Test-retest reliability of a new executive function battery for use in early childhood.
This study reported test-retest reliability for a newly developed executive function battery designed for use in early childhood. A total of 140 predominantly low-income children (M = 48.1 months; 51% male; 43% African American) completed up to six tasks on two occasions an average of 18 (Mdn = 16) days apart. Pearson correlations between individual task scores indicated moderate retest reliability (mean r = .60; range = .52-.66) similar to that observed in other retest studies of executive function in preschool, school-aged, and adult samples. In contrast, confirmatory factor analyses of performance on the task battery across time indicated high retest reliability (ϕ = .95) that was identical to that observed in a recent study that used an identical method involving a sample of older adults. The short-term test-retest reliability of executive function in early childhood is comparable to that observed in childhood and adult samples. The retest reliability of children's performance on batteries of executive function tasks is appreciably stronger than the retest reliability of their performance on individual tasks. Studies that focus on inter- and intraindividual differences in executive function would be better served by using scores that are derived from task batteries than those derived from individual tasks.


SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort.
Heterozygous NSD1 mutations were identified in 60%-90% of patients with Sotos syndrome. Recently, mutations of the SETD2 and DNMT3A genes were identified in patients exhibiting only some Sotos syndrome features. Both NSD1 and SETD2 genes encode epigenetic 'writer' proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The DNMT3A gene encodes an epigenetic 'reader' protein of the H3K36me chromatin mark. We aimed at confirming the implication of DNMT3A and SETD2 mutations in an overgrowth phenotype, through a comprehensive targeted-next generation sequencing (NGS) screening in 210 well-phenotyped index cases with a Sotos-like phenotype and no NSD1 mutation, from a French cohort. Six unreported heterozygous likely pathogenic variants in DNMT3A were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in SETD2 in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. DNMT3A-mutated index cases shared similar clinical features including overgrowth phenotype characterised by postnatal tall stature (≥+2SD), macrocephaly (≥+2SD), overweight or obesity at older age, intellectual deficiency and minor facial features. The phenotype associated with SETD2 mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent DNMT3A somatic mutation in acute leukaemia. Our results illustrate the power of targeted NGS to identify rare disease-causing variants. These observations provided evidence for a unifying mechanism (disruption of apposition and reading of the epigenetic chromatin mark H3K36me) that causes an overgrowth syndrome phenotype. Further studies are needed in order to assess the role of SETD2 and DNMT3A in intellectual deficiency without overgrowth.


Association between time spent interpreting, level of confidence, and accuracy of screening mammography.
The objective of this study was to examine the effect of time spent viewing images and level of confidence on a screening mammography test set on interpretive performance. Radiologists from six mammography registries participated in this study and were randomized to interpret one of four test sets and complete 12 survey questions. Each test set had 109 cases of digitized four-view screening screen-film mammograms with prior comparison screening views. Viewing time for each case was defined as the cumulative time spent viewing all mammographic images before recording which visible feature, if any, was the "most significant finding." Log-linear regression fit via the generalized estimating equation was used to test the effect of viewing time and level of confidence in the interpretation on test set sensitivity and false-positive rate. One hundred nineteen radiologists completed a test set and contributed data on 11,484 interpretations. The radiologists spent more time viewing cases that had significant findings or cases for which they had less confidence in their interpretation. Each additional minute of viewing time increased the probability of a true-positive interpretation among cancer cases by 1.12 (95% CI, 1.06-1.19; p < 0.001) regardless of confidence in the assessment. Among the radiologists who were very confident in their assessment, each additional minute of viewing time increased the adjusted risk of a false-positive interpretation among noncancer cases by 1.42 (95% CI, 1.21-1.68), and this viewing-time effect diminished with decreasing confidence. Longer interpretation times and higher levels of confidence in an interpretation are both associated with higher sensitivity and false-positive rates in mammography screening.


The influence of children's reading ability on initial letter position encoding during a reading-like task.
Previous studies exploring the cost of reading sentences with words that have two transposed letters in adults showed that initial letter transpositions caused the most disruption to reading, indicating the important role that initial letters play in lexical identification (e.g., Rayner et al., 2006). Regarding children, it is not clear whether differences in reading ability would affect how they encode letter position information as they attempt to identify misspelled words in a reading-like task. The aim of this experiment was to explore how initial-letter position information is encoded by children compared to adults when reading misspelled words, containing transpositions, during a reading-like task. Four different conditions were used: control (words were correctly spelled), TL12 (letters in first and second positions were transposed), TL13 (letters in first and third positions were transposed), and TL23 (letters in second and third positions were transposed). Results showed that TL13 condition caused the most disruption, whereas TL23 caused the least disruption to reading of misspelled words. Although disruption for the TL13 condition was quite rapid in adults, the immediacy of disruption was less so for the TL23 and TL12 conditions. For children, effects of transposition also occurred quite rapidly but were longer lasting. The time course was particularly extended for the less skilled relative to the more skilled child readers. This pattern of effects suggests that both adults and children with higher, relative to lower, reading ability encode internal letter position information more flexibly to identify misspelled words, with transposed letters, during a reading-like task. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.
The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.


