Computed tomographic imaging of stapes implants.
Computed tomographic (CT) imaging of stapes prostheses is inaccurate. Clinical situations arise in which it would be helpful to determine the depth of penetration of a stapes prosthesis into the vestibule. The accuracy of CT imaging for this purpose has not been defined. This study was aimed to determine the accuracy of CT imaging to predict the depth of intrusion of stapes prostheses into the vestibule. The measurement of stapes prostheses by CT scan was compared with physical measurements in 8 cadaveric temporal bones. The depth of intrusion into the vestibule of the piston was underestimated in specimens with the fluoroplastic piston by a mean of 0.5 mm when compared with the measurements obtained in the temporal bones. The depth of penetration of the stainless steel implant was overestimated by 0.5 mm when compared with that in the temporal bone. The type of implant must be taken into consideration when estimating the depth of penetration into the vestibule using CT scanning because the imaging characteristics of the implanted materials differ. The position of fluoroplastic pistons cannot be accurately measured in the vestibule. Metallic implants are well visualized, and measurements exceeding 2.2 mm increase the suspicion of otolithic impingement. Special reconstructions along the length of the piston may be more accurate in estimating the position of stapes implants.


Potential of microbial protein from hydrogen for preventing mass starvation in catastrophic scenarios.
Human civilization's food production system is currently unprepared for catastrophes that would reduce global food production by 10% or more, such as nuclear winter, supervolcanic eruptions or asteroid impacts. Alternative foods that do not require much or any sunlight have been proposed as a more cost-effective solution than increasing food stockpiles, given the long duration of many global catastrophic risks (GCRs) that could hamper conventional agriculture for 5 to 10 years. Microbial food from single cell protein (SCP) produced via hydrogen from both gasification and electrolysis is analyzed in this study as alternative food for the most severe food shock scenario: a sun-blocking catastrophe. Capital costs, resource requirements and ramp up rates are quantified to determine its viability. Potential bottlenecks to fast deployment of the technology are reviewed. The ramp up speed of food production for 24/7 construction of the facilities over 6 years is estimated to be lower than other alternatives (3-10% of the global protein requirements could be fulfilled at end of first year), but the nutritional quality of the microbial protein is higher than for most other alternative foods for catastrophes. Results suggest that investment in SCP ramp up should be limited to the production capacity that is needed to fulfill only the minimum recommended protein requirements of humanity during the catastrophe. Further research is needed into more uncertain concerns such as transferability of labor and equipment production. This could help reduce the negative impact of potential food-related GCRs.


Spatiotemporal and demographic history of the HIV-1 circulating recombinant form CRF31_BC in Brazil.
CRF31_BC is an HIVs-1 recombinant form very prevalent in the southernmost capital city of Brazil, Porto Alegre. Recent studies have been describing a growing number of cases of infection by CRF31_BC in other Brazilian cities and countries, suggesting a process of expansion of this strain. Aiming to describe the city of origin, dispersion routes and demographic history of CRF31_BC, this study analyzed all HIV-1 CRF31_BC and Brazilian BC mosaic publicly available sequences. CRF31_BC classification was performed by bootscanning and tree reconstruction methods. Bayesian phylogeographic and phylodynamic model approaches were used to reconstruct the spatiotemporal and demographic history of 95 sequences identified as CRF31_BC-like. Porto Alegre was estimated to be the origin and center of the dispersion of the CRF31_BC for most of the analyzed locations. However, some viral transitions independent from Porto Alegre were observed in other cities from the Rio Grande do Sul state and also in other Brazilian states. The estimated CRF31_BC epidemic growth rate was similar to subtype C and B in Brazil. Our findings suggest that CRF31_BC, although mostly prevalent in south region, is circulating nation-wide with some localities presenting autochthonous transmissions.


Modeling emerging contaminants breakthrough in packed bed adsorption columns by UV absorbance and fluorescing components of dissolved organic matter.
This study investigated, using rapid small-scale column testing, the breakthrough of dissolved organic matter (DOM) and eleven emerging organic contaminants (EOCs) during granular activated carbon (GAC) filtration of different water qualities, including wastewater, surface water and synthetic water (riverine organic matter dissolved in deionized water). Fluorescing organic matter was better adsorbed than UV absorbance at 254 nm (UV254) and dissolved organic carbon (DOC) in all tested water. Furthermore, highest adsorption of DOM (in terms of DOC, UV254 and fluorescence) was observed during wastewater filtration. UV absorbing DOM had fast and similar breakthrough in surface water and synthetic water, whereas fluorescence breakthrough was very rapid only in synthetic water. PARAFAC modeling showed that different fluorescing components were differently adsorbed during GAC process. Particularly, fluorescing components with maxima intensity at higher excitation wavelengths, which are corresponding to humic-like fluorescence substances, were better removed than other components in all waters. As opposed to DOM, EOCs were better adsorbed during synthetic water filtration, whereas the fastest EOCs breakthrough was observed during filtration of wastewater, which was the water that determined the highest carbon fouling. Exception was represented by long-chained perfluoroalkylated substances (i.e., PFOA, PFDA and PFOS). Indeed, adsorption of these compounds resulted independent of water quality. In this study was also investigated the applicability of UV254 and fluorescing PARAFAC components to act as surrogates in predicting EOCs removal by GAC in different water matrices. Empirical linear correlation for the investigated EOCs were determined with UV254 and fluorescing components in all water qualities. However, fluorescence measurements resulted more sensitive than UV254 to predict EOC breakthrough during GAC adsorption. When the data from all water qualities was combined, good correlations between the microbial humic-like PARAFAC component and EOC removals were still observed and they resulted independent of water quality if considering only real water matrices (wastewater and surface water). On the contrary, correlations between EOC removals and UV254 removals were independent of water quality when combining data of surface waters and synthetic water, but a different correlation model was needed to predict EOCs breakthrough in wastewater.


SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia.
Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic to CML cells contribute to response heterogeneity and TKI resistance. Among extrinsic factors, cytokine-mediated TKI resistance has been demonstrated in CML progenitors, but the underlying mechanisms remain obscure. Using RNA-sequencing, we identified differentially expressed splicing factors in primary CD34+ chronic phase (CP) CML progenitors and controls. We found SRSF1 expression to be increased as a result of both BCR-ABL1- and cytokine-mediated signaling. SRSF1 overexpression conferred cytokine independence to untransformed hematopoietic cells and impaired imatinib sensitivity in CML cells, while SRSF1 depletion in CD34+ CP CML cells prevented the ability of extrinsic cytokines to decrease imatinib sensitivity. Mechanistically, PRKCH and PLCH1 were upregulated by elevated SRSF1 levels, and contributed to impaired imatinib sensitivity. Importantly, very high SRSF1 levels in the bone marrow of CML patients at presentation correlated with poorer clinical TKI responses. In summary, we find SRSF1 levels to be maintained in CD34+ CP CML progenitors by cytokines despite effective BCR-ABL1 inhibition, and that elevated levels promote impaired imatinib responses. Together, our data support an SRSF1/PRKCH/PLCH1 axis in contributing to cytokine-induced impaired imatinib sensitivity in CML.


A non-elaborative mental stance and decoupling of executive and pain-related cortices predicts low pain sensitivity in Zen meditators.
Concepts originating from ancient Eastern texts are now being explored scientifically, leading to new insights into mind/brain function. Meditative practice, often viewed as an emotion regulation strategy, has been associated with pain reduction, low pain sensitivity, chronic pain improvement, and thickness of pain-related cortices. Zen meditation is unlike previously studied emotion regulation techniques; more akin to 'no appraisal' than 'reappraisal'. This implies the cognitive evaluation of pain may be involved in the pain-related effects observed in meditators. Using functional magnetic resonance imaging and a thermal pain paradigm we show that practitioners of Zen, compared to controls, reduce activity in executive, evaluative and emotion areas during pain (prefrontal cortex, amygdala, hippocampus). Meditators with the most experience showed the largest activation reductions. Simultaneously, meditators more robustly activated primary pain processing regions (anterior cingulate cortex, thalamus, insula). Importantly, the lower pain sensitivity in meditators was strongly predicted by reductions in functional connectivity between executive and pain-related cortices. Results suggest a functional decoupling of the cognitive-evaluative and sensory-discriminative dimensions of pain, possibly allowing practitioners to view painful stimuli more neutrally. The activation pattern is remarkably consistent with the mindset described in Zen and the notion of mindfulness. Our findings contrast and challenge current concepts of pain and emotion regulation and cognitive control; commonly thought to manifest through increased activation of frontal executive areas. We suggest it is possible to self-regulate in a more 'passive' manner, by reducing higher-order evaluative processes, as demonstrated here by the disengagement of anterior brain systems in meditators.


