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Prostate cancer accounts for a significant proportion of cancer diagnoses in Canadian men. Over the past decade, the therapeutic landscape for the management of metastatic prostate cancer has undergone rapid changes. Novel strategies use hormonal agents, chemotherapy, homologous recombination repair inhibitors, and radioligand therapy or combination strategies in addition to androgen deprivation therapy. In this review, we summarize the available data addressing key therapeutic areas along the disease continuum and focus on practical aspects for general practitioners in oncology managing patients with metastatic prostate cancer.

The question of whether Everettian quantum mechanics (EQM) justifies the existence of metaphysical indeterminacy has recently come to the fore. Metaphysical indeterminacy has been argued to emerge from three sources: coherent superpositions, the indefinite number of branches in the quantum multiverse and the nature of these branches. This paper reviews the evidence and concludes that those arguments don't rely on EQM alone and rest on metaphysical auxiliary assumptions that transcend the physics of EQM. We show how EQM can be ontologically interpreted without positing metaphysical indeterminacy by adopting a deflationary attitude towards branches. Two ways of developing the deflationary view are then proposed: one where branches are eliminated, and another where they are reduced to the universal quantum state., Competing Interests: Competing InterestsThis work was supported by the Swiss National Science Foundation via Le Bihan’s Starting grant Space, Time and Causation in Quantum Gravity (grant 211317). The authors have no competing interests to declare that are relevant to the content of this article., (© The Author(s) 2024.)

The theory that health behaviors spread through social groups implies that efforts to control COVID-19 through vaccination will succeed if people believe that others in their groups are getting vaccinated. But "others" can refer to many groups, including one's family, neighbors, fellow city or state dwellers, or copartisans. One challenge to examining these understudied distinctions is that many factors may confound observed relationships between perceived social norms (what people believe others do) and intended behaviors (what people themselves will do), as there are plausible common causes for both. We address these issues using survey data collected in the United States during late fall 2020 ( n = 824) and spring 2021 ( n = 996) and a matched design that approximates pair-randomized experiments. We find a strong relationship between perceived vaccination social norms and vaccination intentions when controlling for real risk factors (e.g., age), as well as dimensions known to predict COVID-19 preventive behaviors (e.g., trust in scientists). The strength of the relationship declines as the queried social group grows larger and more heterogeneous. The relationship for copartisans is second in magnitude to that of family and friends among Republicans but undetectable for Democrats. Sensitivity analysis shows that these relationships could be explained away only by an unmeasured variable with large effects (odds ratios between 2 and 15) on social norms perceptions and vaccination intentions. In addition, a prediction from the "false consensus" view that intentions cause perceived social norms is not supported. We discuss the implications for public health policy and understanding social norms.

Abstract: Gulf War I veterans who were victims of depleted uranium (DU) "friendly-fire" incidents have undergone longitudinal health surveillance since 1994. During the spring of 2019, 36 members of the cohort were evaluated with a monitoring protocol including exposure assessment for total and isotopic uranium concentrations in urine and a comprehensive review of health outcomes, including measures of bone metabolism and bone mineral density (BMD) determination. Elevated urine U concentrations were observed in cohort members with retained depleted uranium (DU) shrapnel fragments. In addition, a measure of bone resorption, N-telopeptide, showed a statistically significant increase in those in the high DU subgroup, a finding consistent with a statistically significant decrease in bone mass also observed in this high DU subgroup compared to the low DU subgroup. After more than 25 y since first exposure to DU, an aging cohort of military veterans continues to show few U-related health effects in known target organs of U toxicity. The new finding of impaired BMD in the high DU subgroup has now been detected in two consecutive surveillance visits. While this is a biologically plausible uranium effect, it is not reflected in other measures of bone metabolism in the full cohort, which have largely been within normal limits. However, ongoing accrual of the U burden from fragment absorption over time and the effect of aging further impairing BMD suggest the need for future surveillance assessments of this cohort., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Health Physics Society.)

Objective: Mayors have considerable and often direct influence over health policy in their cities, yet little is known about mayors' general perceptions of current public health challenges. The objective of this study was to assess perceptions, attitudes, and priorities related to public health among US mayors., Methods: We collected survey data from a nationally representative sample of US mayors (N = 110) in 2018 and matched survey responses with city-level health surveillance data. We conducted descriptive analyses and multivariable regression modeling to estimate associations of interest., Results: Mayors in our sample most frequently cited obesity/chronic diseases (23.6%; 26 of 110), opioid abuse/drug addiction (22.7%; 25 of 110), and health care access (13.6%; 15 of 110) as the top health challenges facing their cities. However, mayors identified a different set of health issues for which they believed constituents hold them accountable. With the exception of opioid-related deaths, prevalence of a health concern was not associated with perceived accountability for that particular issue, whereas partisanship and sex predicted patterns in perceived accountability., Conclusions: Mayors recognized critical health challenges at the city level but varied widely in their perceived accountability for such challenges. Findings can inform strategies to engage local policy makers in cross-sector collaborations to improve the health and overall well-being of people in cities across the United States.

Electronic medical records now store a wealth of intraoperative hemodynamic data. However, analysis of such data is plagued by artifacts related to the monitoring environment. Here, we present an algorithm for automated identification of artifacts and replacement using interpolation of arterial line blood pressures. After IRB approval, minute-by-minute digital recordings of systolic, diastolic, and mean arterial pressures (MAP) obtained during anesthesia care were analyzed using predetermined metrics to identify values anomalous from adjacent neighbors. Anomalous data points were then replaced with linear interpolation of neighbors. The algorithm was then validated against manual artifact identification in 54 anesthesia records and 41,384 arterial line measurements. To assess the algorithm's effect on data analysis, we calculated the percent of time spent with MAP below 55 mmHg and above 100 mmHg for both raw and conditioned datasets. Manual review of the dataset identified 1.23% of all pressure readings as artifactual. When compared to manual review, the algorithm identified artifacts with 87.0% sensitivity and 99.4% specificity. The average difference between manual review and algorithm in identifying the start of arterial line monitoring was 0.17, and 2.1 min for the end of monitoring. Application of the algorithm decreased the percent of time below 55 mmHg from 4.3 to 2.0% (2.1% with manual review) and time above 100 mmHg from 8.8 to 7.3% (7.3% manual). This algorithm's performance was comparable to manual review by a human anesthesiologist and reduced the incidence of abnormal MAP values identified using a sample analysis tool.

