Search

Background: Whole-mount histopathology (WMH) has been a powerful tool to investigate the characteristics of prostate cancer. However, the latest advancement of WMH was yet under summarization. In this review, we offer a comprehensive exposition of current research utilizing WMH in diagnosing and treating prostate cancer (PCa), and summarize the clinical advantages of WMH and outlines potential on future prospects. Methods: An extensive PubMed search was conducted until February 26, 2023, with the search term "prostate", "whole-mount", "large format histology", which was limited to the last 4 years. Publications included were restricted to those in English. Other papers were also cited to contribute a better understanding. Results: WMH exhibits an enhanced legibility for pathologists, which improved the efficacy of pathologic examination and provide educational value. It simplifies the histopathological registration with medical images, which serves as a convincing reference standard for imaging indicator investigation and medical image-based artificial intelligence (AI). Additionally, WMH provides comprehensive histopathological information for tumor volume estimation, post-treatment evaluation, and provides direct pathological data for AI readers. It also offers complete spatial context for the location estimation of both intraprostatic and extraprostatic cancerous region. Conclusions: WMH provides unique benefits in several aspects of clinical diagnosis and treatment of PCa. The utilization of WMH technique facilitates the development and refinement of various clinical technologies. We believe that WMH will play an important role in future clinical applications. [ABSTRACT FROM AUTHOR]

Unmeasured confounding undermines the validity of observational studies. Although randomized clinical trials (RCTs) are considered the "gold standard" of study types, we often observe divergent findings between RCTs and empirical settings. We present the "L-table", a simulation-based, prior knowledge (e.g., RCTs) guided approach that estimates the true effect adjusting for the potential influence of unmeasured confounders when using observational data. Using electronic health record data from Kaiser Permanente Southern California, we compare the effectiveness of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) on endpoints at 1, 3, 5, and 10 years for patients with stable ischemic heart disease. We applied the L-table approach to the propensity score adjusted cohort to derive the omitted-confounder-adjusted estimated effects. After the L-table adjustment, CABG patients are 57.6% less likely to encounter major adverse cardiac and cerebrovascular event (MACCE) at 1 year (OR [95% CI] 0.424 [0.396, 0.517]), 56.4% less likely at 3 years (OR [95% CI] 0.436 [0.369, 0.527]), and 48.9% less likely at 5 years (OR [95% CI] 0.511 [0.451, 0.538]). CABG patients are also 49.5% less likely to die by the end of 10 years than PCI patients (OR [95% CI] 0.505 [0.446, 0.582]). We found the estimated true effects all shifted towards CABG as a more effective procedure that led to better health outcomes compared to PCI. Unlike existing sensitivity tools, the L-table approach explicitly lays out probable values and can therefore better support clinical decision-making. We recommend using L-table as a supplement to available techniques of sensitivity analysis. [ABSTRACT FROM AUTHOR]

Background: Direct oral anticoagulants such as dabigatran are the preferred anticoagulant in treating atrial fibrillation (AF) patients due to their effectiveness and safety. Whether this applies to severely obese patients needs to be determined. Objective: To compare the effectiveness and safety of dabigatran with warfarin among AF patients with severe obesity. Design: Retrospective cohort study. Participants: AF patients with a BMI >40kg/m2 or a weight >120kg receiving dabigatran or warfarin between 10/01/2010 and 12/31/2019 in a large integrated health system and followed through 08/01/2020. Interventions: Not applicable. Main measures: Primary effectiveness outcome was composite thromboembolism including transient ischemic attack, ischemic stroke, or systemic embolism. Primary safety outcome was composite bleeding including gastrointestinal bleeding, intracranial bleeding, or other bleeding. Secondary outcomes included the individual outcomes and all-cause mortality. Propensity score matching (PSM) was performed to create a 1:1 matched cohort and Cox proportional hazards model was used to estimate the hazard ratio (HR) of each outcome for dabigatran users compared to warfarin users. Key Results: A total of 6848 patients receiving either dabigatran or warfarin were identified. In a 1:1 matched cohort, dabigatran users had a HR of 0.71 (95% confidence interval (CI): 0.56–0.91) for composite thromboembolism, a HR of 1.24 (95%CI: 1.07–1.42) for composite bleeding, and a HR of 0.57 (95% CI: 0.45–0.71) for all-cause mortality when compared to warfarin users. Conclusions: Among AF patients with a BMI >40kg/m2 or a weight >120kg in a real-world clinical setting, dabigatran was effective in reducing the risk of thromboembolism and mortality but was associated with an increased risk of bleeding when compared to warfarin. Dabigatran may be a reasonable option for AF patients with severe obesity. [ABSTRACT FROM AUTHOR]