Oral health status and oral health behaviors in Chinese Children.
The objectives of the study were to describe the oral health status and treatment needs of the 5- to 6-year-old and 12-year-old children in Southern China; to describe the patterns of oral health behaviors, knowledge, and attitudes among the 12-year-olds; and to assess the effects of socio-behavioral factors on the 12-year-old children's dental caries experiences. The study sample was comprised of 1,587 5- to 6-year-old and 1,576 12-year-old urban and rural schoolchildren living in Guangdong Province. Three calibrated dentists clinically examined the children, and trained interviewers interviewed the 12-year-olds. Caries prevalence of the 5- to 6-year-old children was high (urban 78% vs. rural 86%); the mean dmft of the urban and rural children was 4.8 and 7.0, respectively. The caries prevalence and mean DMFT score of the 12-year-olds were 41% and 0.9 (urban) and 42% and 0.9 (rural). Only 2% of the 12-year-olds exhibited no calculus or gingival bleeding, while more than 70% had calculus. In conclusion, there is an urgent need for establishing caries-preventive activities for preschool children. The prevalence of caries among the 12-year-olds was not high, but their periodontal condition was unsatisfactory. Knowledge about gum bleeding and the use of fluoride was low. More oral health education activities should be organized, especially for the rural children.


Consequences of electrical conductivity in an orb spider's capture web.
The glue-coated and wet capture spiral of the orb web of the garden cross spider Araneus diadematus is suspended between the dry silk radial and web frame threads. Here, we experimentally demonstrate that the capture spiral is electrically conductive because of necks of liquid connecting the droplets even if the thread is stretched. We examine how this conductivity of the capture spiral may lead to entrapment of charged airborne particles such as pollen, spray droplets and even insects. We further describe and model how the conducting spiral will also locally distort the Earth's ambient electric field. Finally, we examine the hypothesis that such distortion could be used by potential prey to detect the presence of a web but conclude that any effect would probably be too small to allow an insect to take evasive action.


Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.
To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. EudraCT2011-004720-35, NCT01491815.


Predictive models of glucose control: roles for glucose-sensing neurones.
The brain can be viewed as a sophisticated control module for stabilizing blood glucose. A review of classical behavioural evidence indicates that central circuits add predictive (feedforward/anticipatory) control to the reactive (feedback/compensatory) control by peripheral organs. The brain/cephalic control is constructed and engaged, via associative learning, by sensory cues predicting energy intake or expenditure (e.g. sight, smell, taste, sound). This allows rapidly measurable sensory information (rather than slowly generated internal feedback signals, e.g. digested nutrients) to control food selection, glucose supply for fight-or-flight responses or preparedness for digestion/absorption. Predictive control is therefore useful for preventing large glucose fluctuations. We review emerging roles in predictive control of two classes of widely projecting hypothalamic neurones, orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH) cells. Evidence is cited that ORX neurones (i) are activated by sensory cues (e.g. taste, sound), (ii) drive hepatic production, and muscle uptake, of glucose, via sympathetic nerves, (iii) stimulate wakefulness and exploration via global brain projections and (iv) are glucose-inhibited. MCH neurones are (i) glucose-excited, (ii) innervate learning and reward centres to promote synaptic plasticity, learning and memory and (iii) are critical for learning associations useful for predictive control (e.g. using taste to predict nutrient value of food). This evidence is unified into a model for predictive glucose control. During associative learning, inputs from some glucose-excited neurones may promote connections between the 'fast' senses and reward circuits, constructing neural shortcuts for efficient action selection. In turn, glucose-inhibited neurones may engage locomotion/exploration and coordinate the required fuel supply. Feedback inhibition of the latter neurones by glucose would ensure that glucose fluxes they stimulate (from liver, into muscle) are balanced. Estimating nutrient challenges from indirect sensory cues may become more difficult when the cues become complex and variable (e.g. like human foods today). Consequent errors of predictive glucose control may contribute to obesity and diabetes.


Variation in in-hospital mortality and its association with percutaneous coronary intervention-related bleeding complications: A report from nationwide registry in Japan.
Large-scale registries have demonstrated that in-hospital mortality after percutaneous coronary intervention (PCI) varies widely across institutions. However, whether this variation is related to major procedural complications (e.g., bleeding) is unclear. In this study, institutional variation in in-hospital mortality and its association with PCI-related bleeding complications were investigated. We analyzed 388,866 procedures at 718 hospitals performed from 2017 to 2018, using data from a nationwide PCI registry in Japan. Hospitals were stratified into quintiles according to risk-adjusted in-hospital mortality (very low, low, medium, high, and very high). Incidence of bleeding complications, defined as procedure-related bleeding events that required a blood transfusion, and in-hospital mortality in patients who developed bleeding complications were calculated for each quintile. Overall, 4,048 (1.04%) in-hospital deaths and 1,535 (0.39%) bleeding complications occurred. Among patients with bleeding complications, 270 (17.6%) died during hospitalization. In-hospital mortality ranged from 0.22% to 2.46% in very low to very high mortality hospitals. The rate of bleeding complications varied modestly from 0.27% to 0.57% (odds ratio, 1.95; 95% confidence interval, 1.58-2.39). However, mortality after bleeding complications markedly increased by quintile and was 6-fold higher in very high mortality hospitals than very low mortality hospitals (29.0% vs. 4.8%; odds ratio, 12.2; 95% confidence interval, 6.90-21.7). In conclusion, institutional variation in in-hospital mortality after PCI was associated with procedure-related bleeding complications, and this variation was largely driven by differences in mortality after bleeding complications rather than difference in their incidence. These findings underscore the importance of efforts toward reducing not only bleeding complications but also, even more importantly, subsequent mortality once they have occurred.


Interacting effects of wildlife loss and climate on ticks and tick-borne disease.
Both large-wildlife loss and climatic changes can independently influence the prevalence and distribution of zoonotic disease. Given growing evidence that wildlife loss often has stronger community-level effects in low-productivity areas, we hypothesized that these perturbations would have interactive effects on disease risk. We experimentally tested this hypothesis by measuring tick abundance and the prevalence of tick-borne pathogens (Coxiella burnetii and Rickettsia spp.) within long-term, size-selective, large-herbivore exclosures replicated across a precipitation gradient in East Africa. Total wildlife exclusion increased total tick abundance by 130% (mesic sites) to 225% (dry, low-productivity sites), demonstrating a significant interaction of defaunation and aridity on tick abundance. When differing degrees of exclusion were tested for a subset of months, total tick abundance increased from 170% (only mega-herbivores excluded) to 360% (all large wildlife excluded). Wildlife exclusion differentially affected the abundance of the three dominant tick species, and this effect varied strongly over time, likely due to differences among species in their host associations, seasonality, and other ecological characteristics. Pathogen prevalence did not differ across wildlife exclusion treatments, rainfall levels, or tick species, suggesting that exposure risk will respond to defaunation and climate change in proportion to total tick abundance. These findings demonstrate interacting effects of defaunation and aridity that increase disease risk, and they highlight the need to incorporate ecological context when predicting effects of wildlife loss on zoonotic disease dynamics.


Products and mechanism of acene dimerization. A computational study.
The high reactivity of acenes can reduce their potential applications in the field of molecular electronics. Although pentacene is an important material for use in organic field-effect transistors because of its high charge mobility, its reactivity is a major disadvantage hindering the development of pentacene applications. In this study, several reaction pathways for the thermal dimerization of acenes were considered computationally. The formation of acene dimers via a central benzene ring and the formation of acene-based polymers were found to be the preferred pathways, depending on the length of the monomer. Interestingly, starting from hexacene, acene dimers are thermodynamically disfavored products, and the reaction pathway is predicted to proceed instead via a double cycloaddition reaction (polymerization) to yield acene-based polymers. A concerted asynchronous reaction mechanism was found for benzene and naphthalene dimerization, while a stepwise biradical mechanism was predicted for the dimerization of anthracene, pentacene, and heptacene. The biradical mechanism for dimerization of anthracene and pentacene proceeds via syn or anti transition states and biradical minima through stepwise biradical pathways, while dimerization of heptacene proceeds via asynchronous ring closure of the complex formed by two heptacene molecules. The activation barriers for thermal dimerization decrease rapidly with increasing acene chain length and are calculated (at M06-2X/6-31G(d)+ZPVE) to be 77.9, 57.1, 33.3, -0.3, and -12.1 kcal/mol vs two isolated acene molecules for benzene, naphthalene, anthracene, pentacene, and heptacene, respectively. If activation energy is calculated vs the initially formed complex of two acene molecules, then the calculated barriers are 80.5, 63.2, 43.7, 16.7, and 12.3 kcal/mol. Dimerization is exothermic from anthracene onward, but it is endothermic at the terminal rings, even for heptacene. Phenyl substitution at the most reactive meso-carbon atoms of the central ring of acene blocks the reactivity of this ring but does not efficiently prevent dimerization through other rings.


