Effectiveness and cost of different strategies for information feedback in general practice.
The aim of this study was to determine the effectiveness and relative cost of three forms of information feedback to general practices--graphical, graphical plus a visit by a medical facilitator and tabular. Routinely collected, centrally-held data were used where possible, analysed at practice level. Some non-routine practice data in the form of risk factor recording in medical notes, for example weight, smoking status, alcohol consumption and blood pressure, were also provided to those who requested it. The 52 participating practices were stratified and randomly allocated to one of the three feedback groups. The cost of providing each type of feedback was determined. The immediate response of practitioners to the form of feedback (acceptability), ease of understanding (intelligibility), and usefulness of regular feedback was recorded. Changes introduced as a result of feedback were assessed by questionnaire shortly after feedback, and 12 months later. Changes at the practice level in selected indicators were also assessed 12 and 24 months after initial feedback. The resulting cost per effect was calculated to be 46.10 pounds for both graphical and tabular feedback, 132.50 pounds for graphical feedback plus facilitator visit and 773.00 pounds for the manual audit of risk factors recorded in the practice notes. The three forms of feedback did not differ in intelligibility or usefulness, but feedback plus a medical facilitator visit was significantly less acceptable. There was a high level of self-reported organizational change following feedback, with 69% of practices reporting changes as a direct result; this was not significantly different for the three types of feedback. There were no significant changes in the selected indicators at 12 or 24 months following feedback. The practice characteristic most closely related to better indicators of preventive practice was practice size, smaller practices performing significantly better. Separate clinics were not associated with better preventive practice. It is concluded that feedback strategies using graphical and tabular comparative data are equally cost-effective in general practice with about two thirds of practices reporting organizational change as a consequence; feedback involving unsolicited medical facilitator visits is less cost-effective. The cost-effectiveness of manual risk factor audit is also called into question.


Vector-borne agents detected in fleas of the northern white-breasted hedgehog.
This is the first large-scale molecular investigation of fleas from a geographically widespread and highly urbanized species, the northern white-breasted hedgehog. In this study, 759 fleas (the majority were Archaeopsylla erinacei) collected from 134 hedgehogs were molecularly analyzed individually or in pools for the presence of three groups of vector-borne pathogens. All flea samples were positive for rickettsiae: In two samples (1.5%) Rickettsia helvetica and in 10% of the others a novel rickettsia genotype were identified. Additionally, Bartonella henselae (the causative agent of cat scratch disease in humans) was demonstrated in one flea (0.7%), and hemoplasmas of the hemofelis group were identified in seven other samples (5.2%). The findings of vector-borne agents not detected before in A. erinacei fleas broaden the range of those diseases of veterinary-medical importance, of which hedgehogs may play a role in the epidemiology.


Thymic origin of the prolactin-dependent Nb2 lymphoma cell line.
Blast cells in acute leukemia and lymphoma appear to be "frozen" at various stages of lymphoid cell differentiation. The enzymatic and antigenic phenotypes expressed by these cells often correspond to the gene products of their normal precursors. We have used various immunocytochemical and enzymatic techniques to identify membrane, nuclear, and cytoplasmic markers associated with the prolactin-dependent Nb2 lymphoma cell line. The Nb2 cells, whether stationary or in log-phase growth, did not express any surface immunoglobulin. However, 100% of the Nb2 cells bound both a monoclonal antibody raised to rat thymocyte W3/25-HLK, which specifically binds an antigenic determinant on rat T-helper cells, and second monoclonal antibody OX8-HL, which identifies rat nonhelper T-cells. Transmission electron microscopy showed no evidence of phagocytic vacuoles, and activity of the lysosomal enzyme muramidase was also absent. There was no evidence of the DNA polymerase enzyme terminal deoxynucleotidyl transferase. alpha-Naphthyl acetate esterase activity was indicated in about 50% of the Nb2 cells by a faint particulate cytoplasmic staining similar to that found in thymocytes. Rosette formation with guinea pig erythrocytes, a property of mature rat thymocytes, was not observed with Nb2 cells. The data suggest that the Nb2 tumor may have arisen from a thymocyte at an intermediate stage of differentiation. The presence of Thy-like alpha-naphthyl acetate esterase pattern and the binding of both W3/25-HLK and OX8-HL support the thymic origin and relative immaturity of these lymphoid cells. It is becoming increasingly apparent that a significant proportion of lymphomas and leukemias also originate in undifferentiated thymic cels.


Isoprene Oxidation by the Gram-Negative Model bacterium Variovorax sp. WS11.
Plant-produced isoprene (2-methyl-1,3-butadiene) represents a significant portion of global volatile organic compound production, equaled only by methane. A metabolic pathway for the degradation of isoprene was first described for the Gram-positive bacterium Rhodococcus sp. AD45, and an alternative model organism has yet to be characterised. Here, we report the characterisation of a novel Gram-negative isoprene-degrading bacterium, Variovorax sp. WS11. Isoprene metabolism in this bacterium involves a plasmid-encoded iso metabolic gene cluster which differs from that found in Rhodococcus sp. AD45 in terms of organisation and regulation. Expression of iso metabolic genes is significantly upregulated by both isoprene and epoxyisoprene. The enzyme responsible for the initial oxidation of isoprene, isoprene monooxygenase, oxidises a wide range of alkene substrates in a manner which is strongly influenced by the presence of alkyl side-chains and differs from other well-characterised soluble diiron monooxygenases according to its response to alkyne inhibitors. This study presents Variovorax sp. WS11 as both a comparative and contrasting model organism for the study of isoprene metabolism in bacteria, aiding our understanding of the conservation of this biochemical pathway across diverse ecological niches.


Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis.
Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC1, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1 leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC1 is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.


Multivariate synchrony modules identified through multiple subject community detection in functional brain networks.
The functional connectivity of the human brain may be described by modeling interactions among its neural assemblies as a graph composed of vertices and edges. It has recently been shown that functional brain networks belong to a class of scale-free complex networks for which graphs have helped define an association between function and topology. These networks have been shown to possess a heterogenous structure composed of clusters, dense regions of strongly associated nodes, which represent multivariate relationships among nodes. Network clustering algorithms classify the nodes based on a similarity measure representing the bivariate relationships and similar to unsupervised learning is performed without a priori information. In this paper, we propose a method for partitioning a set of networks representing different subjects and reveal a community structure common to multiple subjects. We apply this community identifying algorithm to functional brain networks during a cognitive control task, in particular the error-related negativity (ERN), to evaluate how the brain organizes itself during error-monitoring.


The infection of human skin by schistosome cercariae: studies using Franz cells.
Franz cells (2-chambered, air/fluid phase static diffusion devices, previously used for the study of drugs across viable human skin) are utilized for the first time to investigate the process of infection of human skin by Schistosoma mansoni cercariae. Skin obtained from cosmetic surgery sources was used in the Franz cells to describe the temporal dynamics of the early interaction of cercariae with skin. At 38 degrees C, about 50% of cercariae applied in water to the epidermal surface of the skin were irreversibly attached within 1 min and after 5 min about 85%, were similarly irrecoverable. The technique also provides the means of following the early penetration path of cercariae by histological methods. Franz cell results on the dynamics of attachment/early penetration have been compared with those obtained using artificial skin equivalents and non-human mammalian skin models in the context of the physical and chemical differences between these systems and viable human skin. It is concluded that Franz cells provide a convenient system for directly investigating the early phases of S. mansoni cercariae interaction with human skin.


Depression in late life: the use of clinical characteristics to focus screening efforts.
The objective of the study was to identify clinical characteristics associated with depressive symptoms in late life so that screening could focus on elderly patients most likely to benefit from further evaluation. We used cross-sectional screening for significant symptoms of depression using the Center for Epidemiologic Studies Depression scale and identification of patients' clinical characteristics from patient interviews and a computerized medical record. The setting was an academic primary care group practice at an urban ambulatory care center. Participants were 1,633 consecutively consenting patients aged 60 and older who visited the center between January and August 1991. Mean age was 70 years; 72% were women, 32% were White, 47% had less than 8 years of education, and 7% had no health insurance. There were 251 (15%) patients with significant symptoms of depression. Antidepressants were prescribed to 1 in 7 patients with such symptoms, with amitriptyline being the most commonly prescribed. Bivariate analyses indicated that patients with significant symptoms of depression were more likely to be White, female, without health insurance, and were more likely to have probable alcoholism, mild cognitive loss, and to receive narcotics, histamine H2 antagonists, and/or benzodiazepines. Depressive symptoms were not significantly correlated with age, education, income, or chronic medical conditions. Significant symptoms of depression were common and correlated with several readily available clinical variables. However, these variables lack sufficient discriminatory power to allow for the selective screening of elderly patients most likely to suffer from symptoms of depression. Thus, formal screening for depression among all elderly patients in primary care may be necessary to improve the recognition of this morbid illness.


