The feasibility of K XRF bone lead measurements in mice assessed using 3D-printed phantoms.

This article describes the development of a system forin vivomeasurements of lead body burden in mice using109Cd K x-ray fluorescence (XRF). This K XRF system could facilitate early-stage studies on interventions that ameliorate or reverse organ tissue damage from lead poisoning by reducing animal numbers through a cross-sectional study approach. A novel mouse phantom was developed based on a mouse atlas and 3D-printed using PLA plastic with plaster of Paris 'bone' inserts. PLA plastic was found to be a good surrogate for soft tissue in XRF measurements and the phantoms were found to be good models of mice. As expected, lead detection limits varied with mouse size, mouse orientation, and mouse position with respect to the source and detector. The work suggests that detection limits of 10 to 20µg Pb per g bone mineral may be possible for a 2 to 3 hour XRF measurement in a single animal, an adequate limit for some pre-clinical studies. The109Cd K XRF mouse measurement system was also modeled using the Monte Carlo code MCNP. The combination of experiment and modeling found that contrary to expectation, accurate measurements of lead levels in mice required calibration using mouse-specific calibration standards due to the coherent scatter peak normalization failing when small animals are measured. MCNP modeling determined that this was because the coherent scatter signal from soft tissue, which until now has been assumed negligible, becomes significant when compared to the coherent scatter signal in bone in small animals. This may have implications for some human measurements. This work suggests that109Cd K x-ray fluorescence measurements of lead body burden are precise enough to make the system feasible for small animals if appropriately calibrated. Further work to validate the technology's measurement accuracy and performancein vivowill be required.

Psychopathy and Corticostriatal Connectivity: The Link to Criminal Behavior in Methamphetamine Dependence.

Methamphetamine use and psychopathy are associated with criminal behavior; however, it is unclear how methamphetamine use and psychopathy interact to promote violent, economic and drug offenses. Abnormalities in corticostriatal functional connectivity are exhibited in both psychopathic and methamphetamine dependent individuals, which may contribute to criminal behavior through maladaptive and impulsive decision-making processes. This study shows that psychopathic traits contribute to weaker corticostriatal connectivity in methamphetamine dependence and contributes to an increase in criminal behavior. As the propensity to engage in criminal activity is dependent on a number of factors, a hierarchical regression identifies the contribution of the impulsive antisocial domain of psychopathy, anxiety, years of methamphetamine use and corticostriatal connectivity on different types of criminal offenses. Methamphetamine use and psychopathic traits reduce treatment responsiveness and increase the likelihood of recidivism, and it is therefore important to understand the factors underlying the propensity to engage in criminal behavior.

Adjustable coupling and in situ variable frequency electron paramagnetic resonance probe with loop-gap resonators for spectroscopy up to X-band.

In standard electron paramagnetic resonance (EPR) spectroscopy, the frequency of an experiment is set and the spectrum is acquired using the magnetic field as the independent variable. There are cases in which it is desirable instead to fix the field and tune the frequency such as when studying avoided level crossings. We have designed and tested an adjustable frequency and variable coupling EPR probe with loop-gap resonators (LGRs) that works at a temperature as low as 1.8 K. The frequency is tuned by adjusting the height of a dielectric piece of sapphire inserted into the gap of an LGR; coupling of the microwave antenna is varied with the height of the antenna above the LGR. Both coupling antenna and dielectric are located within the cryogenic sample chamber, but their motion is controlled with external micrometers located outside the cryostat. The frequency of the LGR (∼4 GHz) can be adjusted by more than 1 GHz (>25%). To cover a wide range of frequencies, different LGRs can be designed to cover frequencies up to X-band. We demonstrate the operation of our probe by mapping out avoided crossings for the Ni4 molecular nanomagnet to determine the tunnel splittings with high precision.

Transition Networks in a Cohort of Patients with Congestive Heart Failure: A Novel Application of Informatics Methods to Inform Care Coordination.