Introduction: The programmed death 1 antibodies (PD-1 Ab) nivolumab and pembrolizumab improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). We evaluated the correlation between immune-related adverse events (irAE) and treatment interruption due to irAE on clinical efficacy of PD-1 Ab in advanced NSCLC., Patients and Methods: Advanced NSCLC patients treated with PD-1 Ab between June 2015 to November 2017 at BC Cancer were identified. Demographic, tumor, treatment details, and frequency and grade (Common Terminology Criteria for Adverse Events, version 4.0) of irAE were abstracted from chart review. Kaplan-Meier curves of OS from initiation of PD-1 Ab were generated. Multivariable analysis with 6- and 12-week landmark analysis was performed by Cox proportional hazard regression models., Results: In a cohort of 271 patients, irAEs were observed in 116 patients (42.8%). Nivolumab recipients developing colitis had lower OS compared to those who did not at the 6-week landmark (P = .010) and 12-week landmark (P = .072). For the entire cohort, 56 patients (20.7%) needed treatment interruption because of an irAE. Treatment interruption correlated with lower OS at the 6-week landmark (P = .005) and 12-week landmark (P = .008). Six-week landmark multivariable analysis identified Charlson Comorbidity Index score of 3 or higher, Eastern Cooperative Oncology Group Performance Status of 2 or higher, presence of liver metastases, and irAE greater than grade 2 versus no irAE to be associated with decreased OS (each P < .05)., Conclusion: Treatment interruption due to irAE was associated with a lower median OS compared to continuous PD-1 Ab therapy. Shorter OS seen with severe irAE might reflect the need for improved physician education in irAE treatment algorithms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Oligometastases refer to a state of disease where cancer has spread beyond the primary site, but is not yet widely metastatic, often defined as 1-3 or 1-5 metastases in number. Stereotactic ablative radiotherapy (SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates., Methods: This is a non-randomized phase II trial where all participants will receive experimental SABR treatment to all sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicity associated with this experimental treatment. The study was powered to give a 95% confidence on the risk of late grade 4 toxicity, anticipating a < 5% rate of grade 4 toxicity., Discussion: SABR treatment of oligometastases is occurring off-trial at a high rate, without sufficient evidence of its efficacy or toxicity. This trial will provide necessary toxicity data in a population-based cohort, using standardized doses and organ at risk constraints, while we await data on efficacy from randomized phase III trials., Trial Registration: Registered through clinicaltrials.gov NCT02933242 on October 14, 2016 prospectively before patient accrual.

