A neural biomarker of psychological vulnerability to future life stress.

We all experience a host of common life stressors such as the death of a family member, medical illness, and financial uncertainty. While most of us are resilient to such stressors, continuing to function normally, for a subset of individuals, experiencing these stressors increases the likelihood of developing treatment-resistant, chronic psychological problems, including depression and anxiety. It is thus paramount to identify predictive markers of risk, particularly those reflecting fundamental biological processes that can be targets for intervention and prevention. Using data from a longitudinal study of 340 healthy young adults, we demonstrate that individual differences in threat-related amygdala reactivity predict psychological vulnerability to life stress occurring as much as 1 to 4 years later. These results highlight a readily assayed biomarker, threat-related amygdala reactivity, which predicts psychological vulnerability to commonly experienced stressors and represents a discrete target for intervention and prevention.

Host gene expression classifiers diagnose acute respiratory illness etiology.

Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.

A cross-site, comparative effectiveness study of an integrated HIV and substance use treatment program.

Co-occurrence of HIV and substance abuse is associated with poor outcomes for HIV-related health and substance use. Integration of substance use and medical care holds promise for HIV patients, yet few integrated treatment models have been reported. Most of the reported models lack data on treatment outcomes in diverse settings. This study examined the substance use outcomes of an integrated treatment model for patients with both HIV and substance use at three different clinics. Sites differed by type and degree of integration, with one integrated academic medical center, one co-located academic medical center, and one co-located community health center. Participants (n=286) received integrated substance use and HIV treatment for 12 months and were interviewed at 6-month intervals. We used linear generalized estimating equation regression analysis to examine changes in Addiction Severity Index (ASI) alcohol and drug severity scores. To test whether our treatment was differentially effective across sites, we compared a full model including site by time point interaction terms to a reduced model including only site fixed effects. Alcohol severity scores decreased significantly at 6 and 12 months. Drug severity scores decreased significantly at 12 months. Once baseline severity variation was incorporated into the model, there was no evidence of variation in alcohol or drug score changes by site. Substance use outcomes did not differ by age, gender, income, or race. This integrated treatment model offers an option for treating diverse patients with HIV and substance use in a variety of clinic settings. Studies with control groups are needed to confirm these findings.

Communication practices in physician decision-making for an unstable critically ill patient with end-stage cancer.

BACKGROUND: Shared decision-making has become the standard of care for most medical treatments. However, little is known about physician communication practices in the decision making for unstable critically ill patients with known end-stage disease. OBJECTIVE: To describe communication practices of physicians making treatment decisions for unstable critically ill patients with end-stage cancer, using the framework of shared decision-making. DESIGN: Analysis of audiotaped encounters between physicians and a standardized patient, in a high-fidelity simulation scenario, to identify best practice communication behaviors. The simulation depicted a 78-year-old man with metastatic gastric cancer, life-threatening hypoxia, and stable preferences to avoid intensive care unit (ICU) admission and intubation. Blinded coders assessed the encounters for verbal communication behaviors associated with handling emotions and discussion of end-of-life goals. We calculated a score for skill at handling emotions (0-6) and at discussing end of life goals (0-16). SUBJECTS: Twenty-seven hospital-based physicians. RESULTS: Independent variables included physician demographics and communication behaviors. We used treatment decisions (ICU admission and initiation of palliation) as a proxy for accurate identification of patient preferences. Eight physicians admitted the patient to the ICU, and 16 initiated palliation. Physicians varied, but on average demonstrated low skill at handling emotions (mean, 0.7) and moderate skill at discussing end-of-life goals (mean, 7.4). We found that skill at discussing end-of-life goals was associated with initiation of palliation (p = 0.04). CONCLUSIONS: It is possible to analyze the decision making of physicians managing unstable critically ill patients with end-stage cancer using the framework of shared decision-making.

Establishing a regional, multisite database for quality improvement and service planning in community-based palliative care and hospice.