BACKGROUND: Unnecessary hospital readmissions are one source of escalating costs that may be reduced through improved care coordination, but how best to design and evaluate coordination programs is poorly understood. Measuring patient flow between service visits could support decisions for coordinating care, particularly for conditions such as congestive heart failure (CHF) which have high morbidity, costs, and hospital readmission rates. OBJECTIVES: To determine the feasibility of using network analysis to explore patterns of service delivery for patients with CHF in the context of readmissions. METHODS: A retrospective cohort study used de-identified records for patients ≥18 years with an ICD-9 diagnosis code 428.0-428.9, and service visits between July 2011 and June 2012. Patients were stratified by admission outcome. Traditional and novel network analysis techniques were applied to characterize care patterns. RESULTS: Patients transitioned between services in different order and frequency depending on admission status. Patient-to-service CoUsage networks were diffuse suggesting unstructured flow of patients with no obvious coordination hubs. In service-to-service Transition networks a specialty heart failure service was on the care path to the most other services for never admitted patients, evidence of how specialist care may prevent hospital admissions for some patients. For patients admitted once, transitions expanded for a clinic-based internal medicine service which clinical experts identified as a Patient Centered Medical Home implemented in the first month for which we obtained data. CONCLUSIONS: We detected valid patterns consistent with a targeted care initiative, which experts could understand and explain, suggesting the method has utility for understanding coordination. The analysis revealed strong but complex patterns that could not be demonstrated using traditional linear methods alone. Network analysis supports measurement of real world health care service delivery, shows how transitions vary between services based on outcome, and with further development has potential to inform coordination strategies.

Developing clinical decision support within a commercial electronic health record system to improve antimicrobial prescribing in the neonatal ICU.

OBJECTIVE: To develop and implement a clinical decision support (CDS) tool to improve antibiotic prescribing in neonatal intensive care units (NICUs) and to evaluate user acceptance of the CDS tool. METHODS: Following sociotechnical analysis of NICU prescribing processes, a CDS tool for empiric and targeted antimicrobial therapy for healthcare-associated infections (HAIs) was developed and incorporated into a commercial electronic health record (EHR) in two NICUs. User logs were reviewed and NICU prescribers were surveyed for their perceptions of the CDS tool. RESULTS: The CDS tool aggregated selected laboratory results, including culture results, to make treatment recommendations for common clinical scenarios. From July 2010 to May 2012, 1,303 CDS activations for 452 patients occurred representing 22% of patients prescribed antibiotics during this period. While NICU clinicians viewed two culture results per tool activation, prescribing recommendations were viewed during only 15% of activations. Most (63%) survey respondents were aware of the CDS tool, but fewer (37%) used it during their most recent NICU rotation. Respondents considered the most useful features to be summarized culture results (43%) and antibiotic recommendations (48%). DISCUSSION: During the study period, the CDS tool functionality was hindered by EHR upgrades, implementation of a new laboratory information system, and changes to antimicrobial testing methodologies. Loss of functionality may have reduced viewing antibiotic recommendations. In contrast, viewing culture results was frequently performed, likely because this feature was perceived as useful and functionality was preserved. CONCLUSION: To improve CDS tool visibility and usefulness, we recommend early user and information technology team involvement which would facilitate use and mitigate implementation challenges.

Identifying consumer's needs of health information technology through an innovative participatory design approach among English- and Spanish-speaking urban older adults.

OBJECTIVES: We describe an innovative community-centered participatory design approach, Consumer-centered Participatory Design (C2PD), and the results of applying C2PD to design and develop a web-based fall prevention system. METHODS: We conducted focus groups and design sessions with English- and Spanish-speaking community-dwelling older adults. Focus group data were summarized and used to inform the context of the design sessions. Descriptive content analysis methods were used to develop categorical descriptions of design session informant's needs related to information technology. RESULTS: The C2PD approach enabled the assessment and identification of informant's needs of health information technology (HIT) that informed the development of a falls prevention system. We learned that our informants needed a system that provides variation in functions/content; differentiates between actionable/non-actionable information/structures; and contains sensory cues that support wide-ranging and complex tasks in a varied, simple, and clear interface to facilitate self-management. CONCLUSIONS: The C2PD approach provides community-based organizations, academic researchers, and commercial entities with a systematic theoretically informed approach to develop HIT innovations. Our community-centered participatory design approach focuses on consumer's technology needs while taking into account core public health functions.

