Health & Demographic Surveillance System Profile: Farafenni Health and Demographic Surveillance System in The Gambia.
The Farafenni Health and Demographic Surveillance System (Farafenni HDSS) is located 170 km from the coast in a rural area of The Gambia, north of the River Gambia. It was set up in 1981 by the UK Medical Research Council Laboratories to generate demographic and health information required for the evaluation of a village-based, primary health care programme in 40 villages. Regular updates of demographic events and residency status have subsequently been conducted every 4 months. The surveillance area was extended in 2002 to include Farafenni Town and surrounding villages to support randomized, controlled trials. With over three decades of prospective surveillance, and through specific scientific investigations, the platform (population ≈ 50,000) has generated data on: morbidity and mortality due to malaria in children and during pregnancy; non-communicable disease among adults; reproductive health; and levels and trends in childhood and maternal mortality. Other information routinely collected includes causes of death through verbal autopsy, and household socioeconomic indicators. The current portfolio of the platform includes tracking Millennium Development Goal 4 (MDG4) attainments in rural Gambia and cause-of-death determination.


Utilization of Minimally Invasive Surgery in Endometrial Cancer Care: A Quality and Cost Disparity.
To describe case mix-adjusted hospital level utilization of minimally invasive surgery for hysterectomy in the treatment of early-stage endometrial cancer. In this retrospective cohort study, we analyzed the proportion of patients who had a minimally invasive compared with open hysterectomy for nonmetastatic endometrial cancer using the U.S. Nationwide Inpatient Sample database, 2007-2011. Hospitals were stratified by endometrial cancer case volumes (low=less than 10; medium=11-30; high=greater than 30 cases). Hierarchical logistic regression models were used to evaluate hospital and patient variables associated with minimally invasive utilization, complications, and costs. Overall, 32,560 patients were identified; 33.6% underwent a minimally invasive hysterectomy with an increase of 22.0-50.8% from 2007 to 2011. Low-volume cancer centers demonstrated the lowest minimally invasive utilization rate (23.6%; P<.001). After multivariable adjustment, minimally invasive surgery was less likely to be performed in patients with Medicaid compared with private insurance (adjusted odds ratio [OR] 0.67, 95% confidence interval [CI] 0.62-0.72), black and Hispanic compared with white patients (adjusted OR 0.43, 95% CI 0.41-0.46 for black and 0.77, 95% CI 0.72-0.82 for white patients), and more likely to be performed in high- compared with low-volume hospitals (adjusted OR 4.22, 95% CI 2.15-8.27). Open hysterectomy was associated with a higher risk of surgical site infection (adjusted OR 6.21, 95% CI 5.11-7.54) and venous thromboembolism (adjusted OR 3.65, 95% CI 3.12-4.27). Surgical cases with complications had higher mean hospitalization costs for all hysterectomy procedure types (P<.001). Hospital utilization of minimally invasive surgery for the treatment of endometrial cancer varies considerably in the United States, representing a disparity in the quality and cost of surgical care delivered nationwide.


Postural tachycardia syndrome following human papillomavirus vaccination.
Postural tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system that may have an autoimmune etiology. Six patients who developed new onset POTS 6 days to 2 months following human papillomavirus vaccination are reported. Three patients also had neurocardiogenic syncope, and three patients were diagnosed with possible small fiber neuropathy. Symptoms in all patients improved over 3 years with pharmacotherapy and non-pharmacological measures but residual symptoms persisted. Molecular mimicry with formation of cross-reacting autoantibodies to the potential targets of the autonomic ganglia, neurons, cardiac proteins or vascular receptors is considered as a possible pathogenesis of new onset POTS after immunization. Correct diagnosis of POTS and awareness that POTS may occur after vaccination in young women is essential for prompt and effective management of this condition.


Outcomes of stereotactic radiosurgery for pilocytic astrocytoma: an international multiinstitutional study.
The current standard initial therapy for pilocytic astrocytoma is maximal safe resection. Radiation therapy is considered for residual, recurrent, or unresectable pilocytic astrocytomas. However, the optimal radiation strategy has not yet been established. Here, the authors describe the outcomes of stereotactic radiosurgery (SRS) for pilocytic astrocytoma in a large multiinstitutional cohort. An institutional review board-approved multiinstitutional database of patients treated with Gamma Knife radiosurgery (GKRS) between 1990 and 2016 was queried. Data were gathered from 9 participating International Radiosurgery Research Foundation (IRRF) centers. Patients with a histological diagnosis of pilocytic astrocytoma treated using a single session of GKRS and with at least 6 months of follow-up were included in the analysis. A total of 141 patients were analyzed in the study. The median patient age was 14 years (range 2-84 years) at the time of GKRS. The median follow-up was 67.3 months. Thirty-nine percent of patients underwent SRS as the initial therapy, whereas 61% underwent SRS as salvage treatment. The median tumor volume was 3.45 cm3. The tumor location was the brainstem in 30% of cases, with a nonbrainstem location in the remainder. Five- and 10-year overall survival rates at the last follow-up were 95.7% and 92.5%, respectively. Five- and 10-year progression-free survival (PFS) rates were 74.0% and 69.7%, respectively. On univariate analysis, an age < 18 years, tumor volumes < 4.5 cm3, and no prior radiotherapy or chemotherapy were identified as positive prognostic factors for improved PFS. On multivariate analysis, only prior radiotherapy was significant for worse PFS. This represents the largest study of single-session GKRS for pilocytic astrocytoma to date. Favorable long-term PFS and overall survival were observed with GKRS. Further prospective studies should be performed to evaluate appropriate radiosurgery dosing, timing, and sequencing of treatment along with their impact on toxicity and the quality of life of patients with pilocytic astrocytoma.


Possible role of Granulocyte Macrophage Colony Stimulating Factor receptor (GM-CSF R) in malaria.
Malaria has been reportedly increasing in incidence on the globe. Evidence from clinical studies supports a role for cytokines in the pathogenesis of cerebral malaria. Given the stimulatory effect of the ligand GM-CSF on the synthesis and release of the pyrogenic cytokine TNF alpha, the present study has been undertaken to investigate a possible role of GMCSF receptor in the pathogenesis of both Plasmodium vivax and Plasmodium falciparum malaria. An enzyme immunoassay developed by us at our laboratory for the quantitation of GM-CSF receptor has been used. No changes in the concentration of the receptor have been indicated either at the time of diagnosis or after treatment. In addition, an intercomparison of the receptor concentration between the P. vivax and P. falciparum groups does not show any significant difference. The results suggest that GM-CSF receptor has no significant role in the pathogenesis of either type of malaria.


Treatment of Diffuse Large B-Cell Lymphoma.
Diffuse large B-cell lymphoma (DLBCL) comprises a heterogeneous group with pathophysiological, genetic and clinical features. Many patients can be cured with R-CHOP therapy, which is the current standard regimen. Despite recent progress in improving patient survival, the 40% survival of DLBCL patients remains poor. Therefore, the most important issue for patients with DLBCL remains the development of a new front-line therapy. Several studies have reported that intensified chemotherapy with dose-adjusted EPOCH-R or R-ACVBP was superior to R-CHOP. Gene expression profiling has identified two distinct forms of DLBCL: activated B cell-like (ABC) and germinal center B-cell-like (GCB) types. ABC DLBCL exhibits a worse prognosis than GCB DLBCL by molecular diagnosis after R-CHOP therapy. Next-generation sequencing has identified unique oncogenic mechanisms and genetic complexity, which has provided rational therapeutic targets. There are also a number of biomarkers, including CD5, and prognostic factors. Efforts to distinguish many biomarkers will be crucial for individualized treatment in the future.


Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis.
Inter-individual differences in cortisol production by the hypothalamus-pituitary-adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity.


Adolescent and Parent Willingness to Participate in Microbicide Safety Studies.
To understand adolescents' and parents' willingness to participate (WTP) in a hypothetical phase I prevention study of sexually transmitted infections, discordance within adolescent-parent dyads, and expectations of each other during decision-making. Adolescent-parent dyads were recruited to participate in a longitudinal study about research participation attitudes. Adolescents (14-17 years old) and their parents (n = 301 dyads) participated. None. Individual interviews at baseline assessed WTP on a 6-level Likert scale. WTP was dichotomized (willing/unwilling) to assess discordance. WTP was reported by 60% (182 of 301) of adolescents and 52% (156 of 300) of parents. In bivariate analyses, older adolescent age, sexual experience, and less involvement of parents in research processes were associated with higher level of WTP for adolescents; only sexual experience remained in the multivariable analysis. For parents, older adolescent age, perceived adolescent sexual experience, and conversations about sexual health were significant; only conversations remained. Dyadic discordance (44%, 132 of 300) was more likely in dyads in which the parent reported previous research experience, and less likely when parents reported higher family expressiveness. Adolescents (83%, 248 of 299) and parents (88%, 263 of 300) thought that the other would have similar views, influence their decision (adolescents 66%, 199 of 300; parents 75%, 224 of 300), and listen (adolescents 90%, 270 of 300; parents 96%, 287 of 300). There were no relationships between these perceptions and discordance. Inclusion of adolescents in phase I clinical trials is necessary to ensure that new methods are safe, effective, and acceptable for them. Because these trials currently require parental consent, strategies that manage adolescent-parent discordance and support adolescent independence and parental guidance are critically needed.


Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.
Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.


Rotavirus gastroenteritis: precursor of functional gastrointestinal disorders?
: Abdominal pain-related functional gastrointestinal disorders (AP-FGIDs) following bacterial acute gastroenteritis (AGE) have been demonstrated in adults and children. An adult study demonstrated AP-FGIDs resulting from an outbreak of viral AGE. Viral AGEs are common in children. Thus, the demonstration of AP-FGIDs occurring after a viral infection in children could constitute a significant finding. The aim of the study was to investigate the development of FGIDs following an episode of acute rotavirus gastroenteritis in children. This is the first pediatric multicenter study designed to assess postviral AP-FGIDs. : It is a cohort study. Inclusion criteria of the study are children ages 4 to 18 years with history of AGE secondary to rotavirus. Sample size is 44 exposed and 44 controls (unidirectional alpha of 0.05, power of 0.80). Children consulting at 2 hospitals (Chicago, IL, and Naples, Italy) for AGE (2002-2004) who tested positive for rotavirus were randomly contacted by telephone >2 years after the episode. Each exposed child who visited the emergency department or outpatient site for acute trauma or well-child visit within 4 weeks of the index case was matched with a control of the same age and sex. Gastrointestinal symptoms and disability were evaluated with a validated pediatric questionnaire. : Eighty-eight patients (46 boys, mean age 5.3 years) were recruited. Contacted patients presented with AGE in 2002 (9), 2003 (11), and 2004 (24). Seven (16%) exposed patients and 3 (7%) controls reported AP-FGIDs (P = 0.31). : Our study suggests that rotavirus infection does not seem to place children at increased risk for AP-FGIDs at long-term follow-up. Larger, prospective studies should be conducted to evaluate whether rotavirus gastroenteritis leads to AP-FGIDs in children.


Parental psychopathology and treatment outcome for anxious youth: roles of family functioning and caregiver strain.
Research has examined the effects of parental psychopathology, family functioning, and caregiver strain on treatment response in anxious youths. Although these variables have shown individual links to youth treatment response, theoretical models for their combined effects remain unexplored. This study tested the hypothesis that improvements in family functioning and reductions in caregiver strain explained the effects of parental psychopathology on youth treatment outcome in an anxiety treatment trial. A multiple mediation technique was used to test the proposed model across independent evaluator (IE), parent, and youth informants in 488 youths, aged 7-17 years (50% female; mean age = 10.7) meeting Diagnostic and Statistical Manual of Mental Disorders criteria for social phobia, separation anxiety, and/or generalized anxiety disorder. Youths were randomized to receive 12 weeks of cognitive-behavioral treatment (Coping Cat), medication (sertraline), their combination, or a pill placebo. At pre- and posttreatment, parents completed self-report measures of global psychopathology symptoms, family functioning, and caregiver strain; parents, youths, and IEs rated youths' anxiety symptom severity. Changes in family functioning and caregiver strain jointly explained relations between parental psychopathology and reductions in youth anxiety. Specifically, across IE and parent informants, families with higher pretreatment parental psychopathology showed more improvement in family functioning and caregiver strain, which in turn predicted greater youth anxiety reductions. Further, higher pretreatment parental psychopathology predicted greater caregiver strain reductions and, in turn, greater youth anxiety reductions, based on youths' reports of their own anxiety. Findings suggest that improvements in family functioning and reductions in caregiver strain can influence treatment outcomes for anxious youths, especially among youths with more distressed parents.


Variations in self-reported nausea, vomiting, and well-being during the first 10 days postchemotherapy in women with breast cancer.
Women with breast cancer undergoing chemotherapy experience nausea and vomiting, both common symptoms affecting quality of life. The aim of the current study was to describe how nausea, vomiting, and well-being vary during the first 10 days after chemotherapy in women with breast cancer. A pilot study with a repeated-measurements design was conducted at a Swedish county hospital where 39 women with breast cancer treated with adjuvant chemotherapy were observed. A structured 10-day diary was used for data collection. Of the 39 women in the study, 33 experienced nausea and 6 also experienced vomiting after chemotherapy. Changes in well-being as a result of nausea or vomiting during any part of the day, as well as distress for other reasons, were reported. Well-being also varied among the individuals. The pattern of change in experienced levels of well-being was not homogeneous, nor did it move in any certain direction. The results of this study show that an individualized treatment approach is required to better meet individual women's needs.


Point-of-care blood tests during home visits by out-of-hours primary care clinicians; a mixed methods evaluation of a service improvement.
We aimed to evaluate test usage and patient and clinician experience following the introduction of point-of-care (POC) blood tests into a primary care out-of-hours service. A mixed methods service evaluation comprising quantitative records of the clinical contexts of tests taken and qualitative interviews with clinicians. Research permissions and governance were obtained for patient interviews. Out-of-hours primary care. All patients requiring home visits from the service during the implementation period. The i-STAT POC blood test platform was introduced to two bases providing home visits for a period of 8 months. Venous blood samples were used and two cartridges were available. The CHEM8 cartridge measures sodium, potassium, chloride, total carbon dioxide (TCO2), anion gap, ionised calcium, glucose, urea, creatinine, haematocrit and haemoglobin. The CG4 cartridge measures lactate, pH, PaO2 and PCO2, TCO2, bicarbonate, base excess and oxygen saturation. The proportion of home visits where tests were taken, the clinical contexts of those tests, the extent to which clinicians felt the tests had influenced their decisions, time taken to perform the test and problems encountered. Clinician and patient experiences of using POC tests. i-STAT POC tests were infrequently used, with successful tests taken at just 47 contacts over 8 months of implementation. The patients interviewed felt that testing had been beneficial for their care. Clinician interviews suggested barriers to POC tests, including practical challenges, concerns about time, doubt over whether they would improve clinical decision making and concern about increased medicolegal risk. Suggestions for improving adoption included sharing learning, adopting a whole team approach and developing protocols for usage. POC tests were not successfully adopted by an out-of-hours home visiting service in Oxfordshire. While some clinicians felt they could not add value, in other cases they resulted in improved patient experience. Adoption could be promoted by improving technical, team and education factors.


Overlapping gene structure of the human neuropeptide Y receptor subtypes Y1 and Y5 suggests coordinate transcriptional regulation.
The human y1 and y5 receptor genes are transcribed in opposite directions from a common promoter region on chromosome 4q31-q32. One of the alternately spliced 5' exons of the y1 receptor gene (1C) is also an integral part of the coding region of a novel neuropeptide Y receptor, Y5. Exon 1C of the y1 receptor gene, if translated from the opposite strand, encodes sequences corresponding to the large third intracellular loop of the Y5 receptor. The close proximity of the two neuropeptide Y receptor genes suggests that they have evolved from a gene duplication event with the small intron interrupting the coding sequence of the y1 gene being converted into a functional sequence within the y5 gene, while the reverse complementary sequence was utilized as an alternatively spliced 5' exon for the y1 gene. The transcription of both genes from opposite strands of the same DNA sequence suggests that transcriptional activation of one will have an effect on the regulation of gene expression of the other. As both Y1 and Y5 receptors are thought to play an important role in the regulation of food intake, coordinate expression of their specific genes may be important in the modulation of NPY activity.


Parent-delivered touchscreen intervention for children with fragile X syndrome.
The use of touchscreen applications for the iPad(®) allows children with disabilities to improve their personal autonomy and quality of life. In light of this emerging literature and our clinical experience with toddlers and children with Fragile X syndrome (FXS), a randomized clinical trial pilot study was conducted of whether an interactive iPad(®)-based parent training program was efficacious for both individuals with FXS and autism spectrum disorder aged 2-to-12 compared to wait-listed controls. As a second goal, we assessed the difference between direct person-to-person therapy vs. online therapy sessions through telehealth. In this case series report it is presented preliminary results of four individuals with FXS enrolled in the study and described the innovative experience including qualitative and quantitative data analysis. Furthermore, we provide professionals with specific guidelines about the use of touchscreen devices as in-home learning tools and parent training strategies to actively involve families in educational treatments in conjunction with clinical guidance.