BACKGROUND: Outpatient palliative care, an evolving delivery model, seeks to improve continuity of care across settings and to increase access to services in hospice and palliative medicine (HPM). It can provide a critical bridge between inpatient palliative care and hospice, filling the gap in community-based supportive care for patients with advanced life-limiting illness. Low capacities for data collection and quantitative research in HPM have impeded assessment of the impact of outpatient palliative care. APPROACH: In North Carolina, a regional database for community-based palliative care has been created through a unique partnership between a HPM organization and academic medical center. This database flexibly uses information technology to collect patient data, entered at the point of care (e.g., home, inpatient hospice, assisted living facility, nursing home). HPM physicians and nurse practitioners collect data; data are transferred to an academic site that assists with analyses and data management. Reports to community-based sites, based on data they provide, create a better understanding of local care quality. CURRENT STATUS: The data system was developed and implemented over a 2-year period, starting with one community-based HPM site and expanding to four. Data collection methods were collaboratively created and refined. The database continues to grow. Analyses presented herein examine data from one site and encompass 2572 visits from 970 new patients, characterizing the population, symptom profiles, and change in symptoms after intervention. CONCLUSION: A collaborative regional approach to HPM data can support evaluation and improvement of palliative care quality at the local, aggregated, and statewide levels.

Medical education as moral formation: an Aristotelian account of medical professionalsim.

The medical professionalism movement, bolstered by many influential medical organizations and institutions, has in the last decade produced a number of conceptual definitions of professionalism and a number of concrete proposals for its measurement and teaching. These projects, however laudable, are misguided when they treat professionalism as a unitary descriptive concept rather than as a contested and therefore primarily evaluative one; when they conceive professionalism as a domain of medical practice separable in principle from other domains; and when they treat professionalism as, in principle, a specifiable goal or product of sufficiently well designed educational curricula. The logic of professionalism-as-product corresponds to the logic of techne (art or practical skill) in Aristotle's Nicomachean Ethics. Aristotle provides a cogent argument, however, that the moral excellences denoted by "professionalism" cannot be "produced" or even prespecified in the concrete; rather, they must be acquired through long practice under the careful concrete guidance of teachers who themselves embody these moral excellences. Phronesis (practical wisdom) rather than techne must therefore be the guiding logic of educational initiatives in medical professional formation, with particular emphasis on close mentorship and on the moral character both of students and of those who teach them.

An integrated alcohol abuse and medical treatment model for patients with hepatitis C.

BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection have high rates of alcohol consumption, which is associated with progression of fibrosis and lower response rates to HCV treatment. AIMS: This prospective cohort study examined the feasibility of a 24-week integrated alcohol and medical treatment to HCV-infected patients. METHODS: Patients were recruited from a hepatology clinic if they had an Alcohol Use Disorders Identification Test score >4 for women and >8 for men, suggesting hazardous alcohol consumption. The integrated model included patients receiving medical care and alcohol treatment within the same clinic. Alcohol treatment consisted of 6 months of group and individual therapy from an addictions specialist and consultation from a study team psychiatrist as needed. RESULTS: Sixty patients were initially enrolled, and 53 patients participated in treatment. The primary endpoint was the Addiction Severity Index (ASI) alcohol composite scores, which significantly decreased by 0.105 (41.7% reduction) between 0 and 3 months (P < 0.01) and by 0.128 (50.6% reduction) between 0 and 6 months (P < 0.01) after adjusting for covariates. Alcohol abstinence was reported by 40% of patients at 3 months and 44% at 6 months. Patients who did not become alcohol abstinent had reductions in their ASI alcohol composite scores from 0.298 at baseline to 0.219 (26.8% reduction) at 6 months (P = 0.08). CONCLUSION: This study demonstrated that an integrated model of alcohol treatment and medical care could be successfully implemented in a hepatology clinic with significant favorable impact on alcohol use and abstinence among patients with chronic HCV.

WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study.

