METHODS: This was an 8-week, three-arm, open-label randomized clinical trial. We studied individuals aged ≥ 18 years old with diabetes risk given by a body mass index ≥ 25 kg/m2 or a FinnRisc score ≥ 13/20. Participants were randomly assigned to receive: 7 ml sunflower oil (control group), 3.5 ml of the study formulation + 3.5 ml of sunflower oil (low-dose group) or 7 ml of study formulation (high-dose group). RESULTS: We randomized 25 individuals. After one withdrawal in the high-dose group, the study sample comprised nine patients in the control, nine in the low-dose and six in the high-dose groups. The insulin sensitivity increased significantly and in a dose-dependent fashion, up to 10% in the high-dose group. At week 8 the low-dose group exhibited lower glycemic excursions during the oral glucose tolerance test (OGTT), especially 1 h after the glucose challenge (32 mg/dl or 23% lower vs. control group). The incremental area under the glucose curve in the OGTT was 17.1% lower in the low-dose group vs. the control group. Waist circumference increased in the control group, remained constant in the low-dose group and decreased in the high-dose group. C-reactive protein decreased in both formulation groups, up to 50% in the high-dose group. Participants in the formulation groups exhibited increased secretion of GLP-1 and plasma irisin at week 8 vs. the control group. CONCLUSION: The formulation induced favorable changes in insulin sensitivity, glucose tolerance, abdominal obesity and inflammation. These effects and their durability will need to be assessed in larger studies. TRIAL REGISTRATION: NCT03512665. FUNDING: Team Foods Colombia.

CD45Rb-low effector T cells require IL-4 to induce IL-10 in FoxP3 Tregs and to protect mice from inflammation.

CD4+ effector/memory T cells (Tem) represent a leading edge of the adaptive immune system responsible for protecting the body from infection, cancer, and other damaging processes. However, a subset of Tem cells with low expression of CD45Rb (RbLoTem) has been shown to suppress inflammation despite their effector surface phenotype and the lack of FoxP3 expression, the canonical transcription factor found in most regulatory T cells. In this report, we show that RbLoTem cells can suppress inflammation by influencing Treg behavior. Co-culturing activated RbLoTem and Tregs induced high expression of IL-10 in vitro, and conditioned media from RbLoTem cells induced IL-10 expression in FoxP3+ Tregs in vitro and in vivo, indicating that RbLoTem cells communicate with Tregs in a cell-contact independent fashion. Transcriptomic and multi-analyte Luminex data identified both IL-2 and IL-4 as potential mediators of RbLoTem-Treg communication, and antibody-mediated neutralization of either IL-4 or CD124 (IL-4Rα) prevented IL-10 induction in Tregs. Moreover, isolated Tregs cultured with recombinant IL-2 and IL-4 strongly induced IL-10 production. Using house dust mite (HDM)-induced airway inflammation as a model, we confirmed that the in vivo suppressive activity of RbLoTem cells was lost in IL-4-ablated RbLoTem cells. These data support a model in which RbLoTem cells communicate with Tregs using a combination of IL-2 and IL-4 to induce robust expression of IL-10 and suppression of inflammation.

Myocardial fibrosis detected by magnetic resonance imaging, elevated U-CRP and higher mRSS are predictors of cardiovascular complications in systemic sclerosis (SSc) patients.

