Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND: Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS: We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS: From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION: ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING: Canadian Institutes of Health Research.

Early improvement in serial echocardiographic studies in heart failure patients predicts long term survival-a pilot study.

BACKGROUND: Several echocardiographic measures have prognostic value in heart failure (HF). However, no definitive data exist on how changes in these parameters with treatment affect survival in this patient population. We hypothesized that early improvement on echocardiography could predict long-term survival. METHODS AND RESULTS: We conducted a retrospective review of 404 patients seen in the HF clinic from 2002 to 2008 (6.5 years). Patients had one echocardiogram ≤1 year before and another ≥1 month (10 ± 7 months) after treatment onset. We studied changes in standard echocardiographic parameters, including left (LV) and right (RV) ventricular size and/or function (systolic and/or diastolic), valvular (mitral and tricuspid) function, and pulmonary artery pressure. Survival curves and hazard ratios were generated for patients showing improvement on the 2nd echocardiogram versus those who did not. Multivariable analyses were performed adjusting for age, sex, ischemic etiology, and significant baseline echocardiographic parameters. Average follow-up was 2.9 ± 1.5 years. Improvement in LV end-systolic dimension, RV function, and mitral regurgitation were independent predictors of 5-year survival (P < .05) and, importantly, more predictive than baseline values of these parameters alone (higher hazard ratios). CONCLUSIONS: Early echocardiographic improvement is strongly associated with 5-year survival in patients with HF. Serial echocardiography may aid in stratifying patient care.

Does electronic medication reconciliation at hospital discharge decrease prescription medication errors?

PURPOSE: Medication errors are an important patient safety issue. Electronic medication reconciliation is a system designed to correct medication discrepancies at transitions in healthcare. The purpose of this paper is to measure types and prevalence of intravenous antibiotic errors at hospital discharge before and after the addition of an electronic discharge medication reconciliation tool (EDMRT). DESIGN/METHODOLOGY/APPROACH: A retrospective study was conducted at a tertiary hospital where house officers order discharge medications. In total, 100 pre-EDMRT and 100 post-EDMRT subjects were randomly recruited from the study center's clinical Outpatient Parenteral Antimicrobial Therapy (OPAT) program. Using infectious disease consultant recommendations as gold standard, each antibiotic listed in these consultant notes was compared to the hospital discharge orders to ascertain the primary outcome: presence of an intravenous antibiotic error in the discharge orders. The primary covariate of interest was pre- vs post-EDMRT group. After generating the crude prevalence of antibiotic errors, logistic regression accounted for potential confounding: discharge day (weekend vs weekday), average years of practice by prescribing physician, inpatient service (medicine vs surgery) and number of discharge mediations per patient. FINDINGS: Prevalence of medication errors decreased from 30 percent (30/100) among pre-EDMRT subjects to 15 percent (15/100) errors among post-EDMRT subjects. Dosage errors were the most common type of medication error. The adjusted odds ratio of discharge with intravenous antibiotic error in the post-EDMRT era was 0.39 (0.18, 0.87) compared to the pre-EDMRT era. In the adjusted model, the total number of discharge medications was associated with increased OR of discharge error. ORIGINALITY/VALUE: To the authors' knowledge, no other study has examined the impact of reconciliation on types and prevalence of medication errors at hospital discharge. The focus on intravenous antibiotics as a class of high-stakes medications with serious risks to patient safety during error events highlights the clinical importance of the findings. Electronic medication reconciliation may be an important tool in efforts to improve patient safety.

The efficacy of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bloodstream infection in patients with impaired renal function.