Second generation sequencing of the mesothelioma tumor genome.
The current paradigm for elucidating the molecular etiology of cancers relies on the interrogation of small numbers of genes, which limits the scope of investigation. Emerging second-generation massively parallel DNA sequencing technologies have enabled more precise definition of the cancer genome on a global scale. We examined the genome of a human primary malignant pleural mesothelioma (MPM) tumor and matched normal tissue by using a combination of sequencing-by-synthesis and pyrosequencing methodologies to a 9.6X depth of coverage. Read density analysis uncovered significant aneuploidy and numerous rearrangements. Method-dependent informatics rules, which combined the results of different sequencing platforms, were developed to identify and validate candidate mutations of multiple types. Many more tumor-specific rearrangements than point mutations were uncovered at this depth of sequencing, resulting in novel, large-scale, inter- and intra-chromosomal deletions, inversions, and translocations. Nearly all candidate point mutations appeared to be previously unknown SNPs. Thirty tumor-specific fusions/translocations were independently validated with PCR and Sanger sequencing. Of these, 15 represented disrupted gene-encoding regions, including kinases, transcription factors, and growth factors. One large deletion in DPP10 resulted in altered transcription and expression of DPP10 transcripts in a set of 53 additional MPM tumors correlated with survival. Additionally, three point mutations were observed in the coding regions of NKX6-2, a transcription regulator, and NFRKB, a DNA-binding protein involved in modulating NFKB1. Several regions containing genes such as PCBD2 and DHFR, which are involved in growth factor signaling and nucleotide synthesis, respectively, were selectively amplified in the tumor. Second-generation sequencing uncovered all types of mutations in this MPM tumor, with DNA rearrangements representing the dominant type.


Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance.
Currently, no consensus has been reached regarding the management of hyperlipidemia in patients who develop statin-associated myalgia (SAM). Many statin-intolerant patients use alternative lipid-lowering therapies, including red yeast rice. The present trial evaluated the tolerability of red yeast rice versus pravastatin in patients unable to tolerate other statins because of myalgia. The study was conducted in a community-based setting in Philadelphia, Pennsylvania. A total of 43 adults with dyslipidemia and a history of statin discontinuation because of myalgia were randomly assigned to red yeast rice 2,400 mg twice daily or pravastatin 20 mg twice daily for 12 weeks. All subjects were concomitantly enrolled in a 12-week therapeutic lifestyle change program. The primary outcomes included the incidence of treatment discontinuation because of myalgia and a daily pain severity score. The secondary outcomes were muscle strength and plasma lipids. The incidence of withdrawal from medication owing to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). The mean pain severity did not differ significantly between the 2 groups. No difference was found in muscle strength between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. In conclusion, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.


Comparison of the laboratory data between Kawasaki disease and enterovirus after intravenous immunoglobulin treatment.
Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. The laboratory findings before and after intravenous immunoglobulin (IVIG) in KD have been discussed, but the characteristics of IVIG therapy still are unclear. This study aimed to compare laboratory data from patients with KD and enterovirus (EV) infection to evaluate the differences after IVIG therapy. The study enrolled 171 KD patients and 38 EV patients treated with a single dose of IVIG from 2003 to 2010. Laboratory data including total white blood cell counts (WBC) and hemoglobin (Hb), platelet, segment, lymphocyte, eosinophil, and monocyte levels were analyzed. Compared with the KD patients, the EV patients had higher Hb, lymphocyte, and monocyte levels and lower eosinophil levels before IVIG treatment (p < 0.05). After IVIG treatment, the KD patients had lower Hb and segment levels but higher platelet, lymphocyte, and eosinophil levels than the EV patients (p < 0.05). In the KD patients, the platelet, eosinophil, and monocyte levels increased after IVIG treatment, whereas Hb, WBC, and segment levels decreased significantly (p < 0.001). In the EV patients, eosinophil levels increased after IVIG treatment, whereas WBC and Hb levels decreased significantly (p < 0.05). The study results provide evidence that eosinophilia may be related to IVIG therapy in KD and EV patients. The KD patients had higher eosinophil levels both before and after IVIG therapy than the EV patients, which may have been due to the inflammatory mechanism of KD. The KD patients had higher platelet levels than the EV patients, suggesting that platelets are involved in the inflammatory response to KD.


Epigenetic regulation of PGU1 transcription in Saccharomyces cerevisiae.
The PGU1 gene of Saccharomyces cerevisiae has been shown to encode a polygalacturonase. The polygalacturonase activity in S. cerevisiae is strain specific. There are no significant differences in the PGU1 promoter regions of strains with and without polygalacturonase activity. The PGU1 gene is subtelomeric because it is located within 25 kb of the right telomere of chromosome X. Expressions of genes located in subtelomeric regions in the yeast S. cerevisiae are inhibited compared with the rest of the genome. In this study, we showed that the deletion of genes involved in telomere silencing enhances polygalacturonase activity. PGU1 transcription and polygalacturonase activity are increased when PGU1 is shifted to a different location in the genome, away from the telomere located close to this gene, and the depletion of the histone H4 leads to an increase in PGU1 transcription. We concluded that PGU1 is silenced in strains without polygalacturonase activity due to an epigenetic effect. The results of this study suggest that PGU1 is silenced by being folded into a heterochromatin-like structure at its subtelomeric position on chromosome X. Formation of this silent structure is dependent on the Isw2p chromatin remodeling complex, its histone fold motif containing subunit Dls1p and the N-terminal tail of the H4 histone.


Peg Biology: Deciphering the Molecular Regulations Involved During Peanut Peg Development.
Peanut or groundnut is one of the most important legume crops with high protein and oil content. The high nutritional qualities of peanut and its multiple usage have made it an indispensable component of our daily life, in both confectionary and therapeutic food industries. Given the socio-economic significance of peanut, understanding its developmental biology is important in providing a molecular framework to support breeding activities. In peanut, the formation and directional growth of a specialized reproductive organ called a peg, or gynophore, is especially relevant in genetic improvement. Several studies have indicated that peanut yield can be improved by improving reproductive traits including peg development. Therefore, we aim to identify unifying principles for the genetic control, underpinning molecular and physiological basis of peg development for devising appropriate strategy for peg improvement. This review discusses the current understanding of the molecular aspects of peanut peg development citing several studies explaining the key mechanisms. Deciphering and integrating recent transcriptomic, proteomic, and miRNA-regulomic studies provide a new perspective for understanding the regulatory events of peg development that participate in pod formation and thus control yield.


Transgenerational Adaptation to Pollution Changes Energy Allocation in Populations of Nematodes.
Assessing the evolutionary responses of long-term exposed populations requires multigeneration ecotoxicity tests. However, the analysis of the data from these tests is not straightforward. Mechanistic models allow the in-depth analysis of the variation of physiological traits over many generations, by quantifying the trend of the physiological and toxicological parameters of the model. In the present study, a bioenergetic mechanistic model has been used to assess the evolution of two populations of the nematode Caenorhabditis elegans in control conditions or exposed to uranium. This evolutionary pressure resulted in a brood size reduction of 60%. We showed an adaptation of individuals of both populations to experimental conditions (increase of maximal length, decrease of growth rate, decrease of brood size, and decrease of the elimination rate). In addition, differential evolution was also highlighted between the two populations once the maternal effects had been diminished after several generations. Thus, individuals that were greater in maximal length, but with apparently a greater sensitivity to uranium were selected in the uranium population. In this study, we showed that this bioenergetics mechanistic modeling approach provided a precise, certain, and powerful analysis of the life strategy of C. elegans populations exposed to heavy metals resulting in an evolutionary pressure across successive generations.


Peripheral Neuropathy Induces HCN Channel Dysfunction in Pyramidal Neurons of the Medial Prefrontal Cortex.
Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its molecular basis. The cationic current Ih mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays an important role in pain by facilitating ectopic firing and hyperexcitability in DRG neurons, however little is known regarding the role of Ih in supraspinal pain pathways. The medial prefrontal cortex (mPFC), which is reported to be involved in the affective aspects of pain, exhibits high HCN channel expression. Using the spared nerve injury (SNI) model of neuropathic pain in Long-Evans rats and patch-clamp recordings in layer II/III pyramidal neurons of the contralateral mPFC, we observed a hyperpolarizing shift in the voltage-dependent activation of Ih in SNI neurons, whereas maximal Ih remained unchanged. Accordingly, SNI mPFC pyramidal neurons exhibited increased input resistance and excitability, as well as facilitated glutamatergic mGluR5-mediated persistent firing, compared with sham neurons. Moreover, intracellular application of bromo-cAMP abolished the hyperpolarizing shift in the voltage-dependent activation of Ih observed in SNI neurons, whereas protein kinase A (PKA) inhibition further promoted this shift in both SNI and sham neurons. Behaviorally, acute HCN channel blockade by local injection of ZD7288 in the mPFC of SNI rats induced a decrease in cold allodynia. These findings suggest that changes in the cAMP/PKA axis in mPFC neurons underlie alterations to HCN channel function, which can influence descending inhibition of pain pathways in neuropathic conditions. Significance statement: Recent studies investigating the role of the medial prefrontal cortex (mPFC) in neuropathic pain have led to an increased awareness of how affective and cognitive factors can influence pain perception. It is therefore imperative that we advance our understanding of the involvement of supraspinal pain pathways. Our electrophysiological and behavioral results support an important role for hyperpolarization-activated cyclic nucleotide-gated channels and the cAMP/protein kinase A signaling axis in promoting hyperexcitability and persistent firing in pyramidal neurons of the mPFC in neuropathic animals. These findings offer novel insights, with potential therapeutic implications, into pathophysiological mechanisms underlying the abnormal contribution of layer II/III prefrontal pyramidal neurons to chronic pain states.