Background: Lung stereotactic body radiotherapy (SBRT) is considered a standard curative treatment for medically inoperable early stage non-small-cell lung cancer (NSCLC). Patients with ultracentral tumors (signifying tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, or pulmonary artery) may be at higher risk of serious toxicities such as bronchial stricture and collapse, esophageal strictures, tracheal-esophageal fistula, and hemorrhage. The primary objective of the study is to determine the maximum tolerated dose of radiotherapy for ultracentral NSCLC., Methods: This multicenter phase 1 dose-escalation study will use a time-to-event continual reassessment method (TITE-CRM). Accrual will start at level 1 (60 Gy in 8 fractions delivered daily). The model will use all available information from previously accrued patients to assign the highest dose with a predicted risk of grade 3-5 toxicity of 30% or less. All patients with newly diagnosed stage T1-3 N0M0 NSCLC (International Union Against Cancer, 8th edition) with tumor size ≤ 6 cm and meeting the criteria for ultracentral location (ie, tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, pulmonary vein, or pulmonary artery) will be eligible for this study., Discussion: It is important to identify a safe dose-fractionation regimen for treating ultracentral tumors with SBRT. In addition, the data from this study may be informative in guiding future studies on the use of SBRT in treating malignancies within the mediastinum-for example, for salvage treatment of mediastinal lymph nodes for recurrent NSCLC or mediastinal oligometastases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To explore and quantify the relationship between esophageal dose and toxicity in the setting of lung stereotactic body radiation therapy (SBRT)., Methods and Materials: This analysis was conducted on the basis of a prospective study of patients treated with SBRT at our institution from October 2004 to December 2015. Most patients were treated with 54 Gy/3 fractions, 48 Gy/4 fractions alternate days, or 60 Gy/8 fractions daily. Toxicity was prospectively graded using Common Terminology Criteria for Adverse Events version 3.0. Logistic regression was used to estimate the risk of esophageal toxicity as a function of radiation therapy dose, in 2-Gy-equivalent dose, using an α/β ratio of 3 Gy in the linear-quadratic model., Results: A total of 632 patients were analyzed. The median follow-up was 20.8 months. Median overall survival was 35.3 months. The rate of late or acute grade ≥1 esophageal toxicity, including dysphagia, odynophagia, and esophagitis, was 3.3% (n = 21). The median (range) esophageal doses were 11.8 Gy (0.2-48.2 Gy), 10.34 Gy (0.17-44.5 Gy), and 9.63 Gy (0.08-43 Gy) for Dmax, D1cc, and D2cc, respectively. A 15% risk of esophageal toxicity was associated with a 2-Gy-equivalent dose of Dmax 141.6 Gy, D1cc 123.61 Gy, and D2cc 117.6 Gy. Of the 21 patients who experienced esophageal toxicity, only 1 patient had grade 3 toxicity, and the remainder had grade 2 or lower toxicity., Conclusions: The observed rate of toxicity was low, despite some patients receiving relatively high doses to the esophagus. A prospective study in a targeted population, for example patients with ultracentral tumors, may provide more accurate dose-toxicity parameters., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to determine the impact of radiation dose to substructures of the heart in lung stereotactic body radiotherapy (SBRT) patients on non-cancer-related deaths., Methods: Patients treated with lung SBRT at a single institution from 2005 to 2013 were included. The heart and its substructures were contoured, and dose was calculated including mean, max, and max 10 cc dose. Clinical variables including stage, histology, age, gender, Charlson comorbidity index (CCI), preexisting cardiac disease, pulmonary function (forced expiratory volume in 1 second, diffusion capacity), and smoking status were explored for association with non-cancer-related deaths in univariable (UVA) and multivariable (MVA) analyses. Heart dosimetric parameters were correlated with the risk of radiation pneumonitis (RP) using UVA and MVA., Results: A total of 189 patients were included with median age of 76 years (range, 48-93 years). Of these patients, 45.5% were female, 27.5% were T2, 16.9% were current smokers, 64% had preexisting cardiac risk factors, and 34.5% had CCI score of ≥ 3. Mean lung dose ± SD was 456 ± 231 cGy. Heart max, mean, and 10 cc doses were 1867 ± 1712 cGy, 265 ± 269 cGy, and 1150 ± 1075 cGy, respectively. There were 14 (7.4%) ≥ Grade 2 RP and 3 (1.6%) were ≥ Grade 3. The median overall survival was 37.3 months (95% confidence interval, 29.8-45.3 months). On UVA, female gender (P < .01), higher Eastern Cooperative Oncology Group (P = .01), cardiac risk (P < .01), CCI (P < .01), and bilateral ventricles max dose (P = .02) were associated with non-cancer-related deaths; on MVA, bilateral ventricles max dose was significant (P = .05). No heart parameters were associated with RP., Conclusions: Higher bilateral ventricles max dose is associated with poorer survival. Heart dose parameters should be considered when planning patients for SBRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to determine the impact of interstitial lung disease (ILD) on radiation pneumonitis (RP) and overall survival (OS) in lung stereotactic body radiation therapy (SBRT)., Methods: Patients treated with lung SBRT from 2004 to 2015 were included. Pretreatment computed tomography scans were reviewed and classified for interstitial changes by thoracic radiologists using American Thoracic Society guidelines and Washko and Kazerooni scores. RP was scored prospectively using Common Terminology Criteria for Adverse Events, version 3.0. Pretreatment imaging characteristics, clinical variables, and dosimetry were assessed by univariate (UVA) and multivariate analysis (MVA). OS was assessed by the log-rank test, and the impact of ILD on OS was assessed by Cox regression., Results: Of the 537 patients assessed, 39 had interstitial changes (13 usual interstitial pneumonia [UIP], 24 possible UIP, and 2 inconsistent with UIP). RP was significantly higher in patients with ILD than in patients without ILD (grade ≥ 2, 20.5% vs. 5.8%; P < .01; grade ≥ 3, 10.3% vs. 1.0%; P < .01). Two of 3 grade 5 RP had imaging features of ILD. On UVA, ILD, Washko score, lung parameters performance status, and dose were significant predictors of grade ≥ 2 RP. On MVA, ILD (odds ratio, 5.81; 95% confidence interval, 2.28-14.83; P < .01) and mean lung dose (odds ratio, 1.40; 95% confidence interval, 1.14-1.71; P < .01) were predictors of RP. ILD did not significantly affect OS on UVA or MVA. Median survival was 27.4 months in the ILD cohort and 34.8 in the ILD-negative cohort (P = .17)., Discussion: ILD is a significant risk factor for RP in patients treated with lung SBRT. Computed tomography scans should be reviewed for evidence of ILD prior to SBRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this paper I elicit a prediction from structural realism and compare it, not to a historical case, but to a contemporary scientific theory. If structural realism is correct, then we should expect physics to develop theories that fail to provide an ontology of the sort sought by traditional realists. If structure alone is responsible for instrumental success, we should expect surplus ontology to be eliminated. Quantum field theory (QFT) provides the framework for some of the best confirmed theories in science, but debates over its ontology are vexed. Rather than taking a stand on these matters, the structural realist can embrace QFT as an example of just the kind of theory SR should lead us to expect. Yet, it is not clear that QFT meets the structuralist's positive expectation by providing a structure for the world. In particular, the problem of unitarily inequivalent representations threatens to undermine the possibility of QFT providing a unique structure for the world. In response to this problem, I suggest that the structuralist should endorse pluralism about structure., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Patients receiving extracorporeal membrane oxygenation (ECMO) are at risk for thrombocytopenia including heparin-induced thrombocytopenia (HIT). The purpose of this study was to determine the frequency of suspected HIT in patients receiving ECMO and unfractionated heparin (UFH)., Materials and Methods: We conducted a retrospective review in adult patients on ECMO. Patients were included if they received ECMO for at least 5 days and concomitant UFH., Results: There were 119 patients who met inclusion criteria. Twenty-three patients (19%) had a heparin-platelet factor 4 immunoassay performed. Patients with suspected HIT had a significantly lower platelet count within the first 3 days of ECMO, 69×10(9)/L (22-126×10(9)/L) vs 87.5×10(9)/L (63-149×10(9)/L); P=.04. The lowest platelet count on the day of HIT testing was 43×10(9)/L (26-73), representing a 71% reduction from baseline. Twenty patients (87%) had an optical density score less than 0.4, and all patients had a score less than 1.0. A functional assay was performed in 7 patients (30%), with only 1 patient having laboratory-confirmed HIT., Conclusions: The evaluation of HIT occurred in a small percentage of patients, with HIT rarely being detected. Patients who had heparin-platelet factor 4 immunoassay testing exhibited lower platelet counts with a similar duration of ECMO and UFH exposure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The interplay of policy, milestone events, and cornerstone documents was critical in the evolution of the specialty of public health nursing (PHN) from 1890-1950. Using our contemporary lens, this article examines PHN development from an historical perspective, including events and milestones driving growth in the early 20th century. Some of the challenges faced by our founding public health nursing leadership are not unlike challenges we face today. In 1950, Ruth Hubbard, a former leader in the National Organization of Public Health Nurses and Director of the Visiting Nurse Society of Philadelphia, spoke of the value of examining the past to forge a new future. This article calls for contemporary public health nurses to act upon the lessons learned from the past, to strengthen the renewed focus on prevention, to develop policies that impact population health, and to foster a vision that will guide us into the future.

