Adoption of a dedicated multidisciplinary team is associated with improved survival in acute pulmonary embolism.

BACKGROUND: Acute pulmonary embolism remains a significant cause of mortality and morbidity worldwide. Benefit of recently developed multidisciplinary PE response teams (PERT) with higher utilization of advanced therapies has not been established. METHODS: To evaluate patient-centered outcomes and cost-effectiveness of a multidisciplinary PERT we performed a retrospective analysis of 554 patients with acute PE at the university of Virginia between July 2014 and June 2015 (pre-PERT era) and between April 2017 through October 2018 (PERT era). Six-month survival, hospital length-of-stay (LOS), type of PE therapy, and in-hospital bleeding were assessed upon collected data. RESULTS: 317 consecutive patients were treated for acute PE during an 18-month period following institution of a multidisciplinary PE program; for 120 patients PERT was activated (PA), the remaining 197 patients with acute PE were considered as a separate, contemporary group (NPA). The historical, comparator cohort (PP) was composed of 237 patients. These 3 groups were similar in terms of baseline demographics, comorbidities and risk, as assessed by the Pulmonary Embolism Severity Index (PESI). Patients in the historical cohort demonstrated worsened survival when compared with patients treated during the PERT era. During the PERT era no statistically significant difference in survival was observed in the PA group when compared to the NPA group despite significantly higher severity of illness among PA patients. Hospital LOS was not different in the PA group when compared to either the NPA or PP group. Hospital costs did not differ among the 3 cohorts. 30-day re-admission rates were significantly lower during the PERT era. Rates of advanced therapies were significantly higher during the PERT era (9.1% vs. 2%) and were concentrated in the PA group (21.7% vs. 1.5%) without any significant rise in in-hospital bleeding complications. CONCLUSIONS: At our institution, all-cause mortality in patients with acute PE has significantly and durably decreased with the adoption of a PERT program without incurring additional hospital costs or protracting hospital LOS. Our data suggest that the adoption of a multidisciplinary approach at some institutions may provide benefit to select patients with acute PE.

Depressive Symptoms and Salivary Telomere Length in a Probability Sample of Middle-Aged and Older Adults.

OBJECTIVE: To examine the association between depressive symptoms and salivary telomere length in a probability sample of middle-aged and older adults, and to evaluate age and sex as potential moderators of this association and test whether this association was incremental to potential confounds. METHODS: Participants were 3,609 individuals from the 2008 wave of the Health and Retirement Study. Telomere length assays were performed using quantitative real-time polymerase chain reaction on DNA extracted from saliva samples. Depressive symptoms were assessed via interview, and health and lifestyle factors, traumatic life events, and neuroticism were assessed via self-report. Regression analyses were conducted to examine the associations between predictor variables and salivary telomere length. RESULTS: After adjusting for demographics, depressive symptoms were negatively associated with salivary telomere length (b = -.003; p = .014). Furthermore, this association was moderated by sex (b = .005; p = .011), such that depressive symptoms were significantly and negatively associated with salivary telomere length for men (b = - .006; p < .001) but not for women (b = - .001; p = .644). The negative association between depressive symptoms and salivary telomere length in men remained statistically significant after additionally adjusting for cigarette smoking, body mass index, chronic health conditions, childhood and lifetime exposure to traumatic life events, and neuroticism. CONCLUSIONS: Higher levels of depressive symptoms were associated with shorter salivary telomeres in men, and this association was incremental to several potential confounds. Shortened telomeres may help account for the association between depression and poor physical health and mortality.

Normative Data on the Beck Depression Inventory--Second Edition (BDI-II) in College Students.

OBJECTIVE: This study was conducted to provide normative data on the Beck Depression Inventory--Second Edition (BDI-II) in college students. METHOD: Data were obtained from 15,233 college students drawn from 17 universities in the United States, weighted to match the gender and race/ethnicity of enrollment in degree-granting institutions. RESULTS: Descriptive statistics, point prevalence of individuals exceeding cutoff scores, and mean differences by gender and race/ethnicity were provided. Because the distribution of BDI-II scores was not normal, percentile ranks for raw scores were provided for the total sample and separately by gender and race/ethnicity for the total sample and by race/ethnicity for men and women. Normative data were used to calculate the Reliable Change Index on the BDI-II for college students. CONCLUSION: Because the distribution of BDI-II scores demonstrated significant skewness and non-normal kurtosis, percentile ranks are important to consider in interpreting scores on the measure, in addition to descriptive statistics.

Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p300 complex in a preclinical model of prostate cancer.

The downstream targets of hypoxia inducible factor-1 alpha (HIF-1α) play an important role in tumor progression and angiogenesis. Therefore, inhibition of HIF-mediated transcription has potential in the treatment of cancer. One attractive strategy for inhibiting HIF activity is the disruption of the HIF-1α/p300 complex, as p300 is a crucial coactivator of hypoxia-inducible transcription. Several members of the epidithiodiketopiperazine (ETP) family of natural products have been shown to disrupt the HIF-1α/p300 complex in vitro; namely, gliotoxin, chaetocin, and chetomin. Here, we further characterized the molecular mechanisms underlying the antiangiogenic and antitumor effects of these ETPs using a preclinical model of prostate cancer. In the rat aortic ring angiogenesis assay, gliotoxin, chaetocin, and chetomin significantly inhibited microvessel outgrowth at a GI50 of 151, 8, and 20 nM, respectively. In vitro co-immunoprecipitation studies in prostate cancer cell extracts demonstrated that these compounds disrupted the HIF-1α/p300 complex. The downstream effects of inhibiting the HIF-1α/p300 interaction were evaluated by determining HIF-1α target gene expression at the mRNA and protein levels. Dose-dependent decreases in levels of secreted VEGF were detected by ELISA in the culture media of treated cells, and the subsequent downregulation of VEGFA, LDHA, and ENO1 HIF-1α target genes were confirmed by semi-quantitative real-time PCR. Finally, treatment with ETPs in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. These results suggest that directly targeting the HIF-1α/p300 complex with ETPs may be an effective approach for inhibiting angiogenesis and tumor growth.