Discovery of the photosynthetic relatives of the "Maltese mushroom" Cynomorium.
Although recent molecular phylogenetic studies have identified the photosynthetic relatives of several enigmatic holoparasitic angiosperms, uncertainty remains for the last parasitic plant order, Balanophorales, often considered to include two families, Balanophoraceae and Cynomoriaceae. The nonphotosynthetic (holoparasitic) flowering plant Cynomorium coccineum has long been known to the Muslim world as "tarthuth" and to Europeans as the "Maltese mushroom"; C. songaricum is known in Chinese medicine as "suo yang." Interest in these plants is increasing and they are being extensively collected from wild populations for use in herbal medicines. Here we report molecular phylogenetic analyses of nuclear ribosomal DNA and mitochondrial matR sequence data that strongly support the independent origin of Balanophoraceae and Cynomoriaceae. Analyses of single gene and combined gene data sets place Cynomorium in Saxifragales, possibly near Crassulaceae (stonecrop family). Balanophoraceae appear related to Santalales (sandalwood order), a position previously suggested from morphological characters that are often assumed to be convergent. Our work shows that Cynomorium and Balanophoraceae are not closely related as indicated in all past and present classifications. Thus, morphological features, such as inflorescences bearing numerous highly reduced flowers, are convergent and were attained independently by these two holoparasite lineages. Given the widespread harvest of wild Cynomorium species for herbal medicines, we here raise conservation concerns and suggest that further molecular phylogenetic work is needed to identify its photosynthetic relatives. These relatives, which will be easier to cultivate, should then be examined for phytochemical activity purported to be present in the more sensitive Cynomorium.


Emergent Properties of Giant Vesicles Formed by a Polymerization-Induced Self-Assembly (PISA) Reaction.
Giant micrometer sized vesicles are of obvious interest to the natural sciences as well as engineering, having potential application in fields ranging from drug delivery to synthetic biology. Their formation often requires elaborate experimental techniques and attempts to obtain giant vesicles from chemical media in a one-pot fashion have so far led to much smaller nanoscale structures. Here we show that a tailored medium undergoing controlled radical polymerization is capable of forming giant polymer vesicles. Using a protocol which allows for an aqueous reaction under mild conditions, we observe the macroscale consequences of amphiphilic polymer synthesis and the resulting molecular self-assembly using fluorescence microscopy. The polymerization process is photoinitiated by blue light granting complete control of the reaction, including on the microscope stage. The self-assembly process leads to giant vesicles with radii larger than 10 microns, exhibiting several emergent properties, including periodic growth and collapse as well as phototaxis.


The use of the Internet by people who die by suicide in England: a cross sectional study.
There is widespread concern regarding the possible influence of the Internet on suicidal behaviour. The aim of this study was to estimate the prevalence and characteristics of Internet-related suicide in England. Cross sectional study based on detailed review of the inquest reports of suicides occurring in the areas served by 12 Coroners in England. Evidence of Internet use in relation to the suicide was sought for each death. Altogether inquest reports for 593 suicides (all methods) in 2005 and 166 suicides using specific methods in 2006-7 were assessed. There was evidence of a direct Internet contribution in nine (1.5% 95%CI 0.7 to 2.9%) of the 593 suicides in 2005. In seven (77.8%) of the cases the individuals had used the Internet to research the methods of suicide they used. Five (55.6%) individuals had used 'unusual' high-lethality methods, whereas such methods were only used in 1.7% of all suicides (p<0.001). There was evidence of Internet involvement in 2.4% (0.7% to 6.1%) of the suicides in 2006-2007. None of the Internet-related suicides appeared to occur as part of a suicide pact. The contribution of the Internet to suicide rates may be under-estimated in this analysis as Coroners are unlikely to comprehensively pursue the possibility of Internet involvement in all the deaths they investigate. Easy access to information about suicide methods and pro-suicide web sites on the Internet appears to contribute to a small but significant proportion of suicides. A key impact of the Internet appears to be in relation to information concerning suicide methods.