BACKGROUND: Concerns regarding the efficacy of daptomycin for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections in patients with impaired renal function are reflected in a recent package insert change by the Food and Drug Administration (FDA). However, this decision was based on a small subgroup analysis and it is unclear if this is a true association. METHODS: We conducted a retrospective cohort study of patients with MRSA bacteremia treated at a tertiary hospital from 2001 to 2011 and who received either vancomycin or daptomycin. We used propensity score and multivariable logistic regression to assess the outcome of treatment failure, via blinded adjudication, in daptomycin- vs vancomycin-treated subjects and the interaction with renal function. RESULTS: One hundred fifty patients were analyzed, 100 in the vancomycin arm and 50 in the daptomycin arm. The average age was 61 years, and 60% were men. Of patients treated with daptomycin or vancomycin, 29 (58%) and 51 (51%), respectively, had an estimated glomerular filtration rate (GFR) <50 mL/minute/1.73 m(2). Compared with vancomycin, the usage of daptomycin in patients was not significantly associated with treatment failure in patients with a GFR >50 mL/minute/1.73 m(2) (odds ratio [OR], 0.45; 95% confidence interval [CI], .11 -1.79), nor in patients with a GFR of <50 mL/minute/1.73 m(2) (OR, 0.46; 95% CI, .11 -1.94). There was no significant interaction between them (P = .54). CONCLUSIONS: In patients with MRSA bacteremia, daptomycin efficacy was not affected by GFR level and was similar to vancomycin's efficacy. Although our sample size was small, it was larger than than the one used by the FDA. However, smaller differences may be significant with a larger sample size.

Is environmental temperature related to renal symptoms, serum lithium levels, and other laboratory test results in current lithium users?

OBJECTIVE: Lithium continues to be an important mood disorder treatment. Although patients exposed to higher environmental temperatures may have serum lithium level elevations due to dehydration, there is conflicting data in the literature. In addition, no study has assessed the association between temperature and other renal laboratory tests and symptoms in lithium users. METHODS: This is a cross-sectional analysis of 63 current lithium users who participated in the McGill Geriatric Lithium-induced Diabetes Insipidus Clinical Study. The relationship between mean daily temperature with diabetes insipidus symptoms, glomerular filtration rate, urine osmolality, serum sodium, lithium level, and lithium dose-level ratio was assessed. RESULTS: Although a higher temperature on the day of laboratory testing trended toward being independently associated with a lower lithium dose-level ratio (Beta = -0.17, p = 0.08), this was not found when using a dichotomous measure of temperature (T > 20°C). No association was observed between temperature and other renal parameters. CONCLUSIONS: The association of temperature with lithium levels, renal symptoms, and laboratory tests appears to be of relatively little clinical importance in lithium users in temperate climates. However, future research should re-examine patients living in climates with extreme temperatures (e.g., >40°C), who may theoretically be at higher risk.

Necrosis on FDG PET/CT correlates with prognosis and mortality in sarcomas.

OBJECTIVE: The purpose of this study was to determine if there is an association between necrosis as identified on staging (18)F-FDG PET/CT and overall survival (OS) and progression-free survival (PFS) in patients with sarcoma. MATERIALS AND METHODS: Sixty-six patients with newly diagnosed limb and girdle sarcoma underwent PET/CT at our institution between June 2004 and July 2009 for sarcoma staging before treatment with curative intent. The tumor maximum standardized up-take values (SUVmax), the presence of necrosis, and the volume of necrosis were measured for each primary tumor and correlated with follow-up data. PFS and OS were analyzed using the Kaplan-Meier method. Proportional hazards models were used to estimate hazard ratios. RESULTS: Median patient age was 49 years, and 51.6% of the patients were men. Sarcomas were categorized as soft tissue (69.2%), bone (23.5%), or other (7.3%). Mean follow-up time was 33.3 months. During the follow-up interval, 53% of patients experienced disease progression, and 40.9% died. There was a statistically significant relationship between the presence of necrosis and OS (by log-rank test, p = 0.001), as well as PFS (by log-rank test, p = 0.0001). Twenty-four-month OS was 96%, 65%, and 38% in patients with tumors with absence necrosis, those with presence of necrosis, and with necrosis volume greater than 50%, respectively. Forty-eight-month OS was 81% in patients with absence of necrosis and 41% in patients with presence of necrosis. Twelve-month PFS was 96%, 60%, and 42% in patients with tumors with absence of necrosis, those with presence of necrosis, and those with necrosis volume greater than 50%, respectively. Twenty-four-month PFS was 83%, 38%, and 22%, respectively, in these groups. CONCLUSION: The presence of necrosis and the volume of necrosis, as identified on the staging FDG PET/CT and after adjusting for SUVmax, are strong independent adverse prognostic factors for disease recurrence and death in patients with limb and girdle sarcomas.