Nomenclature of robotic procedures in urology.
To standardize nomenclature and acronyms applied to robotic procedures in urology. A review of the literature for robotic procedures in urology was performed. In addition, various acronyms were queried and frequency of use was noted. Additional literature reviewed included articles on standardization of scientific nomenclature used in other disciplines of health care. This topic was discussed within the newly formed working group of urologic robotic surgeons (WURS). There is wide variation in the terminology and use of acronyms for robotic prostate and kidney procedures. The application of robotic, robot, robotic laparoscopic, robot laparoscopic, robotic-assisted, robot-assisted, robotic assisted, robot assisted, robotic-assisted laparoscopic, robot-assisted laparoscopic, robotic assisted laparoscopic, robot assisted laparoscopic, and robotic computer-assisted to procedures such as pyeloplasty and radical prostatectomy is far from uniform or standardized. Queries and searches using acronyms such as RALP, RARP, RRP, and RP yielded publications discussing both prostate and renal procedures applying the same acronyms. There are established databases of abbreviations and acronyms, including ARGH, SaRad, Acromed, and the Stanford Biomedical Abbreviation Server. Standardization of the nomenclature applied to urologic robotic surgery is needed as the robotic literature continues to grow. The recommendation from the Scientific Committee of the Working Group of Urologic Robotic Surgeons is to apply "robot assisted" to the already established nomenclature currently used to describe equivalent open procedures. The use of standardized and uniform terminology for procedures performed with robots will facilitate literature search and research efforts in the future. The role of standardized nomenclature for billing purposes remains to be seen.


Photosynthetic light-harvesting is tuned by the heterogeneous polarizable environment of the protein.
In photosynthesis, special antenna proteins that contain multiple light-absorbing molecules (chromophores) are able to capture sunlight and transfer the excitation energy to reaction centers with almost 100% quantum efficiencies. The critical role of the protein scaffold in holding the appropriate arrangement of the chromophores is well established and can be intuitively understood given the need to keep optimal dipole-dipole interactions between the energy-transferring chromophores, as described by Förster theory more than 60 years ago. However, the question whether the protein structure can also play an active role by tuning such dipole-dipole interactions has not been answered so far, its effect being rather crudely described by simple screening factors related to the refractive index properties of the system. Here, we present a combined quantum chemical/molecular mechanical approach to compute electronic couplings that accounts for the heterogeneous dielectric nature of the protein-solvent environment in atomic detail. We apply the method to study the effect of dielectric heterogeneity in the energy migration properties of the PE545 principal light-harvesting antenna of the cryptomonad Rhodomonas CS24. We find that dielectric heterogeneity can profoundly tune by a factor up to ∼4 the energy migration rates between chromophore sites compared to the average continuum dielectric view that has historically been assumed. Our results indicate that engineering of the local dielectric environment can potentially be used to optimize artificial light-harvesting antenna systems.


Associations Between Types of Balance Performance in Healthy Individuals Across the Lifespan: A Systematic Review and Meta-Analysis.
Background: The objective of this systematic review and meta-analysis was to quantify and statistically compare correlations between types of balance performance in healthy individuals across the lifespan. Methods: Literature search was performed in the electronic databases PubMed, Web of Science, and SPORTDiscus. Studies were included if they investigated healthy individuals aged ≥6 years and reported measures of static/dynamic steady-state, proactive, and/or reactive balance. The included studies were coded as follows: age group, gender, and balance type, test, parameter. Pearson's correlation coefficients were extracted, transformed (i.e., Fisher's z-transformed r z -value), aggregated (i.e., weighted mean r z -value), back-transformed to r-values, classified according to their magnitude, and statistically compared. The methodological quality of each study was assessed using the Appraisal tool for Cross-Sectional Studies. Results: We detected twenty-six studies that examined associations between types of balance and exclusively found small-sized correlations, irrespective of the age group considered. More specifically, the weighted mean r z-values amounted to 0.61 (back-transformed r-value: 0.54) in old adults for the correlation of dynamic steady-state with proactive balance. For correlations between dynamic and static steady-state balance, the weighted mean r z-values amounted to 0.09 in children (r-value: 0.09) and to 0.32 in old adults (r-value: 0.31). Further, correlations of proactive with static steady-state balance revealed weighted mean r z-values of 0.24 (r-value: 0.24) in young adults and of 0.31 (r-value: 0.30) in old adults. Additionally, correlations between reactive and static steady-state balance yielded weighted mean r z-values of 0.21 (r-value: 0.21) in young adults and of 0.19 (r-value: 0.19) in old adults. Moreover, significantly different correlation coefficients (z = 8.28, p < 0.001) were only found for the association between dynamic and static steady-state balance in children (r = 0.09) compared to old adults (r = 0.31). Lastly, we detected trivial to considerable heterogeneity (i.e., 0% ≤ I2 ≤ 83%) between studies. Conclusions: Our systematic review and meta-analysis showed exclusively small-sized correlations between types of balance performance across the lifespan. This indicates that balance performance seems to be task-specific rather than a "general ability." Further, our results suggest that for assessment/training purposes a test battery/multiple exercises should be used that include static/dynamic steady-state, proactive, and reactive types of balance. Concerning the observed significant age differences, further research is needed to investigate whether they are truly existent or if they are caused by methodological inconsistencies.


A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia.
We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia. Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25. PTK2 is a well-known non-receptor tyrosine kinase whereas THOC2 encodes a component of the evolutionarily conserved multiprotein THO complex, involved in mRNA export from nucleus. The translocation generated a sterile fusion transcript under the control of the PTK2 promoter, affecting expression of both PTK2 and THOC2 genes. PTK2 is involved in cell adhesion and, in neurons, plays a role in axonal guidance, and neurite growth and attraction. However, PTK2 haploinsufficiency alone is unlikely to be associated with human disease. Therefore, we studied the role of THOC2 in the CNS using three models: 1) THOC2 ortholog knockout in C.elegans which produced functional defects in specific sensory neurons; 2) Thoc2 knockdown in primary rat hippocampal neurons which increased neurite extension; 3) Thoc2 knockdown in neuronal stem cells (LC1) which increased their in vitro growth rate without modifying apoptosis levels. We suggest that THOC2 can play specific roles in neuronal cells and, possibly in combination with PTK2 reduction, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia.


Collaborative Care for Psychiatric Disorders in Older Adults: A Systematic Review.
To evaluate the mode of implementation, clinical outcomes, cost-effectiveness, and the factors influencing uptake and sustainability of collaborative care for psychiatric disorders in older adults. Systematic review. Primary care, home health care, seniors' residence, medical inpatient and outpatient. Studies with a mean sample age of 60 years and older. Collaborative care for psychiatric disorders. PubMed, MEDLINE, Embase, and Cochrane databases were searched up until October 2016. Individual randomized controlled trials and cohort, case-control, and health service evaluation studies were selected, and relevant data were extracted for qualitative synthesis. Of the 552 records identified, 53 records (from 29 studies) were included. Very few studies evaluated psychiatric disorders other than depression. The mode of implementation differed based on the setting, with beneficial use of telemedicine. Clinical outcomes for depression were significantly better compared with usual care across settings. In depression, there is some evidence for cost-effectiveness. There is limited evidence for improved dementia care and outcomes using collaborative care. There is a lack of evidence for benefit in disorders other than depression or in settings such as home health care and general acute inpatients. Attitudes and skill of primary care staff, availability of resources, and organizational support are some of the factors influencing uptake and implementation. Collaborative care for depressive disorders is feasible and beneficial among older adults in diverse settings. There is a paucity of studies on collaborative care in conditions other than depression or in settings other than primary care, indicating the need for further evaluation.


Gastric volvulus in the newborn.
A review of the world literature has revealed only 11 cases of gastric volvulus symptomatic in the first month of life. To those 11, this report adds two cases of intrathoracic organoaxial gastric volvulus that were observed in the first week of life and were managed operatively. Gastric volvulus should be considered in the differential diagnosis of newborn infants initially observed to have persisting regurgitation, vomiting, and respiratory distress. The diagnosis can be made with plain thoracoabdominal roentgenograms and confirmed by upper gastrointestinal contrast studies. Prompt surgical management is indicated and should include reduction and fixation of the stomach and repair of associated anomalies. The results of early surgery are excellent.


Integrated, High-Throughput, Multiomics Platform Enables Data-Driven Construction of Cellular Responses and Reveals Global Drug Mechanisms of Action.
An understanding of how cells respond to perturbation is essential for biological applications; however, most approaches for profiling cellular response are limited in scope to pre-established targets. Global analysis of molecular mechanism will advance our understanding of the complex networks constituting cellular perturbation and lead to advancements in areas, such as infectious disease pathogenesis, developmental biology, pathophysiology, pharmacology, and toxicology. We have developed a high-throughput multiomics platform for comprehensive, de novo characterization of cellular mechanisms of action. Platform validation using cisplatin as a test compound demonstrates quantification of over 10 000 unique, significant molecular changes in less than 30 days. These data provide excellent coverage of known cisplatin-induced molecular changes and previously unrecognized insights into cisplatin resistance. This proof-of-principle study demonstrates the value of this platform as a resource to understand complex cellular responses in a high-throughput manner.


Dietary fat, fat subtypes and hepatocellular carcinoma in a large European cohort.
The role of amount and type of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) is poorly understood, despite suggestive biological plausibility. The associations of total fat, fat subtypes and fat sources with HCC incidence were investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which includes 191 incident HCC cases diagnosed between 1992 and 2010. Diet was assessed by country-specific, validated dietary questionnaires. A single 24-hr diet recall from a cohort subsample was used for measurement error calibration. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazard models. Hepatitis B and C viruses (HBV/HCV) status and biomarkers of liver function were assessed separately in a nested case-control subset with available blood samples (HCC = 122). In multivariable calibrated models, there was a statistically significant inverse association between total fat intake and risk of HCC (per 10 g/day, HR = 0.80, 95% CI: 0.65-0.99), which was mainly driven by monounsaturated fats (per 5 g/day, HR = 0.71, 95% CI: 0.55-0.92) rather than polyunsaturated fats (per 5 g/day, HR = 0.92, 95% CI: 0.68-1.25). There was no association between saturated fats (HR = 1.08, 95% CI: 0.88-1.34) and HCC risk. The ratio of polyunsaturated/monounsaturated fats to saturated fats was not significantly associated with HCC risk (per 0.2 point, HR = 0.86, 95% CI: 0.73-1.01). Restriction of analyses to HBV/HCV free participants or adjustment for liver function did not substantially alter the findings. In this large prospective European cohort, higher consumption of monounsaturated fats is associated with lower HCC risk.