Investigation of the effect of scattering agent and scattering albedo on modulated light propagation in water.
A recent paper described experiments completed to study the effect of scattering on the propagation of modulated light in laboratory tank water [Appl. Opt.48, 2607 (2009)APOPAI0003-693510.1364/AO.48.002607]. Those measurements were limited to a specific scattering agent (Maalox antacid) with a fixed scattering albedo (0.95). The purpose of this paper is to study the effects of different scattering agents and scattering albedos on modulated light propagation in water. The results show that the scattering albedo affects the number of attenuation lengths that the modulated optical signal propagates without distortion, while the type of scattering agent affects the degree to which the modulation is distorted with increasing attenuation length.


Testing isotherm models and recovering empirical relationships for adsorption in microporous carbons using virtual carbon models and grand canonical Monte Carlo simulations.
Using the plausible model of activated carbon proposed by Harris and co-workers and grand canonical Monte Carlo simulations, we study the applicability of standard methods for describing adsorption data on microporous carbons widely used in adsorption science. Two carbon structures are studied, one with a small distribution of micropores in the range up to 1 nm, and the other with micropores covering a wide range of porosity. For both structures, adsorption isotherms of noble gases (from Ne to Xe), carbon tetrachloride and benzene are simulated. The data obtained are considered in terms of Dubinin-Radushkevich plots. Moreover, for benzene and carbon tetrachloride the temperature invariance of the characteristic curve is also studied. We show that using simulated data some empirical relationships obtained from experiment can be successfully recovered. Next we test the applicability of Dubinin's related models including the Dubinin-Izotova, Dubinin-Radushkevich-Stoeckli, and Jaroniec-Choma equations. The results obtained demonstrate the limits and applications of the models studied in the field of carbon porosity characterization.


Low birth weight as a potential risk factor for severe COVID-19 in adults.
The identification of factors predisposing to severe COVID-19 in young adults remains partially characterized. Low birth weight (LBW) alters cardiovascular and lung development and predisposes to adult disease. We hypothesized that LBW is a risk factor for severe COVID-19 in non-elderly subjects. We analyzed a prospective cohort of 397 patients (18-70 years) with laboratory-confirmed SARS-CoV-2 infection attended in a tertiary hospital, where 15% required admission to Intensive Care Unit (ICU). Perinatal and current potentially predictive variables were obtained from all patients and LBW was defined as birth weight ≤ 2.500 g. Age (adjusted OR (aOR) 1.04 [1-1.07], P = 0.012), male sex (aOR 3.39 [1.72-6.67], P < 0.001), hypertension (aOR 3.37 [1.69-6.72], P = 0.001), and LBW (aOR 3.61 [1.55-8.43], P = 0.003) independently predicted admission to ICU. The area under the receiver-operating characteristics curve (AUC) of this model was 0.79 [95% CI, 0.74-0.85], with positive and negative predictive values of 29.1% and 97.6% respectively. Results were reproduced in an independent cohort, from a web-based survey in 1822 subjects who self-reported laboratory-positive SARS-CoV-2 infection, where 46 patients (2.5%) needed ICU admission (AUC 0.74 [95% CI 0.68-0.81]). LBW seems to be an independent risk factor for severe COVID-19 in non-elderly adults and might improve the performance of risk stratification algorithms.


Fatal high-grade skull osteosarcoma 30 years following radiotherapy for Cushing's disease.
Cushing's disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing's disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull. Cushing's disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism. The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30-60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas. Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years. Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy. Overall prognosis in radiation-induced sarcoma of bone is poor. Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.