Vulnerability of Subarctic and Arctic breeding birds.
Recent research predicts that future climate change will result in substantial biodiversity loss associated with loss of habitat for species. However, the magnitude of the anticipated biodiversity impacts are less well known. Studies of species vulnerability to climate change through species distribution models are often limited to assessing the extent of species' exposure to the consequences of climate change to their local environment, neglecting species sensitivity to global change. The likelihood that species or populations will decline or go extinct due to climate change also depends on the general sensitivity and adaptive capacity of species. Hence, analyses should also obtain more accurate assessments of their vulnerability. We addressed this by constructing a vulnerability matrix for 180 bird species currently breeding in Subarctic and Arctic Europe that integrates a climatic exposure-based vulnerability index and a natural-history trait-based vulnerability index. Species that may need extra conservation attention based on our matrix include the Great Snipe (Gallinago media), the Rough-legged Buzzard (Buteo lagopus), the Red-throated Pipit (Anthus cervinus), the Common Swift (Apus apus), the Horned Lark (Eremophila alpestris), and the Bar-tailed Godwit (Limosa lapponica). Our vulnerability matrix stresses the importance of looking beyond exposure to climate change when species conservation is the aim. For the species that scored high in our matrix the future in the region looks grim and targeted conservation actions, incorporating macroecological and global perspectives, may be needed to alleviate severe population declines. We further demonstrate that climate change is predicted to significantly reduce the current breeding range of species adapted to cold climates in Subarctic and Arctic Europe. The number of incubation days and whether the species was a habitat specialist or not were also among the variables most strongly related to predicted contraction or expansion of species' breeding ranges. This approach may aid the identification of vulnerable bird species worldwide.


A dissipative quantum mechanical beam-splitter.
A dissipative beam-splitter (BS) has been analyzed by modeling the losses in the BS due to the excitation of optical phonons. The losses are obtained in terms of the BS medium properties. The model simplies the picture by treating the loss mechanism as a perturbation on the photon modes in a linear, non-lossy medium in the limit of small losses, instead of using the full field quantization in lossy, dispersive media. The model uses second order perturbation in the Markoff approximation and yields the Beer's law for absorption in the first approximation, thus providing a microscopic description of the absorption coecient. It is shown that the fluctuations in the modes get increased because of the losses. We show the existence of quantum interferences due to phase correlations between the input beams and it is shown that these correlations can result in loss quenching. Hence in spite of having such a dissipative medium, it is possible to design a lossless 50-50 BS at normal incidence which may have potential applications in laser optics and dielectric-coated mirrors.


Atlas-Based Mosaicing of Left Atrial 3-D Transesophageal Echocardiography Images.
Transesophageal echocardiography (TEE) is a promising imaging modality used to guide cardiac interventions, such as catheter ablation for the treatment of cardiac arrhythmias. These procedures rely on good visualization of the left atrium and pulmonary veins. To visualize these structures in a single volume, the acquisition, registration and fusion of multiple TEE views of the left atrium are required. We introduce atlas-based mosaicing as a method for the registration of images that are acquired according to a standardized protocol. Inspired by atlas-based segmentation approaches, compounded data of other patients serve as atlases for the registration of new data. The performance of atlas-based mosaicing is studied on 3-D TEE data of the left atrium and compared with that of regular pairwise registration. This study indicates that improved registration robustness and smaller registration errors are achieved with atlas-based mosaicing compared with regular pairwise registration. This is an important step toward the use of TEE for interventional guidance of ablation procedures.


Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling.
Sorafenib inhibits tumor growth primarily by inhibiting vessel formation, however, its efficacy requires improvement, therefore, the development of strategies which augment its antiangiogenic effect are of primary concern. Bufalin inhibits tumor cell proliferation and metastasis, and induces apoptosis. In our previous study, it was demonstrated that the antiangiogenic effect of sorafenib was improved by bufalin in human umbilical vein endothelial cells (HUVECs). However, whether bufalin synergizes with sorafenib by affecting the tumor vascular microenvironment remains to be elucidated. In the present study, it was found that hepatocellular carcinoma (HCC) cell proliferation was inhibited by either bufalin or sorafenib following incubation for 24 h, and the inhibition was enhanced upon treatment with a combination of the two. Conditioned medium (CM), comprising supernatant from HCC cells was collected from each of the treatment groups. The migration and tubule formation were suppressed the most in the combination-CM treated HUVECs. The secretion of vascular endothelial growth factor (VEGF) was decreased in HCC cells treated with the combination-CM, as determined by an angiogenesis array, enzyme-linked immunosorbent assay (ELISA) and western blot analysis. The inhibition of tube formation in HUVECs treated with the combination-CM was reversed by incubation with VEGF. The in vivo experiments demonstrated that subcutaneous HCC cell tumors from mice treated with the combination treatment expressed the lowest levels of VEGF, as evidenced by immunohistochemistry and ELISA. Additionally, the level of phosphorylated mechanistic target of rapamycin (mTOR) was reduced in HUVECs pretreated with the phosphoinositide 3-kinase inhibitor PI103. Furthermore, the migration of HCC cells and HUVEC tube formation were attenuated by PI103 pretreatment. In conclusion, the results revealed a synergistic anti-hepatoma effect of bufalin combined with sorafenib via affecting the tumor vascular microenvironment by targeting mTOR/VEGF signaling.


Divergence of ecosystem services in U.S. National Forests and Grasslands under a changing climate.
The 170 National Forests and Grasslands (NFs) in the conterminous United States are public lands that provide important ecosystem services such as clean water and timber supply to the American people. This study investigates the potential impacts of climate change on two key ecosystem functions (i.e., water yield and ecosystem productivity) using the most recent climate projections derived from 20 Global Climate Models (GCMs) of the Coupled Model Intercomparison Project phase 5 (CMIP5). We find that future climate change may result in a significant reduction in water yield but an increase in ecosystem productivity in NFs. On average, gross ecosystem productivity is projected to increase by 76 ~ 229 g C m(-2) yr(-1) (8% ~ 24%) while water yield is projected to decrease by 18 ~ 31 mm yr(-1) (4% ~ 7%) by 2100 as a result of the combination of increased air temperature (+1.8 ~ +5.2 °C) and precipitation (+17 ~ +51 mm yr(-1)). The notable divergence in ecosystem services of water supply and carbon sequestration is expected to intensify under higher greenhouse gas emission and associated climate change in the future, posing greater challenges to managing NFs for both ecosystem services.


A Descriptive Study of Psychiatric Consultations in a Community Primary Care Center.
BACKGROUND: This retrospective chart review study describes on-site psychiatric consultations at a large, urban community primary care center. The referral population, diagnostic reliability of primary care providers (PCPs) and social workers, appropriateness of PCP-initiated treatment, impact of treatment recommendations, and outcomes are examined. METHOD: Charts of all patients who received psychiatric consultations (N = 78) during an 8-month period (August 1996 to April 1997) were reviewed. RESULTS: Prereferral diagnoses by PCPs matched the psychiatrist's diagnosis based on DSM-IV diagnostic criteria approximately half the time. PCPs initiated psychopharmacology in half the referrals (39/78) and used generally appropriate medications (30/39) based on diagnosis by a psychiatrist, but at subtherapeutic doses (21/39). PCPs tended to continue medications recommended by the psychiatrist. At 1 year, PCPs clearly documented improvement in nearly a third of the consults (24/78). CONCLUSION: Diagnostic disagreement of caregivers, inadequate PCP psychopharmacology practices, and patient nonadherence are 3 main problems that impede optimal care within the model of psychiatric consultation described in this study.


Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer.
Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 × 10(-4)) and UGT1A6 (P = 8 × 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P(additive) = 1 × 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.


The 69 bp circadian regulatory sequence (CRS) mediates per-like developmental, spatial, and circadian expression and behavioral rescue in Drosophila.
The period (per) gene is an essential component of the circadian timekeeping mechanism in Drosophila. This gene is expressed in a circadian manner, giving rise to a protein that feeds-back to regulate its own transcription. A 69 bp clock regulatory sequence (CRS) has been identified previously upstream of the period gene. The CRS confers wild-type mRNA cycling when used to drive a lacZ reporter gene in transgenic flies. To determine whether the CRS also mediates proper developmental and spatial expression and behavioral rescue, we used the CRS to drive either lacZ or per in transgenic flies. The results show that the CRS is able to activate expression in pacemaker neuron precursors in larvae and essentially all tissues that normally express per in pupae and adults. The CRS is sufficient to rescue circadian feedback loop function and behavioral rhythms in per01 flies. However, the period of locomotor activity rhythms shortens if a stronger basal promoter is used. This study shows that regulatory elements sufficient for clock-dependent and tissue-specific per expression in larvae, pupae, and adults are present in the CRS and that the period of adult locomotor activity rhythms is dependent, in part, on the overall level of per transcripts.