Both Weight at Age 20 and Weight Gain Have an Impact on Sleep Disturbances Later in Life: Results of the EpiHealth Study.
Obesity is often associated with impaired sleep, whereas the impact of body mass index (BMI) at younger age and previous weight gain on sleep problems remains unknown. The present study utilized data from the Swedish EpiHealth cohort study. A total of 15845 participants (45-75 years) filled out an internet-based questionnaire. BMI was calculated from both measured data at study time and self-reported data at age 20 from the questionnaire. Sleep-related symptoms were most common among obese individuals (BMI > 30 kg/m2). An association between weight gain and sleep problems was found and those with a low BMI at age 20 were most vulnerable to weight gain when it came to risk of sleep problems. Among those who were underweight (BMI < 18.5 kg/m2) at age 20, weight gain (kg/year) was associated with difficulties initiating sleep with an adjusted OR of 2.64 (95% CI: 1.51-4.62) after adjusting for age, sex, smoking, alcohol consumption, physical activity, education, and civil status. The corresponding adjusted OR's among those who had been normal weight (BMI 18.5-24.99) and overweight (BMI 25-29.99 kg/m2) at age 20 were 1.89 (1.47-2.45) and 1.02 (0.48-2.13), respectively. Also difficulties maintaining sleep and snoring were most strongly related to weight gain among those who were underweight at age 20 with decreasing odds with increasing BMI at that age. Sleep problems are related to weight gain and obesity. The impact of weight is most pronounced among those who had a low BMI when young.


BRIC Health Systems and Big Pharma: A Challenge for Health Policy and Management.
BRIC nations - Brazil, Russia, India, and China - represent 40% of the world's population, including a growing aging population and middle class with an increasing prevalence of chronic disease. Their healthcare systems increasingly rely on prescription drugs, but they differ from most other healthcare systems because healthcare expenditures in BRIC nations have exhibited the highest revenue growth rates for pharmaceutical multinational corporations (MNCs), Big Pharma. The response of BRIC nations to Big Pharma presents contrasting cases of how governments manage the tensions posed by rising public expectations and limited resources to satisfy them. Understanding these tensions represents an emerging area of research and an important challenge for all those who work in the field of health policy and management (HPAM).


Health-related quality of life and its relationship to patient disease course in childhood-onset systemic lupus erythematosus.
To (1) estimate the health-related quality of life (HRQOL) of children with childhood-onset systemic lupus erythematosus (cSLE) and compare it to that of normative cohorts; (2) assess the relationship of HRQOL with cSLE disease activity and damage; and (3) determine the effects of changes of disease activity on HRQOL. Patients with cSLE (n = 98) followed every 3 months completed HRQOL measures, the Pediatric Quality of Life Inventory Generic Core scale (PedsQL-GC), the Rheumatology Module (PedsQL-RM), and the Child Health Questionnaire (CHQ). The British Isles Lupus Activity Group Index (BILAG) was used to measure organ-system-specific disease activity. Physicians rated the course of cSLE between visits. At baseline, mean (standard deviation, SD) score [parent report] of the PedsQL-GC and the PedsQL-RM was 75 (17) and 79 (14), respectively; the mean (SD) of the CHQ physical summary score (CHQ-PHS) was 49 (7) and that of the CHQ psychological summary score was 42 (12). Higher BILAG scores, especially in the general, musculoskeletal, neurological, and vascular, but not the mucocutaneous, renal, cardiovascular, or hematological BILAG domains, were associated with a significantly lower HRQOL. Patients with damage had lower HRQOL than those without damage. All HRQOL measures included were at most modestly responsive to clinically important changes with cSLE. HRQOL with cSLE is significantly lower than that reported in healthy populations. Organ-specific involvement with cSLE has a differential effect on HRQOL. Higher disease activity and damage are associated with significantly lower HRQOL as measured by the PedsQL-RM and the CHQ-PHS, and worsening of cSLE leads to a further decline.


Do modified habitats have direct or indirect effects on epifauna?
Replacing natural habitats with artificial structures such as pier-pilings, jetties, and seawalls has important consequences to abundances of biota. It is, however, not often known whether these are direct (the novel habitat alters abundances of some species) or indirect (the novel habitat directly alters some aspect of the behavior or ecology of some species, which, in turn, alter abundances of other species). Marine animals in some modified habitats in Sydney Harbour provide experimental opportunities to test hypotheses to distinguish between direct and indirect processes. Covers of bryozoans and hydroids were greater on kelp growing on pilings than on kelp growing on natural reefs. The epifauna may be affected directly by the pilings or indirectly, i.e., the structure affects characteristics of the kelp which, in turn, influence covers of epifauna. Thus, differences in covers of epifauna on kelp can be due to: (1) factors associated with the primary habitats (pilings vs. reefs), (2) differences between characteristics of the kelp found in each habitat, or (3) an interaction between these factors (habitat and/or type of kelp). Kelp were experimentally transplanted between pilings and reefs, demonstrating that properties of the habitat directly affected covers of epifauna, which were not influenced by the type of kelp that grows on pilings or rocky reefs. Manipulative experiments to unconfound multiple components of habitats influencing disturbances to biota are needed to understand human impacts on natural systems.


Identification of Evidence for Key Parameters in Decision-Analytic Models of Cost Effectiveness: A Description of Sources and a Recommended Minimum Search Requirement.
This paper proposes recommendations for a minimum level of searching for data for key parameters in decision-analytic models of cost effectiveness and describes sources of evidence relevant to each parameter type. Key parameters are defined as treatment effects, adverse effects, costs, resource use, health state utility values (HSUVs) and baseline risk of events. The recommended minimum requirement for treatment effects is comprehensive searching according to available methodological guidance. For other parameter types, the minimum is the searching of one bibliographic database plus, where appropriate, specialist sources and non-research-based and non-standard format sources. The recommendations draw on the search methods literature and on existing analyses of how evidence is used to support decision-analytic models. They take account of the range of research and non-research-based sources of evidence used in cost-effectiveness models and of the need for efficient searching. Consideration is given to what constitutes best evidence for the different parameter types in terms of design and scientific quality and to making transparent the judgments that underpin the selection of evidence from the options available. Methodological issues are discussed, including the differences between decision-analytic models of cost effectiveness and systematic reviews when searching and selecting evidence and comprehensive versus sufficient searching. Areas are highlighted where further methodological research is required.


Contextualizing SEGUE: Evaluating Residents' Communication Skills Within the Framework of a Structured Medical Interview.
The SEGUE (Set the stage, Elicit information, Give information, Understand the patient's perspective, and End the encounter) Framework is a checklist-style rating scale to facilitate the teaching and assessment of communication skills in medical learners. It has been used for over 15 years, and it is recommended in the Accreditation Council for Graduate Medical Education toolbox of assessment methods for resident training. When it was developed, its ability to provide objective scoring was a substantial improvement over global ratings. In this article we describe the strengths and weaknesses of the SEGUE Framework. We highlight one residency program's experience with using the SEGUE Framework to evaluate residents' communication skills. Specifically, we cite previous studies and describe our own analysis of resident interviewing performance that demonstrates how the SEGUE Framework did not distinguish between different levels of interviewing skill level in our sample. Two case examples illustrate how the SEGUE Framework is not an ideal instrument to measure either the quality or the process of medical interviews. Therefore, we propose a new method of contextualized assessment that builds on the SEGUE Framework. Our system evaluates discrete interviewing behaviors within the context of an ambulatory medical interview. We describe our interview structure, as well as a new instrument (the Wy-Mii, pronounced "why me"), to assess both communication and interpersonal skills. We expect that our new method of contextualized assessment will better differentiate between beginning and advanced levels of medical interviewing skills for residents.


Electroretinographic anomalies in medicated and drug free patients with major depression: Tagging the developmental roots of major psychiatric disorders.
The retina is tagged as an approachable part of the brain due to its common embryonic origin and appears as a promising site of investigation for psychiatric disorders. Retinal function is assessed best with the electroretinogram (ERG), which was obtained in a large sample of patients with major depressive disorder and matched controls. ERG cone and rod luminance response functions were recorded in non-dilated eyes in 100 major depressive disorder patients (MDD) and 100 controls, (mean age of 42.8 and 40.9y. o. respectively). Amongst MDD patients, 17 were drug free (mean age 41.2y. o). In medicated patients, at the cone level, a prolonged b-wave was observed (p≤0.01). In drug free patients a prolonged b-wave was discovered only when averaging the implicit time of the 3 highest b-wave amplitudes of the photopic hill. For the medicated patients, the mixed rods/cones a-wave was reduced (p=0.01) whereas a trend (p=0.06) was observed for the pure rod b-wave (reduced) and the mixed rods/cones (reduced and prolonged; p=0.05). In drug free patients, a similar pattern could be observed in terms of effect sizes. Overall, medicated and drug free MDD patients shared some deficits suggesting that some anomalies are present above and beyond the effect of medication. Of interest, the prolonged cone and reduced rod amplitude were reported by our group in schizophrenia patients, suggesting a common neurodevelopmental root of major psychiatric disorders.