Does K-line (-) in the Neck-flexed Position Predict Surgical Outcome of Cervical Spondylotic Myelopathy?: Results of a Multivariate Analysis After Muscle-preserving Selective Laminectomy.
A retrospective single-center study. The aim of this study was to investigate the influence of the K-line in the neck-flexed position (flexion K-line) on the surgical outcome after muscle-preserving selective laminectomy (SL) for cervical spondylotic myelopathy (CSM). Development of CSM is associated with dynamic factors and cervical alignment. The flexion K-line, which reflects both dynamic and alignment factors, provides an indicator of surgical outcome after posterior decompression surgery for patients with ossification of the posterior longitudinal ligament. However, the value of the flexion K-line for patients with CSM has not been evaluated. Our study group included 159 patients treated with SL for CSM. Patients were divided into a flexion K-line (+) group and a flexion K-line (-) group. The influence of the flexion K-line on radiological and surgical outcomes was analyzed, with multivariate analysis conducted to identify factors affecting the surgical outcome. Patients in the flexion K-line (-) group were younger (P = 0.003), had a less lordotic cervical alignment (pre-and postoperatively, P < 0.001), a smaller C7 slope (pre-and postoperatively, P < 0.001), and a greater mismatch between the C7 slope and the C2-C7 angle (preoperatively, P = 0.047; postoperatively, P = 0.001). The postoperative increase in Japanese Orthopedic Association (JOA) score and the JOA score recovery rate (RR) were lower for the flexion K-line (-) than for the K-line (+) group (P < 0.001 and P < 0.001, respectively). On multivariate regression analysis, the flexion K-line (-) (β = -0.282, P < 0.001), high signal intensity (SI) changes on T2-weighted image (WI) combined with low SI changes on T1-WI in the spinal cord (β = -0.266, P < 0.001), and older age (β= -0.248, P = 0.001) were predictive of a lower JOA score RR. The flexion K-line may be a useful predictor of surgical outcomes after SL in patients with CSM. 4.


Arteriolar changes in developing and chronic stages of two-kidney, one clip hypertension.
Arteriolar internal and external diameters in the cremaster muscle of two-kidney, one clip hypertensive rats (2K1C) were measured in vivo with video microscopy, both before and after the topical application of adenosine (10(-4) M). Arteriolar density was determined by stereologic techniques. Mean arterial blood pressure was significantly elevated in the 2K1C rats, rising to 186 +/- 6 mm Hg by 8 weeks compared with 113 +/- 4 mm Hg in controls. Lumens of larger arterioles showed a structural reduction at 2 weeks of hypertension and remained at the same level through 8 weeks, while arterioles of control rats showed a progressive increase in diameter with age (101 +/- 6 microns in 2K1C vs. 158 +/- 8 microns in controls at 8 weeks after operation). Wall-to-lumen ratios of larger arterioles were significantly increased at 2, 4, and 8 weeks of hypertension, but cross-sectional wall area was significantly reduced at 8 weeks. Medial hypertrophy was not evident at any stage of hypertension. Arteriolar rarefaction of smaller arterioles was functional at 2 weeks and structural at 8 weeks of hypertension. Vascular tone of the smaller arterioles was elevated in the developing and chronic stages of hypertension. At 2 weeks of hypertension when the structural reduction in diameters of larger arterioles was progressing, the increased vasoconstriction and functional rarefaction may have contributed to the elevated resistance. At 8 weeks, the marked diameter reductions of larger arterioles (36% in first-order arterioles and 25% in second-order arterioles) account for most of the increased resistance to flow.


Range separated hybrids of pair coupled cluster doubles and density functionals.
Pair coupled cluster doubles (pCCD) is a size-consistent, size-extensive, low-cost simplification of CCD that has been shown to be able to describe static correlation without breaking symmetry. We combine pCCD with Kohn-Sham functionals of the density and the local pair density in order to incorporate dynamic correlation in pCCD while maintaining its low cost. Double counting is eliminated by splitting the (interelectron) Coulomb operator into complementary short- and long-range parts, and evaluating the two-body energy with pCCD in the long-range and with density functionals in the short-range. This simultaneously suppresses self-interaction in the Hartree-exchange term of the functionals. Generalizations including a fraction of wavefunction two-body energy in the short-range are also derived and studied. The improvement of our pCCD+DFT hybrids over pCCD is demonstrated in calculations on benchmarks where both types of correlation are important.


Agreement and validity of electronic health record prescribing data relative to pharmacy claims data: A validation study from a US electronic health record database.
Granular clinical and laboratory data available in electronic health record (EHR) databases provide researchers the opportunity to conduct investigations that would not be possible in insurance claims databases; however, for pharmacoepidemiology studies, accurate classification of medication exposure is critical. The aim of this study was to evaluate the validity of classifying medication exposure using EHR prescribing (EHR-Rx) data. We conducted a retrospective cohort study among patients with linked claims and EHR data in OptumLabs™ Data Warehouse. The agreement between EHR-Rx data and pharmacy claims (PC-Rx) data (for 40 medications) was determined using the positive predictive value (PPV) and medication possession ratio (MPR)-calculated in 1- and 12-month medication exposure periods (MEPs). Secondary analyses were restricted to incident vs prevalent EHR-Rxs, age ≥65 vs <65, white vs black race, males vs females, and number of EHR-Rxs. The validity metrics varied substantially among the 40 medications assessed. Across all medications, the period PPV and MPR were 62% and 63% in the 1-month MEP. They were 78% and 43% in the 12-month MEP. Overall, PPV and MPR were higher for patients with a prevalent EHR-Rx and age <65. Despite substantial variability among different medications, there was very good agreement between EHR-Rx data and PC-Rx data. To maximize the validity of classifying medication exposure with EHR prescribing data, researchers may consider using longer MEPs (eg, 12 months) and potentially require multiple EHR-Rxs to classify baseline medication exposure.