OBJECTIVES: To assess the performance of WHO's "Guidelines for care at the first-referral level in developing countries" in an area of intense malaria transmission and identify bacterial infections in children with and without malaria. DESIGN: Prospective study. SETTING: District hospital in Muheza, northeast Tanzania. PARTICIPANTS: Children aged 2 months to 13 years admitted to hospital for febrile illness. MAIN OUTCOME MEASURES: Sensitivity and specificity of WHO guidelines in diagnosing invasive bacterial disease; susceptibility of isolated organisms to recommended antimicrobials. RESULTS: Over one year, 3639 children were enrolled and 184 (5.1%) died; 2195 (60.3%) were blood slide positive for Plasmodium falciparum, 341 (9.4%) had invasive bacterial disease, and 142 (3.9%) were seropositive for HIV. The prevalence of invasive bacterial disease was lower in slide positive children (100/2195, 4.6%) than in slide negative children (241/1444, 16.7%). Non-typhi Salmonella was the most frequently isolated organism (52/100 (52%) of organisms in slide positive children and 108/241 (45%) in slide negative children). Mortality among children with invasive bacterial disease was significantly higher (58/341, 17%) than in children without invasive bacterial disease (126/3298, 3.8%) (P<0.001), and this was true regardless of the presence of P falciparum parasitaemia. The sensitivity and specificity of WHO criteria in identifying invasive bacterial disease in slide positive children were 60.0% (95% confidence interval 58.0% to 62.1%) and 53.5% (51.4% to 55.6%), compared with 70.5% (68.2% to 72.9%) and 48.1% (45.6% to 50.7%) in slide negative children. In children with WHO criteria for invasive bacterial disease, only 99/211(47%) of isolated organisms were susceptible to the first recommended antimicrobial agent. CONCLUSIONS: In an area exposed to high transmission of malaria, current WHO guidelines failed to identify almost a third of children with invasive bacterial disease, and more than half of the organisms isolated were not susceptible to currently recommended antimicrobials. Improved diagnosis and treatment of invasive bacterial disease are needed to reduce childhood mortality.

When the library is located in prime real estate: a case study on the loss of space from the Duke University Medical Center Library and Archives.

The Duke University Medical Center Library and Archives is located in the heart of the Duke Medicine campus, surrounded by Duke Hospital, ambulatory clinics, and numerous research facilities. Its location is considered prime real estate, given its adjacency to patient care, research, and educational activities. In 2005, the Duke University Library Space Planning Committee had recommended creating a learning center in the library that would support a variety of educational activities. However, the health system needed to convert the library's top floor into office space to make way for expansion of the hospital and cancer center. The library had only five months to plan the storage and consolidation of its journal and book collections, while working with the facilities design office and architect on the replacement of key user spaces on the top floor. Library staff worked together to develop plans for storing, weeding, and consolidating the collections and provided input into renovation plans for users spaces on its mezzanine level. The library lost 15,238 square feet (29%) of its net assignable square footage and a total of 16,897 (30%) gross square feet. This included 50% of the total space allotted to collections and over 15% of user spaces. The top-floor space now houses offices for Duke Medicine oncology faculty and staff. By storing a large portion of its collection off-site, the library was able to remove more stacks on the remaining stack level and convert them to user spaces, a long-term goal for the library. Additional space on the mezzanine level had to be converted to replace lost study and conference room spaces. While this project did not match the recommended space plans for the library, it underscored the need for the library to think creatively about the future of its facility and to work toward a more cohesive master plan.

Development and usability testing of a Web-based decision aid for families of patients receiving prolonged mechanical ventilation.

BACKGROUND: Web-based decision aids are increasingly important in medical research and clinical care. However, few have been studied in an intensive care unit setting. The objectives of this study were to develop a Web-based decision aid for family members of patients receiving prolonged mechanical ventilation and to evaluate its usability and acceptability. METHODS: Using an iterative process involving 48 critical illness survivors, family surrogate decision makers, and intensivists, we developed a Web-based decision aid addressing goals of care preferences for surrogate decision makers of patients with prolonged mechanical ventilation that could be either administered by study staff or completed independently by family members (Development Phase). After piloting the decision aid among 13 surrogate decision makers and seven intensivists, we assessed the decision aid's usability in the Evaluation Phase among a cohort of 30 surrogate decision makers using the Systems Usability Scale (SUS). Acceptability was assessed using measures of satisfaction and preference for electronic Collaborative Decision Support (eCODES) versus the original printed decision aid. RESULTS: The final decision aid, termed 'electronic Collaborative Decision Support', provides a framework for shared decision making, elicits relevant values and preferences, incorporates clinical data to personalize prognostic estimates generated from the ProVent prediction model, generates a printable document summarizing the user's interaction with the decision aid, and can digitally archive each user session. Usability was excellent (mean SUS, 80 ± 10) overall, but lower among those 56 years and older (73 ± 7) versus those who were younger (84 ± 9); p = 0.03. A total of 93% of users reported a preference for electronic versus printed versions. CONCLUSIONS: The Web-based decision aid for ICU surrogate decision makers can facilitate highly individualized information sharing with excellent usability and acceptability. Decision aids that employ an electronic format such as eCODES represent a strategy that could enhance patient-clinician collaboration and decision making quality in intensive care.