Background: Kaiser Permanente Southern California began offering a 4‐week supplemental benefit of home‐delivered meals to Medicare Advantage members after discharge from a hospitalization for heart failure and other medical conditions in 2021. The purpose of this study is to explore the associations between socioeconomic disadvantage and food insecurity with patient uptake of and satisfaction with the meals. Methods: Data for this cross‐sectional study were drawn from survey and electronic medical record data for members referred for the meals benefit (n = 6169) and linked to a hospitalization encounter (n = 2254) between January and December 2021. Uptake was assessed using vendor records; measures of socioeconomic status included the neighborhood deprivation index (NDI) and prior receipt of medical financial assistance (MFA) from the health system. Patients were invited to complete an email or phone survey about their satisfaction with the meals and food insecurity. Multivariable log‐binomial regression models were used to examine the association between socioeconomic disadvantage and food insecurity with meals uptake and satisfaction. Results: Sixty‐two percent of patients referred for the benefit accepted the meals (mean age: 79 ± 9, 59% people of color). While there was no significant relationship between NDI and meals uptake (RR: 0.99, 95% CI: 0.92–1.07, p = 0.77), patients who received prior MFA were more likely to accept the meals (RR: 1.09, 95% CI: 1.02–1.16, p < 0.01). Sixty‐nine percent of patients who completed the survey (23% response rate) reported that meals were very or extremely helpful. Patients with food insecurity (29% of survey respondents) were more likely to report that the meals were helpful for their recovery compared to food secure patients (RR: 1.21, 95% CI: 1.09–1.35, p < 0.01). Conclusions: The home‐delivered meals appeared to be particularly utilized by and helpful to patients with greater financial strain and/or food insecurity, suggesting that supplemental benefits could be more targeted toward addressing unmet needs of vulnerable adults. See related Editorial by Amit Kumar. [ABSTRACT FROM AUTHOR]