Dietary patterns of adolescents in Germany--associations with nutrient intake and other health related lifestyle characteristics.
The aim of this study was to identify dietary patterns among a representative sample of German adolescents and their associations with energy and nutrient intake, socioeconomic and lifestyle characteristics, and overweight status. In the analysis, data from the German Health Interview and Examination Survey for Children and Adolescents were used. The survey included a comprehensive dietary history interview conducted among 1272 adolescents aged 12 to 17 years. Dietary patterns were determined with principal component analysis (PCA) based on 48 food groups, for boys and girls separately. Three dietary patterns among boys and two among girls were identified. Among boys, high adherence to the 'western' pattern was associated with higher age, lower socioeconomic status (SES), and lower physical activity level (PA). High adherence to the 'healthy' pattern among boys, but not among girls, was associated with higher SES, and higher PA. Among boys, high adherence to the 'traditional' pattern was associated with higher age. Among girls, high adherence to the 'traditional and western' pattern was associated with lower age, lower SES and more hours watching TV per day. The nutrient density of several vitamins and minerals, particularly of B-vitamins and calcium, increased with increasing scores of the 'healthy' pattern among both sexes. Conversely, with increasing scores of the 'western' pattern among boys, most nutrient densities decreased, particularly of fibre, beta-carotene, vitamin D, biotin and calcium. Among girls with higher scores of the 'traditional and western' pattern, nutrient densities of vitamin A, C, E, K and folate decreased. Among boys, high adherence to the 'traditional' pattern was correlated with higher densities of vitamin B12 and vitamin D and lower densities of fibre, magnesium and iron. No significant associations between dietary patterns and overweight were found. Higher scores for dietary patterns characterized by higher consumption of take away food, meat, confectionary and soft drinks ('western' and 'traditional and western') were found particularly among 16- to 17-years old boys and among adolescents with lower SES. These patterns were also associated with higher energy density, higher percent of energy from unsaturated fatty acids and lower percent of energy from carbohydrates as well as lower nutrient densities of several vitamins and minerals. Therefore, nutritional interventions should try to focus more on adolescents with lower SES and boys in general.


An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial.
Biomarker-guided treatment for patients with colon cancer is needed. We tested ABCG2 and topoisomerase 1 (TOP1) mRNA expression as predictive biomarkers for irinotecan benefit in the PETACC-3 patient cohort. The present study included 580 patients with mRNA expression data from Stage III colon cancer samples from the PETACC-3 study, which randomized the patients to Fluorouracil/leucovorin (5FUL) +/- irinotecan. The primary end-points were recurrence free survival (RFS) and overall survival (OS). Patients were divided into one group with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) ("resistant") (n = 216) and another group including all other combinations of these two genes ("sensitive") (n = 364). The rationale for the cut-offs were based on the distribution of expression levels in the PETACC-3 Stage II set of patients, where ABCG2 was unimodal and TOP1 was bimodal with a high expression level mode in the top quarter of the patients. Cox proportional hazards regression was used to estimate the hazard ratios and the association between variables and end-points and log-rank tests to assess the statistical significance of differences in survival between groups. Kaplan-Meier estimates of the survival functions were used for visualization and estimation of survival rates at specific time points. Significant differences were found for both RFS (Hazard ratio (HR): 0.63 (0.44-0.92); p = 0.016) and OS (HR: 0.60 (0.39-0.93); p = 0.02) between the two biomarker groups when the patients received FOLFIRI (5FUL+irinotecan). Considering only the Microsatellite Stable (MSS) and Microsatellite Instability-Low (MSI-L) patients (n = 470), the differences were even more pronounced. In contrast, no significant differences were observed between the groups when patients received 5FUL alone. This study shows that the combination of ABCG2 and TOP1 gene expression significantly divided the Stage III colon cancer patients into two groups regarding benefit from adjuvant treatment with FOLFIRI but not 5FUL.