Purpose: The red-hair phenotype, which is often produced by mutations in the melanocortin-1 receptor gene, has been associated with an increase in sedative, anesthetic, and analgesic requirements in both animal and human studies. Nevertheless, the clinical implications of this phenomenon in red-haired patients undergoing surgery are currently unknown., Methods: In a secondary analysis of a prospective trial of intraoperative awareness, red-haired patients were identified and matched with five control patients, and the relative risk for intraoperative awareness was determined. Overall anesthetic management between groups was compared using Hotelling's T(2) statistic. Inhaled anesthetic requirements were compared between cohorts by evaluating the relationship between end-tidal anesthetic concentration and the bispectral index with a linear mixed-effects model. Time to recovery was compared using Kaplan-Meier analysis, and differences in postoperative pain and nausea/vomiting were evaluated with Chi square tests., Results: A cohort of 319 red-haired patients was matched with 1,595 control patients for a sample size of 1,914. There were no significant differences in the relative risk of intraoperative awareness (relative risk = 1.67; 95% confidence interval 0.34 to 8.22), anesthetic management, recovery times, or postoperative pain between red-haired patients and control patients. The relationship between pharmacokinetically stable volatile anesthetic concentrations and bispectral index values differed significantly between red-haired patients and controls (P < 0.001), but without clinical implications., Conclusion: There were no demonstrable differences between red-haired patients and controls in response to anesthetic and analgesic agents or in recovery parameters. These findings suggest that perioperative anesthetic and analgesic management should not be altered based on self-reported red-hair phenotype.

Two defining characteristics of stem cells are their multilineage differentiation potential (multipotency or pluripotency) and their capacity for self-renewal. Growth factors are well-established regulators of stem cell differentiation and self renewal, but less is known about the influence of the metabolic state on stem cell function. Recent studies investigating cellular metabolism during the differentiation of adult stem cells, human embryonic stem cells (ESCs), and induced pluripotent stem cells have demonstrated that activation of specific metabolic pathways depends on the type of stem cells as well as the lineage cells are differentiating into and that these metabolic pathways can influence the differentiation process. However, some common patterns have emerged, suggesting that undifferentiated stem cells primarily rely on glycolysis to meet energy demands. Our own data indicate that undifferentiated ESCs not only exhibit a low mitochondrial membrane potential but also express high levels of the mitochondrial uncoupling protein 2 and of glutamine metabolism regulators when compared with differentiated cells. More importantly, interventions that target stem cell metabolism are able to either prevent or enhance differentiation. These findings suggest that the metabolic state of stem cells is not just a marker of their differentiation status but also plays an active role in regulating stem cell function. Regulatory metabolic pathways in stem cells may thus serve as important checkpoints that can be modulated to direct the regenerative capacity of stem cells.

Anatomical, neurological and behavioural research has suggested differences between the brains of right- and non-right-handed individuals, including differences in brain structure, electroencephalogram patterns, explicit memory and sleep architecture. Some studies have also found decreased longevity in left-handed individuals. We therefore aimed to determine whether handedness independently affects the relationship between volatile anaesthetic concentration and the bispectral index, the incidence of definite or possible intra-operative awareness with explicit recall, or postoperative mortality. We studied 5585 patients in this secondary analysis of data collected in a multicentre clinical trial. There were 4992 (89.4%) right-handed and 593 (10.6%) non-right-handed patients. Handedness was not associated with (a) an alteration in anaesthetic sensitivity in terms of the relationship between the bispectral index and volatile anaesthetic concentration (estimated effect on the regression relationship -0.52 parallel shift; 95% CI -1.27 to 0.23, p = 0.17); (b) the incidence of intra-operative awareness with 26/4992 (0.52%) right-handed vs 1/593 (0.17%) non-right-handed (difference = 0.35%; 95% CI -0.45 to 0.63%; p = 0.35); or (c) postoperative mortality rates (90-day relative risk for non-right-handedness 1.19, 95% CI 0.76-1.86; p = 0.45). Thus, no change in anaesthetic management is indicated for non-right-handed patients., (© 2014 The Association of Anaesthetists of Great Britain and Ireland.)

Objectives: This study sought to determine whether the combined trajectories of cardiac biomarkers identify those older adults with initial low levels who have an increased risk for structural heart disease, incident heart failure (HF), and cardiovascular (CV) death., Background: Initial low levels of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) identify older adults at lower risk for CV events., Methods: We performed an observational study among older adults without prevalent HF in the CHS (Cardiovascular Health Study). NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years. In those with low baseline levels, a significant increase was defined as cardiac troponin T (cTnT) >50% and NT-proBNP >25% increase to >190 pg/ml. Left ventricular ejection fraction and left ventricular mass were measured by echocardiography at baseline and 5 years. Cox regression was used to estimate the association of change in biomarkers with HF and CV mortality., Results: Among 2,008 participants with initially low biomarker concentrations, significant increases occurred in 14.8% for cTnT only, 13.2% for NT-proBNP only, and 6.1% for both. After 10 years, cumulative HF incidence was 50.4% versus 12.2% among those with both biomarkers versus neither biomarker increased. The adjusted relative risk comparing those with increases in both biomarkers versus neither biomarker was 3.56 for incident HF (95% confidence interval: 2.56 to 4.97) and 2.98 for CV mortality (95% confidence interval: 2.98 to 4.26). Among 1,340 participants with serial echocardiography, the frequency of new abnormal left ventricular ejection fraction was 11.8% versus 4% for those with increases in both biomarkers versus neither biomarker (p = 0.007)., Conclusions: Among older adults without HF with initially low cTnT and NT-proBNP, the long-term trajectory of both biomarkers predicts systolic dysfunction, incident HF, and CV death., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Intraoperative awareness with explicit recall (AWR) is a self-reported outcome of interest in clinical practice, quality assurance initiatives, and clinical trials. Combining structured postoperative interviews with a preoperative description of AWR is assumed to ensure prompt patient disclosure. We describe a volitionally delayed reporting of AWR because of the perceived unimportance of nondistressing awareness experiences, despite preoperative education and 2 postoperative interviews. This delay had implications for a major randomized controlled trial on AWR. Volitionally delayed self-reported outcomes may affect statistical comparisons in clinical trials and quality assurance initiatives, and delay the treatment of subsequent sequelae in clinical practice. This limitation should be considered, even when using structured outcome assessment and preoperative education.