Automated registration of multispectral MR vessel wall images of the carotid artery.
Atherosclerosis is the primary cause of heart disease and stroke. The detailed assessment of atherosclerosis of the carotid artery requires high resolution imaging of the vessel wall using multiple MR sequences with different contrast weightings. These images allow manual or automated classification of plaque components inside the vessel wall. Automated classification requires all sequences to be in alignment, which is hampered by patient motion. In clinical practice, correction of this motion is performed manually. Previous studies applied automated image registration to correct for motion using only nondeformable transformation models and did not perform a detailed quantitative validation. The purpose of this study is to develop an automated accurate 3D registration method, and to extensively validate this method on a large set of patient data. In addition, the authors quantified patient motion during scanning to investigate the need for correction. MR imaging studies (1.5T, dedicated carotid surface coil, Philips) from 55 TIA∕stroke patients with ipsilateral <70% carotid artery stenosis were randomly selected from a larger cohort. Five MR pulse sequences were acquired around the carotid bifurcation, each containing nine transverse slices: T1-weighted turbo field echo, time of flight, T2-weighted turbo spin-echo, and pre- and postcontrast T1-weighted turbo spin-echo images (T1W TSE). The images were manually segmented by delineating the lumen contour in each vessel wall sequence and were manually aligned by applying throughplane and inplane translations to the images. To find the optimal automatic image registration method, different masks, choice of the fixed image, different types of the mutual information image similarity metric, and transformation models including 3D deformable transformation models, were evaluated. Evaluation of the automatic registration results was performed by comparing the lumen segmentations of the fixed image and moving image after registration. The average required manual translation per image slice was 1.33 mm. Translations were larger as the patient was longer inside the scanner. Manual alignment took 187.5 s per patient resulting in a mean surface distance of 0.271 ± 0.127 mm. After minimal user interaction to generate the mask in the fixed image, the remaining sequences are automatically registered with a computation time of 52.0 s per patient. The optimal registration strategy used a circular mask with a diameter of 10 mm, a 3D B-spline transformation model with a control point spacing of 15 mm, mutual information as image similarity metric, and the precontrast T1W TSE as fixed image. A mean surface distance of 0.288 ± 0.128 mm was obtained with these settings, which is very close to the accuracy of the manual alignment procedure. The exact registration parameters and software were made publicly available. An automated registration method was developed and optimized, only needing two mouse clicks to mark the start and end point of the artery. Validation on a large group of patients showed that automated image registration has similar accuracy as the manual alignment procedure, substantially reducing the amount of user interactions needed, and is multiple times faster. In conclusion, the authors believe that the proposed automated method can replace the current manual procedure, thereby reducing the time to analyze the images.


Odontohypophosphatasia treated with asfotase alfa enzyme replacement therapy in a toddler: a case report.
Hypophosphatasia (HPP) is a rare skeletal disorder caused by loss-of-function mutations in Alkaline Phosphatase, Biomineralization associated (ALPL) gene that encodes tissue-nonspecific alkaline phosphatase. Odontohypophosphatasia (odonto-HPP), a mild form of HPP, is characterized only by oral manifestations including premature exfoliation of deciduous teeth. Enzyme replacement therapy (ERT) is effective in severe HPP cases; however, information about its efficacy for odonto-HPP is limited. A 2-yr-old girl was referred to our hospital for mobility of her deciduous teeth with low serum alkaline phosphatase (ALP) level of 253 U/L (reference range: 410-1,150 U/L) and high urine phosphoethanolamine level of 1,419.9 µmol/g·Cre (7-70 µmol/g·Cre). She had no history of bone fractures; however, several members of her family had low serum ALP levels with a history of pathological fractures. She had a novel heterozygous missense mutation (c.1183A>T, p.Ile395Phe) in ALPL, and therefore, was diagnosed with odonto-HPP. After she was provided ERT to prevent premature exfoliation, no tooth mobility was observed. However, two deciduous teeth exfoliated two months after starting ERT, which was possibly triggered by a bout of common cold. Starting ERT following tooth mobility might be relatively late. Previous studies on experimental mice showed that starting ERT at birth may be effective in preventing premature exfoliation of deciduous teeth.


Empirical model for target depth estimation used in the time-domain subsurface imaging.
Monte Carlo simulations were performed in order to obtain reflectance measurements from phantoms typically used in biomedical optics when either unpolarized or circularly polarized incident light is used. Phantoms contain spherical targets of different diameters, placed at different depths, with higher absorption than the surrounding medium, which are detected using a coaxial setup of laser and detector. The considered turbid media have highly anisotropic scattering phase functions, so detected light for the considered times of flight is not diffuse, but rather in the multiple-scattering regime. Therefore, the target reconstruction methods typically used in diffuse optical imaging cannot be employed. However, spatially resolved reflectance measurements in the time domain allow use of a novel reconstruction method based on the approximation of average photon trajectories, which are functions of the separation distance from the point of incidence and of the time of flight. With the approximated average photon trajectories, one can estimate the depth of the target.


The temporal selfish herd: predation risk while aggregations form.
The hypothesis of the selfish herd has been highly influential to our understanding of animal aggregation. Various movement strategies have been proposed by which individuals might aggregate to form a selfish herd as a defence against predation, but although the spatial benefits of these strategies have been extensively studied, little attention has been paid to the importance of predator attacks that occur while the aggregation is forming. We investigate the success of mutant aggregation strategies invading populations of individuals using alternative strategies and find that the invasion dynamics depend critically on the time scale of movement. If predation occurs early in the movement sequence, simpler strategies are likely to prevail. If predators attack later, more complex strategies invade. If there is variation in the timing of predator attacks (through variation within or between individual predators), we hypothesize that groups will consist of a mixture of strategies, dependent upon the distribution of predator attack times. Thus, behavioural diversity can evolve and be maintained in populations of animals experiencing a diverse range of predators differing solely in their attack behaviour. This has implications for our understanding of predator-prey dynamics, as the timing of predator attacks will exert selection pressure on prey behavioural responses, to which predators must respond.


Synthesis of 2-Deoxybrassinosteroids Analogs with 24-nor, 22(S)-23-Dihydroxy-Type Side Chains from Hyodeoxycholic Acid.
Natural brassinosteroids are widespread in the plant kingdom and it is known that they play an important role in regulating plant growth. In this study, two new brassinosteroid analogs with shorter side chains but keeping the diol function were synthesized. Thus, the synthesis of 2-deoxybrassinosteroids analogs of the 3α-hydroxy-24-nor, 22,23-dihydroxy-5α-cholestane side chain type is described. The starting material is a derivative from hyodeoxycholic acid (4), which was obtained with an overall yield of 59% following a previously reported five step route. The side chain of this intermediate was modified by oxidative decarboxylation to get a terminal olefin at the C22-C23 position (compound 20) and subsequent dihydroxylation of the olefin. The resulting epimeric mixture of 21a, 21b was separated and the absolute configuration at the C22 carbon for the main product 21a was elucidated by single crystal X-ray diffraction analysis of the benzoylated derivative 22. Finally, lactonization of 21a through a Baeyer-Villiger oxidation of triacetylated derivative 23, using CF₃CO₃H/CHCl₃ as oxidant system, leads to lactones 24 and 25 in 35% and 14% yields, respectively. Deacetylation of these compounds leads to 2-deoxybrassinosteroids 18 and 19 in 86% and 81% yields. Full structural characterization of all synthesized compounds was achieved using their 1D, 2D NMR, and HRMS data.


Role of oxygen radicals in DNA damage and cancer incidence.
The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC --> TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.


Light-dependent and circadian clock-regulated activation of sterol regulatory element-binding protein, X-box-binding protein 1, and heat shock factor pathways.
The circadian clock is phase-delayed or -advanced by light when given at early or late subjective night, respectively. Despite the importance of the time-of-day-dependent phase responses to light, the underlying molecular mechanism is poorly understood. Here, we performed a comprehensive analysis of light-inducible genes in the chicken pineal gland, which consists of light-sensitive clock cells representing a prototype of the clock system. Light stimulated expression of 62 genes and 40 ESTs by >2.5-fold, among which genes responsive to the heat shock and endoplasmic reticulum stress as well as their regulatory transcription factors heat shock factor (HSF)1, HSF2, and X-box-binding protein 1 (XBP1) were strongly activated when a light pulse was given at late subjective night. In contrast, the light pulse at early subjective night caused prominent induction of E4bp4, a key regulator in the phase-delaying mechanism of the pineal clock, along with activation of a large group of cholesterol biosynthetic genes that are targets of sterol regulatory element-binding protein (SREBP) transcription factor. We found that the light pulse stimulated proteolytic formation of active SREBP-1 that, in turn, transactivated E4bp4 expression, linking SREBP with the light-input pathway of the pineal clock. As an output of light activation of cholesterol biosynthetic genes, we found light-stimulated pineal production of a neurosteroid, 7α-hydroxypregnenolone, demonstrating a unique endocrine function of the pineal gland. Intracerebroventricular injection of 7α-hydroxypregnenolone activated locomotor activities of chicks. Our study on the genome-wide gene expression analysis revealed time-of-day-dependent light activation of signaling pathways and provided molecular connection between gene expression and behavior through neurosteroid release from the pineal gland.


Cranial and ventricular size following shunting or endoscopic third ventriculostomy (ETV) in infants with aqueductal stenosis: further insights from the International Infant Hydrocephalus Study (IIHS).
The craniometrics of head circumference (HC) and ventricular size are part of the clinical assessment of infants with hydrocephalus and are often utilized in conjunction with other clinical and radiological parameters to determine the success of treatment. We aimed to assess the effect of endoscopic third ventriculostomy (ETV) and shunting on craniometric measurements during the follow-up of a cohort of infants with symptomatic triventricular hydrocephalus secondary to aqueductal stenosis. We performed a post hoc analysis of data from the International Infant Hydrocephalus Study (IIHS)-a prospective, multicenter study of infants (< 24 months old) with hydrocephalus from aqueductal stenosis who were treated with either an ETV or shunt. During various stages of a 5-year follow-up period, the following craniometrics were measured: HC, HC centile, HC z-score, and frontal-occipital horn ratio (FOR). Data were compared in an analysis of covariance, adjusting for baseline variables including age at surgery and sex. Of 158 enrolled patients, 115 underwent an ETV, while 43 received a shunt. Both procedures led to improvements in the mean HC centile position and z-score, a trend which continued until the 5-year assessment point. A similar trend was noted for FOR which was measured at 12 months and 3 years following initial treatment. Although the values were consistently higher for ETV compared with shunt, the differences in HC value, centile, and z-score were not significant. ETV was associated with a significantly higher FOR compared with shunting at 12 months (0.52 vs 0.44; p = 0.002) and 3 years (0.46 vs 0.38; p = 0.03) of follow-up. ETV and shunting led to improvements in HC centile, z-score, and FOR measurements during long-term follow-up of infants with hydrocephalus secondary to aqueductal stenosis. Head size did not significantly differ between the treatment groups during follow-up, however ventricle size was greater in those undergoing ETV when measured at 1 and 3 years following treatment.