Spatial topologies affect local food web structure and diversity in evolutionary metacommunities.
An important challenge in theoretical ecology is to better predict ecological responses to environmental change, and in particular to spatial changes such as habitat fragmentation. Classical food-web models have focused on purely ecological predictions, without taking adaptation or evolution of species traits into account. We address this issue using an eco-evolutionary model, which is based on body masses and diets as the key traits that determine metabolic rates and trophic interactions. The model implements evolution by the introduction of new morphs that are related to the existing ones, so that the network structure itself evolves in a self-organized manner. We consider the coupling and decoupling of habitats in multi-trophic metacommunities consisting of 2 or 4 habitats. Our model thus integrates metacommunity models, which describe ecosystems as networks of networks, with large community evolution models. We find that rescue effects and source-sink effects occur within coupled habitats, which have the potential to change local selection pressures so that the local food web structure shows a fingerprint of its spatial conditions. Within our model system, we observe that habitat coupling increases the lifetimes of top predators and promotes local biodiversity.


Routing of spatial solitons by interaction with rod microelectrodes.
We report on what is, to our knowledge, the first experimental observation of spatial soliton interaction with charged conductive microelectrodes in nematic liquid crystals. We show that solitons can undergo voltage-controlled deflection and reflection with a nematicon steering larger than 100° over distances of a few micrometers. Using bias-defined perturbations, we observe reconfigurable soliton geometries with several reflections.


Bacterial artificial chromosome (BAC) library resource for positional cloning of pest and disease resistance genes in cassava (Manihot esculenta Crantz).
Pest and disease problems are important constraints of cassava production and host plant resistance is the most efficient method of combating them. Breeding for host plant resistance is considerably slowed down by the crop's biological constraints of a long growth cycle, high levels of heterozygosity and a large genetic load. More efficient methods such as gene cloning and transgenesis are required to deploy resistance genes. To facilitate the cloning of resistance genes, bacterial artificial chromosome (BAC) library resources have been developed for cassava. Two libraries were constructed from the cassava clones, TMS 30001, resistant to the cassava mosaic disease (CMD) and the cassava bacterial blight (CBB), and MECU72, resistant to cassava white fly. The TMS30001 library has 55, 296 clones with an insert size range of 40-150 kb with an average of 80 kb, while the MECU72 library consists of 92 160 clones and an insert size range of 25-250 kb average of 93 kb. Based on a genome size of 772 Mb, the TMS30001 and MECU72 libraries have a 5 and 11.3 haploid genome equivalents and a 95 and 99 chance of finding any sequence, respectively. To demonstrate the potential of the libraries, the TMS30001 library was screened by southern hybridization using a cassava analog (CBB1) of the Xa21 gene from rice that maps to a region containing a QTL for resistance to CBB as probe. Five BAC clones that hybridized to CBB1 were isolated and a Hind III fingerprint revealed 2-3 copies of the gene in individual BAC clones. A larger scale analysis of resistance gene analogs (RGAs) in cassava has also been conducted in order to understand the number and organization of RGAs. To scan for gene and repeat DNA content in the libraries, end-sequencing was performed on 2,301 clones from the MECU72 library. A total of 1705 unique sequences were obtained with an average size of 715 bp. Database homology searches using BLAST revealed that 458 sequences had significant homology with known proteins and 321 with transposable elements. The use of the library in positional cloning of pest and disease resistance genes is discussed.


Systematic Review of Tobacco Use after Lung or Head/Neck Cancer Diagnosis: Results and Recommendations for Future Research.
Tobacco use after cancer diagnosis is associated with adverse cancer outcomes, yet reliable prevalence estimates for this behavior are lacking. We conducted a systematic literature review of the prevalence of current tobacco use among individuals with a history of lung or head/neck cancer (CRD #42012002625). An extensive search of electronic databases (MEDLINE, EMBASE, Cochrane Library, CINAHL, PsycINFO, and Web of Science) identified 7,777 potentially relevant articles published between 1980 and 2014 and 131 of these yielded pertinent information. Aggregating results across heterogeneous study designs and diverse patient samples, the overall mean prevalence rate of current tobacco use (mostly cigarette smoking) was 33.0% (median, 31.0%). Among current tobacco users at cancer diagnosis, the mean prevalence rate of current tobacco use (mostly cigarette smoking) was 53.8% (median, 50.3%). In many cases, an operational definition of "current" tobacco use was absent, and biochemical verification of self-reported smoking status was infrequent. These and other observed methodologic limitations in the assessment and reporting of cancer patients' tobacco use underscore the necessity of uniform tobacco use assessment in future clinical research and cancer care.