Total body irradiation prior to bone marrow transplantation: efficacy and safety of granisetron in the prophylaxis and control of radiation-induced emesis.
Radiation-induced emesis is one of the most disturbing side effects of total body irradiation (TBI). To evaluate the efficacy and to determine the best schedule of granisetron (a selective 5-hydroxytryptamine3 serotonin receptor antagonist) administration in the prevention of radiation-induced nausea and vomiting, we conducted a trial involving patients receiving single-dose TBI before bone marrow transplantation (BMT). Thirty-six patients with non-Hodgkin's lymphoma (n = 12), multiple myeloma (n = 8), acute lymphoblastic leukemia (n = 7), acute nonlymphoblastic leukemia (n = 6), and chronic myeloid leukemia (n = 3) referred to our department between March 1992 and February 1994 were enrolled in this study to assess the efficacy of granisetron during single-dose TBI before autologous BMT (n = 26), allogeneic BMT (n = 8), or syngeneic BMT (n = 2). The male-to-female ratio was 22:14 (1.57), and the mean age was 41 +/- 11 years (range 16-58). Before TBI, conditioning chemotherapy consisted of cyclophosphamide (CY) alone (60 mg/kg per day on 2 successive days) in 24 patients, CY combined with other drugs in 6, and combinations without CY in 6. All patients received single-dose TBI (10 Gy administered to the midplane at L4, and 8 Gy to the lungs). The mean instantaneous and average dose rates were 0.039 +/- 0.012 Gy/min (range 0.031-0.058), and 0.025-0.006 Gy/min (range 2.08-3.96), respectively. Granisetron was administered 30-45 min before TBI according to two different modalities: a total dose of 3 mg as a 5-min intravenous (i.v.) infusion (Treatment A, n = 15; 42%) or the same treatment plus 3 mg of granisetron as a 24-h continuous i.v. infusion (total dose: 6 mg, Treatment B, n = 21; 58%). Depending on the BMT teams, hyperdiuresis was continued (n = 19, 53%) or suspended (n = 17, 47%) during TBI. Nausea and vomiting were assessed during the TBI session and the following 12 h, and were scored as follows: S1 = no nausea or vomiting; S2 = moderate nausea; S3 = severe nausea and/or single episode of vomiting; and S4 = multiple episodes of vomiting. During TBI, 18 (50%) patients were scored as complete responders (S1), 1 (3%) as a major responder (S2), 9 (25%) as minor responders (S3), and 8 (22%) as nonresponders (S4). During the following 12 h, 28 (78%) patients were free of severe nausea and vomiting (S1 or S2), whereas 8 (22%) vomited (S3 or S4). In univariate analyses, the 12-h probability of emesis was significantly higher in patients undergoing hyperdiuresis (63% vs. 30%; p = 0.05), and in patients older than 45 years (65% for age > 45 vs. 33% for age < or = 45; p = 0.05). The probability of S3 or S4 emesis was 50% with Treatment A and 47% with Treatment B (p = 0.86). Sex, body weight, and type of conditioning chemotherapy did not influence the 12-h probability of emesis. Multivariate analysis revealed that hyperdiuresis (p = 0.02) and Treatment A (p = 0.04) were independently associated with radiation-induced emesis, whereas sex (p = 0.85), body weight (p = 0.13), age (p = 0.12), and type of conditioning chemotherapy (p = 0.92) were not. No early toxicity related to granisetron was observed. Granisetron is a well-tolerated and effective antiemetic agent that can be used as monotherapy during single-dose TBI. Good control of nausea and vomiting is obtained with this antiemetic drug, and its effect is increased when hyperdiuresis is suspended during TBI.


Genetic Interactions in Nonsyndromic Orofacial Clefts in Europe-EUROCRAN Study.
Nonsyndromic cleft lip with or without cleft palate (nsCL±P) and nonsyndromic cleft palate (nsCP) are caused by a combination of genetic and environmental risk factors. We investigated gene-environment and gene-gene joint effects in a large multicenter study of case-parent triads. The nsCL±P or nsCP triads were recruited in 11 European countries between 2001 and 2005. We collected DNA samples from infants and from their mothers and fathers, and mothers completed a questionnaire on exposures, including smoking and folic acid supplement use during pregnancy. We used log-linear regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between nsCL±P or nsCP and variants in MTHFR, MTHFD1, TGFA, SATB2, and MSX1, stratifying by environmental or genetic factors. We obtained genotype and exposure data for 728 nsCL±P triads and 292 nsCP triads. In male infants, there was no association between the mother's homozygous MSX1 p(CA) *4/*4 genotype and nsCL±P (RR, 0.98; 95% CI, 0.63-1.54), but this maternal genotype resulted in a doubling of risk for female infants (RR, 2.21; 95% CI, 1.13-4.34). There was evidence suggestive of gene-gene joint-effects between MTHFR-TGFA for nsCP but not for nsCL±P. Although we chose the genes and their variants and putative joint effects based on associations previously reported in the literature, we replicated few associations. These results do not provide evidence supporting associations between these genes and oral clefts in European populations, although gene-environment and gene-gene interactions could play a role in oral cleft etiology.


Crystallographic snapshots of cyanide- and water-bound C-clusters from bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase.
Nickel-containing carbon monoxide dehydrogenases (CODHs) reversibly catalyze the oxidation of carbon monoxide to carbon dioxide and are of vital importance in the global carbon cycle. The unusual catalytic CODH C-cluster has been crystallographically characterized as either a NiFe(4)S(4) or a NiFe(4)S(5) metal center, the latter containing a fifth, additional sulfide that bridges Ni and a unique Fe site. To determine whether this bridging sulfide is catalytically relevant and to further explore the mechanism of the C-cluster, we obtained crystal structures of the 310 kDa bifunctional CODH/acetyl-CoA synthase complex from Moorella thermoacetica bound both with a substrate H(2)O/OH(-) molecule and with a cyanide inhibitor. X-ray diffraction data were collected from native crystals and from identical crystals soaked in a solution containing potassium cyanide. In both structures, the substrate H(2)O/OH(-) molecule exhibits binding to the unique Fe site of the C-cluster. We also observe cyanide binding in a bent conformation to Ni of the C-cluster, adjacent the substrate H(2)O/OH(-) molecule. Importantly, the bridging sulfide is not present in either structure. As these forms of the C-cluster represent the coordination environment immediately before the reaction takes place, our findings do not support a fifth, bridging sulfide playing a catalytic role in the enzyme mechanism. The crystal structures presented here, along with recent structures of CODHs from other organisms, have led us toward a unified mechanism for CO oxidation by the C-cluster, the catalytic center of an environmentally important enzyme.


Cantor set fiber Bragg grating
The theory of fractals has already been applied to many fields in science, such as physics, biology, and chemistry. One of the most commonly used fractals in these applications is the Cantor set. Novel fiber Bragg gratings are proposed that combine the present technology of fiber Bragg gratings with the theory of Cantor sets. The principal goal of this work is to analyze how Cantor sets, applied to gratings, can alter their reflectivity spectra. Specifically, it is observed that, as the order of the Cantor set increases, the bandpass reflectivity spectra of these gratings broaden and evolve into more-complex patterns. Also, self-similarity properties can be observed in the spectra of these gratings. Numerical examples demonstrate variations in the spectra of these structures as the fractal order increases.


[End-stage renal disease among patients in a referral hospital in El Salvador].
El Salvador is a country with high mortality from end-stage renal disease (ESRD). The objective of this study was to determine the epidemiological characteristics of a series of new cases of ESRD seen in a referral hospital in the country. A cross-sectional study was conducted of all the new cases that initiated chronic dialysis between November 1999 and March 2000. Using a personal interview, data were obtained on the patients' clinical, demographic, and occupational characteristics, among others. During the five months that the study lasted, 205 new cases of ESRD were observed. Among the 202 interviewees, two groups were clearly distinguished. One group, of 67 patients (33%), had known risk factors for ESRD, similar to those for developed countries (basically, diabetes mellitus, hypertension, and chronic consumption of non-steroidal anti-inflammatories). Another group of 135 patients (67%) had unusual characteristics that were not associated with the known risk factors. The majority of the patients in this second group were male, farmers, residents of coastal areas or areas next to rivers, and some years before had been exposed, without adequate protection, to agricultural insecticides or pesticides through their work. We have identified an important group of patients with ESRD who seem to lack a cause for their disease. Their special characteristics make it possible to suspect a relationship with the occupational exposure to insecticides or pesticides. New studies are needed in order to confirm this hypothesis.


From Drug Safety to Drug Security: A Contemporary Shift in the Policing of Health.
The counterfeiting of medication is increasingly seen as a major threat to health, especially in the light of both the everyday reliance on and a broadening of world-wide access to pharmaceuticals. Exaggerated or real, this threat has inaugurated, this article argues, a shift from a drug safety regime to a drug security regime that governs the flow of pharmaceuticals and brings together markets, police, and health actors in new ways. This entails a shift from soft disciplinary means aimed at incremental and continued inclusion of defaulters, to one of drastically sovereign measures of exclusion and banishment aimed at fake goods and the people associated with them, in the name of health. Through a multi-sited ethnographic study, this article shows how such new drug security efforts play themselves out especially in (South) Africa, highlighting a modus operandi of spectacular performativity and of working through suspicion and association rather than factuality, producing value less so for those in need of health than for a petty security industry itself.


