Changes in medical errors after implementation of a handoff program.
Miscommunications are a leading cause of serious medical errors. Data from multicenter studies assessing programs designed to improve handoff of information about patient care are lacking. We conducted a prospective intervention study of a resident handoff-improvement program in nine hospitals, measuring rates of medical errors, preventable adverse events, and miscommunications, as well as resident workflow. The intervention included a mnemonic to standardize oral and written handoffs, handoff and communication training, a faculty development and observation program, and a sustainability campaign. Error rates were measured through active surveillance. Handoffs were assessed by means of evaluation of printed handoff documents and audio recordings. Workflow was assessed through time-motion observations. The primary outcome had two components: medical errors and preventable adverse events. In 10,740 patient admissions, the medical-error rate decreased by 23% from the preintervention period to the postintervention period (24.5 vs. 18.8 per 100 admissions, P<0.001), and the rate of preventable adverse events decreased by 30% (4.7 vs. 3.3 events per 100 admissions, P<0.001). The rate of nonpreventable adverse events did not change significantly (3.0 and 2.8 events per 100 admissions, P=0.79). Site-level analyses showed significant error reductions at six of nine sites. Across sites, significant increases were observed in the inclusion of all prespecified key elements in written documents and oral communication during handoff (nine written and five oral elements; P<0.001 for all 14 comparisons). There were no significant changes from the preintervention period to the postintervention period in the duration of oral handoffs (2.4 and 2.5 minutes per patient, respectively; P=0.55) or in resident workflow, including patient-family contact and computer time. Implementation of the handoff program was associated with reductions in medical errors and in preventable adverse events and with improvements in communication, without a negative effect on workflow. (Funded by the Office of the Assistant Secretary for Planning and Evaluation, U.S. Department of Health and Human Services, and others.).


Is there a timing synergy during multi-finger production of quick force pulses?
We studied whether characteristics of individual finger force profiles covaried across repetitions of a quick force pulse production task to stabilize the required magnitude and timing of the peak force. Subjects produced series of quick force pulses by pressing with all four fingers of the right hand on force sensors under the instruction to keep the magnitude of the peak of total force at 15 N and reach the force peaks at prescribed times. Individual finger force pulses were then reshuffled across trials to create a surrogate data set. The surrogate data set showed a lower average peak force with a larger dispersion. This finding has been interpreted as pointing at predominantly negative covariation among finger force pulses in the actual data that stabilized the required magnitude of the total force, a force synergy. The difference between the actual and surrogate data sets was significant early into the pulse time, starting about 40 ms after the pulse initiation. This finding points at a central nature of the negative covariation without a major role played by visual or proprioceptive feedback. In contrast,the surrogate data set showed smaller dispersion of the timing of the total peak force, suggesting positive covariation of the timings of individual finger force pulses in the actual data interpreted as the lack of a timing synergy. These results have been confirmed with principal component (PC) analysis. The first PC for the timing of the individual finger peak forces accounted for over 90% of the total variance for the actual data set and for under 40% of the total variance for the surrogate data set. The fourth PC for the magnitudes of the finger forces accounted for under 4% of the total variance for the actual data set and for over 15% of the variance for the surrogate data set. The data are interpreted within the uncontrolled manifold hypothesis; they support the hierarchical control scheme suggested by Schöner.


Trends in area-socioeconomic and race-ethnic disparities in breast cancer incidence, stage at diagnosis, screening, mortality, and survival among women ages 50 years and over (1987-2005).
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States and varies systematically by race-ethnicity and socioeconomic status. Previous research has often focused on disparities between particular groups, but few studies have summarized disparities across multiple subgroups defined by race-ethnic and socioeconomic position. Data on breast cancer incidence, stage, mortality, and 5-year cause-specific probability of death (100 - survival) were obtained from the Surveillance, Epidemiology, and End Results program and data on mammography screening from the National Health Interview Survey from 1987 to 2005. We used four area-socioeconomic groups based on the percentage of poverty in the county of residence (<10, 10-15, 15-20, +20%) and five race-ethnic groups (White, Black, Asian, American Indian, and Hispanic). We used summary measures of disparity based on both rate differences and rate ratios. From 1987 to 2004, area-socioeconomic disparities declined by 20% to 30% for incidence, stage at diagnosis, and 5-year cause-specific probability of death, and by roughly 100% for mortality, whether measured on the absolute or relative scale. In contrast, relative area-socioeconomic disparities in mammography use increased by 161%. Absolute race-ethnic disparities declined across all outcomes, with the largest reduction for mammography (56% decline). Relative race-ethnic disparities for mortality and 5-year cause-specific probability of death increased by 24% and 17%, respectively. Our analysis suggests progress towards race-ethnic and area-socioeconomic disparity goals for breast cancer, especially when measured on the absolute scale. However, greater progress is needed to address increasing relative socioeconomic disparities in mammography and race-ethnic disparities in mortality and 5-year cause-specific probability of death.


The Interplay of Host Autophagy and Eukaryotic Pathogens.
For intracellular pathogens, host cells provide a replicative niche, but are also armed with innate defense mechanisms to combat the intruder. Co-evolution of host and pathogens has produced a complex interplay of host-pathogen interactions during infection, with autophagy emerging as a key player in the recent years. Host autophagy as a degradative process is a significant hindrance to intracellular growth of the pathogens, but also can be subverted by the pathogens to provide support such as nutrients. While the role of host cell autophagy in the pathogenesis mechanisms of several bacterial and viral pathogens have been extensively studied, less is known for eukaryotic pathogens. In this review, we focus on the interplay of host autophagy with the eukaryotic pathogens Plasmodium spp, Toxoplasma, Leishmania spp and the fungal pathogens Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. The differences between these eukaryotic pathogens in terms of the host cell types they infect, infective strategies and the host responses required to defend against them provide an interesting insight into how they respond to and interact with host cell autophagy. Due to the ability to infect multiple host species and cell types during the course of their usually complex lifestyles, autophagy plays divergent roles even for the same pathogen. The scenario is further compounded since many of the eukaryotic pathogens have their own sets of either complete or partial autophagy machinery. Eukaryotic pathogen-autophagy interplay is thus a complex relationship with many novel insights for the basic understanding of autophagy, and potential for clinical relevance.


Structure-related variable responses of calcium sensitive MRI probes.
A new series of Gd(3+) complexes based on DO3A (GdL(1)-GdL(4)) was synthesized and investigated. They possess side chains with different structures which determine their varying binding properties and response towards endogenous metal ions, measured by changes in the longitudinal relaxivity (r(1)). GdL(4) exhibits the highest selectivity toward Ca(2+) in comparison to the other complexes, with up to a 63% increase of the r(1). GdL(2) and GdL(3) also respond to different Ca(2+) concentration ranges, however with a lower selectivity since the r(1) changes are also observed in the presence of other cations such as Mg(2+), Zn(2+) or Cu(2+). Assessment of the hydration number (q) via luminescence lifetime measurements confirmed that the change in q is responsible for the r(1) response for all the complexes.


SU-E-T-304: Evaluation of Mammosite Multi-Lumen Rotation and Its Dosimetric Consequences.
To evaluate the dosimetric impact of MammoSite Multi-Lumen (MSML) rotation in phantom and patient studies. A MSML phantom with an asymmetric dose distribution was created. Target volume coverage and dose at a fixed point 1 cm from the MSML were evaluated as functions of rotation about three orthogonal axes (where the origin was set at the center of the MSML and axis one ran along the central catheter). Additionally, for three MSML patients that were set-up by aligning the stem of the MSML to skin marks, CT scans were acquired before each fraction. Rotation about three axes and maximum point dose to skin and chestwall were evaluated. In phantom, 10° rotations about the central, second, and third axes give average absolute point dose changes with respect to the maximum dose of 1.9%, 3.7%, and 4.2%, respectively; and changes in PTV coverage of 0.9%, 1.0%., and 0.8%, respectively. For patients 1-3 the average absolute rotation about the central axis was 13.60, 9.50, and 7.20, respectively; axis two was 7.00, 3.20, and 11.40, respectively; axis three was 2.90, 2.90, and 3.80, respectively. For cases 1-3 the average absolute change per fraction in maximum point dose to the skin was 0.29 Gy, 0.14 Gy, and 0.39 Gy, respectively; to the chestwall was 0.17 Gy, 0.20 Gy, and 0.21 Gy, respectively. Phantom studies showed change in point dose and PTV coverage for a 10° rotation about the central catheter yields < 2% variance. Patient data indicates skin mark alignment is capable of positioning the MSML with 10° accuracy about the central axis. Thus, central axis rotation can be adequately accounted for by skin mark alignment. However, review of the patient data shows that rotations about the other axes are equally important and should be considered and managed.


IS1236, a newly discovered member of the IS3 family, exhibits varied patterns of insertion into the Acinetobacter calcoaceticus chromosome.
Analysis of spontaneous mutations in Acinetobacter calcoaceticus revealed a 1237 bp insertion sequence named IS1236 and possessing a nucleotide sequence resembling those of members of the lS3 family. The chromosome of A. calcoaceticus strain ADP1 contains seven copies of IS1236 which appears to insert preferentially into pobR, the transcriptional activator of the structural gene for p-hydroxybenzoate hydroxylase. IS1236 creates tandem 3 bp DNA duplications flanking the sites of its insertion in pobR. Different duplication patterns are found following insertion of IS1236 into pcaH, a structural gene for protocatechuate 3,4-dioxygenase. Therefore the insertion of properties of IS1236 appear to be influenced by its DNA target. Amino acid sequences associated with the apparent transposase function have been conserved in ORFB of IS1236 whereas the presumed DNA-binding helix-turn-helix region of IS1236 ORFA exhibits substantial amino acid sequence divergence from its IS3 counterparts. IS1236 ORFA and ORFB coding sequences overlap considerably, and sequence evidence indicates mechanisms for ORFB expression in IS1236 may resemble those employed by other members of the IS3 family. Portions of the IS1236 terminal repeats exhibit substantial sequence divergence from other members of the IS3 family, but evolution appears to have conserved a mechanism preventing expression of the insertion sequence genes as a consequence of transcriptional readthrough.