Heart failure is an uncommon diagnosis among pregnant women with limited data on this condition. We sought to describe the characteristics and outcomes of pregnant women with heart failure stratified by etiologies of cardiomyopathy. This is a retrospective population-based cohort study across medical centers in Southern California in the United States. Pregnant women with heart failure were identified using ICD-9 codes and adjudicated by manual review of the medical records. Obstetric complications, fetal birthweight, and maternal mortality outcomes were evaluated. Between 2003 and 2014, there were 488 pregnancies (0.1% of all pregnancies) complicated by heart failure, of which 333 (68.2%) were due to peripartum cardiomyopathy (PPCM) and 155 (31.8%) were due to other etiologies (non-PPCM). Compared to patients with non-PPCM, patients with PPCM were more likely to be Black Americans (26.7% vs 15.5%) or Asian Americans (16.8% vs 7.1%). A high proportion of PPCM patients had preeclampsia (11.1% vs 5.2%, p = 0.04). Infants born to mothers with non-PPCM were more likely to be small for gestational age (SGA) (SGA <3% 4.1% vs 9.7%, p < 0.001; SGA <10% 20% vs 8.8%, p = 0.001). No significant difference in maternal mortality was observed between PPCM and non-PPCM patients. PPCM is the most common etiology of HF during pregnancy. Infants born to mothers with PPCM were likely to be small for gestational age. • Peripartum cardiomyopathy comprised of 68% of heart failure cases in pregnant women. • Pre-eclampsia was more common in patients with peripartum cardiomyopathy • A higher proportion of infants born to mothers with non-peripartum cardiomyopathy were small for gestational age. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: The goal of this study was to describe the pattern of statin adherence in older patients, aged 80 years or older; identify factors associated with high adherence; and determine the association between statin adherence and all‐cause mortality. DESIGN: Retrospective population‐based cohort study. SETTING: An integrated healthcare system in Southern California. PARTICIPANTS: Patients hospitalized with a principal diagnosis of acute myocardial infarction (MI) between January 1, 2006, and December 31, 2016. MEASUREMENTS: Statin adherence, as measured using pharmacy dispensing records over the 365 days following hospital discharge, based on proportion of days covered (PDC). Adherence levels were categorized as high (PDC 80% or higher), partial (PDC 40% or higher and lower than 80%), and low (PDC lower than 40%). RESULTS: Between 2006 and 2016, 5629 patients, 80 years or older, hospitalized for acute MI met the inclusion criteria. Among this group, 68.8% were highly adherent to statin therapy, 20.4% were partially adherent, and 10.8% were not adherent. Male sex (odds ratio [OR] = 1.42; 95% confidence interval [CI] = 1.25‐1.62) and white race (OR = 1.35; 95% CI = 1.18‐1.55) were associated with high statin adherence. Follow‐up was 4.3 ± 2.6 years. Both low and partial adherence were associated with increase mortality (low adherence: adjusted hazard radio [HR] = 1.12; 95% CI = 1.01‐1.25; partial adherence: adjusted HR = 1.22; 95% CI = 1.12‐1.32). CONCLUSIONS: In older patients, aged 80 years or older, high adherence to statins after MI was associated with improved survival. This association may not have been due only to adherence to statins but to other related factors as well. Findings from this study may inform discussions on the potential benefits of statin adherence. J Am Geriatr Soc 67:2045–2049, 2019 [ABSTRACT FROM AUTHOR]

Beta-blockers are one of the most commonly prescribed classes of antihypertensive medications during pregnancy. Previous studies reported an association between beta-blocker exposure and intrauterine growth restriction. Whether some beta-blocker subtypes may be associated with higher risk is not known. This is a retrospective cohort study of pregnant women exposed to beta-blockers in the Kaiser Permanente Southern California Region between 2003 and 2014. Logistic regression models were used to evaluate association between exposure to different beta-blocker agents and risk of low fetal birth weights. In a cohort of 379 238 singleton pregnancies, 4847 (1.3%) were exposed to beta-blockers. The four most commonly prescribed beta-blockers were labetalol (n = 3357), atenolol (n = 638), propranolol (n = 489), and metoprolol (n = 324). Mean birth weight and % low birth weight (<2500 g) were 2926 ± 841 g and 24.4% for labetalol, 3058 ± 748 g and 18.0% for atenolol, 3163 ± 702 g and 13.3% for metoprolol, 3286 ± 651 g and 7.6% for propranolol, and 3353 ± 554 g and 5.2% for non-exposed controls. Exposure to atenolol and labetalol were associated with increased risks of infant born small for gestational age (SGA) (atenolol: adjusted OR 2.4, 95% CI: 1.7-3.3; labetalol: adjusted OR 2.9, 95% CI: 2.6-3.2). Risk of SGA associated with metoprolol or propranolol exposure was not significantly different from the non-exposed group (metoprolol: adjusted OR 1.5, 95% CI: 0.9-2.3; propranolol: adjusted OR 1.3, 95% CI: 0.9-1.9). Association between beta-blocker exposure and SGA does not appear to be a class effect. Variations in pharmacodynamics and confounding by indication may explain these findings. [ABSTRACT FROM AUTHOR]