Exercise for depression in care home residents: a randomised controlled trial with cost-effectiveness analysis (OPERA).

BACKGROUND: Many older people living in care homes (long term residential care or nursing homes) are depressed. Exercise is a promising non-drug intervention for preventing and treating depression in this population. OBJECTIVE: To evaluate the impact of a 'whole-home' intervention, consisting of training for residential and nursing home staff backed up with a twice-weekly, physiotherapist-led exercise class on depressive symptoms in care home residents. DESIGN: A cluster randomised controlled trial with a cost-effectiveness analysis to compare (1) the prevalence of depression in intervention homes with that in control homes in all residents contributing data 12 months after homes were randomised (cross-sectional analysis); (2) the number of depressive symptoms at 6 months between intervention and control homes in residents who were depressed at pre-randomisation baseline assessment (depressed cohort comparison); and (3) the number of depressive symptoms at 12 months between intervention and control homes in all residents who were present at pre-randomisation baseline assessment (cohort comparison). SETTING: Seventy-eight care homes in Coventry and Warwickshire and north-east London. PARTICIPANTS: Care home residents aged ≥ 65 years. INTERVENTIONS: Control intervention: Depression awareness training programme for care home staff. Active intervention: A 'whole-home' exercise intervention, consisting of training for care home staff backed up with a twice-weekly, physiotherapist-led exercise group. MAIN OUTCOME MEASURES: Geriatric Depression Scale-15, proxy European Quality of Life-5 Dimensions (EQ-5D), cost-effectiveness from an National Health Service perspective, peripheral fractures and death. RESULTS: We recruited a total of 1054 participants. Cross-sectional analysis: We obtained 595 Geriatric Depression Scale-15 scores and 724 proxy EQ-5D scores. For the cohort analyses we obtained 765 baseline Geriatric Depression Scale-15 scores and 776 proxy EQ-5D scores. Of the 781 who we assessed prior to randomisation, 765 provided a Geriatric Depression Scale-15 score. Of these 374 (49%) were depressed and constitute our depressed cohort. Resource-use and quality-adjusted life-year data, based on proxy EQ-5D, were available for 798 residents recruited prior to randomisation. We delivered 3191 group exercise sessions with 31,705 person attendances and an average group size of 10 (5.3 study participants and 4.6 non-study participants). On average, our participants attended around half of the possible sessions. No serious adverse events occurred during the group exercise sessions. In the cross-sectional analysis the odds for being depressed were 0.76 [95% confidence interval (CI) 0.53 to 1.09] lower in the intervention group at 12 months. The point estimates for benefit for both the cohort analysis (0.13, 95% CI -0.33 to 0.60) and depressed cohort (0.22, 95% CI -0.52 to 0.95) favoured the control intervention. There was no evidence of differences in fracture rates or mortality (odds ratio 1.07, 95% CI 0.79 to 1.48) between the two groups. There was no evidence of differences in the other outcomes between the two groups. Economic analysis: The additional National Health Service cost of the OPERA intervention was £374 per participant (95% CI -£655 to £1404); the mean difference in quality-adjusted life-year was -0.0014 (95% CI -0.0728 to 0.0699). The active intervention was thus dominated by the control intervention, which was more effective and less costly. CONCLUSION: The results do not support the use of a whole-home physical activity and moderate-intensity exercise programme to reduce depression in care home residents. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43769277. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 18. See the Health Technology Assessment programme website for further project information.

A comparison of usability factors of four mobile devices for accessing healthcare information by adolescents.