Dynamic and reversible self-assembly of photoelectrochemical complexes based on lipid bilayer disks, photosynthetic reaction centers, and single-walled carbon nanotubes.
An aqueous solution containing photosynthetic reaction centers (RCs), membrane scaffold proteins (MSPs), phospholipids, and single-walled carbon nanotubes (SWCNTs) solubilized with the surfactant sodium cholate (SC) reversibly self-assembles into a highly ordered structure upon dialysis of the latter. The resulting structure is photoelectrochemically active and consists of 4-nm-thick lipid bilayer disks (nanodisks, NDs) arranged parallel to the surface of the SWCNT with the RC housed within the bilayer such that its hole injecting site faces the nanotube surface. The structure can be assembled and disassembled autonomously with the addition or removal of surfactant. We model the kinetic and thermodynamic forces that drive the dynamics of this reversible self-assembly process. The assembly is monitored using spectrofluorimetry during dialysis and subsequent surfactant addition and used to fit a kinetic model to determine the forward and reverse rate constants of ND and ND-SWCNT formation. The calculated ND and ND-SWCNT forward rate constants are 79 mM(-1) s(-1) and 5.4 × 10(2) mM(-1) s(-1), respectively, and the reverse rate constants are negligible over the dialysis time scale. We find that the reaction is not diffusion-controlled since the ND-SWCNT reaction, which consists of entities with smaller diffusion coefficients, has a larger reaction rate constant. Using these rate parameters, we were able to develop a kinetic phase diagram for the formation of ND-SWCNT complexes, which indicates an optimal dialysis rate of approximately 8 × 10(-4) s(-1). We also fit the model to cyclic ND-SWCNT assembly and disassembly experiments and hence mimic the thermodynamic forces used in regeneration processes detailed previously. Such forces may form the basis of both synthetic and natural photoelectrochemical complexes capable of dynamic component replacement and repair.


Systemic energy homeostasis in Huntington's disease patients.
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the HTT gene. Apart from neurological impairment, the disease is also accompanied by progressive weight loss, abnormalities in fat and glucose homeostasis and a higher prevalence of diabetes mellitus, the causes of which are unknown. Therefore, a detailed analysis of systemic energy homeostasis in HD patients in relation to disease characteristics was performed. Indirect calorimetry combined with a hyperinsulinaemic-euglycaemic clamp with stable isotopes ([6,6-2H2]-glucose and [2H5]- glycerol) was performed to assess energy expenditure and glucose and fat metabolism in nine early stage, medication free HD patients and nine age, sex and body mass index matched controls. Compared with controls, fasting energy expenditure was higher in HD patients (1616 ± 72 vs 1883 ± 93 kcal/24 h, p=0.037) and increased even further after insulin stimulation (1667 ± 87 vs 2068 ± 122 kcal/24 h, p=0.016). During both basal and hyperinsulinaemic conditions, glucose and glycerol disposal rates, endogenous glucose production and hepatic insulin sensitivity were similar between HD patients and controls. In HD patients, energy expenditure increased with disease duration but not with a greater degree of motor or functional impairment. Moreover, a higher mutant CAG repeat size was associated with lower insulin sensitivity (r=-0.84, p=0.018). These findings suggest sympathetic hyperactivity as an underlying mechanism of increased energy expenditure in HD, as well as peripheral polyglutamine length dependent interference of mutant huntingtin with insulin signalling that may become clinically relevant in carriers of mutations with large CAG repeat sizes.


Tetra-substituted pyridinylimidazoles as dual inhibitors of p38α mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of neurodegenerative diseases.
Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α MAP kinase inhibitors are 6m (IC50: JNK3, 18 nM; p38α, 30 nM) and 14d (IC50: JNK3, 26 nM; p38α, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington's disease.


Quantifying the activity of cis-regulatory elements in the mouse retina by explant electroporation.
Transcription factors within cellular gene networks control the spatiotemporal pattern and levels of expression of their target genes by binding to cis-regulatory elements (CREs), short (˜300-600 bp) stretches of genomic DNA which can lie upstream, downstream, or within the introns of the genes they control. CREs (i.e., enhancers/promoters) typically consist of multiple clustered binding sites for both transcriptional activators and repressors(1-3). They serve as logical integrators of transcriptional input giving a unitary output in the form of spatiotemporally precise and quantitatively exact promoter activity. Most studies of mammalian cis-regulation to date have relied on mouse transgenesis as a means of assaying the enhancer function of CREs(4-5). This technique is time-consuming, costly and, on account of insertion site effects, largely non-quantitative. On the other hand, quantitative assays for mammalian CRE function have been developed in tissue culture systems (e.g., dual luciferase assays), but the in vivo relevance of these results is often uncertain. Electroporation offers an excellent alternative to traditional mouse transgenesis in that it permits both spatiotemporal and quantitative assessment of cis-regulatory activity in living mammalian tissue. This technique has been particularly useful in the analysis of cis-regulation in the central nervous system, especially in the cerebral cortex and the retina(6-8). While mouse retinal electroporation, both in vivo and ex vivo, has been developed and extensively described by Matsuda and Cepko(6-7,9), we have recently developed a simple approach to quantify the activity of photoreceptor-specific CREs in electroporated mouse retinas(10). Given that the amount of DNA that is introduced into the retina by electroporation can vary from experiment to experiment, it is necessary to include a co-electroporated 'loading control' in all experiments. In this respect, the technique is very similar to the dual luciferase assay used to quantify promoter activity in cultured cells. When assaying photoreceptor cis-regulatory activity, electroporation is usually performed in newborn mice (postnatal day 0, P0) which is the time of peak rod production(11-12). Once retinal cell types become post-mitotic, electroporation is much less efficient. Given the high rate of rod birth in newborn mice and the fact that rods constitute more than 70% of the cells in the adult mouse retina, the majority of cells that are electroporated at P0 are rods. For this reason, rod photoreceptors are the easiest retinal cell type to study via electroporation. The technique we describe here is primarily useful for quantifying the activity of photoreceptor CREs.


Prognostic value of psychological testing in patients undergoing spinal cord stimulation: a prospective study.
Associations between psychological and physical states are understood to exist, and the development of standardized psychological tests has allowed quantitative evaluation of this relationship. We tested whether associations exist between psychological test instruments and patients selected for therapeutic trials of spinal cord stimulation (SCS) for chronic, intractable pain. Fifty-eight patients selected for SCS were tested prospectively with a battery of standardized psychological tests: Minnesota Multiphasic Personality Inventory with Wiggins content scales, Symptom Check List-90, and Derogatis Affects Balance Scale. Associations between treatment outcomes and preoperative test scores and clinical variables were tested by univariate and multivariate statistical analyses, in which the dependent variables were as follows: 1) the outcome of a therapeutic trial of stimulation (whether the patient derived sufficient reported pain relief with a temporary electrode to proceed with a permanent implant), and 2) long-term outcome of treatment with the permanent implant, as determined by disinterested third-party interview. Significant associations (P < or = 0.01) were observed between the outcome of the therapeutic trial of stimulation and psychological test results; patients with low "anxiety" scores on the Derogatis Affects Balance Scale and with high "organic symptoms" scores on the Wiggins test were significantly more likely to proceed to permanent implants, as determined by multivariate statistical models. There was an elevation in the Minnesota Multiphasic Personality Inventory hypochondriasis scale in these patients by univariate (P = 0.02), but not by multivariate, models. The multivariate model also identified young age, reproduction of leg pain by straight leg raising, and bilateral leg pain as favorable prognostic factors. The only association with favorable long-term outcome of implantation of a permanent device, by univariate analysis, was an elevated "joy" score on the Derogatis Affects Balance Scale. Multivariate analysis revealed no statistically significant predictors of long-term outcome. Because our study population was selected on the basis of recognized prognostic factors and long clinical experience, it may not be possible to generalize our findings to the overall pain clinic referral population. In the subpopulation we have chosen for SCS trials, psychological testing is of modest value and explains little of the observed variance in outcome. We find little evidence for selecting patients for SCS on the basis of psychological testing. Because self-reported outcome measures may themselves reflect the patient's psychological state, these findings should be considered carefully, in overall clinical context. A prospective study with additional objective outcome measures is underway, which will address some of these issues.