Context: Many patients with ductal carcinoma in situ (DCIS) receive treatment that is too extensive. Objective: To take a holistic approach in comparing the effectiveness in cancer prevention between mastectomy and breast-conserving surgery (BCS) for patients with DCIS. Design: Female Kaiser Permanente Southern California members who underwent surgery for treatment of single primary DCIS from 2004 to 2014 were identified by the Kaiser Permanente Southern California cancer registry and HealthConnect database. Method: Two-stage residual inclusion with the surgeon's preference of surgical procedure type as the instrumental variable was used to examine the effect of surgical choice on DCIS recurrence, breast cancer progression, and other cancer progression. Traditional Cox proportional hazards models were used for comparison. Results: Of qualified subjects, 72.2% underwent BCS and 27.8% underwent mastectomy. Patients were likelier to receive BCS if their surgeon preferred to perform BCS in the past 5 years (odds ratio = 1.02, 95% confidence interval = 1.02-1.03). Although traditional Cox proportional hazards models suggested an association between BCS and higher risk of DCIS recurrence, no significant effect was observed when we adjusted for endogeneity. Neither model showed significant differences between mastectomy and BCS in progression of any cancer. Conclusion: No significant benefit was observed with a more aggressive surgical procedure in preventing DCIS recurrence or cancer progression in a diverse population. Many patients with DCIS could benefit from BCS with preservation of their body image. Breast conservation followed-up with cancer surveillance is a rational approach to ensure affordable, effective care for patients with DCIS. [ABSTRACT FROM AUTHOR]

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by the expansion of GGC trinucleotide repeats in NOTCH2NLC gene. Despite identifying uN2CpolyG, a toxic polyglycine (polyG) protein translated by expanded GGC repeats, the exact pathogenic mechanisms of NIID remain unclear. In this study, we investigated the role of polyG by expressing various forms of NOTCH2NLC in mice: the wild-type, the expanded form with 100 GGC repeats (either translating or not translating into uN2CpolyG), and the mutated form that encodes a pure polyG without GGC-repeat RNA and the C-terminal stretch (uN2CpolyG-dCT). Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and resulted in neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathologic lesions such as white-matter lesions, microgliosis, and astrogliosis. In contrast, expressing GGC-repeat RNA alone was non-pathogenic. Through bulk and single-nuclei RNA sequencing, we identified common molecular signatures linked to the expression of uN2CpolyG and uN2CpolyG-dCT, particularly the upregulation of inflammation and microglia markers, and the downregulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients using positron emission tomography, correlating with levels of white-matter atrophy. Furthermore, microglia ablation ameliorated neurodegenerative phenotypes and transcriptional alterations in uN2CpolyG-expressing mice but did not affect polyG inclusions. Together, these results demonstrate that polyG is crucial for the pathogenesis of NIID and highlight the significant role of microglia in polyG-induced neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Patients with left ventricular thrombus are at high risk for ischemic stroke and systemic embolization. The mainstay of treatment is anticoagulation, but it remains unclear if direct-acting oral anticoagulants (DOACs) are a safe and effective treatment strategy compared to warfarin. We conducted a population-based retrospective cohort study to evaluate the effectiveness and safety of DOACs compared to warfarin in an integrated health system in the United States. Methods: Consecutive patients with left ventricular thrombus on transthoracic echocardiogram from May 2010 to April 2020 were identified. Comparative effectiveness and safety of DOACs and warfarin were evaluated using multivariable Cox proportional hazard models and inverse probability of treatment weighting. Results: Among 433 patients with left ventricular thrombus, 134 (30.9%) were treated with DOACs and 299 (69.1%) were treated with warfarin. Patients were followed for a median of 3.4 years. For the primary effectiveness outcome of ischemic stroke, systemic embolism, and transient ischemic attack, no significant difference was observed between use of DOACs compared to warfarin (adjusted hazard ratio [HR] of 0.75, 95% confidence interval [CI] 0.48–1.18, p = 0.21). For the primary safety outcome of intracranial hemorrhage, gastrointestinal bleeding, and other bleed requiring hospitalization, DOAC usage was associated with a lower risk of bleeding (HR 0.58, 95% CI 0.39–0.87, p = 0.0008). Conclusions: In this diverse population-based cohort of patients, DOAC treatment for left ventricular thrombus appears to be as safe and effective as warfarin treatment. These findings support the use of DOACs for patients with left ventricular thrombus. [ABSTRACT FROM AUTHOR]