Colorectal carcinogenesis: MSI-H versus MSI-L.
Microsatellite instability (MSI) is a well-recognized phenomenon that is classically a feature of tumors in the hereditary non-polyposis colorectal syndrome. Ten to 15% of sporadic colorectal cancers, however, will have MSI. Microsatellite unstable tumors can be divided into two distinct MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L). MSI sporadic colorectal cancers with a high level of MSI (MSI-H) form a well defined group with distinct clinicopathologic features characterized by an overall better long-term prognosis. These sporadic MSI-H colorectal tumors most often arise from the epigenetic silencing of the mismatch repair gene MLH1. In contrast, MSI-L colorectal tumors have not been shown to differ in their clinicopathologic features or in most molecular features from microsatellite stable (MSS) tumors. Unlike MSI-H tumors, MSI-L tumors appear to arise through the chromosomal instability carcinogenesis pathway, similar to MSS tumors. Some groups have reported more frequent mutations in K-ras and in the methylation of methylguanine transferase in MSI-L tumors, but others have questioned these findings. Therefore, although the use of the MSI-L category is widespread, there continues to be some debate as to whether a discrete MSI-L group truly exists. Rather, it has been suggested that MSI-L tumors differ quantitatively from MSS tumors but do not differ qualitatively. Future studies will need to evaluate the specific mutations in non-MSI-H tumors in an attempt to sub-classify MSI-L tumors with regard to MSS tumors so that subtle differences between these two sub-groups can be identified.


Designing HIV Testing Algorithms Based on 2015 WHO Guidelines Using Data from Six Sites in Sub-Saharan Africa.
Our objective was to evaluate the performance of HIV testing algorithms based on WHO recommendations, using data from specimens collected at six HIV testing and counseling sites in sub-Saharan Africa (Conakry, Guinea; Kitgum and Arua, Uganda; Homa Bay, Kenya; Douala, Cameroon; Baraka, Democratic Republic of Congo). A total of 2,780 samples, including 1,306 HIV-positive samples, were included in the analysis. HIV testing algorithms were designed using Determine as a first test. Second and third rapid diagnostic tests (RDTs) were selected based on site-specific performance, adhering where possible to the WHO-recommended minimum requirements of ≥99% sensitivity and specificity. The threshold for specificity was reduced to 98% or 96% if necessary. We also simulated algorithms consisting of one RDT followed by a simple confirmatory assay. The positive predictive values (PPV) of the simulated algorithms ranged from 75.8% to 100% using strategies recommended for high-prevalence settings, 98.7% to 100% using strategies recommended for low-prevalence settings, and 98.1% to 100% using a rapid test followed by a simple confirmatory assay. Although we were able to design algorithms that met the recommended PPV of ≥99% in five of six sites using the applicable high-prevalence strategy, options were often very limited due to suboptimal performance of individual RDTs and to shared falsely reactive results. These results underscore the impact of the sequence of HIV tests and of shared false-reactivity data on algorithm performance. Where it is not possible to identify tests that meet WHO-recommended specifications, the low-prevalence strategy may be more suitable.


Complex relationships between greenness, air pollution, and mortality in a population-based Canadian cohort.
Epidemiological studies have consistently demonstrated that exposure to fine particulate matter (PM2.5) is associated with increased risks of mortality. To a lesser extent, a series of studies suggest that living in greener areas is associated with reduced risks of mortality. Only a handful of studies have examined the interplay between PM2.5, greenness, and mortality. We investigated the role of residential greenness in modifying associations between long-term exposures to PM2.5 and non-accidental and cardiovascular mortality in a national cohort of non-immigrant Canadian adults (i.e., the 2001 Canadian Census Health and Environment Cohort). Specifically, we examined associations between satellite-derived estimates of PM2.5 exposure and mortality across quintiles of greenness measured within 500 m of individual's place of residence during 11 years of follow-up. We adjusted our survival models for many personal and contextual measures of socioeconomic position, and residential mobility data allowed us to characterize annual changes in exposures. Our cohort included approximately 2.4 million individuals at baseline, 194,270 of whom died from non-accidental causes during follow-up. Adjustment for greenness attenuated the association between PM2.5 and mortality (e.g., hazard ratios (HRs) and 95% confidence intervals (CIs) per interquartile range increase in PM2.5 in models for non-accidental mortality decreased from 1.065 (95% CI: 1.056-1.075) to 1.041 (95% CI: 1.031-1.050)). The strength of observed associations between PM2.5 and mortality decreased as greenness increased. This pattern persisted in models restricted to urban residents, in models that considered the combined oxidant capacity of ozone and nitrogen dioxide, and within neighbourhoods characterised by high or low deprivation. We found no increased risk of mortality associated with PM2.5 among those living in the greenest areas. For example, the HR for cardiovascular mortality among individuals in the least green areas was 1.17 (95% CI: 1.12-1.23) compared to 1.01 (95% CI: 0.97-1.06) among those in the greenest areas. Studies that do not account for greenness may overstate the air pollution impacts on mortality. Residents in deprived neighbourhoods with high greenness benefitted by having more attenuated associations between PM2.5 and mortality than those living in deprived areas with less greenness. The findings from this study extend our understanding of how living in greener areas may lead to improved health outcomes.


Mass spectrometric identification of a naturally processed melanoma peptide recognized by CD8+ cytotoxic T lymphocytes.
We and others have previously reported that melanoma-specific, cytotoxic T lymphocytes (CTL) define a minimum of six class I-presented peptide epitopes common to most HLA-A2+ melanomas. Here we show that three of these peptide epitopes are coordinately recognized by a CTL clone obtained by limiting dilution from the peripheral blood of an HLA-A2+ melanoma patient. Tandem mass spectrometry was used to characterize and sequence one of these three naturally processed melanoma peptides. One of the potential forms of the deduced peptide sequence (XXTVXXGVX, X = I or L) matches positions 32-40 of the recently identified melanoma gene MART-1/Melan-A. This peptide (p939; ILTVILGVL) binds to HLA-A2 with an intermediate-to-low affinity and is capable of sensitizing the HLA-A2+ T2 cell line to lysis by CTL lines and clones derived from five different melanoma patients. A relative high frequency of anti-p939-specific effector cells appear to be present in situ in HLA-A2+ melanoma patients, since p939 is also recognized by freshly isolated tumor infiltrating lymphocytes. p939 represents a good candidate for the development of peptide-based immunotherapies for the treatment of patients with melanoma.


Tip-enhanced Raman spectroscopy - from early developments to recent advances.
An analytical technique operating at the nanoscale must be flexible regarding variable experimental conditions while ideally also being highly specific, extremely sensitive, and spatially confined. In this respect, tip-enhanced Raman scattering (TERS) has been demonstrated to be ideally suited to, e.g., elucidating chemical reaction mechanisms, determining the distribution of components and identifying and localizing specific molecular structures at the nanometre scale. TERS combines the specificity of Raman spectroscopy with the high spatial resolution of scanning probe microscopies by utilizing plasmonic nanostructures to confine the incident electromagnetic field and increase it by many orders of magnitude. Consequently, molecular structure information in the optical near field that is inaccessible to other optical microscopy methods can be obtained. In this general review, the development of this still-young technique, from early experiments to recent achievements concerning inorganic, organic, and biological materials, is addressed. Accordingly, the technical developments necessary for stable and reliable AFM- and STM-based TERS experiments, together with the specific properties of the instruments under different conditions, are reviewed. The review also highlights selected experiments illustrating the capabilities of this emerging technique, the number of users of which has steadily increased since its inception in 2000. Finally, an assessment of the frontiers and new concepts of TERS, which aim towards rendering it a general and widely applicable technique that combines the highest possible lateral resolution and extreme sensitivity, is provided.


Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci.
Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P = 5.8 × 10(-9)), RELA (rs1049728, P = 2.7 × 10(-16)), and SH2B3 (rs3184504, P = 2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.


Complete genome sequence of Hirschia baltica type strain (IFAM 1418(T)).
The family Hyphomonadaceae within the Alphaproteobacteria is largely comprised of bacteria isolated from marine environments with striking morphologies and an unusual mode of cell growth. Here, we report the complete genome sequence Hirschia baltica, which is only the second a member of the Hyphomonadaceae with a published genome sequence. H. baltica is of special interest because it has a dimorphic life cycle and is a stalked, budding bacterium. The 3,455,622 bp long chromosome and 84,492 bp plasmid with a total of 3,222 protein-coding and 44 RNA genes were sequenced as part of the DOE Joint Genome Institute Program CSP 2008.


Decreased resting functional connectivity after traumatic brain injury in the rat.
Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.


Responsiveness of gait analysis parameters in a cohort of 71 CMT subjects.
Detection of worsening in the slowly progressive Charcot-Marie-Tooth disease (CMT) is difficult. As previous clinical scales showed low responsiveness, novel outcome measures are under study, including innovative approaches such as quantitative muscle MRI and instrumented movement analysis. Since gait analysis proved able to reliably quantify CMT locomotor deficits, we aimed to explore whether it can be a sensitive-to-change outcome measure in CMT studies. Clinical and biomechanical evaluations were performed in 71 CMT subjects at baseline and after a mean (±sd) of 28.9 ± 9.5 months. Locomotor tasks included natural walking, ascending and descending steps. Instrumented analysis of such tasks provided indexes related to muscle strength (kinetic parameters) and joint movement (kinematic parameters). Parameter responsiveness was expressed as Standardized Response Mean (SRM). Considering the whole CMT group, several parameters showed moderate responsiveness; subgrouping subjects according to disease severity allowed reaching high responsiveness (SRM >0.80). CMT Examination Score showed moderate responsiveness (SRM 0.53) in the minimally affected group; kinematic parameters were more responsive in this group, whereas kinetic parameters in the most severely affected one. Biomechanical parameters can represent suitable outcome measures for CMT by showing moderate-to-high responsiveness. These data suggest that appropriate selection of patient population and outcome measures is crucial for clinical trials' design.