CD31/PECAM-1 is a ligand for alpha v beta 3 integrin involved in adhesion of leukocytes to endothelium.
To protect the body efficiently from infectious organisms, leukocytes circulate as nonadherent cells in the blood and lymph, and migrate as adherent cells into tissues. Circulating leukocytes in the blood have first to adhere to and then to cross the endothelial lining. CD31/PECAM-1 is an adhesion molecule expressed by vascular endothelial cells, platelets, monocytes, neutrophils, and naive T lymphocytes. It is a transmembrane glycoprotein of the immunoglobulin gene superfamily (IgSF), with six Ig-like homology units mediating leukocyte-endothelial interactions. The adhesive interactions mediated by CD31 are complex and include homophilic (CD31-CD31) or heterophilic (CD31-X) contacts. Soluble, recombinant forms of CD31 allowed us to study the heterophilic interactions in leukocyte adhesion assays. We show that the adhesion molecule alpha v beta 3 integrin is a ligand for CD31. The leukocytes revealed adhesion mediated by the second Ig-like domain of CD31, and this binding was inhibited by alpha v beta 3 integrin-specific antibodies. Moreover alpha v beta 3 was precipitated by recombinant CD31 from cell lysates. These data establish a third IgSF-integrin pair of adhesion molecules, CD31-alpha v beta 3 in addition to VCAM-1, MadCAM-1/alpha 4 integrins, and ICAM/beta 2 integrins, which are major components mediating leukocyte-endothelial adhesion. Identification of a further versatile adhesion pair broadens our current understanding of leukocyte-endothelial interactions and may provide the basis for the treatment of inflammatory disorders and metastasis formation.


Recent Trends in Baccalaureate-Prepared Registered Nurses in U.S. Acute Care Hospital Units, 2004-2013: A Longitudinal Study.
To examine the trends in baccalaureate (bachelor of science in nursing)-prepared registered nurses (BSN RNs) in U.S. acute care hospital units and to project the growth in the number of BSN RNs by 2020. This is a longitudinal study using the Registered Nurse Education Indicators data (2004-2013) from the National Database of Nursing Quality Indicators. The level of BSN RNs in each unit was operationalized as the proportion of nurses holding a baccalaureate degree or higher among all the nurses in a unit. Our sample included 12,194 unit-years from 2,126 units of six cohorts in 377 U.S. acute care hospitals. A hierarchical linear regression model was used to examine the trends in BSN RNs and to project future growth in the number of BSN RNs when controlling for hospital and unit characteristics and considering repeated measures in units over time and clustering of units within hospitals. The proportion of BSN RNs in U.S. acute care hospital units increased from 44% in 2004 to 57% in 2013 (a 30% increase); when combining all cohorts, this rate increased from 44% in 2009 to 51% in 2013. On average, the proportion of BSN RNs in a unit increased by 1.3% annually before 2010 and by 1.9% each year from 2010 on. The percentage of units having at least 80% of their nurses with a baccalaureate degree or higher increased from 3% in 2009 to 7% in 2013. Based on the current trends, 64% of the nurses working in a hospital unit will have a baccalaureate degree by 2020, and 22% of the units will reach the 80% goal by 2020. There was a significant increase in the proportion of BSN RNs in U.S. acute care hospital units over the past decade, particularly after 2010. However, given the current trends, it is unlikely that the goal of 80% nurses with a baccalaureate degree will be achieved by 2020. The U.S. nursing workforce is under educational transformation in order to meet the increasing healthcare needs. To help accelerate this transformation, further advocacy, commitment, and investment are needed from all healthcare stakeholders (e.g., policymakers, executives and managers of healthcare facilities, nursing schools, etc.).


The Violence Prevention Potential of Reducing Alcohol Outlet Access in Baltimore, Maryland.
There are few cost-effectiveness analyses that model alcohol outlet zoning policies. This study determines the potential decreases in homicides, disability-adjusted life years (DALYs), and victim and criminal justice costs associated with four policy options that would reduce the alcohol outlet access in Baltimore. This cost-effectiveness analysis used associations between on-premise (incidence rate ratio [IRR] = 1.41), off-premise (IRR = 1.76), and combined on- and off-premise outlet density (IRR = 1.07) and homicide in Baltimore. We determined the potential change in the level of homicide that could occur with changes in the density of alcohol outlets, assuming that 50% of the association was causal. Reducing alcohol outlet density in Baltimore City by one quintile was associated with decreases of 51 homicides per year, $63.7 million, and 764 DALYs. Removing liquor stores in residential zones was associated with 22 fewer homicides, which would cost $27.5 million and lead to 391 DALYs. Removing bars/taverns operating as liquor stores was associated with a decrease of one homicide, $1.2 million, and 17 DALYs. Removing both the liquor stores in residential zones and the bars/taverns operating as liquor stores was associated with 23 fewer homicides, which translated to $28.7 million and 409 DALYs. For preventing homicides, the strategy of removing liquor stores in residential zones was preferred because it was associated with substantial reductions in homicides without closing unacceptably high numbers of outlets. It is possible that policies that close the bars/taverns operating as liquor stores would be associated with decreases in other types of violent crime.


The effect of anterior lumbar interbody fusion staging order on perioperative complications in circumferential lumbar fusions performed within the same hospital admission.
Anterior lumbar interbody fusion (ALIF) is a powerful technique that provides wide access to the disc space and allows for large lordotic grafts. When used with posterior spinal fusion (PSF), the procedures are often staged within the same hospital admission. There are limited data on the perioperative risk profile of ALIF-first versus PSF-first circumferential fusions performed within the same hospital admission. In an effort to understand whether these procedures are associated with different perioperative complication profiles, the authors performed a retrospective review of their institutional experience in adult patients who had undergone circumferential lumbar fusions. The electronic medicals records of patients who had undergone ALIF and PSF on separate days within the same hospital admission at a single academic center were retrospectively analyzed. Patients carrying a diagnosis of tumor, infection, or traumatic fracture were excluded. Demographics, surgical characteristics, and perioperative complications were collected and assessed. A total of 373 patients, 217 of them women (58.2%), met the inclusion criteria. The mean age of the study cohort was 60 years. Surgical indications were as follows: degenerative disease or spondylolisthesis, 171 (45.8%); adult deformity, 168 (45.0%); and pseudarthrosis, 34 (9.1%). The majority of patients underwent ALIF first (321 [86.1%]) with a mean time of 2.5 days between stages. The mean number of levels fused was 2.1 for ALIF and 6.8 for PSF. In a comparison of ALIF-first to PSF-first cases, there were no major differences in demographics or surgical characteristics. Rates of intraoperative complications including venous injury were not significantly different between the two groups. The rates of postoperative ileus (11.8% vs 5.8%, p = 0.194) and ALIF-related wound complications (9.0% vs 3.8%, p = 0.283) were slightly higher in the ALIF-first group, although the differences did not reach statistical significance. Rates of other perioperative complications were no different. In patients undergoing staged circumferential fusion with ALIF and PSF, there was no statistically significant difference in the rate of perioperative complications when comparing ALIF-first to PSF-first surgeries.


Chenodeoxycholic acid attenuates high-fat diet-induced obesity and hyperglycemia via the G protein-coupled bile acid receptor 1 and proliferator-activated receptor γ pathway.
G protein-coupled bile acid receptor 1 (TGR5) serves a key function in regulating glycometabolism. TGR5 is highly expressed in the mitochondria of brown adipose tissue (BAT) and downregulates adenosine triphosphate synthesis via the bile acid-TGR5-cyclic adenosine monophosphate-2-iodothyronine deiodinase (D2)-triiodothyronine-uncoupling protein pathway, thus regulating energy homeostasis and reducing body weight. Chenodeoxycholic acid (CDCA), the primary bile acid, is a natural ligand of TGR5. The present study aimed to characterize the ability of CDCA to reduce high-fat diet-induced obesity and improve glucose tolerance. A mouse model of diet-induced obesity was constructed. The results demonstrated that a high-fat diet significantly increased the weight of mice after 10 weeks (P<0.05), but following the addition of CDCA and continued feeding for another 10 weeks, a decrease in weight was detected and no significant difference in final weight was observed between the high fat diet group treated with CDCA and the group fed a normal diet. Furthermore, CDCA treatment significantly increased glucose tolerance (P<0.001, P<0.01 and P<0.01 at 15, 40 and 60 min after glucose injection, respectively) and significantly decreased serum insulin levels compared with mice fed a high-fat diet alone. Staining of the liver with hematoxylin and eosin and oil red O revealed that the CDCA-treated group exhibited significantly lower fat accumulation in BAT and WAT compared with mice fed a high-fat diet alone (P<0.001). Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the expression of D2 activation system-related factors was significantly increased in BAT from mice treated with CDCA (P<0.001), confirming the role of TGR5 in modulating high-fat diet-induced obesity. In addition, CDCA inhibited adipocyte differentiation in 3T3-L1 cells and inhibited ligand-stimulated peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity. These results suggest that CDCA may prevent high-fat diet-induced obesity and hyperglycemia, and that these beneficial effects are mediated via the activation of TGR5 and inhibition of PPARγ transcriptional activity.