Objectives: The study investigates the risk of obesity for young children prescribed an atypical antipsychotic (AAP) for 6 months or more. AAPs are associated with risk of obesity. They are used in children for a variety of psychiatric conditions and are often prescribed off-label. Long-term risk of obesity in this age group is unknown as most studies are short-term investigations and generally combine younger children with adolescents and adults. Methods: A retrospective cohort of children, 10 years old or younger, prescribed either an AAP or selective serotonin reuptake inhibitor (SSRI) for 6 months or more were followed for up to 9.5 years. The primary endpoint was the body-mass index (BMI) reaching the 95th percentile. Results: One thousand six hundred fifty-five patients met inclusion criteria. One thousand one hundred eighteen patients were prescribed an AAP and 537 were prescribed an SSRI: 1152 (74.5%) patients were male and mean (standard deviation) age was 7.9 [1.90] years at study entry. Median follow-up was 3.58 years for the AAP cohort and 3.28 years for the SSRI cohort (p = 0.02). After adjusting for baseline demographic variables, BMI, and other concomitantly prescribed medications, children prescribed AAPs for 6 months or longer were twice as likely to become obese compared with children prescribed SSRIs (adjusted hazard ratio [HR] 2.06 [95% confidence interval; CI 1.60-2.66], p < 0.0001). Further stratification by AAP revealed that the obesity risk for patients prescribed aripiprazole was 34% greater than for those prescribed risperidone (adjusted HR 1.34 [95% CI 1.01-1.78], p = 0.0033). Conclusions: The risk of obesity for young children prescribed an AAP for 6 months or more is approximately double that of children prescribed an SSRI. The risk of obesity is greater with aripiprazole than risperidone in the first year. Prescribers should consider the risk of obesity when prescribing AAPs and consider alternative treatment modalities in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study is to determine the strength of association between treatment with triptans and acute myocardial infarction, heart failure, and death. Background: Case reports in the literature have raised concerns over an association between treatment of migraine headaches with triptans and cardiovascular events. This study aims to systematically evaluate this association in a contemporary population‐based cohort. We hypothesized that triptan exposure is not associated with increased cardiovascular events. Methods: A retrospective cohort study was conducted within an integrated healthcare delivery system in Southern California. From January 2009 to December 2018, 189,684 patients age ≥18 years had a diagnosis of migraine. In this group, 130,656 were exposed to triptans. Patients treated with triptans were matched 1:1 to those not exposed to triptans by using a propensity score. The primary outcome was acute myocardial infarction; secondary outcomes were heart failure, all‐cause death, and combined acute myocardial infarction, heart failure, and death. Results: The incidence rate of acute myocardial infarction was 0.67 per 1000 person‐year in triptan‐exposed vs 1.44 per 1000 person‐year in not exposed patients. In propensity‐matched analyses, the adjusted hazard ratio for triptan exposure was 0.95 (95% confidence interval [CI] 0.84‐1.08) for acute myocardial infarction; 1.00 (95% CI 0.93‐1.08) for all‐cause death; 0.93 (95% CI 0.81‐1.08) for heart failure; and 0.99 (95% CI 0.93‐1.06) for a composite of acute myocardial infarction, heart failure, or death. Sensitivity analyses focusing on stratified subgroups based on age, gender, ethnicity, and several cardiac risk factors also revealed no significant association between triptan exposure and cardiovascular events. Conclusions: No association was found between exposure to triptans and an increased risk of cardiovascular events. These data provide reassurance regarding the cardiovascular safety of utilizing triptans for the medical management of migraine headaches. [ABSTRACT FROM AUTHOR]