A novel homeobox-like gene associated with reaction to stripe rust and powdery mildew in common wheat.
Stripe rust and powdery mildew, caused by Puccinia striiformis f. sp. tritici and Blumeria graminis f. sp. tritici, respectively, are severe diseases in wheat (Triticum aestivum) worldwide. In our study, differential amplification of a 201-bp cDNA fragment was obtained in a cDNA-amplified fragment length polymorphism (AFLP) analysis between near-isogenic lines Yr10NIL and Avocet S, inoculated with P. striiformis f. sp. tritici race CYR29. A full-length cDNA (1,357 bp) of a homeobox-like gene, TaHLRG (GenBank accession no. EU385606), was obtained in common wheat based on the sequence of GenBank accession AW448633 with high similarity to the above fragment. The genomic DNA sequence (2,396 bp) of TaHLRG contains three exons and two introns. TaHLRG appeared to be a novel homeobox-like gene, encoding a protein with a predicted 66-amino-acid homeobox domain. It was involved in race-specific responses to stripe rust in real-time quantitative polymerase chain reaction (PCR) analyses with Yr9NIL, Yr10NIL, and Avocet S. It was also associated with adult-plant resistance to stripe rust and powdery mildew based on the field trials of doubled haploid lines derived from the cross Bainong 64/Jingshuang 16 and two F(2:3) populations from the crosses Lumai 21/Jingshuang 16 and Strampelli/Huixianhong. A functional marker, THR1 was developed based on the sequence of TaHLRG and located on chromosome 6A using a set of Chinese Spring nulli-tetrasomic lines.


The early development of the frog retinotectal projection.
The guidance of retinal ganglion cell axons has been investigated in embryos of the frog Xenopus. During the initial development of the brain a series of axon tracts are laid down forming a basic 'scaffold' or framework. Retinal axons grow through one of these tracts, the tract of the post-optic commissure (tPOC). This is the only tract that extends through the rostral part of the brain at these early stages of development. The origin and development of the tPOC has been studied using antibodies which label neurons at their earliest stages of differentiation. The first sign of the tPOC is a chain of neurons which differentiate simultaneously in the caudolateral part of the diencephalon. Axons from these neurons grow the short distance between adjacent cells interlinking the chain to form a descending tract. A series of other axon projections are then added to the tPOC, each of which is segregated into a particular subregion of the tract. Retinal axons are added to the tract approximately 18 h after its formation. They grow in the sub-pial part of the tract and always occupy the rostral-most edge. Retinal axons follow the tract to the region of the developing tectum where they leave, turn dorsally, and terminate. The reliance of retinal axons on this pre-existing pathway has been demonstrated by experimentally altering the course of the tPOC during its early development. The caudo-lateral wall of the diencephalon has been rotated through 90 degrees at a stage just before the tPOC neurons differentiate. Confirmation of the predicted alteration in the course of the tPOC has been made using immunocytochemistry. In such manipulated brains, retinal axons maintain their strong affinity for the rostral edge of the tPOC, following its altered course through the diencephalon.


The effect of extracellular pH on matrix turnover by cells of the bovine nucleus pulposus.
It has long been known that very acidic conditions can be found in degenerate discs. The effect of these acid conditions on matrix turnover are, however, unknown. This study aimed to examine the effect of acidity on production of matrix components and on agents which break down the matrix in order to gain insight into the effect of pathological values of pH on matrix turnover. Cells were isolated from the nucleus of bovine discs and from bovine articular cartilage, embedded in alginate beads and cultured at pH levels maintained within the ranges seen in normal and pathological discs: pH 7.4-pH 6.3 for 48 h. Rates of sulphated glycosaminoglycan (GAG) and protein synthesis were measured, as well as rates of production of some agents involved in matrix breakdown, i.e. total and activated matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). The results showed that acid conditions had a profound effect on cell matrix turnover; at pH 6.4, total production of most species measured was inhibited by more than 50% compared to production at pH 7.2; production of sulphated GAGs and of TIMP-1 fell by >90%. However production of active metalloproteinases by disc cells was relatively insensitive to pH, with activity at pH 6.3 not statistically different from that at pH 7.2. These findings indicate that exposure to acid conditions appears particularly deleterious for the disc matrix, as it inhibits the disc cells from synthesising functionally important molecules such as the sulphated GAGs but does not prevent the production of agents able to degrade matrix components. The low values of pH seen in some degenerate discs are thus likely to be involved in breakdown of the disc matrix.


Isolation and Characterisation of Bacteriophages with Activity against Invasive Non-Typhoidal Salmonella Causing Bloodstream Infection in Malawi.
In recent years, novel lineages of invasive non-typhoidal Salmonella (iNTS) serovars Typhimurium and Enteritidis have been identified in patients with bloodstream infection in Sub-Saharan Africa. Here, we isolated and characterised 32 phages capable of infecting S. Typhimurium and S. Enteritidis, from water sources in Malawi and the UK. The phages were classified in three major phylogenetic clusters that were geographically distributed. In terms of host range, Cluster 1 phages were able to infect all bacterial hosts tested, whereas Clusters 2 and 3 had a more restricted profile. Cluster 3 contained two sub-clusters, and 3.b contained the most novel isolates. This study represents the first exploration of the potential for phages to target the lineages of Salmonella that are responsible for bloodstream infections in Sub-Saharan Africa.


Fe-N-C Artificial Enzyme: Activation of Oxygen for Dehydrogenation and Monoxygenation of Organic Substrates under Mild Condition and Cancer Therapeutic Application.
Developing highly efficient biomimetic catalysts that directly use O2 as the terminal oxidant to dehydrogenate and monoxygenate substrates with high selectivity under mild conditions has long been pursued but rarely achieved yet. Herein, we report that heterogeneous Fe-N-C, which is commonly used as an electrocatalyst for oxygen reduction reaction, had unusual biomimetic catalytic activity in both dehydrogenation and monoxygenation of a series of organic molecules (∼100% selectivity) by directly using O2. The Fe-N x center was verified to be the active site that reductively activated O2 by spontaneously generating specific reactive oxygen species (ROS) (1O2, O2•-, and H2O2). Aided by these ROS, under physiological conditions, the Fe-N-C was further successfully exampled to kill proliferative lung cancer cells. Fe-N-C had several striking superior features with respect to natural enzymes, classical heterogeneous nanozymes, and homogeneous artificial enzymes incapable of working under harsh conditions (extreme pH and high temperature), ease of separation and recycling, and direct use of O2. It would open up a new vista of Fe-N-C as an artificial enzyme in biomimetic catalysis, ranging from fundamental simulation of oxidase/oxygenase metabolism to industrial oxidation processes and to disease treatment.


Osteochondral destruction in pigmented villonodular synovitis during the clinical course.
In pigmented villonodular synovitis (PVNS), some cases recur and progress to osteochondral destruction. The aim of our study was to clarify the occurrence of osteochondral destruction according to the location of PVNS during the clinical course. Seventy-two patients with PVNS (43 female, 29 male) with a mean age of 40 years (range 3-87 yrs) had been referred to our institutions. Factors influencing the occurrence of osteochondral destruction were investigated. Mean followup was 60 months (range 12-190 mo). Adjacent bone change occurred in 24 (42%) of 57 patients, who were evaluated at the time of the first consultation. Eight (89%) of 9 patients with hip lesions initially had bone lesions, significantly more frequently than those with other lesions (p = 0.038). Duration of symptoms was significantly correlated with the occurrence of bone lesions in diffuse knee lesions (p = 0.005). During followup, patients with location in the knee had a significantly higher incidence of osteoarthritic change (73%) compared to those with foot and ankle involvement (p = 0.027). Re-operation was more frequently required for knee lesions due to the high recurrence rate (32%). Patients who required re-operation had significantly more marked osteoarthritic change in knees (p = 0.001) during followup than those who did not. For PVNS arising in knees, repeated recurrences followed by re-operation resulted in the progression of osteoarthritic change. PVNS arising in hips, feet, and ankles developed bone lesions initially, probably due to the limited volume of these joints. The indications for re-operation for recurrent knee lesions require careful consideration regarding progression of osteoarthritic change.


Adsorption and desorption of noble gases on activated charcoal: I. 133Xe studies in a monolayer and packed bed.
Detailed desorption studies using petroleum-based activated charcoals were conducted in monolayers and packed beds. Less extensive studies were conducted on several other types of charcoal. Kinetic studies, using 133Xe, demonstrated the existence of a micropore volume with entrance capillaries that together determined the response characteristics of charcoal to external concentration gradients of tracer gases. This new two-phase model, composed of micropores and entrance capillaries, describes the desorption dynamics of an adsorbed gas in the presence of water vapor. Condensed water vapor in the entrance capillaries of the charcoal reduced the effective pore radius and increased the diffusion half-time. Water could also adversely affect the integrating capability of the charcoal dramatically if the adsorbed water completely blocked the entrance capillaries. The amount of adsorbed water required to block the capillaries varied with the charcoal type and was termed here as the "break-point." The desorption parameters measured in this work can be used to design an improved passive Rn monitor to effectively integrate during a 3-7 d exposure period by eliminating the adverse effects of water vapor. The improved canister design would provide more accurate and reproducible measurements of indoor Rn concentrations than are currently available.