Construct and predictive validity of the chronic pain grade in workers with chronic work-related upper-extremity disorders.
To evaluate the ability of Chronic Pain Grade (CPG) questionnaire to predict upper-extremity physical disability, at-work disability, and work status in workers with chronic work-related upper-limb injuries. A total of 448 individuals with chronic work-related injuries were assessed at baseline and 6 months later. At each evaluation, 4 self-reported questionnaires were completed (CPG, QuickDASH, Work Limitations Questionnaire, and Work Instability Scale), and current work status was evaluated. Predictive validity of CPG was evaluated using proportion tests. At baseline, 5% of participants had a CPG at Grade I, 7% at Grade II, 18% at Grade III, and 70% at Grade IV (high disability-severely limiting). Twenty-six percent of workers transitioned in terms of their work status (7% from not working to working, 19% working to not working). Higher Grades on CPG at baseline could not predict improvement or deterioration 6 months after for upper-extremity disability (QuickDASH), at-work productivity loss (Work Limitations Questionnaire), or work instability (Work Instability Scale). Initial CPG could predict 6-month work status in the full sample. However, when considering only participants not working at baseline, CPG did not predict return to work. CPG has low to moderate ability to predict 6-month work status in patients with chronic upper-extremity disorders. Both a lack of CPG and work transition variability may have contributed to this finding. Extension of the upper end of CPG range might be investigated as a means to increase discrimination at the upper end spectrum of chronic pain, which predominate the population of patients with chronic musculoskeletal disorders.


Trm9-Catalyzed tRNA Modifications Regulate Global Protein Expression by Codon-Biased Translation.
Post-transcriptional modifications of transfer RNAs (tRNAs) have long been recognized to play crucial roles in regulating the rate and fidelity of translation. However, the extent to which they determine global protein production remains poorly understood. Here we use quantitative proteomics to show a direct link between wobble uridine 5-methoxycarbonylmethyl (mcm5) and 5-methoxy-carbonyl-methyl-2-thio (mcm5s2) modifications catalyzed by tRNA methyltransferase 9 (Trm9) in tRNAArg(UCU) and tRNAGlu(UUC) and selective translation of proteins from genes enriched with their cognate codons. Controlling for bias in protein expression and alternations in mRNA expression, we find that loss of Trm9 selectively impairs expression of proteins from genes enriched with AGA and GAA codons under both normal and stress conditions. Moreover, we show that AGA and GAA codons occur with high frequency in clusters along the transcripts, which may play a role in modulating translation. Consistent with these results, proteins subject to enhanced ribosome pausing in yeast lacking mcm5U and mcm5s2U are more likely to be down-regulated and contain a larger number of AGA/GAA clusters. Together, these results suggest that Trm9-catalyzed tRNA modifications play a significant role in regulating protein expression within the cell.


Global ecological patterns in uncultured Archaea.
We have applied a global analytical approach to uncultured Archaea that for the first time reveals well-defined community patterns along broad environmental gradients and habitat types. Phylogenetic patterns and the environmental factors governing the creation and maintenance of these patterns were analyzed for c. 2000 archaeal 16S rRNA gene sequences from 67 globally distributed studies. The sequences were dereplicated at 97% identity, grouped into seven habitat types, and analyzed with both Unifrac (to explore shared phylogenetic history) and multivariate regression tree (that considers the relative abundance of the lineages or taxa) approaches. Both phylogenetic and taxon-based approaches showed salinity and not temperature as one of the principal driving forces at the global scale. Hydrothermal vents and planktonic freshwater habitats emerged as the largest reservoirs of archaeal diversity and consequently are promising environments for the discovery of new archaeal lineages. Conversely, soils were more phylogenetically clustered and archaeal diversity was the result of a high number of closely related phylotypes rather than different lineages. Applying the ecological concept of 'indicator species', we detected up to 13 indicator archaeal lineages for the seven habitats prospected. Some of these lineages (that is, hypersaline MSBL1, marine sediment FCG1 and freshwater plSA1), for which ecological importance has remained unseen to date, deserve further attention as they represent potential key archaeal groups in terms of distribution and ecological processes. Hydrothermal vents held the highest number of indicator lineages, suggesting it would be the earliest habitat colonized by Archaea. Overall, our approach provided ecological support for the often arbitrary nomenclature within uncultured Archaea, as well as phylogeographical clues on key ecological and evolutionary aspects of archaeal biology.


Vertebrate sex-determining genes play musical chairs.
Sexual reproduction is one of the most highly conserved processes in evolution. However, the genetic and cellular mechanisms making the decision of whether the undifferentiated gonad of animal embryos develops either towards male or female are manifold and quite diverse. In vertebrates, sex-determining mechanisms range from environmental to simple or complex genetic mechanisms and different mechanisms have evolved repeatedly and independently. In species with simple genetic sex-determination, master sex-determining genes lying on sex chromosomes drive the gonadal differentiation process by switching on a developmental program, which ultimately leads to testicular or ovarian differentiation. So far, very few sex-determining genes have been identified in vertebrates and apart from mammals and birds, these genes are apparently not conserved over a larger number of related orders, families, genera, or even species. To fill this knowledge gap and to better explore genetic sex-determination, we propose a strategy (RAD-Sex) that makes use of next-generation sequencing technology to identify genetic markers that define sex-specific segments of the male or female genome.


The ecological importance of crocodylians: towards evidence-based justification for their conservation.
Large-bodied predators are well represented among the world's threatened and endangered species. A significant body of literature shows that in terrestrial and marine ecosystems large predators can play important roles in ecosystem structure and functioning. By contrast, the ecological roles and importance of large predators within freshwater ecosystems are poorly understood, constraining the design and implementation of optimal conservation strategies for freshwater ecosystems. Conservationists and environmentalists frequently promulgate ecological roles that crocodylians are assumed to fulfil, but often with limited evidence supporting those claims. Here, we review the available information on the ecological importance of crocodylians, a widely distributed group of predominantly freshwater-dwelling, large-bodied predators. We synthesise information regarding the role of crocodylians under five criteria within the context of modern ecological concepts: as indicators of ecological health, as ecosystem engineers, apex predators, keystone species, and as contributors to nutrient and energy translocation across ecosystems. Some crocodylians play a role as indicators of ecosystem health, but this is largely untested across the order Crocodylia. By contrast, the role of crocodylian activities in ecosystem engineering is largely anecdotal, and information supporting their assumed role as apex predators is currently limited to only a few species. Whether crocodylians contribute significantly to nutrient and energy translocation through cross-ecosystem movements is unknown. We conclude that most claims regarding the importance of crocodylians as apex predators, keystone species, ecosystem engineers, and as contributors to nutrient and energy translocation across ecosystems are mostly unsubstantiated speculation, drawn from anecdotal observations made during research carried out primarily for other purposes. There is a paucity of biological research targeted directly at: understanding population dynamics; trophic interactions within their ecological communities; and quantifying the short- and long-term ecological impacts of crocodylian population declines, extirpations, and recoveries. Conservation practices ideally need evidence-based planning, decision making and justification. Addressing the knowledge gaps identified here will be important for achieving effective conservation of crocodylians.


Mokken scales for testing both pre- and postintervention: an analysis of the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) before and after counseling.
Mokken scaling is increasingly being applied to assessing the extent to which clinical scales possess clinically useful properties, especially invariant item ordering (IIO). These scales are often used to track progress in symptoms over time to evaluate the success of an intervention. Such interventions are designed to affect psychopathological trait levels overall but may in some cases act disproportionately on some symptoms over others. As a result, there is no guarantee that the item orderings of a clinical scale will be preserved between the point at which individuals begin treatment and the point at which they can be considered recovered. In these situations, many of the potential benefits of IIO are undermined because an IIO identified at either time point will not be informative about changes in symptoms over time. In this study, we aimed to assess the extent to which the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) retained the same item orderings in a sample of individuals when initially presenting for counseling treatment and when discharged. From the 34 items of the CORE-OM we found a subset of 10 items exhibiting monotonicity, invariant item ordering, and highly similar item orderings when measured at both time points.


The impact of a cancer diagnosis on the health behaviors of cancer survivors and their family and friends.
The aim of this study was to examine the effect of a cancer diagnosis on the health behaviors of cancer survivors and their family and friends, and to determine whether a cancer diagnosis could be a teachable moment for intervention. This was a cross-sectional study of the health behaviors of individuals taking part in a cancer fundraising event. The questionnaire was completed by 657 participants. Participants were 81.4% women, had a mean age of 46 years, and comprised of 17.2% cancer survivors. For cancer survivors, 31.3% reported an increase in physical activity, 50% of smokers quit, and 59 to 72% reported dietary improvements within 1 month of diagnosis. Significant differences in behavior change were found by age, but not by gender or education. For individuals without cancer, 24.3% reported improved physical activity and the majority reported some dietary changes. A greater proportion of family and friends who perceived they were at greater risk of developing cancer increased physical activity and sun-smart behavior but did not improve dietary habits. The results indicate that the cancer survivors made significantly more positive health behavior changes compared to the non-cancer group. For this sample, a personal diagnosis of cancer, or a diagnosis in a family member or friend, may have acted as a 'cue to action' to improve lifestyle health behaviors. This field of research is still at an early stage, and further studies are needed to confirm if this situation could be useful as a 'teachable moment' for intervention purposes.