Background and Aims: To evaluate impact of ambulatory triglyceride levels on risk of recurrent pancreatitis in patients with hypertriglyceridemic pancreatitis.Methods: We conducted a longitudinal retrospective cohort study of patients with serum triglyceride level ≥ 500 mg/dL during index hospitalization for acute pancreatitis within a regional integrated healthcare system between 2006 and 2013 (follow-up through 2015). Cases were identified based on combination of diagnosis codes and serum amylase/lipase. We used multivariable robust Poisson regression to determine independent effect of baseline (first outpatient) triglyceride measurement on risk of recurrent pancreatitis. Ambulatory triglyceride levels were categorized as normal (0-200 mg/dL), moderately elevated (201-500 mg/dL), and highly elevated (> 500 mg/dL). We further assessed factors related to likelihood of normalization of serum triglycerides (< 200 mg/dL) in the outpatient setting.Results: One hundred and fifty-one patients met study inclusion criteria with median follow-up of 3 years. Overall, 45 (29.8%) patients experienced at least 1 recurrent attack with 25 (16.6%) experiencing multiple episodes. In multivariable analysis, patients that continued to have moderately elevated ((adjusted rate ratio RR 5.47 (95% CL 1.80, 16.65)) as well as highly elevated (RR 8.45 (2.55, 27.96)) triglycerides were at increased risk of disease recurrence compared to patients that achieved normalization. Patients with triglyceride measurement performed within 30 days from discharge were more likely to achieve normalization, 40 versus 26%, p = 0.03.Conclusions: For patients with hypertriglyceridemic pancreatitis, even modest elevation in subsequent triglyceride levels was associated with increased risk of recurrence. Future efforts should focus on ensuring timely care in the outpatient setting with a goal of normalizing triglycerides. [ABSTRACT FROM AUTHOR]

This retrospective cohort study of 95 957 patients from a large integrated healthcare organization was conducted to examine whether the frequency and intervals between outpatient encounters were associated with achieving blood pressure (BP) control. Patients were followed up until they were censored or achieved BP control up to 1 year. Additionally, this study examined the time to BP control. On average, follow-up was significantly longer in patients with uncontrolled BP at 292.9 days compared with 232.2 days in those with BP control. The controlled BP group had significantly more encounters on average compared with the uncontrolled BP group (4.1 vs 3.1, standardized difference 0.33). As the number of days increased between encounters from the 1 to < 14 days, there was a consistently lower likelihood of achieving BP control. Encounter intervals of ≥180 days were associated with the lowest likelihood of achieving BP control. These findings suggest that there may be an optimal number of encounters to benefit patients with hypertension. [ABSTRACT FROM AUTHOR]

Children with mucopolysaccharidosis I (MPS I) develop hyperintense white matter foci on T2-weighted brain magnetic resonance (MR) imaging that are associated clinically with cognitive impairment. We report here a diffusion tensor imaging (DTI) and tissue evaluation of white matter in a canine model of MPS I. We found that two DTI parameters, fractional anisotropy (a measure of white matter integrity) and radial diffusivity (which reflects degree of myelination) were abnormal in the corpus callosum of MPS I dogs compared to carrier controls. Tissue studies of the corpus callosum showed reduced expression of myelin-related genes and an abnormal composition of myelin in MPS I dogs. We treated MPS I dogs with recombinant alpha- l -iduronidase, which is the enzyme that is deficient in MPS I disease. The recombinant alpha- l -iduronidase was administered by intrathecal injection into the cisterna magna. Treated dogs showed partial correction of corpus callosum myelination. Our findings suggest that abnormal myelination occurs in the canine MPS I brain, that it may underlie clinically-relevant brain imaging findings in human MPS I patients, and that it may respond to treatment. [ABSTRACT FROM AUTHOR]

Abstract Background A growing number of young women are exposed to statins during their first trimester of pregnancy. The goal of this study is to examine if first trimester statin exposure is associated with an increase in risk of fetal congenital cardiac anomalies. Methods In a cohort of 379,238 pregnancies, we examined the risk of fetal congenital cardiac anomalies in association with maternal exposure to statin therapy during the first trimester of pregnancy using logistic regression models and propensity score matching methods. Results 280 women were exposed to statins. Congenital cardiac anomalies were present in 14 (5.0%) of pregnancies exposed to statin and 5282 (1.4%) of non-exposed pregnancies. First-trimester statin exposure was associated with an increased risk of ventricular septal defect (adjusted odds ratio [OR] 3.3, 95% confidence interval [CI]l 1.8–6.0, p < 0.001). This association was confirmed in an analysis using a propensity score-matched cohort (OR 4.7, 95% CI 2.0–10.8, p < 0.001). Conclusions Exposure to statins during the first trimester of pregnancy is associated with fetal ventricular septal defect. Highlights • A growing number of young women are exposed to statins during their first trimester of pregnancy • The risk of statin exposure to the fetus and the approach to management of this group of patients are not well defined • This study shows an association between first trimester statin exposure during pregnancy and fetal ventricular septal defect • Consider fetal echocardiogram in pregnant women exposed to statins to allow early diagnosis of fetal congenital heart disease [ABSTRACT FROM AUTHOR]