Altered gastrointestinal microbiota in irritable bowel syndrome and its modification by diet: probiotics, prebiotics and the low FODMAP diet.
Irritable bowel syndrome (IBS) is a functional bowel disorder characterised by abdominal pain or discomfort with disordered defecation. This review describes the role of the gastrointestinal (GI) microbiota in the pathogenesis of IBS and how dietary strategies to manage symptoms impact on the microbial community. Evidence suggests a dysbiosis of the luminal and mucosal colonic microbiota in IBS, frequently characterised by a reduction in species of Bifidobacteria which has been associated with worse symptom profile. Probiotic supplementation trials suggest intentional modulation of the GI microbiota may be effective in treating IBS. A smaller number of prebiotic supplementation studies have also demonstrated effectiveness in IBS whilst increasing Bifidobacteria. In contrast, a novel method of managing IBS symptoms is the restriction of short-chain fermentable carbohydrates (low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet). Studies consistently demonstrate clinical effectiveness of the low FODMAP diet in patients with IBS. However, one unintentional consequence of this dietary intervention is its impact on the microbiota. This leads to an interesting paradox; namely, increasing luminal Bifidobacteria through probiotic supplementation is associated with a reduction in IBS symptoms while in direct conflict to this, the low FODMAP diet has clinical efficacy but markedly reduces luminal Bifidobacteria concentration. Given the multifactorial aetiology of IBS, the heterogeneity of symptoms and the complex and diverse nature of the microbiome, it is probable that both interventions are effective in patient subgroups. However combination treatment has never been explored and as such, presents an exciting opportunity for optimising clinical management, whilst preventing potentially deleterious effects on the GI microbiota.


Improving urinary incontinence in overweight and obese women through modest weight loss.
To examine the relationship between magnitude of weight loss and changes in urinary incontinence frequency. Overweight and obese women (N=338) with 10 or more urinary incontinence episodes per week were assigned randomly to an intensive 6-month behavioral weight loss program followed immediately by a 12-month weight maintenance program (intervention; n=226) or to a structured education program (control; n=112). The intervention and control groups were combined to examine the effects of the magnitude of weight loss on changes in urinary incontinence assessed by 7-day voiding diary, pad test, and self-reported satisfaction with change in urinary incontinence. Compared with participants who gained weight (reference), those who lost 5% to less than 10% or 10% or more of their body weight had significantly greater percent reductions in urinary incontinence episodes and were more likely to achieve at least a 70% reduction in the frequency of total and urge urinary incontinence episodes at 6, 12, and 18 months. Satisfaction was also related to magnitude of weight loss; approximately 75% of women who lost 5% to less than 10% of their body weight reported being moderately or very satisfied with their changes in urine leakage. Weight losses between 5% and 10% of body weight were sufficient for significant urinary incontinence benefits. Thus, weight loss should be considered as initial treatment for incontinence in overweight and obese women. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00091988. II.


Utility of a C-jun microsatellite marker in determining gene dosage for fatty (fa).
The Zucker fatty (fa) mutation provides a genetic model for obesity and non-insulin dependent diabetes mellitus. The molecular pathogenesis of the metabolic phenotype of these animals is not known. Detailed molecular maps of the region surrounding the fa locus on rat chromosome 5 can be used for positional cloning experiments as well as to permit genotyping of animals from appropriate crosses before the confounding metabolic effects of obesity have occurred. We describe the development of a polymerase chain reaction (PCR) assay for a polymorphic simple sequence repeat (SSR) in the promoter region of the protooncogene c-Jun. This assay was used to position c-Jun 4.5cM proximal to the fa locus in 111 F2 progeny of a 13MBN fa/+ F1 intercross. Concurrent use of the c-Jun SSR with a previously described assay for a microsatellite in the glucose transporter, Glut1, permits rapid and accurate assessment of genotypes at the fa locus in animals of any age using minimal amounts of DNA. A strategy is described which minimizes the error rate in assigning genotype at the fatty locus for backcross and intercross progeny.


The effect of ribavirin on reactive astrogliosis in experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of CNS inflammatory and demyelinating disease multiple sclerosis. Microglia and astrocytes represent two related cell types involved in the brain pathology in EAE. Accumulations of hypertrophic reactive astrocytes, intensely stained with glial fibrillary acidic protein (GFAP), which also expressed vimentin, are prominent features of EAE lesions. Recent studies from our laboratory reported that ribavirin attenuated the disease process in EAE by reducing clinical and histological manifestations. EAE was induced in genetically susceptible Dark Agouti rats with syngeneic spinal cord homogenate in complete Freund's adjuvant. Real time PCR and immunohistochemistry were used for determination of GFAP and vimentin gene and tissue expression. We have observed the increased gene and tissue expression of GFAP and vimentin in EAE rats. Ribavirin treatment significantly decreased the number of reactive astrocytes at the peak of disease. At the end of the disease, we have observed reactive GFAP(+) and vimentin(+) astrocytes in both immunized and ribavirin-treated groups, accompanied by increased level of GFAP mRNA. The present study indicates that ribavirin may have the ability to attenuate astrocyte proliferation and glial scaring at the peak of the disease and modulate the astroglial response to EAE during the time-course of the disease.


Atlas-free surface reconstruction of the cortical grey-white interface in infants.
The segmentation of the cortical interface between grey and white matter in magnetic resonance images (MRI) is highly challenging during the first post-natal year. First, the heterogeneous brain maturation creates important intensity fluctuations across regions. Second, the cortical ribbon is highly folded creating complex shapes. Finally, the low tissue contrast and partial volume effects hamper cortex edge detection in parts of the brain. We present an atlas-free method for segmenting the grey-white matter interface of infant brains in T2-weighted (T2w) images. We used a broad characterization of tissue using features based not only on local contrast but also on geometric properties. Furthermore, inaccuracies in localization were reduced by the convergence of two evolving surfaces located on each side of the inner cortical surface. Our method has been applied to eleven brains of one- to four-month-old infants. Both quantitative validations against manual segmentations and sulcal landmarks demonstrated good performance for infants younger than two months old. Inaccuracies in surface reconstruction increased with age in specific brain regions where the tissue contrast decreased with maturation, such as in the central region. We presented a new segmentation method which achieved good to very good performance at the grey-white matter interface depending on the infant age. This method should reduce manual intervention and could be applied to pathological brains since it does not require any brain atlas.


Single versus multiple occupancy--effects on toxicity parameters measured on Eisenia fetida in lead nitrate-treated soil.
The mortality (7 and 14 d), weight change (7 and 14 d), and metal uptake of Eisenia fetida (Savigny, 1826) kept in Pb(NO3)2-treated Kettering loam soil in single- and multiple-occupancy (10 earthworms) test containers were determined. The number of earthworms to dry mass (g) ratio of soil was 1:50 in both sets of test containers. Lead concentrations were in the nominal range of 0 to 10,000 mg Pb/kg soil (mg/kg hereafter). Levels of mortality at a given concentration were statistically identical between the single- and multiple-occupancy tests, except at 1,800 mg/kg, at which significantly (p < or = 0.05) more mortality occurred in the multiple-occupancy tests. Death of individual earthworms in the multiple-occupancy tests did not trigger death of the other earthworms in that soil. The LC50 values (concentration statistically likely to kill 50% of the population) were identical between the multiple- and single-occupancy soils: 2,662 mg/kg (2,598-2,984, 7 d) and 2,589 mg/kg (2,251-3,013, 14 d) for the multiple-occupancy soils and 2,827 mg/kg (2,443-3,168, both 7 and 14 d) for the single-occupancy soils (values in brackets represent the 95% confidence intervals). Data were insufficient to calculate the concentration statistically likely to reduce individual earthworm mass by 50% (EC50), but after 14 d, the decrease in earthworm weight in the 1,800 and 3,000 mg/kg tests was significantly greater in the multiple- than in the single-occupancy soils. At 1,000, 1,800, and 3,000 mg/kg tests, earthworm Pb tissue concentration was significantly (p < or = 0.05) greater in earthworms from the multiple-occupancy soils. The presence of earthworms increased the NH3 content of the soil; earthworm mortality increased NH3 concentrations further but not to toxic levels.


Awareness of current recommendations and guidelines regarding strength training for youth.
Physical conditioning of youth has always been a controversial topic as it raises ethical, physiological, and medical issues. Current recommendations and guidelines suggest that strength training is a relatively safe and worthwhile method in conditioning youth. This, however, requires well-informed coaches who follow age-appropriate strength training recommendations and guidelines, compiles well-designed strength training programs, and provides qualified supervision and instructions. The purpose of this study was to investigate coaches' awareness of current recommendations and guidelines regarding strength training for youth. A total of 39 football (US: soccer) coaches (34 males and 5 females) training boys in age groups 8-12 years were included in this study. Data were collected using an attitude statement questionnaire, and the assertions were based upon current recommendations and guidelines. The results revealed significant differences among coaches in terms of knowledge of important aspects of strength training for youth. The results suggested that coaches in the present study were not aware of the latest recommendations and guidelines regarding strength training for youth.


BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases.
Metaphase comparative genomic hybridization was used to analyze the spectrum of genetic alterations in 141 epithelial ovarian cancers from BRCA1 and BRCA2 mutation carriers, individuals with familial non-BRCA1/2 epithelial ovarian cancer, and women with nonfamilial epithelial ovarian cancer. Multiple genetic alterations were identified in almost all tumors. The high frequency with which some alterations were identified suggests the location of genes that are commonly altered during ovarian tumor development. In multiple chromosome regions, there were significant differences in alteration frequency between the four tumor types suggesting that BRCA1/2 mutation status and a family history of ovarian cancer influences the somatic genetic pathway of ovarian cancer progression. These findings were supported by hierarchical cluster analysis, which identified genetic events that tend to occur together during tumorigenesis and several alterations that were specific to tumors of a particular type. In addition, some genetic alterations were strongly associated with differences in tumor differentiation and disease stage. Taken together, these data provide molecular genetic evidence to support previous findings from histopathological studies, which suggest that clinical features of ovarian and breast tumors differ with respect to BRCA1/2 mutation status and/or cancer family history.


Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson's disease.
Cannabidiol (CBD) is one of the main components of Cannabis sativa and has anxiolytic properties, but no study has been conducted to evaluate the effects of CBD on anxiety signs and symptoms in patients with Parkinson's disease (PD). This study aimed to evaluate the impacts of acute CBD administration at a dose of 300 mg on anxiety measures and tremors induced by a Simulated Public Speaking Test (SPST) in individuals with PD. A randomised, double-blinded, placebo-controlled, crossover clinical trial was conducted. A total of 24 individuals with PD were included and underwent two experimental sessions within a 15-day interval. After taking CBD or a placebo, participants underwent the SPST. During the test, the following data were collected: heart rate, systemic blood pressure and tremor frequency and amplitude. In addition, the Visual Analog Mood Scales (VAMS) and Self-Statements during Public Speaking Scale were applied. Statistical analysis was performed by repeated-measures analysis of variance (ANOVA) while considering the drug, SPST phase and interactions between these variables. There were statistically significant differences in the VAMS anxiety factor for the drug; CBD attenuated the anxiety experimentally induced by the SPST. Repeated-measures ANOVA showed significant differences in the drug for the variable related to tremor amplitude as recorded by the accelerometer. Acute CBD administration at a dose of 300 mg decreased anxiety in patients with PD, and there was also decreased tremor amplitude in an anxiogenic situation.


Phosphorylation-dependent differential regulation of plant growth, cell death, and innate immunity by the regulatory receptor-like kinase BAK1.
Plants rely heavily on receptor-like kinases (RLKs) for perception and integration of external and internal stimuli. The Arabidopsis regulatory leucine-rich repeat RLK (LRR-RLK) BAK1 is involved in steroid hormone responses, innate immunity, and cell death control. Here, we describe the differential regulation of three different BAK1-dependent signaling pathways by a novel allele of BAK1, bak1-5. Innate immune signaling mediated by the BAK1-dependent RKs FLS2 and EFR is severely compromised in bak1-5 mutant plants. However, bak1-5 mutants are not impaired in BR signaling or cell death control. We also show that, in contrast to the RD kinase BRI1, the non-RD kinases FLS2 and EFR have very low kinase activity, and we show that neither was able to trans-phosphorylate BAK1 in vitro. Furthermore, kinase activity for all partners is completely dispensable for the ligand-induced heteromerization of FLS2 or EFR with BAK1 in planta, revealing another pathway specific mechanistic difference. The specific suppression of FLS2- and EFR-dependent signaling in bak1-5 is not due to a differential interaction of BAK1-5 with the respective ligand-binding RK but requires BAK1-5 kinase activity. Overall our results demonstrate a phosphorylation-dependent differential control of plant growth, innate immunity, and cell death by the regulatory RLK BAK1, which may reveal key differences in the molecular mechanisms underlying the regulation of ligand-binding RD and non-RD RKs.


From the channel model of an InSb-based superresolution optical disc system to impulse response and resolution limits.
The signal model of a superresolution optical channel can be an efficient tool for developing components of an associated high-density optical disc system. While the behavior of the laser diode, aperture, lens, and detector are properly described, a general mathematical model of the superresolution disc itself has not yet been available until recently. Different approaches have been made to describe the properties of a mask layer, mainly based on temperature- or power-dependent nonlinear effects. A complete signal-based or phenomenological optical channel model--from non-return-to-zero inverted input to disc readout signal--has recently been developed including the reflectivity of a superresolution disc with InSb used for the mask layer. In this contribution, the model is now extended and applied to a moving disc including a land-and-pit structure, and results are compared with data read from real superresolution discs. Both impulse response and resolution limits are derived and discussed. Thus the model provides a bridge from physical to readout signal properties, which count after all. The presented approach allows judging of the suitability of a mask layer material for storage density enhancement already based on static experiments, i.e., even before developing an associated disc drive.


Functional outcome scales in traumatic brain injury: a comparison of the Glasgow Outcome Scale (Extended) and the Functional Status Examination.
Clinical trials aimed at developing therapies for traumatic brain injury (TBI) require outcome measures that are reliable, validated, and easily administered. The most widely used of these measures, the Glasgow Outcome Scale (GOS) and the GOS-Extended (GOS-E), have been criticized as suffering from ceiling effects. In an attempt to develop a more useful and dynamic outcome measure, the Functional Status Examination (FSE) was developed, which grades outcome across 10 functional domains. The FSE has been demonstrated to be reliable and sensitive in monitoring recovery after TBI. This manuscript compares FSE with GOS-E in a cohort of patients with a wide range of injury severities. 177 individuals who survived at least 6 months after TBI were studied. The FSE and GOS-E were administered 6-12 months after injury. FSE and GOS-E scores correlated well with each other. FSE scores were distributed throughout the range, indicating that ceiling and floor effects were not present. Physiologic measures of injury severity (Glasgow Coma Score [GCS]) did not correlate with anatomic measures (Abbreviated Injury Scale [AIS] and Injury Severity Score [ISS]). GCS correlated weakly with both outcome measures, but AIS/ISS did not. We conclude that FSE and GOS-E are reliable outcome measures for TBI survivors, and FSE may offer some advantages over GOS-E due its ability to provide a more detailed description of deficits. The majority of the variance in outcome is not accounted for by currently available measures of injury severity.


Treatment of lower eyelid retraction by expansion of the lower eyelid with hyaluronic Acid gel.
To report our preliminary experience utilizing a nonsurgical alternative in the treatment of lower eyelid retraction: expansion and reinforcement of the lower eyelid with hyaluronic acid gel. Retrospective review of patients with lower eyelid retraction treated with hyaluronic acid gel. Pretreatment, post-treatment, and follow-up photographs were digitized and overall outcomes assessed. Measurements of inferior scleral show were standardized and compared. Sixty-five procedures (31 patients; 14 male; mean age 58 years, range, 33-78 years) with lower eyelid retraction of various etiologies were treated with hyaluronic acid gel. A mean change in scleral show of 1.04 mm was found when pre- and post-treatment measurements were compared. The overall mean follow-up period was 6.2 months (range, 1-12 months). During the interval from initial treatment to follow-up visit (mean 4.6 months, range, 1-12 months), the effect of the hyaluronic acid gel diminished, with a mean increase in inferior scleral show of 0.52 mm. Twelve patients underwent a second, and 6 patients underwent a third, maintenance treatment with an improvement in scleral show of 0.87 mm and 1.13 mm, respectively. Complications were minor and included swelling, redness, bruising, and tenderness at the sites of injection. Based on our preliminary results, hyaluronic acid gel shows promise as a treatment modality for the management of lower eyelid retraction. Long-term follow-up will better clarify the required frequency of maintenance injections, the degree of hyaluronic acid gel retention, and the position of the lower eyelid over time.


Keep calm and have a good night: nurses' strategies to promote inpatients' sleep in the hospital environment.
Patients in the hospital environment are suffering from disrupted sleep, which adversely affects their recovery process, health and well-being. The aim of this study was to explore nurses' experiences and their strategies to promote inpatients' sleep. An empirical qualitative design was applied. Eight nurses at a hospital in Sweden were purposefully selected to be included in semi-structured interviews. Burnard's method for inductively analysing interview transcripts was applied. The findings are presented in four categories: (i) prevention and planning as a sleep-promoting nursing strategy; (ii) adaptation of the environment as a sleep-promoting nursing strategy; (iii) use of drugs as a sleep-promoting nursing strategy; and (iv) caring conversation as a sleep-promoting nursing strategy. Using strategies to promote sleep is important as it affects the recovery of the patients. We argue for the use of simple strategies of sensory reduction as cost-effective sleep-promoting measures that also reduce the use of sedative drugs.


Genomic mutations with amino acid substitutions of circulating hepatitis B virus found in non-B, non-C patients with hepatocellular carcinoma.
Most hepatocellular carcinoma (HCC) in Japan is caused by chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). HBV DNA has been detected in the serum and liver tissue of some proportion of those patients who are HBs antigen-negative and HCV antibody-negative; i.e., non-B, non-C (NBNC) patients with HCC. We sought to detect HBV DNA in the serum from NBNC HCC cases and to investigate genomic mutations of HBV in seronegative cases. The sera from 26 NBNC HCC patients were examined by polymerase chain reaction (PCR) followed by southern blotting for existence of HBV DNA. The precore/core and polymerase regions of the HBV genome in the sera from five seronegative cases were analyzed by direct sequence. HBV DNA was detected in 17 of 26 patients (65.4%). Demographic factors such as age, gender, anti-HBs positivity, anti-HBc positivity, complication with cirrhosis, and excessive alcohol intake did not affect circulating HBV positivity. Genomic mutations with amino acid substitutions were detected in the polymerase and the precore regions from one of the five cases, and in the core region from four of the five cases. PCR-based HBV screening is necessary in patients suffering from liver diseases of unknown etiology, although its etiological importance and benefit of viral elimination have not been established. Genomic mutations in the precore/core and the polymerase region detected in this study might be involved in the lack of HBsAg in NBNC HCC cases.


Phylogenetic and ecological factors influencing the number and distribution of electroreceptors in elasmobranchs.
Electroreception is found throughout the animal kingdom from invertebrates to mammals and has been shown to play an important role in prey detection, facilitating social behaviours, the detection of predators and orientation to the earth's magnetic field for navigation. Electroreceptors in elasmobranchs, the ampullae of Lorenzini, detect minute electric fields and independently process these stimuli, thereby providing spatial information to the central nervous system on the location of a source, often potential prey. The ampullae of Lorenzini are individually connected to a single somatic pore on the surface of the skin, with the spatial separation of each pore directly influencing how electrical stimuli are detected and processed. Pore abundance varies across taxonomic groups resulting in unique species-specific differences. The intricate distribution patterns created by the specific positioning of somatic pores on the head are, however, consistent within families, resulting in patterns that are identifiable at higher taxonomic levels. As elasmobranchs evolved, the electrosensory system became more complex and highly specialized, which is evident by a general trend of increasing pore abundance over time. The elasmobranch electrosensory system has evolved to operate efficiently under the environmental conditions of the particular habitat in which a species lives. For example, reduced pore abundance is evident in oceanic pelagic elasmobranchs, for whom visual cues are thought to be of great importance. Pore abundance and spatial distribution may be influenced by multiple factors including head morphology, phylogeny, feeding behaviour and habitat.