Primary aldosteronism and aldosterone-associated hypertension.
The field of primary aldosteronism (PA) and aldosterone-related hypertension has undergone rapid evolution. From a relatively rare curiosity PA has become a common problem particularly in selected hypertensive populations. Patients with PA and aldosterone-related hypertension appear to be at higher cardiovascular and renal risk than comparable patients with essential hypertension probably due to the pleiotropic effects of aldosterone. Aldosterone is also linked to metabolic syndrome and diabetes. The aldosterone-to-renin ratio (ARR) has allowed the widespread screening for PA, but the exact cut-off values may vary in different population groups. All patients with hypertension and hypokalaemia, and young patients with hypertension, hypertension with an incidental adrenal mass, and severe or resistant hypertension should be screened. The use of the ARR to screen all hypertensives for PA is controversial as the test lacks specificity and many patients with false-positive tests will undergo complex and expensive testing to confirm the diagnosis. The fludrocortisone suppression test, the saline infusion test or 24-hour aldosterone excretion may be used to confirm PA in patients with a positive ARR. Adrenal venous sampling is the most reliable test to detect the presence of an aldosterone-producing adenoma, but spiral CT scan or adrenocortical scintigraphy may be useful in centres without facilities for adrenal venous sampling. Spironolactone is emerging as an important antihypertensive agent in patients with resistant hypertension and aldosterone-related hypertension. The ARR may be a useful guide to drug selection in hypertensives patients, but further research is needed to make more definitive recommendations.


Present and future global distributions of the marine Cyanobacteria Prochlorococcus and Synechococcus.
The Cyanobacteria Prochlorococcus and Synechococcus account for a substantial fraction of marine primary production. Here, we present quantitative niche models for these lineages that assess present and future global abundances and distributions. These niche models are the result of neural network, nonparametric, and parametric analyses, and they rely on >35,000 discrete observations from all major ocean regions. The models assess cell abundance based on temperature and photosynthetically active radiation, but the individual responses to these environmental variables differ for each lineage. The models estimate global biogeographic patterns and seasonal variability of cell abundance, with maxima in the warm oligotrophic gyres of the Indian and the western Pacific Oceans and minima at higher latitudes. The annual mean global abundances of Prochlorococcus and Synechococcus are 2.9 ± 0.1 × 10(27) and 7.0 ± 0.3 × 10(26) cells, respectively. Using projections of sea surface temperature as a result of increased concentration of greenhouse gases at the end of the 21st century, our niche models projected increases in cell numbers of 29% and 14% for Prochlorococcus and Synechococcus, respectively. The changes are geographically uneven but include an increase in area. Thus, our global niche models suggest that oceanic microbial communities will experience complex changes as a result of projected future climate conditions. Because of the high abundances and contributions to primary production of Prochlorococcus and Synechococcus, these changes may have large impacts on ocean ecosystems and biogeochemical cycles.


European Regional Differences in All-Cause Mortality and Length of Stay for Patients with Hip Fracture.
The objective of this study was to compare healthcare performance for the surgical treatment of hip fractures across and within Finland, Hungary, Italy, the Netherlands, Norway, Scotland, and Sweden. Differences in age-adjusted and sex-adjusted 30-day and one-year all-cause mortality rates following hip fracture, as well as the length of stay of the first hospital episode in acute care and during a follow up of 365 days, were investigated, and associations between selected country-level and regional-level factors with mortality and length of stay were assessed. Hungary showed the highest one-year mortality rate (mean 39.7%) and the lowest length of stay in one year (12.7 days), whereas Italy had the lowest one-year mortality rate (mean 19.1 %) and the highest length of stay (23.3 days). The observed variations were largely explained by country-specific effects rather than by regional-level factors. The results show that there should still be room for efficiency gains in the acute treatment of hip fracture, and clinicians, healthcare managers, and politicians should learn from best practices. This study demonstrates that an international comparison of acute hospital care is possible using pooled individual-level administrative data.


Design of a single-polarization single-mode photonic crystal fiber with a near-Gaussian mode field and wide bandwidth.
Single-polarization single-mode (SPSM) fiber can efficiently eliminate polarization mode coupling, polarization mode dispersion, and polarization-dependent loss. Up to now, most single-polarization fibers have been designed based on form birefringence, which would result in a non-Gaussian field distribution and a small effective mode field area. In this paper, a novel structure of SPSM photonic crystal fibers based on the resonant coupling phenomena is proposed and analyzed by using a full-vector finite-element method with a second-order transparent boundary condition. From the numerical results it is confirmed that this fiber has a near-Gaussian mode field within the wavelength range from 1.46 to 2.2 μm, where only one polarized mode exists effectively, and the mode field area is about 79 μm(2) at the wavelength of 1.55 μm, matching that of the conventional single-mode fiber.


Technology assessment and the sociopolitics of health technologies.
In a growing number of countries, health technology assessment (HTA) has come to be seen as a vital component in policy making. Even though the assessment of the social, political, and ethical aspects of health technology is listed as one of its main objectives, in practice, the integration of such dimensions into HTA remains limited. Recent social scientific research on the inherently political nature of technology strongly supports such a comprehensive approach. The growing claims by and on behalf of consumer groups also suggest that HTA should be informed by a broader set of perspectives. Using the example of the cochlear implant in children, this essay compares the professed objectives of HTA with typical practice and explores possible explanations for the discrepancies observed. A second example, home telemonitoring for elderly persons, demonstrates how the types of evidence considered by HTA and the process through which assessments are produced may be reconsidered. We argue for the formal integration of the sociopolitical dimensions of health care technologies into assessments. The ability of HTA to more fully address important issues from a public policy point of view will increase by making explicit the sociopolitical nature of health care technologies.


Wild-type p53 protein potentiates cytotoxicity of therapeutic agents in human colon cancer cells.
Wild-type p53 is induced by DNA damage. In different cell types, this induction is suggested either to facilitate DNA repair by inducing a cell cycle pause or to potentiate cell death via apoptosis. Wild-type p53 in different cell types has similarly been associated with either enhancement of or increased resistance to the cytotoxicity of many cancer therapeutic agents. We have constructed a colorectal cancer cell line bearing, in addition to endogenous mutant p53 alleles, an exogenous wild-type p53 allele that is under the regulatable control of the lac repressor. Induction of wild-type p53 by isopropyl-beta-thiogalactopyranoside in these cells induces a reversible growth arrest but does not induce cell death. However, we find that the induction of wild-type p53 powerfully potentiates the cytotoxicity of both irradiation and 5-fluorouracil, two agents that are used clinically in the treatment of colorectal cancer. We also find that induction of wild-type p53 potentiates the cytotoxicity of topotecan, a member of the camptothecin family of drugs that also has clinical activity against colon cancer. These findings suggest that the common loss of wild-type p53 in many colorectal cancers may play a role in the clinical resistance of these tumors to anticancer agents. Although some cancer cells may not be directly killed by p53 gene therapy, our findings suggest that genetic alteration of some cancers to induce wild-type p53 may increase their sensitivity to cytotoxic gene therapy.


Unstable rocker shoes promote recovery from marathon-induced muscle damage in novice runners.
We recently reported that wearing unstable rocker shoes (Masai Barefoot Technology: MBT) may enhance recovery from marathon race-induced fatigue. However, this earlier study only utilized a questionnaire. In this study, we evaluated MBT utilizing objective physiological measures of recovery from marathon-induced muscle damages. Twenty-five university student novice runners were divided into two groups. After running a full marathon, one group wore MBT shoes (MBT group), and the control group (CON) wore ordinary shoes daily for 1 week following the race. We measured maximal isometric joint torque, muscle hardness (real time tissue elastography of the strain ratio) in the lower limb muscles before, immediately after, and 1, 3, and 8 days following the marathon. We calculated the magnitude of recovery by observing the difference in each value between the first measurement and the latter measurements. Results showed that isometric torques in knee flexion recovered at the first day after the race in the MBT group while it did not recover even at the eighth day in the CON group. Muscle hardness in the gastrocnemius and vastus lateralis showed enhanced recovery in the MBT group in comparison with the CON group. Also for muscle hardness in the tibialis anterior and biceps femoris, the timing of recovery was delayed in the CON group. In conclusion, wearing MBT shoes enhanced recovery in lower leg and thigh muscles from muscle damage induced by marathon running.


Environmental Enrichment Induces Epigenomic and Genome Organization Changes Relevant for Cognition.
In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization.