Dynamics of vitamin D in patients with mild or inactive inflammatory bowel disease and their families.

BACKGROUND: 25(OH) vitamin D levels may be low in patients with moderately or severely active inflammatory bowel diseases (IBD: Crohn's disease and Idiopathic Ulcerative Colitis) but this is less clear in patients with mild or inactive IBD. Furthermore there is limited information of any family influence on 25(OH) vitamin D levels in IBD. As a possible risk factor we hypothesize that vitamin D levels may also be low in families of IBD patients. OBJECTIVES: To evaluate 25[OH] vitamin D levels in patients with IBD in remission or with mild activity. A second objective is to evaluate whether there are relationships within IBD family units of 25[OH] vitamin D and what are the influences associated with these levels. METHODS: Participants underwent medical history, physical examination and a 114 item diet questionnaire. Serum 25[OH] vitamin D was measured, using a radioimmunoassay kit, (replete ≥ 75, insufficient 50-74, deficient < 25-50, or severely deficient < 25 nmol/L). Associations between 25[OH] vitamin D and twenty variables were evaluated using univariate regression. Multivariable analysis was also applied and intrafamilial dynamics were assessed. RESULTS: 55 patients and 48 controls with their respective families participated (N206). 25[OH] vitamin D levels between patients and controls were similar (71.2 ± 32.8 vs. 68.3 ±26.2 nmol/L). Vitamin D supplements significantly increased intake but correlation with serum 25[OH] vitamin D was significant only during non sunny months among patients. Within family units, patients' families had mean replete levels (82.3 ± 34.2 nmol/L) and a modest correlation emerged during sunny months between patients and family (r2 =0.209 p = 0.032). These relationships were less robust and non significant in controls and their families. CONCLUSIONS: In patients with mild or inactive IBD 25[OH] vitamin D levels are less than ideal but are similar to controls. Taken together collectively, the results of this study suggest that patient family dynamics may be different in IBD units from that in control family units. However contrary to the hypothesis, intra familial vitamin D dynamics do not pose additional risks for development of IBD.

Incidence, risk factors, and obstetrical outcomes of women with breast cancer in pregnancy.

Breast cancer in pregnancy is a rare condition. The objective of our study was to describe the incidence, risk factors, and obstetrical outcomes of breast cancer in pregnancy. We conducted a population-based cohort study on 8.8 million births using data from the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample from 1999-2008. The incidence of breast cancer was calculated and logistic regression analysis was used to evaluate the independent effects of demographic determinants on the diagnosis of breast cancer and to estimate the adjusted effect of breast cancer on obstetrical outcomes. There were 8,826,137 births in our cohort of which 573 cases of breast cancer were identified for an overall 10-year incidence of 6.5 cases per 100,000 births with the incidence slightly increasing over the 10-year period. Breast cancer appeared to be more common among women >35 years of age, odds ratio (OR)=3.36 (2.84-3.97); women with private insurance plans, OR=1.39 (1.10-1.76); and women who delivered in an urban teaching hospital, OR=2.10 (1.44-3.06). After adjusting for baseline characteristics, women with pregnancy-associated breast cancer were more likely to have an induction of labor, OR=2.25 (1.88, 2.70), but similar rates of gestational diabetes, preeclampsia, instrumental deliveries, and placental abruption. The incidence of breast cancer in pregnancy appears higher than previously reported with women over 35 being at greatest risk. Aside from an increased risk for induction of labor, women with breast cancer in pregnancy have similar obstetrical outcomes.

Combination of serum biomarkers to differentiate malignant from benign ovarian tumours.