PROMIS, global analysis of PROtein-metabolite interactions using size separation in Arabidopsis thaliana.
Small molecules not only represent cellular building blocks and metabolic intermediates, but also regulatory ligands and signaling molecules that interact with proteins. Although these interactions affect cellular metabolism, growth, and development, they have been largely understudied. Herein, we describe a method, which we named PROtein-Metabolite Interactions using Size separation (PROMIS), that allows simultaneous, global analysis of endogenous protein-small molecule and of protein-protein complexes. To this end, a cell-free native lysate from Arabidopsis thaliana cell cultures was fractionated by size-exclusion chromatography, followed by quantitative metabolomic and proteomic analyses. Proteins and small molecules showing similar elution behavior, across protein-containing fractions, constituted putative interactors. Applying PROMIS to an A. thaliana extract, we ascertained known protein-protein (PPIs) and protein-metabolite (PMIs) interactions and reproduced binding between small-molecule protease inhibitors and their respective proteases. More importantly, we present examples of two experimental strategies that exploit the PROMIS dataset to identify novel PMIs. By looking for similar elution behavior of metabolites and enzymes belonging to the same biochemical pathways, we identified putative feedback and feed-forward regulations in pantothenate biosynthesis and the methionine salvage cycle, respectively. By combining PROMIS with an orthogonal affinity purification approach, we identified an interaction between the dipeptide Tyr-Asp and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase. In summary, we present proof of concept for a powerful experimental tool that enables system-wide analysis of PMIs and PPIs across all biological systems. The dataset obtained here comprises nearly 140 metabolites and 5000 proteins, which can be mined for putative interactors.


Rapid ABO genotyping using whole blood without DNA purification.
ABO genotyping is commonly used in cases of an ABO discrepancy between cell typing and serum typing, as well as in forensic practice for personal identification and paternity testing. We evaluated ABO genotyping via multiplex allele-specific PCR (ASPCR) amplification using whole blood samples without DNA purification. A four-reaction multiplex ASPCR genotyping assay was designed to detect specific nucleotide sequence differences between the six ABO alleles A101, A102, B101, O01, O02, and cis-AB01. The ABO genotypes of 127 randomly chosen samples were determined using the new multiplex ASPCR method. The genotypes of the 127 samples were found to be A101/A102 (n=1), A102/A102 (n=9), A101/O01 (n=3), A102/O01 (n=12), A102/O02 (n=14), B101/B101 (n=5), B101/O01 (n=18), B101/O02 (n=15), O01/O01 (n=14), O02/O02 (n=8), O01/O02 (n=14) and A102/B101 (n=14), from which phenotypes were calculated to be A (n=39), B (n=38), O (n=36) and AB (n=14). The multiplex ASPCR assay results were compared with the serologically determined blood group phenotypes and genotypes determined by DNA sequencing, and there were no discrepancies. This convenient multiplex ASPCR assay, performed using whole blood samples, provides a supplement to routine serological ABO typing and might also be useful in other genotyping applications.


Dis-integration of communication in healthcare education: Workplace learning challenges and opportunities.
The purpose of this paper, based on a 2016 Heidelberg International Conference on Communication in Healthcare (ICCH) plenary presentation, is to examine a key problem in communication skills training for health professional learners. Studies have pointed to a decline in medical students' communication skills and attitudes as they proceed through their education, particularly during their clinical workplace training experiences. This paper explores some of the key factors in this disintegration, drawing on selected literature and highlighting some curriculum efforts and research conducted at the University of Iowa Carver College of Medicine as a case study of these issues. Five key factors contributing to the disintegration of communication skills and attitudes are presented including: 1) lack of formal communication skills training during clinical clerkships; 2) informal workplace teaching failing to explicitly address learner clinical communication skills; 3) emphasizing content over process in relation to clinician-patient interactions; 4) the relationship between ideal communication models and the realities of clinical practice; and 5) clinical teachers' lack of knowledge and skills to effectively teach about communication in the clinical workplace. Within this discussion, potential practical responses by individual clinical teachers and broader curricular and faculty development efforts to address each of these factors are presented.


Enzymes involved in DNA ligation and end-healing in the radioresistant bacterium Deinococcus radiodurans.
Enzymes involved in DNA metabolic events of the highly radioresistant bacterium Deinococcus radiodurans are currently examined to understand the mechanisms that protect and repair the Deinococcus radiodurans genome after extremely high doses of gamma-irradiation. Although several Deinococcus radiodurans DNA repair enzymes have been characterised, no biochemical data is available for DNA ligation and DNA endhealing enzymes of Deinococcus radiodurans so far. DNA ligases are necessary to seal broken DNA backbones during replication, repair and recombination. In addition, ionizing radiation frequently leaves DNA strand-breaks that are not feasible for ligation and thus require end-healing by a 5'-polynucleotide kinase or a 3'-phosphatase. We expect that DNA ligases and end-processing enzymes play an important role in Deinococcus radiodurans DNA strand-break repair. In this report, we describe the cloning and expression of a Deinococcus radiodurans DNA ligase in Escherichia coli. This enzyme efficiently catalyses DNA ligation in the presence of Mn(II) and NAD+ as cofactors and lysine 128 was found to be essential for its activity. We have also analysed a predicted second DNA ligase from Deinococcus radiodurans that is part of a putative DNA repair operon and shows sequence similarity to known ATP-dependent DNA ligases. We show that this enzyme possesses an adenylyltransferase activity using ATP, but is not functional as a DNA ligase by itself. Furthermore, we identified a 5'-polynucleotide kinase similar to human polynucleotide kinase that probably prepares DNA termini for subsequent ligation. Deinococcus radiodurans contains a standard bacterial DNA ligase that uses NAD+ as a cofactor. Its enzymatic properties are similar to E. coli DNA ligase except for its preference for Mn(II) as a metal cofactor. The function of a putative second DNA ligase remains unclear, but its adenylyltransferase activity classifies it as a member of the nucleotidyltransferase family. Characterization of another protein from the same operon revealed a 5'-polynucleotide kinase with a possible role in DNA strand-break repair.


Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab.
In pivotal trials, canakinumab has been shown to be effective in the treatment of systemic juvenile idiopathic arthritis (JIA), but reported adverse events have included macrophage activation syndrome (MAS). This study was undertaken to assess the impact of canakinumab on MAS incidence. An independent MAS Adjudication Committee (MASAC), consisting of 3 of the authors, was convened, and a search of databases from clinical studies of canakinumab treatment in systemic JIA was performed using MASAC-specified adverse event terms to identify potential MAS events. These were then adjudicated as "probable MAS," "possible MAS," or "MAS unlikely," using criteria developed by the MASAC. MAS rates were expressed as numbers of cases per 100 patient-years. Of 72 potential MAS cases identified, 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 patients were adjudicated as being probable MAS and 10 events in 9 patients as being possible MAS. Systemic JIA was well controlled in the majority of canakinumab-treated patients at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1,358 days (median 292 days). When the rates of probable MAS events were compared between canakinumab-treated patients (2.8 per 100 patient-years) and placebo-treated patients (7.7 per 100 patient-years), the difference was not significant (-4.9 [95% confidence interval -15.6, 5.9]). There were 3 deaths due to MAS-related complications (2 in patients receiving canakinumab; 1 in a patient receiving placebo); full recovery was reported in all other patients. Infections were the most common trigger of MAS, and the clinical features of MAS were not modified by canakinumab. Canakinumab does not have a significant effect on MAS risk or its clinical features in patients with systemic JIA. Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well controlled with this treatment.


Dendritic cells mediate the anti-inflammatory action of omega-3 long-chain polyunsaturated fatty acids in experimental autoimmune uveitis.
We previously showed that dietary omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) suppress inflammation in mice with experimental autoimmune uveitis (EAU). We have now investigated the role of antigen presenting cells (APCs) in this action of ω-3 LCPUFAs. C57BL/6 mice were fed a diet supplemented with ω-3 or ω-6 LCPUFAs for 2 weeks, after which splenocytes were isolated from the mice and cocultured with CD4+ T cells isolated from mice with EAU induced by injection of a human interphotoreceptor retinoid-binding protein peptide together with complete Freund's adjuvant. The proliferation of and production of interferon-γ and interleukin-17 by T cells from EAU mice in vitro were attenuated in the presence of splenocytes from ω-3 LCPUFA-fed mice as compared with those from mice fed ω-6 LCPUFAs. Splenocyte fractionation by magnetic-activated cell sorting revealed that, among APCs, dendritic cells (DCs) were the target of ω-3 LCPUFAs. Adoptive transfer of DCs from mice fed ω-3 LCPUFAs attenuated disease progression in EAU mice as well as the production of pro-inflammatory cytokines by T cells isolated from these latter animals. The proliferation of T cells from control Balb/c mice was also attenuated in the presence of DCs from ω-3 LCPUFA-fed mice as compared with those from ω-6 LCPUFA-fed mice. Furthermore, T cell proliferation in such a mixed lymphocyte reaction was inhibited by prior exposure of DCs from mice fed an ω-6 LCPUFA diet to ω-3 LCPUFAs in vitro. Our results thus suggest that DCs mediate the anti-inflammatory action of dietary ω-3 LCPUFAs in EAU.


Toolbox for the sampling and monitoring of benthic cyanobacteria.
Benthic cyanobacteria are a nuisance because they produce highly potent toxins and taste and odour compounds. Despite this, benthic cyanobacteria remain far less studied than their planktonic counterparts. For example, little is known about their growth or the seasonality of their secondary metabolite production. Moreover, sampling and monitoring techniques commonly used for the survey of planktonic species are not necessarily applicable to benthic forms. This study aimed to develop and validate a new sampling device for the routine monitoring of benthic mats. Molecular monitoring techniques were established and validated on environmental samples collected in a South Australian reservoir (SA-L2). A total of eight qPCR assays were applied to samples in order to track seasonal variations in cyanobacteria concentrations and associated secondary metabolite production. Next Generation Sequencing was utilised to conduct a microbial community composition analysis and to select the most appropriate substrate material for the sampling of benthic cyanobacteria. The concentration of the secondary metabolites geosmin and 2-methyl-isoborneol were quantified using High-Performance Liquid Chromatography, and concentrations of key nutrients (N, P) were quantified in water samples. The sampling device designed proved efficient and easy to use in the field. The qPCR assay designed for the amplification of the cyanobacterial MIB synthase had a high efficiency with a minimum limit of quantification of 4 cell-equivalents per reaction and identified a potential source of MIB in SA-L2 Reservoir. The peak season for benthic growth and secondary metabolite production was observed in spring. Proportionally, 35% of the variability in water geosmin concentrations can be explained by benthic actinobacterial and cyanobacterial activity, showing that freshwater benthic mats represent a significant source of taste and odour compounds.


Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality.
Signal transducer and activator of transcription (STAT) proteins have been shown to mediate biological actions in response to cytokines. Stat3, a member of the STAT family, is activated by a variety of cytokines, including the interleukin 6 family of cytokines, leptin, granulocyte colony-stimulating factor, and epidermal growth factor. To address the biological function of Stat3, we generated mice deficient in Stat3 by gene targeting. No viable Stat3-deficient mice could be obtained from heterozygote intercross. Analysis of embryos at several gestation times revealed that Stat3-deficient embryos showed a rapid degeneration between embryonic days 6.5 and 7.5, although they developed into the egg cylinder stage until embryonic day 6.0. These results demonstrate that Stat3 is essential for the early development of mouse embryos.


Hyperbaric oxygen therapy in branch retinal artery occlusion in a 15-year-old boy with methylenetetrahydrofolate reductase mutation.
Purpose. To report the efficacy of hyperbaric oxygen (HBO) therapy in a case of branch retinal artery occlusion (BRAO) in a 15-year-old boy. Methods. We report a 15-year-old boy with sudden loss of vision due to BRAO. Examination included laboratory evaluation for systemic risk factors. Follow-up exams included visual acuity, fundus examination, fundus fluorescein angiography, and visual field testing. HBO therapy was employed for treatment. Results. Medical history was positive for isolated glucocorticoid deficiency. Laboratory evaluation disclosed hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) mutation. The visual acuity 0.05 at presentation improved to 0.8 after 20 days of HBO therapy. There was no change on visual fields. Conclusion. In this pediatric case, HBO therapy was useful in the treatment of BRAO.


[Immunologic clinical evaluation of a biological response modifier, AM3, in the treatment of childhood infectious respiratory pathology].
To assess the immunoclinical effectiveness of a biological response immunomodulator, we used AM3 (glycophosphopeptide ), a glucomannan polysaccharide extracted from the cell wall of a strain of Candida utilis, in 20 children with asthmatic bronchitis. They received 2 envelopes (1 g) daily for 4 months. The results were compared with a control group of 20 untreated children with the same pathology. The following clinical and immunological parameters were assessed in all of them: cough, dyspnea, expectoration, frequency and intensity of the bronchospasm, time of administration of the symptomatic medication, and the delayed cutaneous cells response by means of the intradermal reaction of 5 antigens (Trichophyton, Candida albicans, tuberculin, E. coli and bacterial antigens). In the treated group, the immunoferon (AM3) reduced the symptoms, the intensity and frequency of the bronchospasm, and the symptomatic medication (table I, II and III). In basal conditions, the 40 children presented a state of 75% anergy; after 4 months of treatment, the treated group experienced a 45% decrease in their anergic situation, variation which was statistically significant when compared with the control group. In our 20 treated patients, AM3 behaved like and immunostimulant, improving the clinical situation and progress in patients with infectious respiratory disorders. We consider that the immunoferon constitutes a coadjuvant therapy to bacterial immunotherapy.


Quantification of Hemoglobin and White Blood Cell DNA Adducts of the Tobacco Carcinogens 2-Amino-9H-pyrido[2,3-b]indole and 4-Aminobiphenyl Formed in Humans by Nanoflow Liquid Chromatography/Ion Trap Multistage Mass Spectrometry.
Aromatic amines covalently bound to hemoglobin (Hb) as sulfinamide adducts at the cysteine 93 residue of the Hb β chain have served as biomarkers to assess exposure to this class of human carcinogens for the past 30 years. In this study, we report that 2-amino-9H-pyrido[2,3-b]indole (AαC), an abundant carcinogenic heterocyclic aromatic amine formed in tobacco smoke and charred cooked meats, also reacts with Hb to form a sulfinamide adduct. A novel nanoflow liquid chromatography/ion trap multistage mass spectrometry (nanoLC-IT/MS3) method was established to assess exposure to AαC and the tobacco-associated bladder carcinogen 4-aminobiphenyl (4-ABP) through their Hb sulfinamide adducts. Following mild acid hydrolysis of Hb in vitro, the liberated AαC and 4-ABP were derivatized with acetic anhydride to form the N-acetylated amines, which were measured by nanoLC-IT/MS3. The limits of quantification (LOQ) for AαC- and 4-ABP-Hb sulfinamide adducts were ≤7.1 pg/g Hb. In a pilot study, the mean level of Hb sulfinamide adducts of AαC and 4-ABP were, respectively, 3.4-fold and 4.8-fold higher in smokers (>20 cigarettes/day) than nonsmokers. In contrast, the major DNA adducts of 4-ABP, N-(2'-deoxyguanosin-8-yl)-4-aminobiphenyl, and AαC, N-(2'-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole, were below the LOQ (3 adducts per 109 bases) in white blood cell (WBC) DNA of smokers and nonsmokers. These findings reaffirm that tobacco smoke is a major source of exposure to AαC. Hb sulfinamide adducts are suitable biomarkers to biomonitor 4-ABP and AαC; however, neither carcinogen binds to DNA in WBC, even in heavy smokers, at levels sufficient for biomonitoring.


Use of bosentan for digital ulcers related to systemic sclerosis: a real-life retrospective French study of 89 patients treated since specific approval.
Ischaemic digital ulcers (DUs) are a common complication of systemic sclerosis (SSc). This study aimed to characterize patients with SSc and ongoing DUs treated with the endothelin receptor antagonist bosentan in clinical practice in France. An observational, retrospective, longitudinal study was conducted in 10 French expert centres. Medical records from randomly selected adult SSc patients who received treatment with bosentan for DU prevention from March 2007 to December 2010 were analysed. The primary objective was to determine the profile of patients at treatment initiation. Secondary objectives were to monitor bosentan dosing, treatment schedule, and reasons for treatment termination. The study included 89 patients (mean age 52 years, 69% female, 44% diffuse cutaneous SSc). At bosentan treatment initiation, the mean duration of Raynaud's phenomenon was 15 ± 12 years, and the mean time since first episode with DU was 6.5 ± 7 years. Most patients had a history of at least two episodes with DUs, separated by < 12 months (61%), and had received intravenous iloprost (63%). Previous DU complications included auto-amputation (8%), surgical amputation (6%), osteitis (6%), and gangrene (4.5%). Active smokers (25%) had a history of significantly more surgical amputation (p = 0.004) and osteitis (p = 0.004) than non-smokers. At least one active DU at bosentan initiation was detected in 82% of patients. Bosentan was used according to prescription guidelines and was well tolerated; six patients (7%) withdrew from treatment because of raised liver enzymes. Patients treated with bosentan for DU prevention in France have severe, refractory, ongoing ulcerative disease. Active smoking was correlated to a history of DU complications. Tolerance of bosentan was comparable to previous studies.


Population genetics models of local ancestry.
Migrations have played an important role in shaping the genetic diversity of human populations. Understanding genomic data thus requires careful modeling of historical gene flow. Here we consider the effect of relatively recent population structure and gene flow and interpret genomes of individuals that have ancestry from multiple source populations as mosaics of segments originating from each population. This article describes general and tractable models for local ancestry patterns with a focus on the length distribution of continuous ancestry tracts and the variance in total ancestry proportions among individuals. The models offer improved agreement with Wright-Fisher simulation data when compared to the state-of-the art and can be used to infer time-dependent migration rates from multiple populations. Considering HapMap African-American (ASW) data, we find that a model with two distinct phases of "European" gene flow significantly improves the modeling of both tract lengths and ancestry variances.


The Experience of a Sustainable Large Scale Brazilian Telehealth Network.
In Brazil, the majority of healthcare resources are concentrated in the largest cities, whereas most communities lack proper healthcare assistance in primary care and have difficulties accessing specialists and diagnostic examinations. Considering this, the Telehealth Network of Minas Gerais (TNMG) was created. It is a public telehealth initiative that provides support to primary healthcare (PHC), performing teleconsultation and telediagnosis (electrocardiogram [ECG], Holter, ambulatory blood pressure monitoring, spirometry, and retinography analysis) mainly for small and remote cities in the state of Minas Gerais, Brazil. To describe the successful experience of the TNMG in 10 years of activities. The TNMG was created in 2005 and supported PHC in 82 cities as a research project and was progressively expanded. A methodology for implementation and maintenance was developed, including quality control. Nowadays it provides support to 750 cities, 88.0% of Minas Gerais state. The examinations performed by the PHC team, with additional basic clinical data, are transmitted through the Internet to the TNMG specialists for remote interpretation. The TNMG teleconsultations system has been used by the PHC team to address written clinical questions to university staff. Until December 2015, 2,464,999 ECGs and 73,698 teleconsultations have already been performed: on average, 2,000 ECGs and 40 teleconsultations per day in 2015. More than 95% of users have declared to be satisfied or very satisfied with the service. A recent cost-benefit analysis of the project showed that for each dollar invested, 6.1 dollars are saved as a consequence of patient referral reduction. The TNMG is a successful example of a sustainable telehealth service, integrated to primary care centers of remote and small cities. It overcomes geographical barriers to provide specialized healthcare, reducing the number of unnecessary referrals, and contributing to improve the case-resolving capacity and the quality of the PHC.