Risk Factors Associated With Attempted Suicide Among US Army Soldiers Without a History of Mental Health Diagnosis.
The US Army suicide attempt rate increased sharply during the wars in Afghanistan and Iraq. Although soldiers with a prior mental health diagnosis (MH-Dx) are known to be at risk, little is known about risk among those with no history of diagnosis. To examine risk factors for suicide attempt among soldiers without a previous MH-Dx. In this retrospective longitudinal cohort study using administrative data from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), person-month records were identified for all active-duty Regular Army enlisted soldiers who had a medically documented suicide attempt from January 1, 2004, through December 31, 2009 (n = 9650), and an equal-probability sample of control person-months (n = 153 528). Data analysis in our study was from September 16, 2017, to June 6, 2018. In a stratified sample, it was examined whether risk factors for suicide attempt varied by history of MH-Dx. Suicide attempts were identified using Department of Defense Suicide Event Report records and International Classification of Diseases, Ninth Revision, Clinical Modification E95 × diagnostic codes. Mental health diagnoses and related codes, as well as sociodemographic, service-related, physical health care, injury, subjection to crime, crime perpetration, and family violence variables, were constructed from Army personnel, medical, legal, and family services records. Among 9650 enlisted soldiers with a documented suicide attempt (74.8% male), 3507 (36.3%) did not have a previous MH-Dx. Among soldiers with no previous diagnosis, the highest adjusted odds of suicide attempt were for the following: female sex (odds ratio [OR], 2.6; 95% CI, 2.4-2.8), less than high school education (OR, 1.9; 95% CI, 1.8-2.0), first year of service (OR, 6.0; 95% CI, 4.7-7.7), previously deployed (OR, 2.4; 95% CI, 2.1-2.8), promotion delayed 2 months or less (OR, 2.1; 95% CI, 1.7-2.6), past-year demotion (OR, 1.6; 95% CI, 1.3-1.8), 8 or more outpatient physical health care visits in the past 2 months (OR, 3.3; 95% CI, 2.9-3.8), past-month injury-related outpatient (OR, 3.0; 95% CI, 2.8-3.3) and inpatient (OR, 3.8; 95% CI, 2.3-6.3) health care visits, previous combat injury (OR, 1.6; 95% CI, 1.0-2.4), subjection to minor violent crime (OR, 1.6; 95% CI, 1.1-2.4), major violent crime perpetration (OR, 2.0; 95% CI, 1.3-3.0), and family violence (OR, 2.9; 95% CI, 1.9-4.4). Most of these variables were also associated with suicide attempts among soldiers with a previous MH-Dx, although the strength of associations differed. Suicide attempt risk among soldiers with unrecognized mental health problems is a significant and important challenge. Administrative records from personnel, medical, legal, and family services systems can assist in identifying soldiers at risk.


Nanoparticle-Mediated Targeting of Pitavastatin to Small Pulmonary Arteries and Leukocytes by Intravenous Administration Attenuates the Progression of Monocrotaline-Induced Established Pulmonary Arterial Hypertension in Rats.
Statins are known to improve pulmonary arterial hypertension (PAH) by their anti-inflammatory and anti-proliferative effects in animal models. However, recent clinical studies have reported that clinically approved statin doses failed to improve clinical outcomes in patients with PAH. We therefore hypothesized that nanoparticle (NP) -mediated targeting of pitavastatin could attenuate the progression of established PAH.We induced PAH by subcutaneously injecting monocrotaline (MCT) in Sprague-Dawley rats. On day 14 after the MCT injection, animals that displayed established PAH on echocardiography were included. On day 17, they were randomly assigned to the following 5 groups: daily intravenous administration of (1) vehicle, (2) fluorescein-isothiocyanate-NP, (3) pitavastatin, (4) pitavastatin-NP, or (5) oral sildenafil. Intravenous NP was selectively delivered to small pulmonary arteries and circulating CD11b-positive leukocytes. On day 21, pitavastatin-NP attenuated the progression of PAH at lower doses than pitavastatin alone. This was associated with the inhibition of monocyte-mediated inflammation, proliferation, and remodeling of the pulmonary arteries. Interestingly, sildenafil attenuated the development of PAH, but had no effects on inflammation or remodeling of the pulmonary arteries. In separate experiments, only treatment with pitavastatin-NP reduced the mortality rate at day 35.NP-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes attenuated the progression of established MCT-induced PAH and improved survival. Therapeutically, pitavastatin-NP was associated with anti-inflammatory and anti-proliferative effects on small pulmonary arteries, which was completely distinct from the vasodilatory effect of sildenafil. Pitavastatin-NP can be a novel therapeutic modality for PAH.


Protease-activated receptor 2 exerts local protection and mediates some systemic complications in acute pancreatitis.
Protease-activated receptor 2 can be stimulated by interstitially released trypsin during acute inflammation of the pancreas. In this study, we investigated the roles of pancreatic and circulatory protease-activated receptor 2 in the pathogenesis of acute pancreatitis by using in vitro and in vivo model systems. Physiological and pathologic effects of protease-activated receptor 2 activation were measured in isolated pancreatic cells and in rats with experimental pancreatitis. Consequences of protease-activated receptor 2 activation on the systemic and inflammatory responses were measured after treatments with trypsin or protease-activated receptor 2-activating peptide. Stimulation of protease-activated receptor 2 in rat pancreatic acinar cells activated short-lasting (Ca(2+) signaling) and long-lasting (extracellular signal-related kinase) signaling pathways and protected the cells against bile-induced cell damage. More importantly, protease-activated receptor 2 activation ameliorated the pathologic effects observed in the in vivo model of cerulein-induced pancreatitis. Trypsin in the circulation of rats with taurocholate-induced severe acute pancreatitis reached levels sufficient to activate endothelial and immune cells to stimulate nitric oxide and interleukin-8 production, respectively. Most notably, activation of systemic protease-activated receptor 2 by circulating protease-activated receptor 2 agonists induced a hemodynamic response pattern similar to that observed in rats with severe acute pancreatitis. The effects of protease-activated receptor 2 agonists and acute pancreatitis were not additive. These findings suggest that protease-activated receptor 2 may have a dual role in acute pancreatitis: protecting acinar and duct cells against pancreatitis-induced cell damage while mediating or aggravating the systemic complications of acute pancreatitis, which are the major cause of mortality in the early phase of necrotizing pancreatitis.


Prunus armeniaca L (apricot) protects rat testes from detrimental effects of low-dose x-rays.
Exposure to low x-ray doses damages the spermatozoa, mainly by late-onset (ie, after 3 months) oxidative stress. Antioxidants ameliorate oxidation and prevent tissue damage. Prunus armeniaca L (apricot), rich in carotenoids and vitamins, is a potent natural antioxidant. We hypothesized that an apricot-rich diet might ameliorate the detrimental effects of low-dose x-rays on testis tissue. A 20% apricot diet was composed isoenergetically to the regular rodent diet. The total phenolic content, reducing power, and antioxidant capacity of both diets were determined. Sprague-Dawley rats received apricot-rich diets before and after x-ray exposure. Regular diets were given to controls. Rats were exposed to 0.2 Gy x-rays at the eighth week and were euthanized at the 20th postexposure week. Testicular oxidative status was determined by tissue thiobarbituric acid-reactive substances, reduced glutathione, superoxide dismutase, and catalase activities. For histologic evaluation, qualitative and quantitative microscopic determinations were performed, and Leydig and Sertoli cell counts and Johnsen scores were measured. The control diet group had significant testicular oxidative stress and mild tissue deterioration. Leydig and Sertoli cell counts, tubule diameters, and Johnsen scores were significantly decreased in the exposure groups. Apricot-rich diet significantly ameliorated the oxidative status and prevented the damage in tubular histology. The protective effects were prominent when the diet was maintained throughout the time course and were partially protected when the diet was initiated after exposure. The natural antioxidant activity of apricot ameliorates the delayed detrimental effects of low-dose irradiation on testis tissue. The high total antioxidant capacity of the apricot deserves further investigation.


Differences in the structural features of atypical adenomatous hyperplasia and low-grade prostatic adenocarcinoma.
Atypical adenomatous hyperplasia (AAH) is a small glandular proliferation that has histological similarities with Gleason grade 1 and 2 prostatic adenocarcinoma (PACG1,2). There are no distinct histomorphological criteria distinguishing these two lesions from each other and other small glandular proliferations. Because treatment approaches are different for these lesions, it is necessary to determine histological criteria. The aim of this study is to review the histological features of these two lesions and to define new histological criteria distinguishing AAH from PACG1,2. We, therefore, assessed 18 anatomical and structural parameters. We found 11 AAH (22 foci) and 15 PACG1,2 (22 foci) cases in 105 radical prostatectomy specimens. Basal cell-specific antikeratin was applied to these lesions. We assumed that PACG1,2 lesions did have not basal cells and we grouped the lesions as AAH and PACG1,2 based on this assumption. We found differences between AAH and PACG1,2 lesions for some parameters including the number of glands, structures such as the main ductus and basal cells. We found similar properties in the two lesions for the following parameters: localization, multiplicity, diameter of the lesion, focus asymmetry, distance between glands, inflammatory cells in and out of the lesions, secretory cell shape on the luminal side, papillary projection towards the luminal side of gland, the shape of the outer gland, the infiltrative pattern of the gland, glandular pleomorphism, biggest gland diameter and median gland diameter. We determined that concurrent evaluation of histomorphological features was important to differentiate between AAH and PACG1,2.