OBJECTIVE: To investigate biomarkers and clinical parameters to distinguish ovarian cancers from benign ovarian tumours. METHODS: Serum biomarkers (CA 125, human epididymis protein 4 [HE 4], interleukin-18 [IL-18], leptin, macrophage migration inhibitory factor [MIF], fibroblast growth factor 2 [FGF-2], insulin-like growth factor, osteopontin, prolactin) and the risk of malignancy indexes I and II (RMI-I and RMI-II) scores were obtained prior to surgery in 52 patients with ovarian tumours (37 malignant and 15 benign). ROC curves were built for each individual marker, for logistic regression models using all markers, and for models combining both biomarkers and RMI scores. RESULTS: The model with nine biomarkers performed well (specificity 93%, sensitivity 84%) and was more reliable than the RMI-I or RMI-II alone. A regression model combining RMI-II and six of the biomarkers (CA 125, HE  4, IL-18, leptin, MIF, and FGF-2) allowed differentiation between the cancer and non-cancer cases in this pilot study. CONCLUSION: The regression models using biomarkers combined with clinical scoring systems warrant further investigation to improve triage of patients with ovarian tumours to enhance utilization of resources and optimize patient care.

Inadequate prenatal care utilization and risks of infant mortality and poor birth outcome: a retrospective analysis of 28,729,765 U.S. deliveries over 8 years.

OBJECTIVE: To evaluate the association between adequacy of prenatal care utilization and risk of fetal and neonatal mortality and adverse outcomes. METHODS: We conducted a population-based cohort study using the Center for Disease Control and Prevention's Linked Birth-Infant Death and Fetal Death data on all deliveries in the United States between 1995 and 2002. Inclusion criteria were singleton births ≥22 weeks of gestation with no known congenital malformation. Inadequate prenatal care was defined according to the Adequacy of Prenatal Care Utilization Index, and its effect on fetal and neonatal death was estimated using unconditional logistic regression analysis adjusting for maternal age, race, education, and other confounding variables. RESULTS: During our 8-year study period, 32,206,417 births occurred, 28,729,765 (89.2%) of which met inclusion criteria. Inadequate prenatal care utilization occurred in 11.2% of expectant mothers, more commonly among women ≤20 years, black non-Hispanic and Hispanic women, and those without high school education. Relative to adequate care, inadequate care was associated with increased risk of prematurity 3.75 (3.73 to 3.77), stillbirth 1.94 (1.89 to 1.99), early neonatal dearth 2.03 (1.97 to 2.09), late neonatal death 1.67 (1.59 to 1.76), and infant death 1.79 (1.76 to 1.82). CONCLUSION: Risk of prematurity, stillbirth, early and late neonatal death, and infant death increased linearly with decreasing care. Given the population effect of this association, public health initiatives should target program expansion to ensure timely and adequate access, particularly for women ≤20 years, Black non-Hispanic and Hispanic women, and those without high school education.

Assessing the relationship between physical fitness activities, cognitive health, and quality of life among older cancer survivors.

Chemotherapy-related cognitive impairment, known as "chemobrain," has been described as a side effect of chemotherapy and is associated with cognitive changes on quality of life especially among older cancer survivors. This longitudinal feasibility study examined the relationship between physical fitness, cognitive health, and quality of life among two groups of older adults: those on chemotherapy, and those who have completed chemotherapy. To assess cognitive health, we used the Montreal Cognitive Assessment and demographic information from the Healthy Brain Questionnaire. For quality of life, we used the McGill Quality of Life assessment. Physical activity was assessed using Metabolic Equivalency Tasks from the Compendium of Physical Activities classification system. t-Tests and regression analyses indicated that at Time 1 those on chemotherapy had lower cognitive health scores than those off chemotherapy. Yet at Time 2, as physical activities increased, cognitive health and quality of life improved for those on chemotherapy. However, those who had completed chemotherapy also benefited from an increase in physical activities over time. The results have implications for health care practitioners in oncology settings to better inform patients of cognitive challenges resulting from chemotherapy and the importance of participation in physical activities. Future research should compare different age groups among a larger sample.

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma.