Purpose: To assess changes in the electrocardiogram (ECG) associated with intraoperative infusion of adenosine in patients undergoing open abdominal gynecological surgery., Methods: One hundred and sixty-six patients undergoing gynecological surgery were randomly assigned to receive one of four doses of adenosine infusion (25, 50, 100, or 200 μg/kg/min) or matching placebo. Study drug administration was started at skin incision and discontinued at end of surgery. A standardized general anesthetic regimen was used and adjusted based on hemodynamic and bispectral index values. Heart rate and rhythm variables, and PR, QRS, QT, and QTc intervals were recorded from 12-lead ECGs before anesthesia and immediately after patient arrival in the postanesthesia care unit. In addition, a rhythm strip was obtained during administration of the loading dose of the study drug. ECG variables were compared within and between groups. Incidence of ECG and hemodynamic abnormalities was recorded., Results: One hundred and fifty-one subjects had a full set of electrocardiographic data: placebo (n = 38), group adenosine 25 μg/kg/min (n = 31), group adenosine 50 μg/kg/min (n = 29), group adenosine 100 μg/kg/min (n = 28), and group adenosine 200 μg/kg/min (n = 25). Statistically significant postoperative QTc prolongation was observed in all study groups when compared with baseline except for the adenosine 200 μg/kg/min group. However, these changes from baseline were not different among the groups. There were also no significant differences in PR, QRS, and QT intervals between the treatment groups., Conclusion: There was no difference in QTc prolongation following intraoperative administration of adenosine infusion compared with placebo during isoflurane general anesthesia. However, QTc prolongation is common following general anesthesia.

Study Objective: To determine the incidence and nature of allergic reactions to amiodarone in hospitalized patients with a listed allergy to iodine or iodinated radiocontrast agents., Design: Retrospective medical record review., Setting: Two academic medical centers., Patients: A total of 234 sequential hospitalized patients with a listed iodine and/or iodinated radiocontrast agent allergy who received oral or intravenous amiodarone between January 2006 and December 2010., Measurements and Main Results: Demographic and clinical data, as well as documentation of an allergic reaction to amiodarone, were collected for each patient from electronic medical records. Mean ± SD age was 69 ± 12 years, and 51% were male. Of the 234 patients, 167 (71%) had a listed previous allergy to iodinated contrast agents, 55 (24%) to iodine, and 12 (5%) to both. Patients received an average inpatient total dose of 2.9 ± 3.2 g of either oral (106 patients [45%]), intravenous (39 patients [17%]), or both oral and intravenous (89 patients [38%]) amiodarone. Only 1 (0.4%) of the 234 patients was identified as having a probable allergic reaction to amiodarone (score of 6 on the Naranjo adverse drug reaction probability scale). One additional patient receiving intravenous amiodarone experienced a rash that was determined to be caused by an antibiotic. All other patients received amiodarone without any identifiable allergic reactions., Conclusion: The incidence of hypersensitivity reaction to amiodarone in hospitalized patients with a listed allergy to iodine or iodinated contrast agents was less than 1%, and all identified reactions were without long-term sequelae. Allergy to iodine and iodinated contrast agents may not be a valid absolute contraindication to amiodarone administration in the inpatient setting., (© 2012 Pharmacotherapy Publications, Inc. All rights reserved.)

BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. While the BNip3 protein is constitutively expressed in adult liver from fed mice, we have shown that its expression is superinduced by fasting of mice, consistent with a role in responses to nutrient deprivation. Loss of BNip3 resulted in increased lipid synthesis in the liver that was associated with elevated ATP levels, reduced AMP-regulated kinase (AMPK) activity, and increased expression of lipogenic enzymes. Conversely, there was reduced β-oxidation of fatty acids in BNip3 null liver and also defective glucose output under fasting conditions. These metabolic defects in BNip3 null liver were linked to increased mitochondrial mass and increased hepatocellular respiration in the presence of glucose. However, despite elevated mitochondrial mass, an increased proportion of mitochondria exhibited loss of mitochondrial membrane potential, abnormal structure, and reduced oxygen consumption. Elevated reactive oxygen species, inflammation, and features of steatohepatitis were also observed in the livers of BNip3 null mice. These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver that has consequences for lipid metabolism and disease.

The purpose of this study is to describe the characteristics and health status of a sample of migrant farmworkers in the Shenandoah Valley. The methodology for this study is a retrospective record review and analysis of data on 390 male migrant farmworkers. The group included men from Mexico (57. 2%), Jamaica (26. 9%), and Haiti (13. 0%) with a mean age of 38.5 years. The most common health problems reported were work-related and included musculoskeletal pain, irritated eyes, and respiratory symptoms. This study identifies areas for community and public health nurses to target interventions to address health promotion/disease prevention efforts.