Dietary behaviours during pregnancy: findings from first-time mothers in southwest Sydney, Australia.
Limited prevalence data are available for nutrition related health behaviours during pregnancy. This study aimed to assess dietary behaviours during pregnancy among first-time mothers, and to investigate the relationships between these behaviours and demographic characteristics, so that appropriate dietary intervention strategies for pregnant women can be developed. An analysis of cross-sectional survey was conducted using data from 409 first-time mothers at 26-36 weeks of pregnancy, who participated in the Healthy Beginnings Trial conducted in southwestern Sydney, Australia. Dietary behaviours, including consumption of vegetables, fruit, water, milk, soft drinks, processed meat products, fast foods/take away and chips, were assessed using the New South Wales Health Survey questionnaire through face-to-face interviews. Factors associated with dietary behaviours were determined by logistic regression modeling. Log-binomial regression was used to calculate adjusted risk ratios (ARR). Only 7% of mothers reported meeting the recommended vegetable consumption and 13% reported meeting the recommended fruit consumption. Mean and median intakes per day were 2.3 (SD 1.3) and 2 serves of vegetables, and 2.1 (SD 1.4) and 2 serves of fruit respectively. About one fifth of mothers (21%) reported drinking 2 cups (500 ml) or more of soft drink per day and 12% reported consuming more than 2 meals or snacks from fast-food or takeaway outlets per week. A small percentage of mothers (5%) had experienced food insecurity over the past 12 months. There were significant inverse associations between water and soft drink consumption (Spearman's rho -0.20, P < 0.001), and between fruit and fast food/takeaway consumption (Spearman's rho -0.16, P = 0.001). The dietary behaviours were associated with a variety of socio-demographic characteristics, but no single factor was associated with all the dietary behaviours. There were low reported levels of vegetable and fruit consumption and high reported levels of soft drink and takeaway/fast food consumption among pregnant women. Dietary interventions to prevent adverse health consequences need to be tailored to meet the needs of pregnant women of low socio-economic status in order to improve their own healthy eating behaviors. Increasing water and fruit consumption could lead to reduced consumption of soft drink and takeaway/fast food among pregnant women. HBT is registered with the Australian Clinical Trial Registry (ACTRNO12607000168459).


No Serologic Evidence of Middle East Respiratory Syndrome Coronavirus Infection Among Camel Farmers Exposed to Highly Seropositive Camel Herds: A Household Linked Study, Kenya, 2013.
AbstractHigh seroprevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) among camels has been reported in Kenya and other countries in Africa. To date, the only report of MERS-CoV seropositivity among humans in Kenya is of two livestock keepers with no known contact with camels. We assessed whether persons exposed to seropositive camels at household level had serological evidence of infection. In 2013, 760 human and 879 camel sera were collected from 275 and 85 households respectively in Marsabit County. Data on human and animal demographics and type of contact with camels were collected. Human and camel sera were tested for anti-MERS-CoV IgG using a commercial enzyme-linked immunosorbent assay (ELISA) test. Human samples were confirmed by plaque reduction neutralization test (PRNT). Logistic regression was used to identify factors associated with seropositivity. The median age of persons sampled was 30 years (range: 5-90) and 50% were males. A quarter (197/760) of the participants reported having had contact with camels defined as milking, feeding, watering, slaughtering, or herding. Of the human sera, 18 (2.4%) were positive on ELISA but negative by PRNT. Of the camel sera, 791 (90%) were positive on ELISA. On univariate analysis, higher prevalence was observed in female and older camels over 4 years of age (P < 0.05). On multivariate analysis, only age remained significantly associated with increased odds of seropositivity. Despite high seroprevalence among camels, there was no serological confirmation of MERS-CoV infection among camel pastoralists in Marsabit County. The high seropositivity suggests that MERS-CoV or other closely related virus continues to circulate in camels and highlights ongoing potential for animal-to-human transmission.


Correlates of unprotected anal intercourse in HIV positive men attending an HIV/AIDS clinic in Sydney.
We examined the impact of cognitive and biomedical variables on unprotected anal intercourse between HIV-1 infected men and casual sexual partners in a Sydney-based cohort. Participants answered questionnaires examining insertive and receptive intercourse with and without ejaculation. They completed a modified optimism-scepticism scale, a sexual beliefs scale and a clinical/demographics questionnaire. CD4 count, blood and semen VL were assessed. 43 of 109 reported anal intercourse with HIV+ partners, 33 with HIV- partners and 38 with partners of unknown status. With HIV+ partners past sexually transmittable infections were associated with receptive intercourse without ejaculation (p = 0.03) and insertive intercourse without ejaculation (p = 0.06) while sexual beliefs were associated with insertive intercourse without ejaculation (p = 0.038), receptive intercourse with ejaculation (p = 0.016) and insertive intercourse with ejaculation (p = 0.077). Sexual beliefs were found to have some association with unprotected receptive intercourse without ejaculation with HIV- partners (p = 0.071). With unknown serostatus partners, treatment-optimism (p = 0.026) had association with insertive intercourse with ejaculation while optimism (p = 0.002), sexual beliefs (p = 0.039) and recent VL (p = 0.059) had associations with insertive intercourse without ejaculation. Current STI had association with receptive intercourse with ejaculation with unknown status partners (p = 0.014). We found between-group differences in variables associated with different types of unprotected anal intercourse that may guide the development of prevention strategies.


EPSPs of dentate gyrus granule cells during epileptiform bursts of dentate hilar "mossy" cells and area CA3 pyramidal cells in disinhibited rat hippocampal slices.
When hippocampal slices are exposed to GABAA antagonists, area CA3 pyramidal cells and dentate hilar "mossy" cells discharge in synchronized epileptiform bursts (Müller and Misgeld, 1991; Scharfman, 1994b). Dentate interneurons are excited simultaneously, but the degree of discharge varies (Scharfman, 1994b). This study primarily examined the activity of dentate granule cells simultaneous to the epileptiform bursts of pyramidal cells and mossy cells. EPSPs followed by large GABAB receptor-mediated IPSPs were generated in granule cells during all epileptiform bursts of pyramidal cells and mossy cells, regardless of whether they were evoked or spontaneous. By simultaneous recording it was determined that granule cell EPSPs began several milliseconds after the start of pyramidal cell bursts (n = 48 simultaneous recordings) and immediately after the first action potential of a mossy cell burst (n = 77). Interneurons were similar to granule cells in the timing of their depolarizations relative to the onset of pyramidal cell (n = 24; Scharfman, 1994b) and mossy cell (n = 9) bursts. All excitatory activity was blocked by bath application of the glutamatergic AMPA/kainate receptor antagonist CNQX (5 microM, n = 5), but not the NMDA receptor antagonist D-APV (25-50 microM, n = 9). Granule cell EPSPs were decreased after focal application of CNQX to the molecular layer at a site close to the impaled granule cell (n = 5), whereas D-APV had no effect (n = 3). EPSPs also decreased after focal application of CNQX to the hilus, in two of four slices tested. The extracellularly recorded EPSP of granule cells was maximal in the inner molecular layer (n = 33), the site of the mossy cell axonal plexus. Severing the junction of the dentate gyrus and area CA3 blocked all spontaneous and evoked activity of dentate neurons without affecting burst discharges in area CA3a and CA3b (n = 6). None of the excitatory activity of any cell type was affected by cholinergic antagonists (atropine and mecamylamine, 25 microM each, n = 5; pirenzipine and dihydro-beta-erythroidine, 25 microM each, n = 5). The results suggest that there is a glutamatergic, AMPA/kainate receptor-mediated, excitatory pathway from area CA3 to the dentate gyrus in disinhibited slices. The pharmacological results, analyses of latency, as well as the known axonal projections of the sampled cells, suggest that the excitatory pathway begins within area CA3 and leads to granule cells via mossy cells. The data also suggest that dentate interneurons are excited by mossy cells, and possibly by pyramidal cells as well.(ABSTRACT TRUNCATED AT 400 WORDS)


Sirtuin-1 regulates acinar-to-ductal metaplasia and supports cancer cell viability in pancreatic cancer.
The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD(+)-dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-to-cytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and β-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of β-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis.


Opa proteins and CEACAMs: pathways of immune engagement for pathogenic Neisseria.
Neisseria meningitidis and Neisseria gonorrhoeae are globally important pathogens, which in part owe their success to their ability to successfully evade human immune responses over long periods. The phase-variable opacity-associated (Opa) adhesin proteins are a major surface component of these organisms, and are responsible for bacterial adherence and entry into host cells and interactions with the immune system. Most immune interactions are mediated via binding to members of the carcinoembryonic antigen cell adhesion molecule (CEACAM) family. These Opa variants are able to bind to different receptors of the CEACAM family on epithelial cells, neutrophils, and T and B lymphocytes, influencing the innate and adaptive immune responses. Increased epithelial cell adhesion creates the potential for prolonged infection, invasion and dissemination. Furthermore, Opa proteins may inhibit T-lymphocyte activation and proliferation, B-cell antibody production, and innate inflammatory responses by infected epithelia, in addition to conferring increased resistance to antibody-dependent, complement-mediated killing. While vaccines containing Opa proteins could induce adhesion-blocking and bactericidal antibodies, the consequence of CEACAM binding by a candidate Opa-containing vaccine requires further investigation. This review summarizes current knowledge of the immunological consequences of the interaction between meningococcal and gonococcal Opa proteins and human CEACAMs, considering the implications for pathogenesis and vaccine development.