BACKGROUND: Mobile health (mHealth) is a growing field aimed at developing mobile information and communication technologies for healthcare. Adolescents are known for their ubiquitous use of mobile technologies in everyday life. However, the use of mHealth tools among adolescents is not well described. OBJECTIVE: We examined the usability of four commonly used mobile devices (an iPhone, an Android with touchscreen keyboard, an Android with built-in keyboard, and an iPad) for accessing healthcare information among a group of urban-dwelling adolescents. METHODS: Guided by the FITT (Fit between Individuals, Task, and Technology) framework, a thinkaloud protocol was combined with a questionnaire to describe usability on three dimensions: 1) task-technology fit; 2) individual-technology fit; and 3) individual-task fit. RESULTS: For task-technology fit, we compared the efficiency, and effectiveness of each of the devices tested and found that the iPhone was the most usable had the fewest errors and prompts and had the lowest mean overall task time For individual-task fit, we compared efficiency and learnability measures by website tasks and found no statistically significant effect on tasks steps, task time and number of errors. Following our comparison of success rates by website tasks, we compared the difference between two mobile applications which were used for diet tracking and found statistically significant effect on tasks steps, task time and number of errors. For individual-technology fit, interface quality was significantly different across devices indicating that this is an important factor to be considered in developing future mobile devices. CONCLUSIONS: All of our users were able to complete all of the tasks, however the time needed to complete the tasks was significantly different by mobile device and mHealth application. Future design of mobile technology and mHealth applications should place particular importance on interface quality.

Cognitive analysis of decision support for antibiotic ordering in a neonatal intensive care unit.

BACKGROUND: Clinical decision support systems (CDSS) are a method used to support prescribing accuracy when deployed within a computerized provider order entry system (CPOE). Divergence from using CDSS is exemplified by high alert override rates. Excessive cognitive load imposed by the CDSS may help to explain such high rates. OBJECTIVES: The aim of this study was to describe the cognitive impact of a CPOE-integrated CDSS by categorizing system use problems according to the type of mental processing required to resolve them. METHODS: A qualitative, descriptive design was used employing two methods; a cognitive walkthrough and a think-aloud protocol. Data analysis was guided by Norman's Theory of Action and a theory of cognitive distances which is an extension to Norman's theory. RESULTS: The most frequently occurring source of excess cognitive effort was poor information timing. Information presented by the CDSS was often presented after clinicians required the information for decision making. Additional sources of effort included use of language that was not clear to the user, vague icons, and lack of cues to guide users through tasks. CONCLUSIONS: Lack of coordination between clinician's task-related thought processes and those presented by a CDSS results in excessive cognitive work required to use the system. This can lead to alert overrides and user errors. Close attention to user's cognitive processes as they carry out clinical tasks prior to CDSS development may provide key information for system design that supports clinical tasks and reduces cognitive effort.

Prophylactic feeding tubes for patients with locally advanced head-and-neck cancer undergoing combined chemotherapy and radiotherapy-systematic review and recommendations for clinical practice.

GOALS: This work aimed to determine the benefits and risks of prophylactic feeding tubes for adult patients with squamous cell carcinoma of the head and neck who receive combined chemotherapy and radiotherapy with curative intent and to make recommendations on the use of prophylactic feeding tubes and the provision of adequate nutrition to this patient population. METHODS: A national multidisciplinary panel conducted a systematic review of the evidence and formulated recommendations to guide clinical decision-making. The draft evidence summary and recommendations were distributed to clinicians across Canada for their input. MAIN RESULTS: No randomized controlled trials have directly addressed this question. Evidence from studies in the target population was limited to seven descriptive studies: two with control groups (one prospective, one retrospective) and five without control groups. Results from ten controlled studies in patients treated with radiotherapy alone were also reviewed. CONCLUSIONS: The available evidence was insufficient to draw definitive conclusions about the effectiveness of prophylactic feeding tubes in the target patient population or to support an evidence-based practice guideline. After review of the evidence, of guidelines from other groups, and of current clinical practice in Canada, the multidisciplinary panel made consensus-based recommendations regarding comprehensive interdisciplinary clinical care before, during, and after cancer treatment. The recommendations are based on the expert opinion of the panel members and on their understanding of best clinical practice.