PURPOSE: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers. PATIENTS AND METHODS: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS). RESULTS: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome. CONCLUSIONS: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.

Elevated plasma gas6 levels are associated with venous thromboembolic disease.

Growth arrest-specific 6 (gas6), a novel vitamin K-dependent protein, has been demonstrated to have a role in thrombus stabilization as gas6 null mice are resistant to lethal venous and arterial thrombosis. However, the association between gas6 and venous thromboembolism has not been elucidated in humans. The present study aims to assess the role of gas6 in human venous thromboembolic (VTE) disease. Using a highly specific ELISA method, we measured plasma levels of gas6 in plasma samples obtained from 279 patients with VTE and 79 healthy volunteers. Medication history, comorbid conditions and VTE characteristics were documented. Mean gas6 levels were higher in patients with VTE as compared to healthy volunteers, being 46 ±11 ng/ml and 35 ±6.4 ng/ml respectively (P < 0.001). Odds ratios (OR) for VTE given elevated (≥90th percentile of healthy volunteers) gas6 levels were estimated in regression models in the whole study population. After adjustment for age, sex, medications and comorbidity, subjects with elevated gas6 had an increased risk of VTE (OR of 16.3 (95% CI 5.8-45.7, P < 0.001) compared to those with lower levels of gas6. This association remains significant even among patients with a comparable age distribution. Among patients with VTE, mean gas levels showed a trend of higher levels in those with more extensive thrombi. There was no correlation between elevated gas6 levels and recurrent VTE. In conclusion, we demonstrate an association between VTE and elevated gas6 levels consistent with in vivo murine models of thrombosis. This constitutes a potential novel mechanism for thrombosis in humans and may aid in the understanding of the pathophysiology of VTE.

Placebos in clinical practice: comparing attitudes, beliefs, and patterns of use between academic psychiatrists and nonpsychiatrists.

Controversial and ethically tenuous, the use of placebos is central to medicine but even more pivotal to psychosocial therapies. Scholars, researchers, and practitioners largely disagree about the conceptualization of placebos. While different professionals often confound the meanings of placebo effects with placebo responses, physicians continue to prescribe placebos as part of clinical practice. Our study aims to review attitudes and beliefs concerning placebos outside of clinical research. Herein we compare patterns of placebo use reported by academic psychiatrists with those reported by physicians from different specialties across Canadian medical schools. Using a web-based tool, we circulated an online survey to all 17 Canadian medical schools, with a special emphasis on psychiatry departments therein and in university-affiliated teaching hospitals. A variation on earlier efforts, our 5-minute, 21-question survey was anonymous. Among the 606 respondents who completed our online survey, 257 were psychiatrists. Our analysis revealed that psychiatrists prescribed significantly more subtherapeutic doses of medication than physicians in other specialties, although about 20% of both psychiatrists and nonpsychiatrists prescribed placebos regularly as part of routine clinical practice. However, compared with 6% of nonpsychiatrists, only 2% of psychiatrists deemed placebos of no clinical benefit. In addition, more than 60% of psychiatrists either agreed or strongly agreed that placebos had therapeutic effects relative to fewer than 45% of other practitioners. Findings from this pan-Canadian survey suggest that, compared with other physicians, psychiatrists seem to better value the influence placebos wield on the mind and body and maintain more favourable beliefs and attitudes toward placebo phenomena.

The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome.