INTRODUCTION: In previous studies we showed that prevalence of myocardial fibrosis as assessed by late enhancement on cardiac MRI in SSc patients is 45% and is associated to diffuse disease (dcSSc) and lower left ventricle ejection fraction; microvascular damage defined as decreased perfusion on cardiac MRI after adenosine infusion, was also very frequent (79%). Our aim was to identify baseline characteristics associated to the development of cardiovascular outcomes (heart failure, coronary artery disease, arrhythmias, vasculopathy, elevated systolic pulmonary artery pressure and death) in SSc patients with previously documented myocardial fibrosis and microvascular damage. PATIENTS AND METHODS: We included 62 SSc patients who participated in the study of prevalence of myocardial fibrosis (2008-2010) and in our local SSc cohort. We performed baseline clinical evaluation, cardiac MRI, coronary CT angiography, transthoracic echocardiogram, and yearly clinical and cardiovascular evaluation that included Medsger's severity scale items, electrocardiogram, echocardiogram, chest X-ray or HRCT and spirometry; we registered presence and severity of internal organ involvement and cardiovascular outcomes. Ordinal variables were analyzed using Chi square test and Fisher test when appropriate, numeric variables were compared using Student's t-test or Mann Whitney U when appropriate, logistic regression and Cox proportional hazard ratio were used to perform multivariable analysis. RESULTS: We obtained follow-up information from 62 patients (29 dcSSc, 33 lcSSc), mean follow-up was 43.5 months. Multivariable analysis showed that elevated basal ultrasensitive CRP was associated to mortality (p = 0.004, OR: 11.9, 95% CI 2.1-65.7) and recurrent digital tip ischemic ulcers (p = 0.001, OR 26.8, 95% CI 3,9-181.3) on follow-up. Myocardial fibrosis, particularly in the middle segments (p = 0.01, OR: 11.49, 95% CI 1.6-83), and older age (p = 0.02, OR: 1.11, 95% CI 1.01-1.22) were associated to heart failure on follow-up. Higher maximum mRSS was associated to coronary artery disease (p = 0.02, OR: 1.2, 95% CI 1.02-1.38), while insertion point fibrosis (p = 0.001, OR: 12.5 95% CI 2.7-56.6) was associated to recurrent digital tip ischemic ulcers. CONCLUSIONS: This study shows that myocardial fibrosis, elevated ultrasensitive CRP, and higher maximum mRSS are independent predictors of cardiovascular outcomes in SSc patients. Future studies should focus on early preventive and therapeutic strategies for this group of patients.

Impact of piperacillin/tazobactam on nephrotoxicity in patients with Gram-negative bacteraemia.

Piperacillin/tazobactam (TZP) has been associated with nephrotoxicity in patients receiving vancomycin. Its impact on nephrotoxicity in patients with Gram-negative bacteraemia (GNB) is unclear. This study evaluated the impact of TZP on nephrotoxicity in patients with GNB. This retrospective cohort included patients aged ≥18 years receiving ≥48 h of therapy for bacteraemia due to Escherichia coli, Pseudomonas aeruginosa, Enterobacter, Klebsiella, Acinetobacter or Stenotrophomonas maltophilia from 1/01/2008-8/31/2011. Patients with baseline serum creatinine (SCr) ≥3.5 mg/dL, polymicrobial infection or recurrent bacteraemia were excluded. Nephrotoxicity was defined as a ≥0.5 mg/dL increase in SCr or ≥50% increase from baseline for ≥2 consecutive days. Any variable demonstrating a 10% change in exposure effect was retained in the final model. All variables biologically reasonable causes of nephrotoxicity were also considered for inclusion. The median age of the cohort (n = 292) was 76 years; 38.0% had a cancer diagnosis and ICU residence was common (21.9%). There was no difference in nephrotoxicity incidence based on days of TZP received (0 days, 13.6%; 1-2 days, 14.7%; 3-4 days, 6.9%; ≥5 days, 16.7%; P = 0.71). In multivariable analysis, baseline SCr, total body weight and vasopressor use were independently associated with nephrotoxicity. Duration of TZP was not associated with nephrotoxicity in multivariable analysis (1-2 days, OR = 0.91, 95% CI 0.39-2.12; 3-4 days, OR = 0.48, 95% CI 0.10-2.46; ≥5 days, OR = 0.57, 95% CI 0.11-3.02). In this cohort of GNB patients, duration of TZP was not associated with nephrotoxicity.

Anti-RNP/Sm antibodies in patients with systemic lupus erythematosus and its role in thrombosis: a case-control study.

OBJECTIVE: To validate the association of thrombotic events with positive lupus anticoagulant (LA) and co-presence of anti-RNP/Sm, as well as the diagnostic accuracy of this combination of antibodies for thrombosis. METHODS: Case-control study of patients with systemic lupus erythematosus (SLE) who presented thrombosis after SLE diagnosis and controls with SLE without thrombosis. Comorbidities, traditional risk factors, clinical variables, and treatment were evaluated. Antiphospholipid (aPL) and anti-RNP/Sm antibodies were determined. RESULTS: Sixty-three cases and 63 controls were studied, 88% women, median age of 40 years, and disease duration of 135 months at study inclusion. No differences were found between groups regarding age, comorbidities, or clinical characteristics at SLE diagnosis. Patients with thrombosis were more frequently positive for anti-RNP/Sm (p = 0.001), IgG aCL (p = 0.02), IgG anti-B2GPI (p = 0.02), IgM anti-B2GPI (p = 0.02), LA (p < 0.001), the combination of anti-RNP/Sm + LA (p < 0.001), and aPL triple marker (p = 0.002), compared to controls. The combination of anti-RNP/Sm + LA, SLEDAI-2 K, and prednisone dose was associated with thrombosis (p < 0.05). The combination of anti-RNP/Sm + LA showed 56% sensitivity, 79% specificity, 73% positive predictive value, 64% negative predictive value, positive likelihood ratio (LR) 2.69, and negative LR 0.56 for predicting thrombosis. No difference was found in the comparison of area under the curve between LA alone and the combination of anti-RNP/Sm + LA (p = 0.73). CONCLUSION: Thrombosis was associated with disease activity, dose of prednisone, and the combination of anti-RNP/Sm antibodies and LA. This combination of antibodies could be useful in the identification of SLE patients at risk of thrombosis.