Background: Unintended intraoperative awareness, which occurs when general anesthesia is not achieved or maintained, affects up to 1% of patients at high risk for this complication. We tested the hypothesis that a protocol incorporating the electroencephalogram-derived bispectral index (BIS) is superior to a protocol incorporating standard monitoring of end-tidal anesthetic-agent concentration (ETAC) for the prevention of awareness., Methods: We conducted a prospective, randomized, evaluator-blinded trial at three medical centers. We randomly assigned 6041 patients at high risk for awareness to BIS-guided anesthesia (with an audible alert if the BIS value was <40 or >60, on a scale of 0 to 100, with 0 indicating the suppression of detectable brain electrical activity and 100 indicating the awake state) or ETAC-guided anesthesia (with an audible alert if the ETAC was <0.7 or >1.3 minimum alveolar concentration). In addition to audible alerts, the protocols included structured education and checklists. Superiority of the BIS protocol was assessed with the use of a one-sided Fisher's exact test., Results: A total of 7 of 2861 patients (0.24%) in the BIS group, as compared with 2 of 2852 (0.07%) in the ETAC group, who were interviewed postoperatively had definite intraoperative awareness (a difference of 0.17 percentage points; 95% confidence interval [CI], -0.03 to 0.38; P=0.98). Thus, the superiority of the BIS protocol was not demonstrated. A total of 19 cases of definite or possible intraoperative awareness (0.66%) occurred in the BIS group, as compared with 8 (0.28%) in the ETAC group (a difference of 0.38 percentage points; 95% CI, 0.03 to 0.74; P=0.99), with the superiority of the BIS protocol again not demonstrated. There was no difference between the groups with respect to the amount of anesthesia administered or the rate of major postoperative adverse outcomes., Conclusions: The superiority of the BIS protocol was not established; contrary to expectations, fewer patients in the ETAC group than in the BIS group experienced awareness. (Funded by the Foundation for Anesthesia Education and Research and others; BAG-RECALL ClinicalTrials.gov number, NCT00682825.).

The purpose of this systematic literature review was to determine the relationship between the diagnosis of diabetes and depression and missed appointments in a low-income, uninsured, racially heterogeneous, adult population. Research demonstrates that individuals with diabetes have an increased incidence of depression across socioeconomic and racial groups. Low-income individuals have an increased prevalence of depression. The cost and burden of diabetes are greatly increased among individuals with both diabetes and depression versus diabetes alone. The prevalence and effects of diabetes and depression in a low-income, uninsured, racially heterogeneous population have not been determined. Further research to explore the relationship of diabetes, depression, and missed appointments in this vulnerable population is needed before effective treatment models can be developed. Longitudinal studies are also needed to determine the cause and effect between diabetes and depression among all populations., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Study Objective: To compare the Mapleson D circuit and the bag-valve-mask device for mask ventilation of patients undergoing electroconvulsive therapy (ECT)., Design: Cross-over study., Setting: Single-center academic medical center., Patients: 18 patients undergoing ECT for major depressive disorder., Interventions: Patients were randomized to undergo mask ventilation by the Mapleson D circuit or the bag-valve-mask device., Measurements: End-tidal CO(2), seizure duration, and airway pressure values were recorded., Main Results: End-tidal CO(2) was significantly lower with the bag-valve-mask device. When compared with the bag-valve-mask device, ventilation with the Mapleson circuit resulted in rebreathing of CO(2) in nearly all patients, shorter expiratory time, and lower pressure ramp slope., Conclusions: Hypocapnia was not associated with longer seizures, and the user-device interaction might affect device performance., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Prevention of illness has become a central theme in debates over strategies to reduce healthcare costs. Severe mental illness poses a special challenge to the paradigm of rational prevention, the principal strategy of which is adherence to pharmacological therapies. With the contraction in the US of in-patient psychiatric care from the 1960s onwards, the mentally ill have become more visible among the homeless and among those caught up in the penal system. Their characteristic visibility contributes to their image as threatening. The perceived dangerousness and the combined societal and economic costs associated with the illness have generated a heightened, and in some venues even a sensationalized rhetoric surrounding the questions of responsibility and control, which we consider in terms of compliance. Using the linguistic method of discourse analysis, we analyze one high profile instance - an episode of CNN's 'Special Investigations Unit', which aired several times in the summer of 2007 - to demonstrate a narrative linking of the high social costs and failures associated with noncompliance and, therefore, the imperative of enforcing it for the safety of society. Through the semiotic reduction of a 'poetic parallelism', the episode reflects and reinforces existing cultural models for mental illness, including its status as straightforward biological disease amenable to pharmacological therapy but which remains uncontrolled due to widespread noncompliance.

Autophagy is a fundamental and phylogenetically conserved self-degradation process that is characterized by the formation of double-layered vesicles (autophagosomes) around intracellular cargo for delivery to lysosomes and proteolytic degradation. The increasing significance attached to autophagy in development and disease in higher eukaryotes has placed greater importance on the validation of reliable, meaningful and quantitative assays to monitor autophagy in live cells and in vivo in the animal. To date, the detection of processed LC3B-II by western blot or fluorescence studies, together with electron microscopy for autophagosome formation, have been the mainstays for autophagy detection. However, LC3 expression levels can vary markedly between different cell types and in response to different stresses, and there is also concern that over-expression of tagged versions of LC3 to facilitate imaging and detection of autophagy interferes with the process itself. In addition, the realization that it is not sufficient to monitor static levels of autophagy but to measure 'autophagic flux' has driven the development of new or modified approaches to detecting autophagy. Here, we present a critical overview of current methodologies to measure autophagy in cells and in animals., (Copyright (c) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease., (Copyright (c) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: Awareness with explicit recall of intra-operative events is a rare and distressing complication that may lead to severe psychological symptoms. Candidate depth of anesthesia monitors have been developed, partly with the aim of preventing this complication. Despite conflicting results from clinical trials and the lack of incisive validation, such monitors have enjoyed widespread clinical adoption, in particular the bispectral index. The American Society of Anesthesiologists has called for adequately powered and rigorously designed clinical trials to determine whether the use of such monitors decreases the incidence of awareness in various settings. The aim of this study is to determine with increased precision whether incorporating the bispectral index into a structured general anesthesia protocol decreases the incidence of awareness with explicit recall among a subset of surgical patients at increased risk for awareness and scheduled to receive an inhalation gas-based general anesthetic., Methods/design: BAG-RECALL is a multi-center, randomized, controlled clinical trial, in which 6,000 patients are being assigned to bispectral index-guided anesthesia (target range, 40 to 60) or end-tidal anesthetic gas-guided anesthesia (target range, 0.7 to 1.3 age-adjusted minimum alveolar concentration). Postoperatively, patients are being assessed for explicit recall at two intervals (0 to 72 hours, and 30 days after extubation). The primary outcome of the trial is awareness with explicit recall. Secondary outcomes include postoperative mortality, psychological symptoms, intensive care and hospital length of stay, average anesthetic gas administration, postoperative pain and nausea and vomiting, duration of stay in the recovery area, intra-operative dreaming, and postoperative delirium., Discussion: This trial has been designed to complement two other clinical trials: B-Unaware and MACS (ClinicalTrials.gov numbers, NCT00281489 and NCT00689091). With the large patient numbers and complementary rigorous designs, it is envisaged that pre-specified meta-analyses will address some of the outstanding controversies and questions relating to processed electroencephalography monitoring., Trial Registration: ClinicalTrials.gov Identifier: NCT00682825.