The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer.
A number of polycyclic aromatic hydrocarbons (PAH) are widespread environmental contaminants that cause mammary cancer experimentally. We investigated whether exposure and susceptibility to PAH, as measured by PAH-DNA adducts in breast tissue, are associated with human breast cancer. We carried out a hospital-based case-control study using immunohistochemical methods to analyze PAH-DNA adducts in tumor and nontumor breast tissue from cases and benign breast tissue from controls. The subjects were white, African-American and Latina women without prior cancer or treatment, including 119 women with breast cancer and 108 with benign breast disease without atypia. PAH-DNA adducts measured in breast tumor tissue of 100 cases and in normal tissue from 105 controls were significantly associated with breast cancer (OR=4.43, 96% CI 1.09-18.01) after controlling for known breast cancer risk factors and current active and passive smoking, and dietary PAH. There was substantial interindividual (17-fold) variability in adducts overall, with 27% of cases and 13% of controls having elevated adducts. The odds ratio for elevated adducts in tumor tissue compared with control tissue was 2.56 (1. 05-6.24), after controlling for potential confounders. Adduct levels in tumor tissue did not vary by stage or tumor size. Among 86 cases with paired tumor and nontumor tissue, adducts levels in these two tissues were highly correlated (r=0.56, P<0.001). However, the corresponding associations between case-control status and adducts measured in nontumor tissue from 90 cases and in normal tissue from 105 controls were positive but not statistically significant. Overall, neither active nor passive smoking, or dietary PAH were significantly associated with PAH-DNA adducts or breast cancer case-control status. These results suggest that genetic damage reflecting individual exposure and susceptibility to PAH may play a role in breast cancer; but more research is needed to determine whether the findings are relevant to causation or progression of breast cancer.


The burden of heat-related mortality attributable to recent human-induced climate change.
Climate change affects human health; however, there have been no large-scale, systematic efforts to quantify the heat-related human health impacts that have already occurred due to climate change. Here, we use empirical data from 732 locations in 43 countries to estimate the mortality burdens associated with the additional heat exposure that has resulted from recent human-induced warming, during the period 1991-2018. Across all study countries, we find that 37.0% (range 20.5-76.3%) of warm-season heat-related deaths can be attributed to anthropogenic climate change and that increased mortality is evident on every continent. Burdens varied geographically but were of the order of dozens to hundreds of deaths per year in many locations. Our findings support the urgent need for more ambitious mitigation and adaptation strategies to minimize the public health impacts of climate change.


Systematic review of active workplace interventions to reduce sickness absence.
The workplace is used as a setting for interventions to prevent and reduce sickness absence, regardless of the specific medical conditions and diagnoses. To give an overview of the general effectiveness of active workplace interventions aimed at preventing and reducing sickness absence. We systematically searched PubMed, Embase, Psych-info, and ISI web of knowledge on 27 December 2011. Inclusion criteria were (i) participants over 18 years old with an active role in the intervention, (ii) intervention done partly or fully at the workplace or at the initiative of the workplace and (iii) sickness absence reported. Two reviewers independently screened articles, extracted data and assessed risk of bias. A narrative synthesis was used. We identified 2036 articles of which, 93 were assessed in full text. Seventeen articles were included (2 with low and 15 with medium risk of bias), with a total of 24 comparisons. Five interventions from four articles significantly reduced sickness absence. We found moderate evidence that graded activity reduced sickness absence and limited evidence that the Sheerbrooke model (a comprehensive multidisciplinary intervention) and cognitive behavioural therapy (CBT) reduced sickness absence. There was moderate evidence that workplace education and physical exercise did not reduce sickness absence. For other interventions, the evidence was insufficient to draw conclusions. The review found limited evidence that active workplace interventions were not generally effective in reducing sickness absence, but there was moderate evidence of effect for graded activity and limited evidence for the effectiveness of the Sheerbrooke model and CBT.


Prediction of IBD based on population history for fine gene mapping.
A novel multiple regression method (RM) is developed to predict identity-by-descent probabilities at a locus L (IBDL), among individuals without pedigree, given information on surrounding markers and population history. These IBDL probabilities are a function of the increase in linkage disequilibrium (LD) generated by drift in a homogeneous population over generations. Three parameters are sufficient to describe population history: effective population size (Ne), number of generations since foundation (T), and marker allele frequencies among founders (p). IBDL are used in a simulation study to map a quantitative trait locus (QTL) via variance component estimation. RM is compared to a coalescent method (CM) in terms of power and robustness of QTL detection. Differences between RM and CM are small but significant. For example, RM is more powerful than CM in dioecious populations, but not in monoecious populations. Moreover, RM is more robust than CM when marker phases are unknown or when there is complete LD among founders or Ne is wrong, and less robust when p is wrong. CM utilises all marker haplotype information, whereas RM utilises information contained in each individual marker and all possible marker pairs but not in higher order interactions. RM consists of a family of models encompassing four different population structures, and two ways of using marker information, which contrasts with the single model that must cater for all possible evolutionary scenarios in CM.


Imprinting bulk amorphous alloy at room temperature.
We present investigations on the plastic deformation behavior of a brittle bulk amorphous alloy by simple uniaxial compressive loading at room temperature. A patterning is possible by cold-plastic forming of the typically brittle Hf-based bulk amorphous alloy through controlling homogenous flow without the need for thermal energy or shaping at elevated temperatures. The experimental evidence suggests that there is an inconsistency between macroscopic plasticity and deformability of an amorphous alloy. Moreover, imprinting of specific geometrical features on Cu foil and Zr-based metallic glass is represented by using the patterned bulk amorphous alloy as a die. These results demonstrate the ability of amorphous alloys or metallic glasses to precisely replicate patterning features onto both conventional metals and the other amorphous alloys. Our work presents an avenue for avoiding the embrittlement of amorphous alloys associated with thermoplastic forming and yields new insight the forming application of bulk amorphous alloys at room temperature without using heat treatment.


Disaster Response on September 11, 2001 Through the Lens of Statistical Network Analysis.
The rescue and relief operations triggered by the September 11, 2001 attacks on the World Trade Center in New York City demanded collaboration among hundreds of organisations. To shed light on the response to the September 11, 2001 attacks and help to plan and prepare the response to future disasters, we study the inter-organisational network that emerged in response to the attacks. Studying the inter-organisational network can help to shed light on (1) whether some organisations dominated the inter-organisational network and facilitated communication and coordination of the disaster response; (2) whether the dominating organisations were supposed to coordinate disaster response or emerged as coordinators in the wake of the disaster; and (3) the degree of network redundancy and sensitivity of the inter-organisational network to disturbances following the initial disaster. We introduce a Bayesian framework which can answer the substantive questions of interest while being as simple and parsimonious as possible. The framework allows organisations to have varying propensities to collaborate, while taking covariates into account, and allows to assess whether the inter-organisational network had network redundancy-in the form of transitivity-by using a test which may be regarded as a Bayesian score test. We discuss implications in terms of disaster management.


Commentary: toward a unified theory of personal and professional ethics.
In response to Dr. Ezra Griffith's essay, we support the view that forensic practice cannot be cleanly divided from its ethics foundation in medical and general psychiatric practice. Personal and professional values cannot be separated in formulating a unified theory of ethics for professionalism in forensic practice. We support Dr. Griffith's narrative perspective and offer a delineation of how narratives may be considered in forensic work. We would like readers to focus on both the duties and the moral ideals that ultimately define professional ethics. By honoring personal and professional narratives together, forensic professionals can advocate and reshape a system that devalues non-dominant cultures. They can also recognize more easily the influences that affect their forensic work. This kind of forensic practice, informed by narrative ethics while respecting fundamental principles, can be an essential part of what we aspire to as forensic professionals. As we argued in an earlier work, a robust professionalism for forensic psychiatry cannot ignore our physician background or our diverse personal histories. Dr. Griffith's essay contributes forcefully to the development of such a view.


Hybrid axial and radial Si-GaAs heterostructures in nanowires.
Hybrid structures are formed from materials of different families. Traditionally, group IV and III-V semiconductors have not been integrated together in the same device or application. In this work we present a new approach for obtaining Si-GaAs hybrid heterostructures in nanowires based on a combination of molecular beam epitaxy and plasma enhanced chemical vapor deposition. Crystalline Si segments are integrated into GaAs nanowires grown by the Ga-assisted growth method at temperatures as low as 250 °C. We find that one of the most important factors leading to the successful growth of Si segments on GaAs is the silane-hydrogen dilution, which affects the concentration of silicon and hydrogen-based radicals (SiHx with x < 3) in the plasma, and determines if the Si shell is amorphous, polycrystalline or crystalline, and also if the growth takes place in the axial and/or radial directions. This work opens the path for the successful integration of silicon and III-V materials in one single nanowire.


Characterization of purinergic receptor expression in ARPKD cystic epithelia.
Polycystic kidney diseases (PKDs) are a group of inherited nephropathies marked by formation of fluid-filled cysts along the nephron. Growing evidence suggests that in the kidney formation of cysts and alteration of cystic electrolyte transport are associated with purinergic signaling. PCK/CrljCrl-Pkhd1pck/CRL (PCK) rat, an established model of autosomal recessive polycystic kidney disease (ARPKD), was used here to test this hypothesis. Cystic fluid of PCK rats and their cortical tissues exhibited significantly higher levels of ATP compared to Sprague Dawley rat kidney cortical interstitium as assessed by highly sensitive ATP enzymatic biosensors. Confocal calcium imaging of the freshly isolated cystic monolayers revealed a stronger response to ATP in a higher range of concentrations (above 100 μM). The removal of extracellular calcium results in the profound reduction of the ATP evoked transient, which suggests calcium entry into the cyst-lining cells is occurring via the extracellular (ionotropic) P2X channels. Further use of pharmacological agents (α,β-methylene-ATP, 5-BDBD, NF449, isoPPADS, AZ10606120) and immunofluorescent labeling of isolated cystic epithelia allowed us to narrow down potential candidate receptors. In conclusion, our ex vivo study provides direct evidence that the profile of P2 receptors is shifted in ARPKD cystic epithelia in an age-related manner towards prevalence of P2X4 and/or P2X7 receptors, which opens new avenues for the treatment of this disease.