Background: Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents. Objectives: Our objective was to examine the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in RA, SpA, and IBD, and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis. Methods: We conducted a comprehensive literature search using three databases (PubMed, Web of Science, and the Cochrane library) to identify studies examining the immunogenicity of TNF inhibitors in autoimmune diseases between 1966 and 31 December 2013. Inclusion criteria required that studies be in English, be randomized controlled trials, observational studies, or case reports involving more than five patients, and that the patients be aged 18 years or older. Studies were excluded if they were strictly genetic with no clinical correlate, if the patients had concomitant cancer within 5 years of the study, or if the patients had a renal disease requiring dialysis. Double extraction was followed by a third extraction if needed. Consensus was reached by discussion when disagreements occurred. Random-effect models were generated for the meta-analysis of 68 studies to estimate the odds ratio (OR) of the ADAB effects on TNF inhibitor response. Regression analysis was used to compare among the drugs and diseases. Results: A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5-16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5-32.3) developed ADABs compared with 14.1 % (95 % CI 8.6-22.3) using adalimumab, 6.9 % (95 % CI 3.4-13.5) for certolizumab, 3.8 % (95 % CI 2.1-6.6) for golimumab, and 1.2 % (95 % CI 0.4-3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated OR (with ADABs vs. without) of 0.42 (95 % CI 0.30-0.58); the summary effect for adalimumab yielded an estimated OR (as above) of 0.13 (95 % CI 0.08-0.22); and the OR (as above) for golimumab was 0.42 (95 % CI 0.22-0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when we only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The OR for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21-0.32). Conclusion: ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation. [ABSTRACT FROM AUTHOR]

Autocrine VEGF is necessary for endothelial survival, although the cellular mechanisms supporting this function are unknown. Here, we show that -- even after full differentiation and maturation -- continuous expression of VEGF by endothelial cells is needed to sustain vascular integrity and cellular viability. Depletion of VEGF from the endothelium results in mitochondria fragmentation and suppression of glucose metabolism, leading to increased autophagy that contributes to cell death. Gene-expression profiling showed that endothelial VEGF contributes to the regulation of cell cycle and mitochondrial gene clusters, as well as several -- but not all -- targets of the transcription factor FOXO1. Indeed, VEGF-deficient endothelium in vitro and in vivo showed increased levels of FOXO1 protein in the nucleus and cytoplasm. Silencing of FOXO1 in VEGF-depleted cells reversed expression profiles of several of the gene clusters that were de-regulated in VEGF knockdown, and rescued both cell death and autophagy phenotypes. Our data suggest that endothelial VEGF maintains vascular homeostasis through regulation of FOXO1 levels, thereby ensuring physiological metabolism and endothelial cell survival. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma and probably also non-Hodgkin's B-cell lymphoma. The molecular mechanisms of HCV-associated carcinogenesis are unknown. Here we demonstrated that peripheral blood mononuclear cells obtained from hepatitis C patients and hepatocytes infected with HCV in vitro showed frequent chromosomal polyploidy. HCV infection or the expression of viral core protein alone in hepatocyte culture or transgenic mice inhibited mitotic spindle checkpoint function because of reduced Rb transcription and enhanced E2F-1 and Mad2 expression. The silencing of E2F-1 by RNA interference technology restored the function of mitotic checkpoint in core-expressing cells. Taken together, these data suggest that HCV infection may inhibit the mitotic checkpoint to induce polyploidy, which likely contributes to neoplastic transformation. [ABSTRACT FROM AUTHOR]