International variations in harsh child discipline.
Although the history of recognition of child abuse in Europe and North America extends over 40 years, recognition and data are lacking in other parts of the world. Cultural differences in child-rearing complicate cross-cultural studies of abuse. To ascertain rates of harsh and less-harsh parenting behavior in population-based samples. We used parallel surveys of parental discipline of children in samples of mothers in Brazil, Chile, Egypt, India, Philippines, and the United States. Data were collected between 1998 and 2003. The instrument used was a modification of the Parent-Child Conflict Tactics Scale, along with a study-developed survey of demographic characteristics and other parent and child variables. Women (N=14 239) from 19 communities in 6 countries were surveyed. We interviewed mothers aged 15 to 49 years (18-49 years in the United States) who had a child younger than 18 years in her home. Sample selection involved either random sampling or systematic sampling within randomly selected blocks or neighborhoods. Nearly all parents used nonviolent discipline and verbal or psychological punishment. Physical punishment was used in at least 55% of the families. Spanking rates (with open hand on buttocks) ranged from a low of 15% in an educated community in India to a high of 76% in a Philippine community. Similarly, there was a wide range in the rates of children who were hit with objects (9%-74% [median: 39%]) or beaten by their parents (0.1%-28.5%). Extremely harsh methods of physical punishment, such as burning or smothering, were rare in all countries. It is concerning that >or=20% of parents in 9 communities admitted shaking children younger than 2 years. Physical and verbal punishments of children are common in high-, middle-, and low-income communities around the world. The forms and rates of punishment vary among countries and among communities within countries. A median of 16% of children experienced harsh or potentially abusive physical discipline in the previous year.


Biology and genetics of oculocutaneous albinism and vitiligo - common pigmentation disorders in southern Africa.
Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 - 2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in our understanding of the pathobiology of both albinism and vitiligo may herald novel treatment strategies for these disorders.


Recovery after stroke: perspectives of young stroke survivors in Taiwan.
To learn about the experiences of stroke recovery among young stroke survivors in Taiwan and to elucidate the beliefs, goals, and facilitators of and barriers to their recovery. A qualitative approach was used for data collection, and data were obtained from five focus groups consisting of stroke survivors aged 20-64 years (n = 25). Data were transcribed verbatim and analyzed thematically by two independent coders using NVivo version 10. "Returning to prestroke status" was a common belief of recovery for stroke survivors; their goals of recovery changed overtime from regaining physical functions, independent living, and participating in work and leisure activities to maintaining functions or returning to normality. Their perceived personal and environmental facilitators of recovery included positive attitude, family and friends, and rehabilitation, whereas barriers to recovery included psychological factors, social stigma, and physical environment. These findings provide useful insights for rehabilitation clinicians to develop culturally tailored interventions to improve poststroke recovery outcomes in young stroke survivors.Implications for rehabilitationRehabilitation clinicians should understand stroke survivors' beliefs and goals of recovery to provide tailored services.Optimizing the goal-setting process and patient-provider communication may help clinicians and survivors examine and adjust their expectations toward recovery during rehabilitation.Interventions will be needed to address personal and environmental supports and barriers, such as motivation, psychological factors, social support, and the physical environment to help survivors achieve their recovery goals.


A new approach for the analysis of facial growth and age estimation: Iris ratio.
The study of facial growth is explored in many fields of science, including anatomy, genetics, and forensics. In the field of forensics, it acts as a valuable tool for combating child pornography. The present research proposes a new method, based on relative measurements and fixed references of the human face-specifically considering measurements of the diameter of the iris (iris ratio)-for the analysis of facial growth in association with age in children and sub-adults. The experimental sample consisted of digital photographs of 1000 Brazilian subjects, aged between 6 and 22 years, distributed equally by sex and divided into five specific age groups (6, 10, 14, 18, and 22 year olds ± one month). The software package SAFF-2D® (Forensic Facial Analysis System, Brazilian Federal Police, Brazil) was used for positioning 11 landmarks on the images. Ten measurements were calculated and used as fixed references to evaluate the growth of the other measurements for each age group, as well the accumulated growth (6-22 years old). The Intraclass Correlation Coefficient (ICC) was applied for the evaluation of intra-examiner and inter-examiner reliability within a specific set of images. Pearson's Correlation Coefficient was used to assess the association between each measurement taken and the respective age groups. ANOVA and Post-hoc Tukey tests were used to search for statistical differences between the age groups. The outcomes indicated that facial structures grow with different timing in children and adolescents. Moreover, the growth allometry expressed in this study may be used to understand what structures have more or less proportional variation in function for the age ranges studied. The diameter of the iris was found to be the most stable measurement compared to the others and represented the best cephalometric measurement as a fixed reference for facial growth ratios (or indices). The method described shows promising potential for forensic applications, especially as part of the armamentarium against crimes involving child pornography and child abuse.


Toll-like receptors in brain development and homeostasis.
Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogens. Recent reports now reveal intriguing roles for TLRs in the central nervous system (CNS). These include the regulation of neuroinflammation and of neurite outgrowth. The archetypal Toll protein in Drosophila melanogaster was implicated in the development of the nervous system. Now similar functions have been uncovered for the mammalian orthologs, the TLRs. TLRs expressed on CNS glia and neurons may recognize endogenous ligands and participate both in development and in responses associated with CNS injury.


Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells.
The transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into the functions of Ebf1 at distinct stages of differentiation, we conditionally inactivated Ebf1. We found that Ebf1 is required for the proliferation, survival, and signaling of pro-B cells and peripheral B-cell subsets, including B1 cells and marginal zone B cells. The proliferation defect of Ebf1-deficient pro-B cells and the impaired expression of multiple cell cycle regulators are overcome by transformation with v-Abl. The survival defect of transformed Ebf1(fl/fl) pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-x(L). In mature B cells, Ebf1 deficiency interferes with signaling via the B-cell-activating factor receptor (BAFF-R)- and B-cell receptor (BCR)-dependent Akt pathways. Moreover, Ebf1 is required for germinal center formation and class switch recombination. Genome-wide analyses of Ebf1-mediated gene expression and chromatin binding indicate that Ebf1 regulates both common and distinct sets of genes in early and late stage B cells. By regulating important components of transcription factor and signaling networks, Ebf1 appears to be involved in the coordination of cell proliferation, survival, and differentiation at multiple stages of B lymphopoiesis.


The management of forearm fractures in children: a plea for conservatism.
A retrospective review was undertaken to evaluate the efficacy of primary nonoperative treatment (closed reduction and long-arm casting) along with pins and plaster as a salvage technique for those reduction failures. A total of 730 closed fractures (1987-1993) was compiled, of which 300 required closed reductions and casting. Excluded from the study were teenagers whose growth plates were closed. Of the 300 fractures requiring closed reductions, 22 went on to require remanipulations, and 12 required the use of pins-and-plaster technique to obtain or maintain satisfactory reduction. Complications in the group treated in this manner included two superficial pin infections treated with antibiotics and two forearms with moderate loss of pronation/supination not requiring treatment. We believe that closed reduction of pediatric forearm fractures remains the accepted standard and the technique of pins and plaster should be considered a reliable alternative for the unstable injuries.


Context matters: a qualitative study of the practicalities and dilemmas of delivering integrated chronic care within primary and secondary care settings in a rural Malawian district.
With the increasing double burden of communicable and non-communicable diseases (NCDs) in sub-Saharan Africa, health systems require new approaches to organise and deliver services for patients requiring long-term care. There is increasing recognition of the need to integrate health services, with evidence supporting integration of HIV and NCD services through the reorganisation of health system inputs, across system levels. This study investigates current practices of delivering and implementing integrated care for chronically-ill patients in rural Malawi, focusing on the primary level. A qualitative study on chronic care in Phalombe district conducted between April 2016 and May 2017, with a sub-analysis performed on the data following a document analysis to understand the policy context and how integration is conceptualised in Malawi; structured observations in five of the 15 district health facilities, selected purposively to represent different levels of care (primary and secondary), and ownership (private and public). Fifteen interviews with healthcare providers and managers, purposively selected from the above facilities. Meetings with five non-governmental organisations to study their projects and support towards chronic care in Phalombe. Data were analysed using a thematic approach and managed in NVivo. Our study found that, while policies supported integration of various disease-specific programmes at point of care, integration efforts on the ground were severely hampered by human and health resource challenges e.g. inadequate consultation rooms, erratic supplies especially for NCDs, and an overstretched health workforce. There were notable achievements, though most prominent at the secondary level e.g. the establishment of a combined NCD clinic, initiating NCD screening within HIV services, and initiatives for integrated information systems. In rural Malawi, major impediments to integrated care provision for chronically-ill patients include the frail state of primary healthcare services and sub-optimal NCD care at the lowest healthcare level. In pursuit of integrative strategies, opportunities lie in utilising and expanding community-based outreach strategies offering multi-disease screening and care with strong referral linkages; careful task delegation and role realignment among care teams supported with proper training and incentive mechanisms; and collaborative partnership between public and private sector actors to expand the resource-base and promoting cross-programme initiatives.