Seasonal variation of Ralstonia solanacearum biovar 2 populations in a Spanish river: recovery of stressed cells at low temperatures.
The presence of Ralstonia solanacearum biovar 2 in the watercourses of European countries is increasing, but little is known about its ecology in aquatic habitats. The detection of this pathogen in 2000 in one Spanish river led us to study its population density at different locations on the river over a period of 3 years. During 2000 and 2001, the pathogen was recovered at low densities (10 to 80 CFU/ml) by direct plating on modified SMSA agar from water samples at 14 degrees C or higher, but its isolation was usually unsuccessful at temperatures below 9 degrees C. To monitor the pathogen's abundance in winter, we used two liquid selective media for enrichment (at 29 and 35 degrees C) and compared them by using spiked river water samples: modified Wilbrink broth (MWB) was more efficient than modified SMSA broth for double-antibody-sandwich indirect enzyme-linked immunosorbent assay (DASI-ELISA) detection of R. solanacearum. Enrichment in MWB at both temperatures allowed us to recover R. solanacearum cells that were nonculturable on solid media up to 25 days after their entry into the viable but nonculturable state. When we applied this technique to water samples during the cold months of 2001 and 2002, we obtained the best detection results by the most-probable-number method after enrichment at 35 degrees C with MWB. The enrichment protocol was combined with DASI-ELISA and validated by Co-PCR to detect both naturally and artificially starved and cold-stressed cells in water, which were still infective. Overall, the data from this study demonstrate the effects of temperature variation on the population and culturability of R. solanacearum cells on solid media and their survival at low temperatures.


Infant cerebral ventricle volume: a comparison of 3-D ultrasound and magnetic resonance imaging.
Enlargement of the cerebral lateral ventricles is observed in several neuropsychiatric disorders with origins in early brain development. Lateral ventricle size is also predictive of poor neurodevelopmental outcome in premature infants. Three-dimensional (3-D) ultrasound (US) offers an improved methodology for the study of lateral ventricle volume in neonates and infants. To assess the validity of ventricle volume measures obtained with 3-D US, we compared the volumes obtained by 3-D US with magnetic resonance imaging (MRI) in seven infants. Ventricle volumes were determined using a computer-assisted image analysis program, IRIS. There was excellent correlation between ventricle volumes obtained with 3-D US and those obtained with MRI (intraclass correlation coefficient 0.92, F = 23.28, p = 0.00027), indicating that 3-D US provides valid measures of overall lateral ventricle volume compared to the "gold standard" of MRI. 3-D US can provide an economical and practical means of studying lateral ventricle volume in neonates, a neurostructural marker of abnormal brain development.


A Trypanosoma cruzi alkaline antigen induces polyclonal B-cell activation of normal murine spleen cells by T-cell-independent, BCR-directed stimulation.
We have previously reported that a cytosolic alkaline fraction (FI) obtained from epimastigotes of Trypanosoma cruzi promotes the activation, proliferation and differentiation of normal murine B cells into antibody-secreting plasmocytes. Neither the mechanism nor the cells involved in the FI-induced polyclonal B-cell activation were established. In this work we report that accessory cells are required for FI-induced polyclonal B-cell activation as no proliferative responses were obtained following treatment of normal spleen mononuclear cells (NSMC) with L-leucine methyl ester. Furthermore, FI did not induce the expression of CD25 on T cells and it promoted the proliferation of a T-cell-depleted population, indicating that it acts in a T-independent manner. We observed that NSMC were stimulated in vitro by FI-released cytokines, such as interleukin (IL)-4, IL-6 and IL-10, which are involved in B-cell proliferation and differentiation. Interestingly, while significant amounts of interferon-gamma (IFN-gamma) were found in culture supernatants we did not observe detectable levels of IL-2. Additionally, we found that B-cell receptor (BCR) and major histocompatibility complex (MHC) class II antigens were involved in the proliferative response induced by FI because antibodies directed against cell-surface immunoglobulin M (IgM), CD45 and MHC class II molecules inhibited the FI-induced B-cell proliferation. CD40 ligand (CD40L) did not participate in such a phenomenon.


An international perspective on the basis for payment for performance.
This discussion paper reflects on the pay-for-performance system in UK general practice - the Quality and Outcomes Framework (QOF) - from an international viewpoint. The QOF intends to bring the best scientific evidence to bear on primary care practice. However, the QOF and patient-centred medicine are often at odds. Inadequacies and commercial bias in the creation of evidence make the scientific basis of the QOF questionable. The framework for the QOF does not align well with the scope of primary care, making its basis as a tool for quality measurement questionable. The extent of impact of the QOF on health outcomes and on equity of health outcomes needs examination. Attention to resolution of patients' problems is an important aim of quality improvement activities. Alternative modes of improving patient care may be better than the QOF.


Developing a risk model for in-hospital adverse events following implantable cardioverter-defibrillator implantation: a report from the NCDR (National Cardiovascular Data Registry).
To better inform patients and physicians of the expected risk of adverse events and to assist hospitals' efforts to improve the outcomes of patients undergoing implantable cardioverter-defibrillator (ICD) implantation, we developed and validated a risk model using data from the NCDR (National Cardiovascular Data Registry) ICD Registry. ICD prolong life in selected patients, but ICD implantation carries the risk of periprocedural complications. We analyzed data from 240,632 ICD implantation procedures between April 1, 2010, and December 31, 2011 in the registry. The study group was divided into a derivation (70%) and a validation (30%) cohort. Multivariable logistic regression was used to identify factors associated with in-hospital adverse events (complications or mortality). A parsimonious risk score was developed on the basis of beta estimates derived from the logistic model. Hierarchical models were then used to calculate risk-standardized complication rates to account for differences in case mix and procedural volume. Overall, 4,388 patients (1.8%) experienced at least 1 in-hospital complication or death. Thirteen factors were independently associated with an increased risk of adverse outcomes. Model performance was similar in the derivation and validation cohorts (C-statistics = 0.724 and 0.719, respectively). The risk score characterized patients into low- and-high risk subgroups for adverse events (≤10 points, 0.3%; ≥30 points, 4.2%). The risk-standardized complication rates varied significantly across hospitals (median: 1.77, interquartile range 1.54, 2.14, 5th/95th percentiles: 1.16/3.15). We developed a simple model that predicts risk for in-hospital adverse events among patients undergoing ICD placement. This can be used for shared decision making and to benchmark hospital performance.


Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients.
Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. However, its clinical significance remains to be established. In this study, the main aims were to discover whether reclassification of breast cancer into molecular subtypes provides more precise information regarding outcome compared to conventional histopathological grading and to study breast cancer-specific survival in the different molecular subtypes. Cases of breast cancer occurring in a cohort of women born between 1886 and 1928 with long-term follow-up were included in the study. Tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded tissue from 909 cases. Using immunohistochemistry and in situ hybridisation as surrogates for gene expression analyses, all cases were reclassified into the following molecular subtypes: Luminal A; Luminal B (HER2-); Luminal B (HER2+); HER2 subtype; Basal phenotype; and five negative phenotype. Kaplan-Meier survival curves and Cox proportional hazards models were used in the analyses. During the first 5 years after diagnosis, there were significant differences in prognosis according to molecular subtypes with the best survival for the Luminal A subtype and the worst for HER2 and five negative phenotype. In this historic cohort of women with breast cancer, differences in breast cancer-specific survival according to subtype occur almost exclusively amongst the histopathological grade 2 tumours. From 5 years after time of diagnosis until the end of follow-up, there appears to be no difference in survival according to molecular subtype or histopathological grade.


Critical computational aspects of near infrared circular tomographic imaging: Analysis of measurement number, mesh resolution and reconstruction basis.
The image resolution and contrast in Near-Infrared (NIR) tomographic image reconstruction are affected by parameters such as the number of boundary measurements, the mesh resolution in the forward calculation and the reconstruction basis. Increasing the number of measurements tends to make the sensitivity of the domain more uniform reducing the hypersensitivity at the boundary. Using singular-value decomposition (SVD) and reconstructed images, it is shown that the numbers of 16 or 24 fibers are sufficient for imaging the 2D circular domain for the case of 1% noise in the data. The number of useful singular values increases as the logarithm of the number of measurements. For this 2D reconstruction problem, given a computational limit of 10 sec per iteration, leads to choice of forward mesh with 1785 nodes and reconstruction basis of 30x30 elements. In a three-dimensional (3D) NIR imaging problem, using a single plane of data can provide useful images if the anomaly to be reconstructed is within the measurement plane. However, if the location of the anomaly is not known, 3D data collection strategies are very important. Further the quantitative accuracy of the reconstructed anomaly increased approximately from 15% to 89% as the anomaly is moved from the centre to boundary, respectively. The data supports the exclusion of out of plane measurements may be valid for 3D NIR imaging.


Current Practices in Global/International Advanced Pharmacy Practice Experiences: Home/Host Country or Site/Institution Considerations.
International outreach by schools and colleges of pharmacy is increasing. In this paper, we provide current practice guidelines to establish and maintain successful global/international advanced pharmacy practice experiences (G/I APPEs) with specific recommendations for home/host country and host site/institution. The paper is based on a literature review (2000-2014) in databases and Internet searches with specific keywords or terms. Educational documents such as syllabi and memoranda of understanding (MoUs) from pharmacy programs were also examined. In addition, a preliminary draft was developed and the findings and recommendations were reviewed in a 90-minute roundtable discussion at the 2014 American Association of Colleges of Pharmacy Annual Meeting. Recommendations for the host country include travel considerations (eg, passport, visa, air travel), safety, housing, transportation, travel alerts and warnings, health issues, and financial considerations. For the home country, considerations for establishment of G/I APPE site (eg, vetting process, MoU, site expectations) are described. The paper is a resource for development of new G/I APPEs and provides guidance for continuous quality improvement of partnerships focusing on G/I pharmacy education.