Sex differences in duration judgments: a meta-analytic review.
We quantitatively reviewed human sex differences in the magnitude and variability of duration judgments. Data from 4,794 females and 4,688 males yielded 87 effect size estimates of magnitude and 28 of variability. The overall sex difference in duration judgment magnitude was small but statistically significant. It was moderated by whether study participants knew in advance (prospective paradigm) or only later (retrospective paradigm) that they would be required to judge duration. Although prospective judgments showed no overall sex effect, some levels of moderator variables showed a small but statistically significant effect. Retrospective judgments showed a larger subjective-to-objective duration ratio for females than for males, and several variables moderated this effect. Females' judgments also showed more intersubject variability than did males' judgments. Relative to males, females sustain attention to time more in the prospective paradigm and have better episodic memory in the retrospective paradigm.


The LKA gene is a BRASSINOSTEROID INSENSITIVE 1 homolog of pea.
Brassinosteroids (BRs) are growth-promoting plant steroid hormones, and in garden pea (Pisum sativum L.), the lka mutant is defective in BR perception. Here, we show that LKA encodes P. sativum BRI1 (PsBRI1), a homolog of BRI1, which is the Arabidopsis leucine-rich repeat receptor-like kinase/BR receptor. PsBRI1 was isolated by screening a pea cDNA library using Arabidopsis BRI1 cDNA as the probe. PsBRI1 is predicted to encode a 1188-amino-acid protein that has 78% similarity with Arabidopsis BRI1. Sequence analysis of PsBRI1 in the lka mutant led to the identification of a missense mutation that converts the highly conserved aspartic acid residue to asparagine, which is located in the leucine-rich repeat, just before the island domain that may bind BR or a BR-protein complex. The mutation identified in PsBRI1 co-segregated with the semi-erectoide lka phenotype. Transcript analysis of LKA/PsBRI1 indicates that it is ubiquitously expressed in pea and that the expression was downregulated by exogenous BR. The lka mutant was then utilized in further studies to analyze the independent actions of BR and gibberellin (GA) through the characterization of BR response on GA mutants and GA response on BR mutants.


The evolutionary advantage of recombination.
The controversy over the evolutionary advantage of recombination initially discovered by Fisher and by Muller is reviewed. Those authors whose models had finite-population effects found an advantage of recombination, and those whose models had infinite populations found none. The advantage of recombination is that it breaks down random linkage disequilibrium generated by genetic drift. Hill and Robertson found that the average effect of this randomly-generated linkage disequilibrium was to cause linked loci to interfere with each other's response to selection, even where there was no gene interaction between the loci. This effect is shown to be identical to the original argument of Fisher and Muller. It also predicts the "ratchet mechanism" discovered by Muller, who pointed out that deleterious mutants would more readily increase in a population without recombination. Computer simulations of substitution of favorable mutants and of the long-term increase of deleterious mutants verified the essential correctness of the original Fisher-Muller argument and the reality of the Muller ratchet mechanism. It is argued that these constitute an intrinsic advantage of recombination capable of accounting for its persistence in the face of selection for tighter linkage between interacting polymorphisms, and possibly capable of accounting for its origin.


CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl]butyl]-2,4-imidazolinedione): antihypertensive profile and pharmacology.
CI-926 (10(-7)-10(-6) M) selectively antagonized the contraction of isolated rabbit aortae to phenylephrine and displaced the alpha-1 adrenoceptor ligand WB4101 (IC50: 82 nM) in rat brain. In the spontaneously hypertensive rat, single oral doses of either CI-926 (0.3-10 mg/kg) or prazosin (0.3-100 mg/kg) caused dose-related reductions in blood pressure; however, CI-926 was more efficacious. The maximal antihypertensive response to CI-926 was unchanged with three consecutive days of oral dosing in the spontaneously hypertensive rat, whereas a first dose effect was noted with prazosin. In two-kidney, one-clip, renal hypertensive rats, CI-926 and prazosin (1-10 mg/kg) lowered blood pressure; however, prazosin was more efficacious. In perinephritic hypertensive dogs, CI-926 (10 mg/kg) lowered blood pressure 20%. In anesthetized dogs, CI-926 in the presence of supermaximal blood pressure-lowering doses of prazosin caused an additional reduction in pressure. With equivalent alpha-1 blockade in anesthetized rats, CI-926 tended to have greater hypotensive activity than prazosin. These results demonstrate that CI-926 is a potent, orally active antihypertensive agent in renin-dependent and -independent hypertension. The profile of CI-926 suggests that it lowers blood pressure in part by interacting with peripheral alpha-1 adrenoceptors and in part via an additional mechanism(s). Although weak relative to its affinity for alpha-1 adrenoceptors, CI-926 was found in preliminary experiments to interact with alpha-2 adrenoceptors, serotonergic receptors and dopaminergic receptors. The importance of these interactions to the blood pressure response of CI-926 remains to be elucidated.


Caffeine for apnea of prematurity: a neonatal success story.
Caffeine, a methylxanthine and nonspecific inhibitor of adenosine receptors, is an example of a drug that has been in use for more than 40 years. It is one of the most commonly prescribed drugs in neonatal medicine. However, until 2006, it had only a few relatively small and short-term studies supporting its use. It is thanks to the efforts of Barbara Schmidt and the Caffeine for Apnea of Prematurity (CAP) Trial Group that we now have high-quality and reliable data not only on short-term but also long-term outcomes of caffeine use for apnea of prematurity. CAP was an international, multicenter, placebo-controlled randomized trial designed to determine whether survival without neurodevelopmental disability at a corrected age of 18 months is improved if apnea of prematurity is managed without methylxanthines in infants at a high risk of apneic attacks. CAP was kept simple and pragmatic in order to allow for maximum generalizability and applicability. Infants with birth weights of 500-1,250 g were enrolled during the first 10 days of life if their clinicians considered them to be candidates for methylxanthine therapy. The most frequent indication for therapy reported in CAP was treatment of documented apnea, followed by the facilitation of the removal of an endotracheal tube. Only about 20% of the neonatologists in the trial started caffeine for the prevention of apnea and the findings of CAP cannot automatically be extrapolated to an exclusive prophylactic indication. However, recent data suggest that the administration of prophylactic methylxanthine by neonatologists is now common practice.


Autoinflammatory diseases: clinical and genetic advances.
We conducted a literature review to investigate the recent advances in genetics, molecular biology, clinical manifestations, and therapy of 7 inherited diseases that are characterized by seemingly unprovoked inflammation. These autoinflammatory diseases include familial Mediterranean fever; tumor necrosis factor receptor-associated periodic syndrome; hyperimmunoglobulinemia D with periodic fever syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne syndrome; and the 3 cryopyrinopathies: neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous and arthropathy syndrome, familial cold autoinflammatory syndrome, and Muckle-Wells syndrome. Recent identification of the susceptibility genes for autoinflammatory diseases has broadened the clinical spectrum as well as the molecular basis of these diseases. The cryopyrinopathies represent a continuum of diseases associated with mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene that encodes cryopyrin. Cryopyrin and pyrin (protein mutated in familial Mediterranean fever) belong to the family of PYRIN domain-containing proteins. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome is associated with mutations in the gene that encodes for CD2-binding protein 1 (CD2BP1), which binds pyrin. Recent studies have shown that activation of the interleukin 1beta pathway is a common mechanism in the pathogenesis of autoinflammatory diseases, further unifying these diseases. Recent advances in genetics and molecular biology have advanced our understanding of the pathogenesis of autoinflammatory diseases. Understanding autoinflammatory diseases will further our knowledge of cutaneous as well as systemic inflammation. Anakinra, a recombinant human interleukin 1 receptor antagonist, is a promising new biologic agent for the treatment of cryopyrinopathies as well other autoinflammatory diseases, such as tumor necrosis factor receptor-associated periodic syndrome and hyperimmunoglobulinemia D with periodic fever syndrome.


Multimodal neuroimaging computing: a review of the applications in neuropsychiatric disorders.
Multimodal neuroimaging is increasingly used in neuroscience research, as it overcomes the limitations of individual modalities. One of the most important applications of multimodal neuroimaging is the provision of vital diagnostic data for neuropsychiatric disorders. Multimodal neuroimaging computing enables the visualization and quantitative analysis of the alterations in brain structure and function, and has reshaped how neuroscience research is carried out. Research in this area is growing exponentially, and so it is an appropriate time to review the current and future development of this emerging area. Hence, in this paper, we review the recent advances in multimodal neuroimaging (MRI, PET) and electrophysiological (EEG, MEG) technologies, and their applications to the neuropsychiatric disorders. We also outline some future directions for multimodal neuroimaging where researchers will design more advanced methods and models for neuropsychiatric research.


Sleep and ageing: from human studies to rodent models.
Sleep duration and lifespan vary greatly across Animalia. Human studies have demonstrated that ageing reduces the ability to obtain deep restorative sleep, and this may play a causative role in the development of age-related neurodegenerative disorders. Animal models are widely used in sleep and ageing studies. Importantly, in contrast to human studies, evidence from laboratory rodents suggests that sleep duration is increased with ageing, while evidence for reduced sleep intensity and consolidation is inconsistent. Here we discuss two possible explanations for these species differences. First, methodological differences between studies in humans and laboratory rodents may prevent straightforward comparison. Second, the role of ecological factors, which have a profound influence on both ageing and sleep, must be taken into account. We propose that the dynamics of sleep across the lifespan reflect both age-dependent changes in the neurobiological substrates of sleep as well as the capacity to adapt to the environment.


[Attic exposure-antrum exclusion as an on demand surgical technique for cholesteatoma].
Attic exposure and antrum exclusion (AE-AE) is an on demand surgical technique for the treatment of cholesteatoma. Several techniques have been described with variable recurrence rates. The aim of the study was to describe this surgical technique and its indications and to analyse long-term outcomes. Forty-two patients were included. They received AE-AE in a tertiary centre and were followed-up from 6 months to 7 years. The surgical technique exposes the attic by drilling the superior wall of the external auditory canal and excludes the antrum and the mastoid cells by closing the aditus with a cartilage graft. It is indicated if the lesion does not go beyond the aditus or, if it does, it is a delimited cholesteatoma not damaging the labyrinth. The patients were followed-up by physical examination and radiology (CT scan and Non-EPI diffusion-weighted MRI since 2009). The recurrence rate of the cholesteatoma was 4.8%. At recurrence, an open canal-wall-down mastoidectomy technique was performed. The rate of otorrhea (2/42 cases), serous otitis (2/42) and other complications was low, so aquatic activities were not contraindicated. The AE-AE did not modify ossicular chain reconstruction with respect to the rest of surgical techniques. AE-AE is a canal-wall-down technique. Its purpose is to remove the lesion and to reduce the recurrence of cholesteatoma. In addition, it allows the entrance of water and reduces the need for 2(nd) look surgery. Non-EPI diffusion-weighted MRI is a reliable technique for follow-up, especially for the excluded mastoid.