Systematic review and metasummary of attitudes toward research in emergency medical conditions

Emergency departments are challenging research settings, where truly informed consent can be difficult to obtain. A deeper understanding of emergency medical patients' opinions about research is needed. We conducted a systematic review and meta-summary of quantitative and qualitative studies on which values, attitudes, or beliefs of emergent medical research participants influence research participation. We included studies of adults that investigated opinions toward emergency medicine research participation. We excluded studies focused on the association between demographics or consent document features and participation and those focused on non-emergency research. In August 2011, we searched the following databases: MEDLINE, EMBASE, Google Scholar, Scirus, PsycINFO, AgeLine and Global Health. Titles, abstracts and then full manuscripts were independently evaluated by two reviewers. Disagreements were resolved by consensus and adjudicated by a third author. Studies were evaluated for bias using standardised scores. We report themes associated with participation or refusal. Our initial search produced over 1800 articles. A total of 44 articles were extracted for full-manuscript analysis, and 14 were retained based on our eligibility criteria. Among factors favouring participation, altruism and personal health benefit had the highest frequency. Mistrust of researchers, feeling like a 'guinea pig' and risk were leading factors favouring refusal. Many studies noted limitations of informed consent processes in emergent conditions. We conclude that highlighting the benefits to the participant and society, mitigating risk and increasing public trust may increase research participation in emergency medical research. New methods for conducting informed consent in such studies are needed.

Safety-critical medical device development using the UPP2SF model translation tool

Software-based control of life-critical embedded systems has become increasingly complex, and to a large extent has come to determine the safety of the human being. For example, implantable cardiac pacemakers have over 80,000 lines of code which are responsible for maintaining the heart within safe operating limits. As firmware-related recalls accounted for over 41% of the 600,000 devices recalled in the last decade, there is a need for rigorous model-driven design tools to generate verified code from verified software models. To this effect, we have developed the UPP2SF model-translation tool, which facilitates automatic conversion of verified models (in UPPAAL) to models that may be simulated and tested (in Simulink/Stateflow). We describe the translation rules that ensure correct model conversion, applicable to a large class of models. We demonstrate how UPP2SF is used in themodel-driven design of a pacemaker whosemodel is (a) designed and verified in UPPAAL (using timed automata), (b) automatically translated to Stateflow for simulation-based testing, and then (c) automatically generated into modular code for hardware-level integration testing of timing-related errors. In addition, we show how UPP2SF may be used for worst-case execution time estimation early in the design stage. Using UPP2SF, we demonstrate the value of integrated end-to-end modeling, verification, code-generation and testing process for complex software-controlled embedded systems. © 2014 ACM.

Monte Carlo Analysis and Physics Characterization of a Novel Nanoparticle Detector for Medical and Micro-dosimetry Applications

The outcomes for both (i) radiation therapy and (ii) preclinical small animal radio- biology studies are dependent on the delivery of a known quantity of radiation to a specific and intentional location. Adverse effects can result from these procedures if the dose to the target is too high or low, and can also result from an incorrect spatial distribution in which nearby normal healthy tissue can be undesirably damaged by poor radiation delivery techniques. Thus, in mice and humans alike, the spatial dose distributions from radiation sources should be well characterized in terms of the absolute dose quantity, and with pin-point accuracy. When dealing with the steep spatial dose gradients consequential to either (i) high dose rate (HDR) brachytherapy or (ii) within the small organs and tissue inhomogeneities of mice, obtaining accurate and highly precise dose results can be very challenging, considering commercially available radiation detection tools, such as ion chambers, are often too large for in-vivo use.

In this dissertation two tools are developed and applied for both clinical and preclinical radiation measurement. The first tool is a novel radiation detector for acquiring physical measurements, fabricated from an inorganic nano-crystalline scintillator that has been fixed on an optical fiber terminus. This dosimeter allows for the measurement of point doses to sub-millimeter resolution, and has the ability to be placed in-vivo in humans and small animals. Real-time data is displayed to the user to provide instant quality assurance and dose-rate information. The second tool utilizes an open source Monte Carlo particle transport code, and was applied for small animal dosimetry studies to calculate organ doses and recommend new techniques of dose prescription in mice, as well as to characterize dose to the murine bone marrow compartment with micron-scale resolution.