Purpose: The purpose of this project is to identify rates of depression and document mental health needs of adults with diabetes who obtained care in free clinics. Data were collected to determine if there is a relationship between diabetes and depression and missed appointments in a sample of patients who were low-income, uninsured, and represented a variety of racial groups., Methods: A sample of 183 adults with diabetes participated by completing paper and computerized questionnaires. Instruments included the Patient Health Questionnaire 9 (to measure prevalence of depression), the RAND 36 Health Survey (to measure quality of health), the Audit of Diabetes Dependent Quality of Life (to measure diabetes-dependent quality of life), and the Diabetes Empowerment Scale (to measure self-efficacy)., Results: The prevalence of depression at a moderate or greater level in the sample was found to be 30.1%. Levels of quality of health and self-efficacy were found to be reduced among those with the presence of depression. A significant increase in the rate of depression was found among those who had attended the free clinic for a longer period. No significant differences were found in diabetes-dependent quality of life and missed appointments among those with depression compared with those without., Conclusions: Rates of depression among adults with diabetes in a free clinic setting were found to be comparable with the highest rates reported by other studies of insured populations. Results of this study support the need to develop mental health treatment programs for free clinic settings.

Pulmonary edema after electroconvulsive therapy (ECT) is a rarely reported condition that can result in serious morbidity and even death if not promptly recognized and treated. We report the case of 21-year-old man with FG syndrome and schizophrenia who developed negative-pressure pulmonary edema after his 28th ECT. The patient developed acute hypoxemia requiring positive-pressure ventilation and was observed overnight in the intensive care unit. He recovered fully and received 43 subsequent ECT treatments without complication. This case illustrates the importance of taking steps to prevent airway obstruction as well as recognizing this rare but serious complication.

Overexpression of cyclin E in breast tumors is associated with a poor response to tamoxifen therapy, greater genomic instability, more aggressive behavior, and a poor clinical prognosis. These tumors also express low molecular weight isoforms of cyclin E that are associated with higher kinase activity and increased metastatic potential. In the current study, we show that cyclin E overexpression in MCF7 cells transactivates the expression of calpain 2, leading to proteolysis of cyclin E as well as several known calpain substrates including focal adhesion kinase (FAK), calpastatin, pp60src, and p53. In vivo inhibition of calpain activity in MCF7-cyclin E cells impedes cyclin E proteolysis, whereas in vivo induction of calpain activity promotes cyclin E proteolysis. An analysis of human breast tumors shows that high levels of cyclin E are coincident with the expression of the low molecular weight isoforms, high levels of calpain 2 protein, and proteolysis of FAK. Lastly, studies using a mouse model of metastasis reveal that highly metastatic tumors express proteolyzed cyclin E and FAK when compared to tumors with a low metastatic potential. Our results suggest that cyclin E-dependent deregulation of calpain may be pivotal in modifying multiple cellular processes that are instrumental in the etiology and progression of breast cancer.

Aims: To determine the effect that the presence of some beetles have on the species of bacteria found in their flour., Methods and Results: Bacteria were isolated from flour that either did not contain beetles, contained Tribolium beetles in different environments, or contained either Stegobium paniceum or Lasioderma serricorne. These bacteria were tentatively identified by both the gas chromatography-fatty acid methyl esters (GC-FAME) method and partial sequencing of the 16S rRNA gene. All samples contained Bacillus species including the controls, but the non-Tribolium beetles and a Tribolium beetle line known to have low benzoquinones also contained Enterococcus and Enterobacter species. Additionally an unidentified bacteria isolate in the Enterobacteriaceae was also found in the L. serricorne sample. Our results also suggest incongruent identifications when using the GC-FAME method vs sequencing., Conclusions: Certain species of bacteria can be introduced by the presence of insect pests, but the diversity of species is far less in stocks of Tribolium beetles., Significance and Impact of the Study: Stored product pests can alter the bacterial community. Isolated species from this study show a strong genetic relationship to each other, suggesting an isolated evolving system. A unique bacteria was also isolated. GC and sequencing methods of identification are compared.

Two patients who had failed outpatient treatment of depression were given electroconvulsive therapy while simultaneously being treated with monoamine oxidase inhibitors. Both were administered propofol-alfentanil anesthesia without complications.

Behavioral genetics is the identification of behavioral traits that are genetically determined, the identification of the genes that are involved, and the discovery of modes of intervention to alter the expected course of the disease. Unlike the classical Mendelian traits, many specific aspects of behavior are, in part, determined by several genes. The corresponding abnormalities of behavior or deficiencies are therefore polygenic. New genetic techniques are leading to the discovery of these genes, and the techniques and knowledge developed in the Human Genome Project make it possible to screen the genome of any individual for the presence of known polymorphisms. This raises great hopes for diagnosis and the individualization of therapy. However, the genetic prediction of unacceptable behavior can further lead to social and occupational discrimination and enforced therapy. This raises serious concerns about how this information will be collected and who will have access to it.