5-Formylcytosine does not change the global structure of DNA.
The mechanism by which the recently identified DNA modification 5-formylcytosine (fC) is recognized by epigenetic writer and reader proteins is not known. Recently, an unusual DNA structure, F-DNA, has been proposed as the basis for enzyme recognition of clusters of fC. We used NMR and X-ray crystallography to compare several modified DNA duplexes with unmodified analogs and found that in the crystal state the duplexes all belong to the A family, whereas in solution they are all members of the B family. We found that, contrary to previous findings, fC does not significantly affect the structure of DNA, although there are modest local differences at the modification sites. Hence, global conformation changes are unlikely to account for the recognition of this modified base, and our structural data favor a mechanism that operates at base-pair resolution for the recognition of fC by epigenome-modifying enzymes.


Improving the Validity of Causal Inferences in Observational Studies.
Editor's note: This is the 13th article in a series on clinical research by nurses. The series is designed to be used as a resource for nurses to understand the concepts and principles essential to research. Each column will present the concepts that underpin evidence-based practice-from research design to data interpretation. To see all the articles in the series, go to https://links.lww.com/AJN/A204.


Multiscale modeling of two-dimensional contacts.
A hybrid simulation method is introduced and used to study two-dimensional single-asperity and multi-asperity contacts both quasistatically and dynamically. The method combines an atomistic treatment of the interfacial region with a finite-element method description of subsurface deformations. The dynamics in the two regions are coupled through displacement boundary conditions applied at the outer edges of an overlap region. The two solutions are followed concurrently but with different time resolution. The method is benchmarked against full atomistic simulations. Accurate results are obtained for contact areas, pressures, and static and dynamic friction forces. The time saving depends on the fraction of the system treated atomistically and is already more than a factor of 20 for the relatively small systems considered here.


Use of expert knowledge in evaluating costs and benefits of alternative service provisions: a case study.
A treatment pathway model was developed to examine the costs and benefits of the current bowel cancer service in England and to evaluate potential alternatives in service provision. To use the pathway model, various parameters and probability distributions had to be specified. They could not all be determined from empirical evidence and, instead, expert opinion was elicited in the form of statistical quantities that gave the required information. The purpose of this study is to describe the procedures used to quantify expert opinion and note examples of good practice contained in the case study. The required information was identified and preparatory discussion with four experts refined the questions they would be asked. In individual elicitation sessions they quantified their opinions, mainly in the form of point and interval estimates for specified variables. New methods have been developed for quantifying expert opinion and these were implemented in specialized software that uses interactive graphics. This software was used to elicit opinion about quantities related to measurable covariates. Assessments for thirty-four quantities were elicited and available checks supported their validity. Eight points of good practice in eliciting and using expert judgment were evident. Parameters and probability distributions needed for the pathway model were determined from the elicited assessments. Simulation results from the pathway model were used to inform policy on bowel cancer service provision. The study illustrates that quantifying and using expert judgment can be acceptable in real problems of practical importance. For full benefit to be gained from expert knowledge, elicitation must be conducted carefully and should be reported in detail.


Dissecting nuclear Wingless signalling: recruitment of the transcriptional co-activator Pygopus by a chain of adaptor proteins.
Members of the Wingless (Wg)/Wnt family of secreted glycoproteins control cell fate during embryonic development and adult homeostasis. Wnt signals regulate the expression of target genes by activating a conserved signal transduction pathway. Upon receptor activation, the signal is transmitted intracellularly by stabilization of Armadillo (Arm)/beta-catenin. Arm/beta-catenin translocates to the nucleus, interacts with DNA-binding factors of the Pangolin (Pan)/TCF/LEF class and activates transcription of target genes in cooperation with the recently identified proteins Legless/BCL9 (Lgs) and Pygopus (Pygo). Here, we analyse the mode of action of Pan, Arm, Lgs, and Pygo in Drosophila cultured cells. We provide evidence that together these four proteins form a 'chain of adaptors' linking the NH2-terminal homology domain (NHD) of Pygo to the DNA-binding domain of Pan. We show that the NHD has potent transcriptional activation capacity, which differs from that of acidic activator domains and depends on a conserved NPF tripeptide. A single point mutation within this NPF motif abolishes the transcriptional activity of the Pygo NHD in vitro and strongly reduces Wg signalling in vivo. Together, our results suggest that the transcriptional output of Wg pathway activity largely relies on a 'chain of adaptors' design to direct the Pygo NHD to Wg target promoters in an Arm-dependent manner.


Pulmonary embolism diagnosis and mortality with pulmonary CT angiography versus ventilation-perfusion scintigraphy: evidence of overdiagnosis with CT?
The purposes of this study were to determine whether pulmonary emboli diagnosed with pulmonary CT angiography (CTA) represent a milder disease spectrum than those diagnosed with ventilation-perfusion (V/Q) scintigraphy, to determine the trends in incidence and mortality among patients with the diagnosis of pulmonary embolism from 2000 to 2007, and to correlate incidence and mortality trends with imaging modality trends. Diagnoses of pulmonary embolism from 2000 to 2007 at an urban academic medical center were retrospectively identified. Patient data were collected from the hospital database and the Social Security Death Index. Incident diagnoses, type of imaging used, and date of death were documented. Bivariate and multivariate analyses were used to explore the relations between imaging use and the incidence and mortality of pulmonary embolism. Logistic regression analysis was used to estimate the odds of death of pulmonary embolism diagnosed with pulmonary CTA versus V/Q scintigraphy. The cases of 2087 patients (1361 women, 726 men; mean age, 61.8 years) with pulmonary embolism were identified. From 2000 to 2007 the incidence of pulmonary embolism increased from 0.69 to 0.91 per 100 admissions in strong correlation with increased use of pulmonary CTA. There was no change in mortality, but the case-fatality rate decreased from 5.7% to 3.3%. On average, pulmonary emboli diagnosed with pulmonary CTA were one half as lethal as those diagnosed with V/Q scintigraphy (odds ratio, 0.538; 95% CI, 0.314-0.921). The results of this study are evidence that the shift in imaging from V/Q scintigraphy to pulmonary CTA resulted in increased diagnosis of a less fatal spectrum of pulmonary embolic disease, raising the possibility of overdiagnosis. Outcome-based clinical trials with long-term follow-up would be helpful to further guide management.


Seeing red: the origin of grain pigmentation in US weedy rice.
Weedy forms of crop species infest agricultural fields worldwide and are a leading cause of crop losses, yet little is known about how these weeds evolve. Red rice (Oryza sativa), a major weed of cultivated rice fields in the US, is recognized by the dark-pigmented grain that gives it its common name. Studies using neutral molecular markers have indicated a close relationship between US red rice and domesticated rice, suggesting that the weed may have originated through reversion of domesticated rice to a feral form. We have tested this reversion hypothesis by examining molecular variation at Rc, the regulatory gene responsible for grain pigmentation differences between domesticated and wild rice. Loss-of-function mutations at Rc account for the absence of proanthocyanidin pigments in cultivated rice grains, and the major rc domestication allele has been shown to be capable of spontaneous reversion to a functional form through additional mutations at the Rc locus. Using a diverse sample of 156 weedy, domesticated and wild Oryzas, we analysed DNA sequence variation at Rc and its surrounding 4 Mb genomic region. We find that reversion of domestication alleles does not account for the pigmented grains of weed accessions; moreover, we find that haplotypes characterizing the weed are either absent or very rare in cultivated rice. Sequences from genomic regions flanking Rc are consistent with a genomic footprint of the rc selective sweep in cultivated rice, and they are compatible with a close relationship of red rice to Asian Oryzas that have never been cultivated in the US.


Use of a structured functional evaluation process for independent medical evaluations of claimants presenting with disabling mental illness: rationale and design for a multi-center reliability study.
Work capacity evaluations by independent medical experts are widely used to inform insurers whether injured or ill workers are capable of engaging in competitive employment. In many countries, evaluation processes lack a clearly structured approach, standardized instruments, and an explicit focus on claimants' functional abilities. Evaluation of subjective complaints, such as mental illness, present additional challenges in the determination of work capacity. We have therefore developed a process for functional evaluation of claimants with mental disorders which complements usual psychiatric evaluation. Here we report the design of a study to measure the reliability of our approach in determining work capacity among patients with mental illness applying for disability benefits. We will conduct a multi-center reliability study, in which 20 psychiatrists trained in our functional evaluation process will assess 30 claimants presenting with mental illness for eligibility to receive disability benefits [Reliability of Functional Evaluation in Psychiatry, RELY-study]. The functional evaluation process entails a five-step structured interview and a reporting instrument (Instrument of Functional Assessment in Psychiatry [IFAP]) to document the severity of work-related functional limitations. We will videotape all evaluations which will be viewed by three psychiatrists who will independently rate claimants' functional limitations. Our primary outcome measure is the evaluation of claimant's work capacity as a percentage (0 to 100 %), and our secondary outcomes are the 12 mental functions and 13 functional capacities assessed by the IFAP-instrument. Inter-rater reliability of four psychiatric experts will be explored using multilevel models to estimate the intraclass correlation coefficient (ICC). Additional analyses include subgroups according to mental disorder, the typicality of claimants, and claimant perceived fairness of the assessment process. We hypothesize that a structured functional approach will show moderate reliability (ICC ≥ 0.6) of psychiatric evaluation of work capacity. Enrollment of actual claimants with mental disorders referred for evaluation by disability/accident insurers will increase the external validity of our findings. Finding moderate levels of reliability, we will continue with a randomized trial to test the reliability of a structured functional approach versus evaluation-as-usual.