Hardware design changes were implemented to reduce the overall fiber diameter to <0.9 mm for the nano-crystalline scintillator based fiber optic detector (NanoFOD) system. Lower limits of device sensitivity were found to be approximately 0.05 cGy/s. Herein, this detector was demonstrated to perform quality assurance of clinical 192Ir HDR brachytherapy procedures, providing comparable dose measurements as thermo-luminescent dosimeters and accuracy within 20% of the treatment planning software (TPS) for 27 treatments conducted, with an inter-quartile range ratio to the TPS dose value of (1.02-0.94=0.08). After removing contaminant signals (Cerenkov and diode background), calibration of the detector enabled accurate dose measurements for vaginal applicator brachytherapy procedures. For 192Ir use, energy response changed by a factor of 2.25 over the SDD values of 3 to 9 cm; however a cap made of 0.2 mm thickness silver reduced energy dependence to a factor of 1.25 over the same SDD range, but had the consequence of reducing overall sensitivity by 33%.

For preclinical measurements, dose accuracy of the NanoFOD was within 1.3% of MOSFET measured dose values in a cylindrical mouse phantom at 225 kV for x-ray irradiation at angles of 0, 90, 180, and 270˝. The NanoFOD exhibited small changes in angular sensitivity, with a coefficient of variation (COV) of 3.6% at 120 kV and 1% at 225 kV. When the NanoFOD was placed alongside a MOSFET in the liver of a sacrificed mouse and treatment was delivered at 225 kV with 0.3 mm Cu filter, the dose difference was only 1.09% with use of the 4x4 cm collimator, and -0.03% with no collimation. Additionally, the NanoFOD utilized a scintillator of 11 µm thickness to measure small x-ray fields for microbeam radiation therapy (MRT) applications, and achieved 2.7% dose accuracy of the microbeam peak in comparison to radiochromic film. Modest differences between the full-width at half maximum measured lateral dimension of the MRT system were observed between the NanoFOD (420 µm) and radiochromic film (320 µm), but these differences have been explained mostly as an artifact due to the geometry used and volumetric effects in the scintillator material. Characterization of the energy dependence for the yttrium-oxide based scintillator material was performed in the range of 40-320 kV (2 mm Al filtration), and the maximum device sensitivity was achieved at 100 kV. Tissue maximum ratio data measurements were carried out on a small animal x-ray irradiator system at 320 kV and demonstrated an average difference of 0.9% as compared to a MOSFET dosimeter in the range of 2.5 to 33 cm depth in tissue equivalent plastic blocks. Irradiation of the NanoFOD fiber and scintillator material on a 137Cs gamma irradiator to 1600 Gy did not produce any measurable change in light output, suggesting that the NanoFOD system may be re-used without the need for replacement or recalibration over its lifetime.

For small animal irradiator systems, researchers can deliver a given dose to a target organ by controlling exposure time. Currently, researchers calculate this exposure time by dividing the total dose that they wish to deliver by a single provided dose rate value. This method is independent of the target organ. Studies conducted here used Monte Carlo particle transport codes to justify a new method of dose prescription in mice, that considers organ specific doses. Monte Carlo simulations were performed in the Geant4 Application for Tomographic Emission (GATE) toolkit using a MOBY mouse whole-body phantom. The non-homogeneous phantom was comprised of 256x256x800 voxels of size 0.145x0.145x0.145 mm3. Differences of up to 20-30% in dose to soft-tissue target organs was demonstrated, and methods for alleviating these errors were suggested during whole body radiation of mice by utilizing organ specific and x-ray tube filter specific dose rates for all irradiations.

Monte Carlo analysis was used on 1 µm resolution CT images of a mouse femur and a mouse vertebra to calculate the dose gradients within the bone marrow (BM) compartment of mice based on different radiation beam qualities relevant to x-ray and isotope type irradiators. Results and findings indicated that soft x-ray beams (160 kV at 0.62 mm Cu HVL and 320 kV at 1 mm Cu HVL) lead to substantially higher dose to BM within close proximity to mineral bone (within about 60 µm) as compared to hard x-ray beams (320 kV at 4 mm Cu HVL) and isotope based gamma irradiators (137Cs). The average dose increases to the BM in the vertebra for these four aforementioned radiation beam qualities were found to be 31%, 17%, 8%, and 1%, respectively. Both in-vitro and in-vivo experimental studies confirmed these simulation results, demonstrating that the 320 kV, 1 mm Cu HVL beam caused statistically significant increased killing to the BM cells at 6 Gy dose levels in comparison to both the 320 kV, 4 mm Cu HVL and the 662 keV, 137Cs beams.