OBJECTIVE: To evaluate safety and tolerability and exploratory efficacy end points for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). METHODS: Gaboxadol is a highly selective orthosteric agonist that activates δ-subunit-containing extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose and gaboxadol 15 mg evening dose (qd), gaboxadol 10 mg morning dose and 15 mg evening dose (bid), or placebo morning and evening dose. Safety and tolerability were monitored throughout the study. Prespecified exploratory efficacy end points included adapted Clinical Global Impression-Severity and Clinical Global Impression-Improvement (CGI-I) scales, which documented the clinical severity at baseline and change after treatment, respectively. RESULTS: Eighty-eight individuals were randomized. Of 87 individuals (aged 13-45 years) who received at least 1 dose of study drug, 78 (90%) completed the study. Most adverse events (AEs) were mild to moderate, and no life-threatening AEs were reported. Efficacy of gaboxadol, as measured by CGI-I improvement in an exploratory analysis, was observed in gaboxadol qd vs placebo (p = 0.0006). CONCLUSION: After 12 weeks of treatment, gaboxadol was found to be generally well-tolerated with a favorable safety profile. The efficacy as measured by the AS-adapted CGI-I scale warrants further studies. CLINICALTRIALSGOV IDENTIFIER: NCT02996305. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for individuals with AS, gaboxadol is generally safe and well-tolerated.

Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1.

The objective of this study was to ascertain the impact of aging and Alzheimer's disease (AD) on brain cholesterol (CH), CH precursors, and oxysterol homeostasis. Altered CH metabolism and up-regulation of heme oxygenase-1 (HO-1) are characteristic of AD-affected neural tissues. We recently determined that HO-1 over-expression suppresses total CH levels by augmenting liver X receptor-mediated CH efflux and enhances oxysterol formation in cultured astroglia. Lipids and proteins were extracted from postmortem human frontal cortex derived from subjects with sporadic AD, mild cognitive impairment (MCI), and no cognitive impairment (n = 17 per group) enrolled in the Religious Orders Study, an ongoing clinical-pathologic study of aging and AD. ELISA was used to quantify human HO-1 protein expression from brain tissue and gas chromatography-mass spectrometry to quantify total CH, CH precursors, and relevant oxysterols. The relationships of sterol/oxysterol levels to HO-1 protein expression and clinical/demographic variables were determined by multivariable regression and non-parametric statistical analyses. Decreased CH, increased oxysterol and increased CH precursors concentrations in the cortex correlated significantly with HO-1 levels in MCI and AD, but not no cognitive impairment. Specific oxysterols correlated with disease state, increasing neuropathological burden, neuropsychological impairment, and age. A model featuring compensated and de-compensated states of altered sterol homeostasis in MCI and AD is presented based on the current data set and our earlier in vitro work.

Levels of inflammatory markers and the development of the post-thrombotic syndrome.

The post-thrombotic syndrome (PTS) occurs frequently after deep venous thrombosis (DVT) despite appropriate anticoagulant therapy. A close relationship between inflammation and thrombosis exists. While the inflammatory process at the time of DVT appears to improve thrombus resolution, it may promote destruction of venous valves, valvular reflux and subsequent development of PTS. We prospectively evaluated the association between levels of four cytokines (IL-6, IL-8, IL-10 and MCP-1), two adhesion molecules (ICAM-1 and VCAM-1) and the development of PTS in a well-defined cohort of patients with DVT. The study population consisted of 387 patients with objectively diagnosed symptomatic DVT who were followed for two years to determine the incidence of PTS. At the end of followup, plasma samples frozen at the four-month visit in 307 study patients were thawed and analyzed for the above inflammatory markers using the Luminex beads technology. Mean levels of IL-6 were significantly higher in patients with PTS compared to patients without PTS (7.35 pg/ml +/- 14.26 [SD] vs. 4.60 pg/ml +/- 4.90; p = 0.03). Logistic regression analyses showed significant associations between PTS and levels above vs. below the median of IL-6 [odds ratio (OR) 1.66; 95% confidence interval (CI) 1.05, 2.62 (p = 0.03)] and ICAM-1 [OR 1.63; 95% CI 1.03, 2.58 (p = 0.04)]. None of the other markers showed any association with PTS. Our study suggests the presence of significant associations between markers of inflammation such as IL-6 and ICAM-1 and the development of PTS. Further work is needed to evaluate this relationship and to analyse other candidate markers that could be implicated etiologically in the association between DVT and PTS. If confirmed, this could lead to identification of new therapeutic targets for preventing PTS after DVT.

Pattern of Local Recurrence and Distant Metastasis in Breast Cancer By Molecular Subtype.