Real World Home Blood Pressure Variability in Over 56,000 Individuals With Nearly 17 Million Measurements.
Using the data from 56,365 individuals, from 185 countries, and a Nokia Health Wireless blood pressure (BP) monitor, we investigated real-world characteristics of BP variability (BPV). All included individuals self-measured and uploaded their BP using Bluetooth at least 20 times over a period of ≥1 month at a frequency and duration of their choosing. In total, 16,904,844 BP measurements were analyzed, with a median of 146 measurements per person (interquartile range [IQR] 73-321) over a median of 14 months (IQR 7-31). SD, coefficient of variation, maximum BP, and maximum minus minimum BP difference were all calculated as measures of BPV. BPV showed a distinct pattern, influenced by season of year, day of week, and time of day. BPV index was higher in females compared with males (P < 0.001) and increased with age (P < 0.001). Compared to the weekend, the weekday BPV index was significantly higher, and this finding was more prominent in females (P = 0.001). In multivariate analysis, BPV index were significantly associated with age, gender, geographic location, and mean BP values. Using the largest BP data set we are aware of, with the benefits and limitations of real-world measurement, we could show the pattern of BPV and provide reference values that may be helpful in understanding the nature of BPV as self-measurement at home becomes more common, and help guide individualized management.


Permanent neonatal diabetes mellitus.
Neonatal diabetes is a rare cause of hyperglycemia, affecting 1: 500,000 births, with persistent hyperglycemia occurring in the first months of life lasting more than 2 weeks and requiring insulin. This condition in infants less than 6 months of age is considered as permanent neonatal diabetes mellitus. A rare case of permanent neonatal diabetes mellitus presented with intrauterine growth retardation (IUGR; birth weight: 1460 grams; female), hyperglycemia, glycosuria, and mild dehydration, a normal Apgar score of 8 and 9 at 1 and 5 minutes, respectively. The parents, of consanguineous union, had no prior history of diabetes mellitus. Of their 4 children, the first child had a diagnosis similar to the patient (their last child). The patient was initially started on continuous infusion of insulin, and then switched to regular insulin subcutaneously, but response was sub-optimal. She was started on neutral protamine Hagedorn, following which her condition improved. She was discharged on neutral protamine Hagedorn with regular follow-up. In view of widespread consanguinity in Saudi Arabia it appears prudent and pertinent to suspect permanent neonatal diabetes mellitus following diagnosis of hyperglycemia in small-for-age infants, especially those with positive family history of diabetes. Close blood glucose monitoring is essential as long as hyperglycemia persists. Prolong follow-up is imperative.


Genome-wide single-generation signatures of local selection in the panmictic European eel.
Next-generation sequencing and the collection of genome-wide data allow identifying adaptive variation and footprints of directional selection. Using a large SNP data set from 259 RAD-sequenced European eel individuals (glass eels) from eight locations between 34 and 64(o) N, we examined the patterns of genome-wide genetic diversity across locations. We tested for local selection by searching for increased population differentiation using F(ST) -based outlier tests and by testing for significant associations between allele frequencies and environmental variables. The overall low genetic differentiation found (F(ST) = 0.0007) indicates that most of the genome is homogenized by gene flow, providing further evidence for genomic panmixia in the European eel. The lack of genetic substructuring was consistent at both nuclear and mitochondrial SNPs. Using an extensive number of diagnostic SNPs, results showed a low occurrence of hybrids between European and American eel, mainly limited to Iceland (5.9%), although individuals with signatures of introgression several generations back in time were found in mainland Europe. Despite panmixia, a small set of SNPs showed high genetic differentiation consistent with single-generation signatures of spatially varying selection acting on glass eels. After screening 50 354 SNPs, a total of 754 potentially locally selected SNPs were identified. Candidate genes for local selection constituted a wide array of functions, including calcium signalling, neuroactive ligand-receptor interaction and circadian rhythm. Remarkably, one of the candidate genes identified is PERIOD, possibly related to differences in local photoperiod associated with the >30° difference in latitude between locations. Genes under selection were spread across the genome, and there were no large regions of increased differentiation as expected when selection occurs within just a single generation due to panmixia. This supports the conclusion that most of the genome is homogenized by gene flow that removes any effects of diversifying selection from each new generation.


Coronavirus disease 2019 (COVID-19): the portrait of a perfect storm.
The "novel" coronavirus disease 2019 (abbreviated "COVID-19") is the third coronavirus outbreak emerging during the past two decades. This infectious disease, sustained by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has been recently declared a global pandemic by the World Health Organization. Despite the concerning epidemiological burden, many people, including some policymakers, are underestimating this pandemic and are remaining enigmatically inactive against a human pathology which, for a combination of reasons, can be reasonably defined as a perfect storm (i.e., the "wrong virus" at the "wrong time"). These many paradigmatic aspects include SARS-CoV-2 structure and peculiar biology of infection, high risk of inter-human transmission, long incubation time combined with early and sustained viral load, existence of asymptomatic or mildly-symptomatic carriers, viral shedding for days after symptom relief, unfavorable progression towards respiratory distress and death in up to 5-10% of patients thus causing dramatic healthcare challenges, as well as environmental contamination. Last but not least, the combination of the current case fatality rate with the extraordinary number of people that could be potentially infected by SARS-CoV-2 would permit to estimate that the worldwide deaths for COVID-19 may even approximate those recorded during World War II if appropriate restrictive measures for preventing human-to-human transmission are not readily undertaken. Everybody should be inexcusably aware that this is not a drill, and that the consequences of inadequate action will be tragedy.


Transient ischemic attack in heavy cannabis smokers--how 'safe' is it?
Drugs are lately considered high-risk factors for cerebrovascular disease. Three male patients (mean age 24.6 years) who were heavy cannabis smokers presented with transient ischemic attacks (TIA) shortly after cannabis abuse. The complete examination of all 3 consisted of: EEG, brain CT scan, brain MRI, cerebral vessel angiography (digital subtraction and magnetic resonance angiography); also a full cerebrospinal fluid, urine and blood analysis (immunological, biochemical and hormonal tests were included). Urine was further examined for drug metabolites. An extensive cardiological investigation was carried out. Small vessel leukoencephalopathy was revealed by the brain CT and MRI. EEG recordings of the first patient showed paroxysmal sharp waves with left hemispheric dominance. The other 2 patients had diffuse delta and theta activity in their EEG tracings. The urine analysis was positive for cannabis metabolites. There were no other abnormal findings in the rest of the meticulous and thorough study of all 3 patients, which leads to the conclusion that cannabis was the only risk factor responsible for the observed TIA, contradictory to other studies, which support that cannabis is a 'safe' drug. More research is required in order for this issue to be completely elucidated.


Socioeconomic status does not moderate the familiality of cognitive abilities in the Hawaii family study of cognition.
Data from 949 families of Caucasian and 400 families of Japanese ancestry who took part in the Hawaii Family Study of Cognition were used to ascertain the associations of parental cognitive ability, parental education and paternal occupation with offspring cognitive ability. In particular, analyses were focused on testing the possible moderating effects of parental socioeconomic status on the familial transmission of cognitive abilities. Parental cognitive ability was substantially associated and parental education and paternal occupation only trivially associated with offspring performance. In contrast to the findings of Turkheimer et al. (2003), there was no evidence in these data that familiality for cognitive abilities was lower in the lower as opposed to upper levels of socioeconomic status. These results were consistent across measures, ethnicity and sex of offspring.


An optimized web-based approach for collaborative stereoscopic medical visualization.
Medical visualization tools have traditionally been constrained to tethered imaging workstations or proprietary client viewers, typically part of hospital radiology systems. To improve accessibility to real-time, remote, interactive, stereoscopic visualization and to enable collaboration among multiple viewing locations, we developed an open source approach requiring only a standard web browser with no added client-side software. Our collaborative, web-based, stereoscopic, visualization system, CoWebViz, has been used successfully for the past 2 years at the University of Chicago to teach immersive virtual anatomy classes. It is a server application that streams server-side visualization applications to client front-ends, comprised solely of a standard web browser with no added software. We describe optimization considerations, usability, and performance results, which make CoWebViz practical for broad clinical use. We clarify technical advances including: enhanced threaded architecture, optimized visualization distribution algorithms, a wide range of supported stereoscopic presentation technologies, and the salient theoretical and empirical network parameters that affect our web-based visualization approach. The implementations demonstrate usability and performance benefits of a simple web-based approach for complex clinical visualization scenarios. Using this approach overcomes technical challenges that require third-party web browser plug-ins, resulting in the most lightweight client. Compared to special software and hardware deployments, unmodified web browsers enhance remote user accessibility to interactive medical visualization. Whereas local hardware and software deployments may provide better interactivity than remote applications, our implementation demonstrates that a simplified, stable, client approach using standard web browsers is sufficient for high quality three-dimensional, stereoscopic, collaborative and interactive visualization.


Treating patients as persons: a capabilities approach to support delivery of person-centered care.
Health services internationally struggle to ensure health care is "person-centered" (or similar). In part, this is because there are many interpretations of "person-centered care" (and near synonyms), some of which seem unrealistic for some patients or situations and obscure the intrinsic value of patients' experiences of health care delivery. The general concern behind calls for person-centered care is an ethical one: Patients should be "treated as persons." We made novel use of insights from the capabilities approach to characterize person-centered care as care that recognizes and cultivates the capabilities associated with the concept of persons. This characterization unifies key features from previous characterisations and can render person-centered care applicable to diverse patients and situations. By tying person-centered care to intrinsically valuable capability outcomes, it incorporates a requirement for responsiveness to individuals and explains why person-centered care is required independently of any contribution it may make to health gain.