Relevant Measures to Prevent the Spread of African Swine Fever in the European Union Domestic Pig Sector.
During the past decade, African swine fever (ASF) has spread from the Caucasus region to eastern European Union countries affecting domestic pig and wild boar populations. In order to avert ASF spread, mitigation measures targeting both populations have been established. However, despite these efforts, ASF has been reported in thirteen different countries (Georgia, Azerbaijan, Armenia, the Russian Federation, Ukraine, Belarus, Estonia, Latvia, Lithuania, Poland, Moldova, Czech Republic, and Romania). In the absence of an effective vaccine or treatment to ASF, introduction and spread of ASF onto domestic pig farms can only be prevented by strict compliance to control measures. This study systematically reviewed available measures to prevent the spread of ASF in the EU domestic pig sector distinguishing between commercial, non-commercial, and outdoor farms. The search was performed in PubMed and using a common browser. A total of 52 documents were selected for the final review process, which included scientific articles, reports, EU documents and official recommendations, among others. From this literature review, 37 measures were identified as preventive measures for the introduction and spread of ASF. Subsequently, these measures were assessed by ASF experts for their relevance in the mitigation of ASF spread on the three mentioned types of farms. All experts agreed that some of the important preventive measures for all three types of farms were: the identification of animals and farm records; strict enforcement of the ban on swill feeding; and containment of pigs, so as to not allow direct or indirect pig-pig and/or pig-wild boar contacts. Other important preventive measures for all farms were education of farmers, workers, and operators; no contact between farmers and farm staff and external pigs; appropriate removal of carcasses, slaughter residues, and food waste; proper disposal of manure and dead animals, and abstaining from hunting activities during the previous 48 h (allowing a 48 h interval between hunting and being in contact with domestic pigs). Finally, all experts identified that the important preventive measures for non-commercial and outdoor farms is to improve access of those farms to veterinarians and health services.


Reactivity of monoclonal antibodies to Rickettsia rickettsii with spotted fever and typhus group rickettsiae.
Analysis of 15 spotted fever group (SFG) and 2 typhus group strains of rickettsiae with a panel of monoclonal antibodies revealed a number of shared and unique epitopes of the 120- and 155-kilodalton surface proteins. All of the SFG strains but neither of the typhus group strains reacted with antibody to the lipopolysaccharidelike antigen of Rickettsia rickettsii; possibly the lipopolysaccharidelike antigen is the common antigen which defines the SFG. North Carolina and Montana strains of R. rickettsii known to differ slightly in virulence for guinea pigs differed in at least one epitope of the 120-kilodalton protein.


Model membrane size-dependent amyloidogenesis of Alzheimer's amyloid-β peptides.
We herein report the mechanism of amyloid formation of amyloid-β (Aβ) peptides on small (SUV) and large unilamellar vesicles (LUVs), which consist of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. Although Aβ1-42 formed fibrils on SUVs at all POPC concentrations used, the lag time, elongation rate, maximum thioflavin T intensity, and fibrillar morphology were distinct, indicating polymorphic amyloid formation. LUVs, at low POPC concentrations, did not markedly affect fibrillation kinetics; however, increases in POPC concentrations suppressed amyloid formation. No significant differences in the thermal stabilities of Aβ1-42 fibrils formed with and without vesicles were observed, although fibrils formed on SUVs showed some differences with dilution. SUVs markedly promoted Aβ1-40 fibrillation by condensing Aβ1-40, whereas no effects of LUVs on amyloidogenesis were detected. Salts greatly increased Aβ1-40 amyloidogenicity on vesicles. We proposed comprehensive models for vesicle size-dependent Aβ amyloidogenesis. Inhomogeneous packing defects in SUVs may induce distinct nucleation in the polymorphisms of amyloids and decreasing local concentrations of Aβ with higher amounts of LUVs inhibits amyloid formation. We also pointed out that C-terminal hydrophobicity of Aβ is important for amyloidogenesis on membranes.


Scanning electro-optic microscope based on surface plasmon resonance.
An optical scanning probe microscope, based on surface plasmon resonance (SPR) in the attenuated total reflection geometry, is shown to successfully image the polarization structures in self-assembled monolayers of hemicyanine adsorbed on a gold surface. Application of an ac field to the tip gives rise to the linear electro-optic effect in the monolayer just below the tip and the local change in the refractive index of the monolayer was detected via the ac component of the reflected light intensity, in which SPR-based detection intensifies the ac component. Polarization structures in a monolayer can be clearly imaged by this technique.


A computational model for signal processing by the dorsal cochlear nucleus. II. Responses to broadband and notch noise.
In a previous paper a computational model was developed which was shown to account for most of the essential features of the variety of experimentally observed response maps of type-IV cells in the dorsal cochlear nucleus to pure tones. In the present study, the responses of the same model DCN to broadband noise and notch noise are investigated. It is shown that the previous model qualitatively accounts for the observed responses to these more complex sounds. Predictions of the model for inverted notches and for the behavior of type-IV cell output as notch center is varied for different amplitudes are presented. It is shown that the model is suitable for feature detection of auditory signals and an expansion is given as to how this ability arises from the properties of the stellate, type-II, and type-IV cells and the variations in the connectional patterns that were previously shown to account for the response patterns of type-IV cells to pure tones.


A reporter assay in lamprey embryos reveals both functional conservation and elaboration of vertebrate enhancers.
The sea lamprey is an important model organism for investigating the evolutionary origins of vertebrates. As more vertebrate genome sequences are obtained, evolutionary developmental biologists are becoming increasingly able to identify putative gene regulatory elements across the breadth of the vertebrate taxa. The identification of these regions makes it possible to address how changes at the genomic level have led to changes in developmental gene regulatory networks and ultimately to the evolution of morphological diversity. Comparative genomics approaches using sea lamprey have already predicted a number of such regulatory elements in the lamprey genome. Functional characterisation of these sequences and other similar elements requires efficient reporter assays in lamprey. In this report, we describe the development of a transient transgenesis method for lamprey embryos. Focusing on conserved non-coding elements (CNEs), we use this method to investigate their functional conservation across the vertebrate subphylum. We find instances of both functional conservation and lineage-specific functional evolution of CNEs across vertebrates, emphasising the utility of functionally testing homologous CNEs in their host species.


Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during Pavlovian fear conditioning in behaving rats.
Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS-) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS- trials during training and early extinction. In contrast, they were lower during CS+ than CS- trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS- trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.


Human health impacts of antibiotic use in agriculture: A push for improved causal inference.
Resistant bacterial infections in humans continue to pose a significant challenge globally. Antibiotic use in agriculture contributes to this problem, but failing to appreciate the relative importance of diverse potential causes represents a significant barrier to effective intervention. Standard epidemiologic methods alone are often insufficient to accurately describe the relationships between agricultural antibiotic use and resistance. The integration of diverse methodologies from multiple disciplines will be essential, including causal network modeling and population dynamics approaches. Because intuition can be a poor guide in directing investigative efforts of these non-linear and interconnected systems, integration of modeling efforts with empirical epidemiology and microbiology in an iterative process may result in more valuable information than either in isolation.


Plaque formation and isolation of pure lines with poliomyelitis viruses.
Plaques have been produced with the three types of poliomyelitis viruses on monolayer tissue cultures of monkey kidney and monkey testis. The number of plaques was proportional to the concentration of the virus. Each plaque originates, therefore, from a single virus particle, defined as the virus unit that is unseparable by dilution. The plaques are due to the specific action of the virus since they are suppressed by type-specific antiserum. Pure virus lines were established by isolating the virus population produced in single plaques. These derived virus lines had the same morphological, serological, and pathogenic properties as the parent strain. High titer virus stocks, with titers up to 7 x 10(8) plaque-forming particles per ml., were obtained.


Locations of human and mouse genes encoding the RFX1 and RFX2 transcription factor proteins.
RFX transcription factors constitute a highly conserved family of site-specific DNA binding proteins involved in the expression of a variety of cellular and viral genes, including major histocompatibility complex class II genes and genes in human hepatitis B virus. Five members of the RFX gene family have been isolated from human and mouse, and all share a highly characteristic DNA binding domain that is distinct from other known DNA binding motifs. The human RFX1 and RFX2 genes have been assigned by in situ hybridization to chromosome 19p13.1 and 19p13.3, respectively. In this paper, we present data that localize RFX1 and RFX2 precisely within the detailed physical map of human chromosome 19 and genetic data that assign Rfx1 and Rfx2 to homologous regions of mouse chromosomes 8 and 17, respectively. These data define the established relationships between these homologous mouse and human regions in further detail and provide new tools for linking cloned genes to phenotypes in both species.