The Relationship Between Acuity of Organ Failure and Predictive Validity of Sepsis-3 Criteria.

The Sepsis-3 taskforce defined sepsis as suspicion of infection and an acute rise in the Sequential Organ Failure Assessment score by 2 points over the preinfection baseline. Sepsis-3 studies, though, have not distinguished between acute and chronic organ failure, and may not accurately reflect the epidemiology, natural history, or impact of sepsis. Our objective was to determine the extent to which the predictive validity of Sepsis-3 is attributable to chronic rather than acute organ failure. DESIGN: Retrospective cohort study. SETTING: General medicine inpatient service at a tertiary teaching hospital. PATIENTS: A total of 3,755 adult medical acute-care encounters (1,864 confirmed acute infections) over 1 year. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the total Sequential Organ Failure Assessment score at the onset of infection and separated its components (baseline and acute rise) using case-by-case chart reviews. We compared the predictive validities of acuity-focused (acute rise in Sequential Organ Failure Assessment ≥ 2) and conventional (total Sequential Organ Failure Assessment ≥ 2) implementations of Sepsis-3 criteria. Measures of predictive validity were change in the rate of outcomes and change in the area under receiver operating characteristic curves after adding sepsis criteria to multivariate logistic regression models of baseline risk (age, sex, race, and Charlson comorbidity index). Outcomes were inhospital mortality (primary) and ICU transfer or inhospital mortality (secondary). Acuity-focused implementations of Sepsis-3 were associated with neither a change in mortality (2.2% vs 1.2%; p = 0.18) nor a rise in area under receiver operating characteristic curves compared with baseline models (0.67 vs 0.66; p = 0.75). In contrast, conventional implementations were associated with a six-fold change in mortality (2.4% vs 0.4%; p = 0.01) and a rise in area under receiver operating characteristic curves compared with baseline models (0.70 vs 0.66; p = 0.04). Results were similar for the secondary outcome. CONCLUSIONS: The evaluation of the validity of organ dysfunction-based clinical sepsis criteria is prone to bias, because acute organ dysfunction consequent to infection is difficult to separate from preexisting organ failure in large retrospective cohorts.

Visual attention and driving behaviors among community-living older persons.

BACKGROUND: Older drivers have higher rates of crashes per mile driven compared with most other drivers, and these crashes result in greater morbidity and mortality. Various aspects of cognition, particularly visual attention, have been linked with crash risk among older individuals. The current study was designed to specify those cognitive variables associated with specific on-road driving behaviors in a sample of older, nonclinic-referred individuals. METHODS: 35 community-residing active drivers aged 72 years and older (M = 80) underwent a standardized, on-road driving evaluation involving parking lot maneuvers, and urban, suburban, and highway driving. They were also administered tests of visual attention, executive function, visuospatial cognition, and memory. RESULTS: Driving score was significantly correlated with visual attention, visual memory, and executive function. Visual attention was associated with 25 of 36 driving behaviors, including those involving scanning the environment, interaction with traffic or pedestrians, and distance judgments. Executive function and visual memory were associated with fewer maneuvers, most of which were a subset of maneuvers that correlated with visual attention. CONCLUSIONS: Visual attention, a cognitive function involving search, selection, and switching, plays an important role in driving risk among older drivers. In the current study, key driving maneuvers involving interaction with other vehicles/pedestrians, such as yielding right of way and negotiating safe turns or merges, have the greatest association with visual attention. Specification of both the cognitive risk factors and their impact on problematic driving maneuvers may provide guidelines for developing targeted interventions to reduce risk among older adults.

The effect of raloxifene on cognitive function in postmenopausal women: a randomized clinical trial.

To determine whether treatment with raloxifene has a beneficial effect on cognitive function in postmenopausal women, 50 postmenopausal women were randomized to receive raloxifene 60 mg, or placebo, for eight weeks. Participants completed pre- and post-treatment assessment of cognitive and psychological function including the Beck Anxiety and Beck Depression inventories, the SF-36 Scale of physical and emotional well-being, five tests of cognitive function including Block Design and Digit Span subtests of the Wechsler Adult Intelligence Scale-III (WAIS-III), the Logical Memory and Paired Associates subtests of the Wechsler Memory Scale-III, and the Digit Cancellation test. Results showed no significant effect attributable to eight weeks of treatment with raloxifene on cognitive, psychological, or health variables.

Significant addition to treatment options for bone metastasis in prostate cancer.

Pathologic fractures, spinal compression, and pain take a great toll on the healthcare costs and well-being of men with prostate cancer metastatic to the bone. For almost 10 years, the only drug proven to prevent these skeletal-related adverse events was the bisphosphonate zoledronic acid. In a study published by Fizazi et al. in The Lancet, the monoclonal antibody to RANKL, denosumab, is shown to be superior to zoledronic acid in the prevention of these events. The only notable adverse event more frequent in either arm was increased hypocalcemia in the denosumab arm. There was a greater frequency of osteonecrosis of the jaw in the denosumab treatment group that did not reach statistical significance, but is of great concern. While further analysis is needed to determine the value of denosumab in preventing adverse events and improving quality of life, this new therapy is a significant addition to the treatment of men living with metastatic prostate cancer.

Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia.

PURPOSE: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. EXPERIMENTAL DESIGN: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. RESULTS: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 µmol/L; K(i) = 11.7 µmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. CONCLUSIONS: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.