Polypharmacy and patterns of prescription medication use among cancer survivors.

BACKGROUND: The population of cancer survivors is rapidly growing in the United States. Long-term and late effects of cancer, combined with the ongoing management of other chronic conditions, make survivors particularly vulnerable to polypharmacy and its adverse effects. In the current study, the authors examined patterns of prescription medication use and polypharmacy in a population-based sample of cancer survivors. METHODS: Using data from the Medical Expenditure Panel Survey (MEPS), the authors matched cancer survivors (5216 survivors) with noncancer controls (19,588 controls) by age, sex, and survey year. Polypharmacy was defined as ≥5 unique medications. The authors estimated the percentage of respondents prescribed medications within therapeutic classes and total prescription expenditures. RESULTS: A higher percentage of cancer survivors were prescribed ≥5 unique medications (64.0%; 95% confidence interval [95% CI], 62.3%-65.8%) compared with noncancer controls (51.5%; 95% CI, 50.4%-52.6%), including drugs with abuse potential. Across all therapeutic classes, a higher percentage of newly (≤1 year since diagnosis) and previously (>1 years since diagnosis) diagnosed survivors were prescribed medications compared with controls, with large differences observed with regard to central nervous system agents (65.8% [95% CI, 62.3%-69.3%] vs 57.4% [95% CI, 55.3%-59.5%] vs 46.0% [95% CI, 45.0%-46.9%]). Specifically, nearly 10% of survivors were prescribed benzodiazepines and/or opioids compared with approximately 5% of controls. Survivors had more than double the prescription expenditures (median of $1633 vs $784 among controls). Findings persisted across age and comorbidity categories. CONCLUSIONS: Cancer survivors were prescribed a higher number of unique medications, including drugs with abuse potential, thereby increasing their risk of adverse drug events, financial toxicity, poor adherence, and drug-drug interactions. Cancer 2018;124:2850-2857. © 2018 American Cancer Society.

Impact of total body weight on 30-day mortality in patients with gram-negative bacteremia.

BACKGROUND: The impact of total body weight (TBW) on 30-day mortality associated with gram-negative bacteremia has not been previously evaluated. METHODS: The cohort included 323 patients >/ = 18 years old with gram-negative bacteremia (1/1/2008-8/31/2011) who received >/ = 48 hours of antibiotics. We compared 30-day mortality of TBW <70 kg vs. >/ = 70 kg with a multivariable stepwise logistic regression adjusting for age >/ = 70 years, cancer diagnosis, and Pitt bacteremia score of >/ = 4. RESULTS: The cohort was 57% TBW >/ = 70 kg and 43% TBW <70 kg. TBW >/ = 70 kg patients had lower 30-day mortality (11.0% vs. 16.3%), which was significant in the multivariable analysis (OR 0.45, 95% CI 0.21-0.97). Cancer and Pitt bacteremia score >/ = 4 were also independently associated with 30-day mortality. TBW was no longer significant when TBW <50 kg patients were excluded. CONCLUSION: TBW >/ = 70 kg was associated with an improved 30-day mortality; however, the high mortality rates for patients with a TBW < 50 kg is responsible for this association.

High Initiation of Adjuvant Hormonal Therapy Among Uninsured Stages I-III Breast Cancer Patients Treated in a Safety-Net Healthcare System.