Identification of cellular mechanisms operational in vivo during the regression of established pulmonary metastases by the systemic administration of high-dose recombinant interleukin 2.
The systemic administration of high-dose recombinant IL 2 mediated significant reductions of established 3-day pulmonary micrometastases from both weakly immunogenic and nonimmunogenic sarcomas. However, when treatment with IL 2 was delayed for 10 days after the injection of tumor cells in an attempt to treat grossly visible pulmonary macrometastases, only those established from weakly immunogenic sarcomas remained susceptible. Established 10-day pulmonary nodules from the nonimmunogenic sarcomas became refractory to IL 2 therapy. We utilized selective depletion of lymphocyte subsets in vivo by the systemic administration of specific monoclonal antibodies to cells bearing either the L3T4 or Lyt-2 marker or a heteroantiserum to cells bearing the ASGM-1 glycosphingolipid to identify lymphocytes involved in IL 2-induced tumor regression. Cells with potent lymphokine-activated killer (LAK) activity against fresh tumor targets in vitro were identified in the lungs of IL 2-treated mice. By flow cytometry analysis, the majority of these effector cells were Thy-1+, L3T4-, Lyt-2-, ASGM-1+. Depletion in vivo of ASGM-1+ cells before the onset of IL 2 administration eliminated the successful therapy of 3-day pulmonary metastases from nonimmunogenic sarcomas, with concurrent elimination of LAK cell activity in the lungs. In mice with 3-day pulmonary metastases from weakly immunogenic sarcomas, both Lyt-2+ cells and ASGM-1+ cells were involved in IL 2-mediated tumor regression, but Lyt-2+ cells appeared to be the more potent mediator in the response. Lyt-2+ cells were also involved in the elimination of grossly visible 10-day macrometastases from these weakly immunogenic tumors. Depletion of L3T4+ cells had no effect on tumor regression. Thus, although LAK effectors derived from ASGM-1+ precursors can eliminate pulmonary micrometastases regardless of tumor immunogenicity, Lyt-2+ cells are predominant effectors in the elimination of both pulmonary micro- and macrometastases from weakly immunogenic sarcomas.


The senior SHO rotation in Wales--a basis for BST training.
Between 1969-1992 there was a successful surgical registrar rotation in South Wales (1). This was a three-year rotation comprising two years general surgery, six months trauma and orthopaedics and six months surgical specialty. The rotation was aimed at those doctors who had completed senior house officer (SHO) posts in accident and emergency, 6-12 months general surgery and had already obtained the primary FRCS. However, with the recent recommendations of the Calman Report concerning general surgical training (2) changes to this rotation have become necessary, namely to reduce the number of surgical registrars in order to achieve a balance in numbers entering higher surgical training and to shorten the period of training to seven years with two years Basic Surgical Training (BST) and five years Higher Surgical Training (HST). A modified rotation was therefore designed and implemented in South Wales since July 1992. The previous registrar rotation was shortened to two years instead of three ensuring the pre-requirements for entry into HST and eligibility to sit the second part FRCS. The aim of this study was to assess whether the new senior SHO/BST rotation in South Wales is providing adequate training for our surgical trainees to enter into HST. We present our data as a potential basis for setting up a formal BST rotation.


The effectiveness of risk mitigation interventions in divers with persistent (patent) foramen ovale.
Persistent (patent) foramen ovale (PFO) is a recognized risk for decompression sickness (DCS) in divers, which may be mitigated by conservative diving or by PFO closure. Our study aimed to compare the effectiveness of these two risk mitigation interventions. This was a prospective study on divers who tested positive for PFO or an atrial septal defect (ASD) and either decided to continue diving without closure ('conservative group'), or to close their PFO/ASD and continue diving ('closure group'). Divers' characteristics, medical history, history of diving and history of DCS were reported at enrollment and annually after that. The outcome measures were the incidence rate of DCS, frequency and intensity of diving activities, and adverse events of closure. Divers in both groups dived less and had a lower incidence rate of confirmed DCS than before the intervention. In the closure group (n = 42) the incidence rate of confirmed DCS decreased significantly. Divers with a large PFO experienced the greatest reduction in total DCS. In the conservative group (n = 23), the post-intervention decrease in confirmed DCS incidence rate was not significant. Of note, not all divers returned to diving after closure. Seven subjects reported mild adverse events associated with closure; one subject reported a serious adverse event. PFO closure should be considered on an individual basis. In particular, individuals who are healthy, have a significant DCS burden, a large PFO or seek to pursue advanced diving may benefit from closure.


Kinetic Analysis of Lesions Identified on a Rapid Abridged Multiphase (RAMP) Breast MRI Protocol.
We implemented a rapid abridged multiphase (RAMP) breast magnetic resonance imaging (MRI) protocol to reduce scan time and increase workflow efficiency. In this study, we compared delayed-phase kinetic analyses of benign and malignant lesions on the RAMP protocol versus a full dynamic contrast-enhanced (DCE) MRI protocol. Consecutive breast MRI examinations obtained from October 2015 to August 2016 with tissue diagnoses of suspicious MRI lesions were identified. RAMP MRI included one precontrast and two postcontrast phases. Full DCE MRI included one precontrast and at least three postcontrast phases. Lesion kinetic analyses including mean delayed-phase volume percentage of washout, predominant curve type, and worst curve type were assessed. Kinetic analyses assessed on RAMP and DCE MRI protocols were compared using Wilcoxon rank-sum test and Chi-Square test. Receiver operating characteristic analysis was performed to discriminate benign and malignant lesions based on delayed-phase parameters. The study included 177 consecutive breast lesions (50 benign, 127 malignant) in 162 women. RAMP MRI (23 benign, 61 malignant) and DCE MRI examinations (27 benign, 66 malignant) demonstrated 8.4% vs 9.3% washout (p = 0.36) for benign lesions and 18.5% vs 17% washout (p = 0.66) for malignancies, respectively. There was no difference in the predominant and worst curve types for malignant and benign lesions or in area under the receiver operating characteristic curves for delayed-phased parameters between the two protocols (p > 0.05). Lesion kinetic analyses from the RAMP MRI protocol can achieve the same discriminatory ability as the full DCE protocol. By reducing scan time, the RAMP MRI protocol improves patient comfort and enhances workflow efficiency and can be easily implemented in any clinical setting.


Re-embodying eating: patients' experiences 5 years after bariatric surgery.
Health experts advise and expect patients to eat healthily after bariatric surgery. For patients, difficulties with eating might have been a long-standing, problematic part of life-a part that is not necessarily healed by surgery. Empirical research on patients' experiences of eating practices after bariatric surgery is lacking. Aiming to contribute to the development of clinical practice, we explored meanings attached to eating in the long term and sought descriptions of change and bodily sensations. We interviewed 14 patients at least 5 years after bariatric surgery. The surgical restriction forced changes in the way patients sensed their own body in eating, but the uncertainty related to maintaining weight loss in the long term remained. Meanings attached to eating transcended food as choices situated in a nourishment and health perspective, and were not necessarily changed. Eating was an existential and embodied practice, which remained an ambiguous and sensitive matter after surgery.


Chronic Kidney Disease Testing Among At-Risk Adults in the U.S. Remains Low: Real-World Evidence From a National Laboratory Database.
An estimated 37 million Americans have chronic kidney disease (CKD). Nearly 90% do not know about their condition because of low awareness about the importance of CKD testing and diagnosis among practitioners and people at risk for CKD. This study uses data from a national clinical laboratory to identify guideline-recommended CKD testing rates across the U.S. Patients with Laboratory Corporation of America Holdings (Labcorp) testing between 2013 and 2019 were defined as at risk for CKD if they had any testing ordered with diagnosis codes for diabetes and/or hypertension. Guideline-concordant CKD assessment was defined by estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (uACR) testing within the study year. We identified 28,295,982 at-risk patients (mean age 60.6 ± 14.8 years; 53.6% women): 16.2% had diabetes, 63.8% had hypertension, and 20.1% had both comorbidities. Of these, 80.3% did not receive guideline-concordant assessment during the study period. Furthermore, only 21.0% had uACR testing versus 89.6% with eGFR. CKD assessment occurred at least once in 28.7% of patients with diabetes, 10.5% of patients with hypertension, and 41.4% of patients with both conditions. In a state-by-state comparison, annual testing rates ranged from 5 to 30%. The nationwide rate increased modestly each year between 2013 and 2018 (from 10.7% to 15.2%). Despite guideline recommendations, testing for CKD with uACR and eGFR in U.S. adults with diabetes and hypertension is low in routine clinical care. These data highlight the need for strategies to improve routine CKD assessment nationwide.


Results of a pilot diabetes prevention intervention in East Harlem, New York City: Project HEED.
Our community-academic partnership employed community-based participatory research to develop and pilot a simple, peer-led intervention to promote weight loss, which can prevent diabetes and eliminate racial/ethnic disparities in incident diabetes among overweight adults with prediabetes. We recruited overweight adults at community sites, performed oral glucose tolerance testing to identify persons with blood glucose levels in the prediabetes range, and randomized eligible people to a peer-led lifestyle intervention group or delayed intervention in 1 year. Outcomes, including weight, blood pressure, and health behaviors, were measured at baseline and 3, 6, and 12 months. More than half of those tested (56%, or 99 of 178) had prediabetes and enrolled in the study. Participants were predominantly Spanish-speaking, low-income, undereducated women. The intervention group lost significantly more weight than the control group and maintained weight loss at 12 months (7.2 versus 2.4 pounds; P < .01). One fourth (24 of 99) of participants progressed to diabetes. In underserved minority communities, prediabetes prevalence may be higher than previously reported. Low-cost, community-based interventions can succeed in encouraging weight loss to prevent diabetes.