Humans possess a surprisingly low number of genes and intensively use pre-mRNA splicing to achieve the high molecular complexity needed to sustain normal body functions and facilitate responses to altered conditions. Because hundreds of thousands of proteins are generated by 25,000 to 40,000 genes, pre-mRNA processing events are highly important for the regulation of human gene expression. Both inherited and acquired defects in pre-mRNA processing are increasingly recognized as causes of human diseases, and almost all pre-mRNA processing events are controlled by a combination of protein factors. This makes defects in these processes likely candidates for causes of diseases with complicated inheritance patterns that affect seemingly unrelated functions. The elucidation of genetic mechanisms regulating pre-mRNA processing, combined with the development of drugs targeted at consensus RNA sequences and/or corresponding proteins, can lead to novel diagnostic and therapeutic approaches.

Acute Care of the Elderly (ACE) units have been shown to improve outcomes for hospitalized elders. Because the literature offers little to describe the appropriate staffing of such units, we surveyed ACE units about their size, configuration, staffing, patient selection, training, and outcomes data. Although we had anticipated speaking with staff from 30 to 40 units, we were able to poll key personnel on only 18 ACE units. This article describes staffing and continuous quality improvement data for these sites.

To explore neuronal mechanisms underlying long-term consequences of stress, we studied stress-induced changes in the neuritic translocation of acetylcholinesterase (AChE) splice variants. Under normal conditions, we found the synaptic AChE-S mRNA and protein in neurites. Corticosterone, anticholinesterases, and forced swim, each facilitated a rapid (minutes), yet long-lasting (weeks), shift from AChE-S to the normally rare AChE-R mRNA, promoted AChE-R mRNA translocation into neurites, and induced enzyme secretion. Weeks after stress, electrophysiological measurements in hippocampus slices displayed apparently normal evoked synaptic responses but extreme hypersensitivity to both anticholinesterases and atropine. Our findings suggest that neuronal hypersensitivity under stress involves neuritic replacement of AChE-S with AChE-R.

This critical review of program revision processes is guided by the program management model and considers issues germane to community-oriented health care programs, illustrated by examples from the literature. Options for program revision lie on a continuum from discontinuing a program, to various degrees of adjustments, to no change. Sustainability is the ultimate issue that must be addressed, and community and staff participation is critical for successful program revision.

The IBRO World Congress of Neuroscience covered the full spectrum of neuroscience, from molecular and developmental neurobiology to behavioral pharmacology and neurodegeneration.

Apart from its catalytic function in hydrolyzing acetylcholine, acetylcholinesterase (AChE) affects cell proliferation, differentiation and responses to various insults, including stress. These responses are at least in part specific to the three C-terminal variants of AChE which are produced by alternative splicing of the single ACHE gene. 'Synaptic' AChE-S constitutes the principal multimeric enzyme in brain and muscle; soluble, monomeric 'readthrough' AChE-R appears in embryonic and tumor cells and is induced under psychological, chemical and physical stress; and glypiated dimers of erythrocytic AChE-E associate with red blood cell membranes. We postulate that the homology of AChE to the cell adhesion proteins, gliotactin, glutactin and the neurexins, which have more established functions in nervous system development, is the basis of its morphogenic functions. Competition between AChE variants and their homologs on interactions with the corresponding protein partners would inevitably modify cellular signaling. This can explain why AChE-S exerts process extension from cultured amphibian, avian and mammalian glia and neurons in a manner that is C-terminus-dependent, refractory to several active site inhibitors and, in certain cases, redundant to the function of AChE-like proteins. Structural functions of AChE variants can explain their proliferative and developmental roles in blood, bone, retinal and neuronal cells. Moreover, the association of AChE excess with amyloid plaques in the degenerating human brain and with progressive cognitive and neuromotor deficiencies observed in AChE-transgenic animal models most likely reflects the combined contributions of catalytic and structural roles.

Community nursing centers are unique arenas for advanced practice community health nursing. These innovative nurse-managed delivery models are grounded in a holistic approach to the community-as-client. They provide the public with direct access to a range of advanced practice professional nursing services that are not otherwise available. Community Nursing Centers are collaborative with other health professions and organizations. They aim to meet the assessed needs of underserved populations using extant resources to achieve optimal health for all members of the community. This article discusses the underlying conceptual basis for development of community nursing centers and provides a case study example.

The goal of the present study was to evaluate the antileishmanial effects of topically applied lipid-based formulations containing amphotericin B (AmB) in CBA mice as a model for human cutaneous leishmaniasis. Such treatment, if efficacious, is expected to be superior to systemic treatments since, by acting in a localized manner, it will require lower, and therefore less toxic, drug dosages. Three preparations of AmB complexed to polar lipids were tested: Fungizone (mixed micelles composed of AmB and deoxycholate), Amphocil (AmB and cholesteryl sulfate complex), and ABPLC (AmB and phospholipid complex). All these formulations killed parasites in vitro with similar efficacies but were ineffective when they were applied topically. However, Amphocil and ABPLC, but not Fungizone, when dispersed in an aqueous solution containing 5 to 25% ethanol, induced a statistically significant improvement in lesion size from week 2 or 3 onward (a total of 15 mg of AmB per kg of body weight was applied over 3 weeks). AmB biodistribution measurements following topical application of Amphocil, determined by high-pressure liquid chromatography, showed that AmB was detectable in the skin but not in the internal organs. Application of at least 10 times more drug was necessary to obtain detectable levels of AmB in the internal organs. After application of therapeutic doses of ABPLC, very low levels of AmB were detected in the internal organs. These experiments show for the first time that AmB administered topically as a complex either with cholesteryl sulfate or with phospholipids and in the presence of ethanol can penetrate the skin and kill sensitive organisms in a localized manner by using very low total drug concentrations.