OBJECTIVE: Despite benefits of adjuvant hormonal therapy (AHT), many eligible breast cancer patients do not complete therapy as recommended. Patterns of AHT use have not been well studied among uninsured breast cancer patients who fall into coverage gaps or are ineligible for public insurance programs. METHODS: We identified 291 patients newly diagnosed with stages I-III hormone receptor-positive breast cancer from January 2008 to December 2012. All patients were treated at a safety-net healthcare system and enrolled in an income-based medical assistance program that fills AHT prescriptions at low cost. We extracted and linked cancer registry, pharmacy claims, and medical record data to assess AHT initiation (defined as a new AHT prescription ≤18 months since diagnosis) and sociodemographic and healthcare utilization variables. Log-binomial regression was used to identify correlates of initiation. RESULTS: Overall, 239 (82%) patients initiated AHT. Tamoxifen (42%) and anastrozole (55%) were most commonly prescribed. The mean copay was $4.90 for tamoxifen and $6.00 for anastrozole. Although crude analyses revealed small, statistically significant prevalence ratios for race/ethnicity (Hispanic vs. white, other vs. white), year of diagnosis (2008 vs. 2012), primary care visit before diagnosis (any vs. none), and smoking status (current vs. never), there were no significant correlates of initiation in the adjusted model. CONCLUSION: Safety-net healthcare systems providing access to AHT (i.e., through reduced copays) could improve the number of eligible patients initiating therapy. Continuity and integration of care in these settings may reduce disparities frequently observed in uninsured, low-income breast cancer populations.

Venous and Arterial Thrombotic Events in Systemic Lupus Erythematosus.

OBJECTIVE: The incidence of thrombosis in patients with systemic lupus erythematosus (SLE) is 25 to 50-fold higher than in the general population; we aimed to define the characteristics of venous thrombotic events (VTE) and arterial thrombotic events (ATE) to identify the patients at highest risk. METHODS: The study included 219 patients with recent-onset SLE. At baseline, standardized medical history and laboratory tests were done. Followup visits occurred quarterly, and information about damage accrual, comorbidities, and cardiovascular risk factors was updated annually. Main outcome was development of TE after SLE diagnosis. RESULTS: Thirty-five patients (16%) developed TE (27 VTE, 8 ATE) during 5.21 years of followup; incidence rate 31/1000 patient-years. Most events (57%) developed within the first year of diagnosis, and 69% were not associated with lupus anticoagulant (LAC), determined with 1 method. VTE developed earlier than ATE (2.0 vs 57.5 mos, p = 0.02). In the multivariate analysis, variables preceding VTE included cutaneous vasculitis, nephrotic syndrome, dose of prednisone, and LAC in combination with anti-RNP/Sm antibodies (p < 0.03). Patients with ATE were older (median age 44 vs 29 yrs, p = 0.04), smokers, and had hypertension, diabetes mellitus, dyslipidemia, at least 2 traditional risk factors, nephrotic syndrome, chronic damage, and a higher cumulative dose of prednisone (p < 0.05). LAC in combination with anti-RNP/Sm antibodies was associated with VTE and improved the accuracy for predicting it. CONCLUSION: Our study suggests that in SLE, VTE and ATE have different risk factors. Understanding these differences is helpful for identifying patients at highest risk. The use of LAC plus anti-RNP/Sm for predicting VTE deserves further study.

The amount of citrullinated proteins in synovial tissue is related to serum anti-cyclic citrullinated peptide (anti-CCP) antibody levels.

The objective of this study was to determine the relationship between citrullinated proteins in synovial tissue with peripheral anti-citrullinated peptides autoantibodies (ACPA) and peptidylarginine deiminase (PADI) PADI2, PADI3, and PADI4 messenger RNA (mRNA) expressions in synovial tissue and fibroblast-like synoviocytes in rheumatoid arthritis (RA) patients. Eleven RA and 12 osteoarthritis (OA) patients who underwent knee replacement surgery were studied. We detected citrullinated proteins in synovial tissue homogenates by western blot and serum ACPA by ELISA to anti-cyclic citrullinated peptide (anti-CCP) antibodies, and PADI2, PADI3, and PADI4 mRNA expressions in synovial tissue and in fibroblast-like synoviocytes. Patients with high amount of citrullinated proteins in synovial tissue (3 out of 7) have high levels of anti-CCP in serum. However, in the remaining 4 patients, the amount of synovial citrullinated proteins was minimal and their sera showed low levels of anti-CCP antibodies. Furthermore, we observed an increase in PADI2 mRNA expression in RA synovial tissue compared with OA patients (p = 0.02). We detected PADI3 mRNA in the synovial tissue of RA patients, but not in the tissue of OA patients. Even though fibroblast-type synoviocytes in RA are not the main source of PADs in the synovial tissue, they express PADI2 mRNA moderately, PADI4 mRNA weakly, while there is no detectable expression of PADI3 mRNA. In conclusion, we found a variety of citrullinated proteins in the synovial tissue of RA patients and the amount of such proteins is related to serum concentration of anti-CCP antibodies. We identified the presence of PADI3 mRNA expression in synovial tissue and PADI2 and PADI4 mRNA expressions in fibroblast-like synoviocytes from patients with RA.