Impact of anthelminthic treatment in pregnancy and childhood on immunisations, infections and eczema in childhood: a randomised controlled trial.
Helminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects. A randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly single-dose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15-2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73-0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome. Routine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct. Current Controlled Trials ISRCTN32849447.


Association of Cryptosporidium parvum with suspended particles: impact on oocyst sedimentation.
The association of Cryptosporidium parvum oocysts with suspended particles can alter the oocysts' effective physical properties and influence their transport in aquatic systems. To assess this behavior, C. parvum oocysts were mixed with various suspended sediments under a variety of water chemical conditions, and the resulting settling of the oocysts was observed. Direct microscopic observations showed that oocysts attached to suspended sediments. Settling column and batch experiments demonstrated that oocysts are removed from suspension at a much higher rate when associated with sediments. The rate of oocyst sedimentation depended primarily on the type of sediment with which the oocysts were mixed. Changes in background water conditions had a relatively small impact on the extent of oocyst-particle association and the resulting oocyst deposition. We believe that the ubiquitous association of C. parvum oocysts with suspended particles enhances the sedimentation of oocysts in natural waters and that this interaction should generally be considered when predicting the migration of pathogens in the environment.


Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients.
Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders ("putative neoantigens").


Role of canine parainfluenza virus and Bordetella bronchiseptica in kennel cough.
The effect of Bordetella bronchiseptica upper airway colonization on the clinical, radiographic, serologic, pathologic, and pulmonary function changes caused by canine parainfluenza-2 virus (CPIV-2) infection was studied in 24 purebred Beagle pups (10.5 +/- 1.4 weeks old). Eight control dogs (group I) were not colonized or inoculated with CPIV-2. Of the 12 noncolonized dogs inoculated with CPIV-2 (group II), 9 developed antibody titers to CPIV-2 and 10 had clinical signs of infectious canine tracheobronchitis (kennel cough). Group I and group II dogs did not differ in radiographic findings or pulmonary function. Four group II dogs necropsied 1 to 5 days after clinical signs developed had laryngotracheobronchitis and bronchiolar inflammation not present at necropsy on 2 group I dogs. Four dogs had B bronchiseptica upper airway colonization and were inoculated with CPIV-2 (group III). All 4 group III dogs developed positive antibody titers, had clinical signs of kennel cough, and had radiographic changes. Pulmonary dynamic compliance was lower in group III than in group I or group II animals. Respiratory rate and tidal volume did not differ among the 3 groups. The 1 group III dog that was necropsied had changes similar to group II dogs with the addition of lobar bronchopneumonia. The present study indicates that asymptomatic B bronchiseptica colonization may effect the clinical, radiographic, and pulmonary function changes produced by CPIV-2 respiratory tract infections.


Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases.
Canonical activation of NF-kappa B is mediated via phosphorylation of the inhibitory I kappa B proteins by the I kappa B kinase complex (IKK). IKK is composed of a heterodimer of the catalytic IKK alpha and IKK beta subunits and a presumed regulatory protein termed NEMO (NF-kappa B essential modulator) or IKK gamma. NEMO/IKK gamma is indispensable for activation of the IKKs in response to many signals, but its mechanism of action remains unclear. Here we identify TANK (TRAF family member-associated NF-kappa B activator) as a NEMO/IKK gamma-interacting protein via yeast two-hybrid analyses. This interaction is confirmed in mammalian cells, and the domains required are mapped. TANK was previously shown to assist NF-kappa B activation in a complex with TANK-binding kinase 1 (TBK1) or IKK epsilon, two kinases distantly related to IKK alpha/beta, but the underlying mechanisms remained unknown. Here we show that TBK1 and IKK epsilon synergize with TANK to promote interaction with the IKKs. The TANK binding domain within NEMO/IKK gamma is required for proper functioning of this IKK subunit. These results indicate that TANK can synergize with IKK epsilon or TBK1 to link them to IKK complexes, where the two kinases may modulate aspects of NF-kappa B activation.


Ontology-Oriented Programming for Biomedical Informatics.
Ontologies are now widely used in the biomedical domain. However, it is difficult to manipulate ontologies in a computer program and, consequently, it is not easy to integrate ontologies with databases or websites. Two main approaches have been proposed for accessing ontologies in a computer program: traditional API (Application Programming Interface) and ontology-oriented programming, either static or dynamic. In this paper, we will review these approaches and discuss their appropriateness for biomedical ontologies. We will also present an experience feedback about the integration of an ontology in a computer software during the VIIIP research project. Finally, we will present OwlReady, the solution we developed.