BACKGROUND AND PURPOSE:  No longer considered a single disease entity, breast cancer is being classified into several distinct molecular subtypes based on gene expression profiling. These subtypes appear to carry prognostic implications and have the potential to be incorporated into treatment decisions. In this study, we evaluated patterns of local recurrence (LR), distant metastasis (DM), and association of survival with molecular subtype in breast cancer patients in the post-adjuvant radiotherapy setting. MATERIAL AND METHODS:  The medical records of 1,088 consecutive, non-metastatic breast cancer patients treated at a single institution between 2004 and 2012 were reviewed. Estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2) enrichment were evaluated by immunohistochemistry. Patients were categorized into one of four subtypes: luminal-A (LA; ER/PR+, HER2-, Grade 1-2), luminal-B (LB; ER/PR+, HER2-, Grade > 2), HER2 over-expression (HER2; ER/PR-, HER2+), and triple negative (TN; ER/PR-, HER2-).  Results: The median follow-up time was 6.9 years. During the follow-up, 16% (174/1,088) of patients failed initial treatment and developed either LR (48) or DM (126). The prevalence of LR was the highest in TN (12%) and the lowest in LA (2%). Breast or chest wall relapse was the most frequent site (≈80%) of recurrence in LA, LB, and HER2 subtypes, whereas the regional lymph nodes and chest wall were the common sites of relapse in the TN group (50.0%). DM rates were 6.4% in LA, 12.1% in LB, 19.2% in HER2, and 27.4% in TN subgroups. Five-year survival rates were 84%, 83%, 84%, and 77% in the LA, LB, HER2 and TN subgroups, respectively. There was a statistically significant association between survival and molecular subtypes in an univariate analysis. In the adjusted multivariate analysis, the following variables were independent prognostic factors for survival: T stage, N stage, and molecular subtype. CONCLUSIONS:  Of the four subtypes, the LA subtype tends to have the best prognosis, fairly high survival, and low recurrent or metastases rates. The TN and HER2 subtypes of breast cancer were associated with significantly poorer overall survival and prone to earlier recurrence and metastases. Our results demonstrate a significant association between molecular subtype and survival. The risk of death and relapse/metastases increases fewfold in TN compared to LA. Future prospective studies are warranted and could ultimately lead to the tailoring of adjuvant radiotherapy treatment fields based on both molecular subtype and the more conventional clinicopathologic characteristics.

The impact of individual variation analysis on myocardial perfusion imaging utilization within a hospitalist group.

BACKGROUND: Increased recognition of ionizing radiation risks has placed an emphasis on the appropriate use of myocardial perfusion imaging (MPI). Hospitalists frequently order MPI in the evaluation of chest pain and are thus at the forefront of its inpatient utilization. METHODS: We collected baseline figures for a group MPI rate (March 2010-February 2011) as well as individual MPI rates for hospitalists caring for cardiac floor patients at a community teaching hospital. We performed a 2-part intervention; we presented the individual MPI rate data back to the hospitalist division and carried out longitudinal educational efforts on MPI appropriateness criteria. We then calculated the group MPI utilization rate for 3 postintervention periods (March 2011-February 2012, March 2012-February 2013, and March 2013-February 2014) and the MPI rate for the subgroup of cardiac floor patients. Finally, we calculated the percentage of inappropriately performed stress tests before and after our intervention. RESULTS: Group MPI rate declined from 6.1% to 5.0% in the first year after our intervention (P = 0.009); a decrease was maintained a year later-MPI rate 4.9% (P = 0.004)-and became even more pronounced 2 years later-MPI rate 3.9% (P < 0.0001). The MPI rate for the subgroup of patients on the cardiac floor similarly decreased from 8.0% to 6.7% (P = 0.039). Finally, we report a particularly encouraging and significant trend of a 46% postintervention decrease (from 16.5% to 9%, P = 0.034) in the proportion of inappropriate stress tests ordered. CONCLUSIONS: Analyzing individual ordering rates and combining them with educational efforts was an effective strategy for impacting MPI utilization in the hospitalist group studied.