Electronic reporting to improve patient safety.

BACKGROUND: Limited data are available on the experiences of voluntary event reporting systems to improve patient safety. OBJECTIVE: Development and implementation of educational initiatives to facilitate the use of an electronic reporting system (ERS) in an academic medical center to measure the impact on knowledge of the ERS on reporting behavior and safety attitudes and to evaluate the accuracy of the information being reported. METHODS: A voluntary internal confidential electronic system for reporting safety events was implemented which involved patients and visitors. A multifaceted educational program was developed to promote safety awareness and use of the ERS system. The safety event detail reported for the calendar year 2002 was tracked and trended and central event analyses were performed for five high event clinical areas. A survey was administered to assess safety knowledge and attitudes of patient care personnel. RESULTS: 2843 safety events were entered into the ERS during 2002 with an increase during the course of the year (p = 0.055, linear trend) for all events. Nurses entered 73% of the events and physicians only 2%. 453 events (16%) were unsafe conditions or near misses and 623 (22%) were associated with patient harm. System factors were considered by the reporter as contributing to the event in only a few cases (5%). Central event analysis revealed that 39% of events had coding errors either in event classification, level of impact, or location; significant underreporting was also present. Although survey response rates were low (10.3%), responders showed a high degree of knowledge on general questions of patient safety and an increase in knowledge on use of the ERS (p = 0.0015, linear trend). CONCLUSIONS: Knowledge on the use of the reporting system and the frequency of reported events increased over the first year of the study. More work is needed to involve physicians in reporting, to improve the accuracy of submitted information, and to better prioritize, organize, and streamline event analysis.

Somatization among older primary care attenders.

BACKGROUND: The importance of somatization among older primary care attenders is unclear. We aimed to establish the prevalence, persistence and associations of somatization among older primary care attenders, and the associations of frequent attendance. METHOD: One hundred and forty primary care attenders over 65 years were rated twice, 10 months apart, on measures of somatization, psychiatric status, physical health and attendance. RESULTS: The syndrome of GMS hypochondriacal neurosis had a prevalence of 5% but was transient. Somatized symptoms and attributions were persistent and associated with depression, physical illness and perceived poor social support. Frequent attenders (top third) had higher rates of depression, physical illness and somatic symptoms, and lower perceived support. CONCLUSION: Somatization is common among older primary care attenders and has similar correlates to younger primary care somatizers. Psychological distress among older primary care attenders is associated with frequent attendance. Improved recognition should result in benefits to patients and services.

[Cu,Zn]-Superoxide dismutase mutants of the swine pathogen Actinobacillus pleuropneumoniae are unattenuated in infections of the natural host.

Actinobacillus pleuropneumoniae, the causative agent of porcine pleuropneumonia, contains a periplasmic Cu- and Zn-cofactored superoxide dismutase ([Cu,Zn]-SOD, or SodC) which has the potential, realized in other pathogens, to promote bacterial survival during infection by dismutating host-defense-derived superoxide. Here we describe the construction of a site-specific, [Cu,Zn]-SOD-deficient A. pleuropneumoniae serotype 1 mutant and show that although the mutant is highly sensitive to the microbicidal action of superoxide in vitro, it remains fully virulent in experimental pulmonary infection in pigs.

The virulence plasmid of Salmonella typhimurium contains an autoregulated gene, rlgA, that codes for a resolvase-like DNA binding protein.

The virulence plasmid of Salmonella typhimurium contains a gene, rlgA, that shows strong homology to several reported resolvase-like proteins. This gene maps 5 kb upstream of spv locus, the major virulence determinant on the plasmid. Regulation of rlgA was studied using a lacZ transcriptional reporter fusion. The rlgA gene was found to be repressed at the level of transcription by its own product and to be expressed maximally in the late exponential phase of growth. The transcription start site of the rlgA gene was determined and the RlgA binding site was mapped and found to overlap with the transcription initiation signals. A derivative of the virulence plasmid was constructed with a knockout mutation in rlgA. This mutation did not alter the stability of the virulence plasmid nor did it affect the ability of S. typhimurium to cause systemic disease in mice.

A role for the leucine-responsive regulatory protein and integration host factor in the regulation of the Salmonella plasmid virulence (spv ) locus in Salmonella typhimurium.

The Salmonella plasmid virulence (spv ) genes of Salmonella typhimurium are activated at the level of transcription as the bacteria enter stationary phase in vitro or in response to signals received during intracellular growth. Activation requires the LysR-like transcription factor SpvR and the alternative sigma factor RpoS. In this report, we show by biochemical and genetic analyses that two chromosomally encoded DNA-binding proteins contribute to the control of spv expression. These are the integration host factor (IHF), which binds to DNA sequences upstream of the spvR regulatory gene, and the leucine-responsive regulatory protein (Lrp), which binds to sequences upstream of the spvABCD operon. Under all conditions tested, inactivation of IHF expression reduces the level of spvR transcription by twofold. It also alters the response of the spv regulon to loss of DNA gyrase activity, consistent with a role for IHF in organizing DNA structure in the vicinity of the spvR promoter. Lrp represses spvA gene expression by up to fivefold and Lrp-mediated repression is antagonized by leucine. The Lrp binding site upstream of the spvA gene overlaps one of the binding sites for the positive regulator SpvR, suggesting a mechanism by which Lrp repression is exerted. This is a first demonstration of a role for Lrp in controlling genes that are also subject to intracellular regulation. These data show that the spv virulence genes belong simultaneously to several regulons in the cell, raising the possibility that spv expression can be fine-tuned in response to multiple environmental inputs.

Review: Somatization in the elderly.

Somatization is a common medical problem encountered at all levels of medical care. It is strongly associated with use of services and may be difficult to treat. Somatization in the elderly has been traditionally seen as a masked presentation of depression. Population studies have shown no consistent increase in somatization among the elderly, and the elderly may down-play physical symptoms. Among the elderly depressed, somatization is common and may be commoner if physical illness is also present. Psychological distress is usually acknowledged, not masked, in the elderly depressed. Neuroticism, as well as psychiatric illness, may be an important aetiological factor for somatization in the elderly. Treatment strategies must attend to underlying psychiatric disorders, but there is a need for studies of treatment of the phenomenon in the elderly.

Environmentally constrained mutation and adaptive evolution in Salmonella.

The relationship between environment and mutation is complex [1]. Claims of Lamarkian mutation [2] have proved unfounded [3-5]; it is apparent, however, that the external environment can influence the generation of heritable variation, through either direct effects on DNA sequence [6] or DNA maintenance and copying mechanisms [7-10], or as a consequence of evolutionary processes [11-16]. The spectrum of mutational events subject to environmental influence is unknown [6] and precisely how environmental signals modulate mutation is unclear. Evidence from bacteria suggests that a transient recombination-dependent hypermutational state can be induced by starvation [5]. It is also apparent that changes in the mutability of specific loci can be influenced by alterations in DNA topology [10,17]. Here we describe a remarkable instance of adaptive evolution in Salmonella which is caused by a mutation that occurs in intermediate-strength osmotic environments. We show that the mutation is not 'directed' and describe its genetic basis. We also present compelling evidence in support of the hypothesis that the mutational event is constrained by signals transmitted from the external environment via changes in the activity of DNA gyrase.

The use of dexamethasone in elderly patients with antidepressant-resistant depressive illness.

Many depressed patients do not respond to first-line antidepressant treatment. Dexamethasone is a synthetic steroid which may have antidepressant properties. Its use in two elderly patients with resistant depression is reported. Both patients appeared to benefit from the treatment. The possible modes of action of this treatment, and its potential benefits to the elderly, are discussed.