Development and initial validation of the Swedish Family Satisfaction Intensive Care Questionnaire (SFS-ICQ).
Measuring patients satisfaction is an important part of continuous quality improvement in health care. In intensive care, family satisfaction is often used as a proxy for patient experience. At present, no suitable instrument to measure this has been fully validated in Sweden. The purpose of this study was to develop and validate a questionnaire intended to evaluate families' satisfaction of quality of care in Swedish intensive care units. Based on literature and the modification of pertinent items in two existing North American questionnaires, a Swedish questionnaire was developed. Content validity was assessed by experts, and the cognitive method Think Aloud was used with twelve family members of intensive care patients in two different intensive care units. Data was analysed using qualitative content analysis. Seven items in the questionnaire were identified as problematic, causing eight problems concerning questioning of content and 23 concerning misunderstanding. Six of these items were changed in order to be understood the way they were intended, and one item was removed. A family satisfaction questionnaire applicable in Swedish intensive care units has been developed and validated for respondents' understanding of the questions being asked. However, further psychometric testing should be performed when more data are available.


Repeatability and agreement of five imaging systems for measuring anterior segment parameters in healthy eyes.
The purpose of this study is to assess the repeatability and agreement of five imaging devices, namely, the Pentacam (Oculus), Sirius (CSO), Orbscan IIz (Bausch and Lomb), Corvis (Oculus), and ultrasound pachymetry (UP, Tomey) in measuring steep keratometry (sKm), flat keratometry (fKm), central corneal thickness (CCT), thinnest corneal thickness (TCT), and anterior chamber depth (ACD) in healthy individuals. This was prospective, comparative study. Forty-six healthy Indian patients. Forty-six eyes of 46 healthy participants underwent three consecutive scans on each device by a single examiner. Within-subject standard deviation, test-retest repeatability (TRT), and coefficient of variation (COV) for assessing repeatability and Bland-Altman plots for the agreement between the mean measurements of each machine were analyzed. The repeatability and agreement between the five devices for the measurements of sKm, fKm, CCT, TCT, and ACD. The TRT of sKm measurements ranged between 0.23 diopter (D) (with Pentacam) and 0.83 D (with Orbscan). The same of fKm, TCT, ACD, and CCT measurements ranged between 0.28 D (with Pentacam) and 0.74 D (with Sirius), 7.78 μm (Sirius) and 19.81 μm (Orbscan), 0.05 mm (Orbscan) and 0.07 (Sirius), and 7.36 μm (Sirius) and 18.02 μm (Orbscan), respectively. The TRT of sKm and fKm measurements with Pentacam was significantly lower than those with Orbscan and Sirius. The TRT of TCT measurement with Sirius was significantly lower than that with Pentacam (4.53 μm) and Orbscan (7.15 μm). There were statistically significant differences in the mean measurements of all parameters between the devices. The 95% limit of agreement on the Bland-Altman analysis was wide for the measurement pairs with all the devices. Significant proportional bias in the agreement was detected for TCT measurements with all the device pairs and for the ACD measurements between Sirius and Pentacam. The repeatability estimates of sKm, fKm, TCT, ACD, and CCT measurements with Pentacam, Orbscan, Sirius, Corvis, and UP in Indian eyes were good. However, the differences in the measurements between the devices were statistically significant and the same cannot be used interchangeably for anterior segments measurements.


MHC antigen expression by melanomas recovered from mice treated with allogeneic mouse fibroblasts genetically modified for interleukin-2 secretion and the expression of melanoma-associated antigens.
Recent approaches toward the immunotherapy of neoplastic disease involve the introduction of expression-competent genes for interleukin-2 (IL-2) into autologous malignant cells. Treatment of tumor-bearing experimental animals with the IL-2-secreting cells successfully induces partial and at times complete remissions. In most instances, however, although delayed, progressive tumor growth continues. Here, certain of the characteristics of B16 melanomas (H-2b) persisting in C57BL/6 mice (H-2b) treated with an IL-2-secreting, melanoma-antigen-positive cellular immunogen (RLBA-IL-2 cells) are described. Unlike the melanoma cells first injected, B16 cells recovered from mice treated with RLBA-IL-2 cells were deficient in the expression of MHC class I, but not class II determinants. Deficient MHC class I expression correlated with the cells' resistance to cytotoxic T lymphocytes (CTL) from the spleens of mice immunized with RLBA-IL-2 cells. Melanomas persisting in mice treated with non-IL-2-secreting, melanoma-antigen-positive cell constructs (RLBA-ZipNeo cells) were also deficient in the expression of MHC class I determinants, and the melanoma cells were resistant to CTL from mice immunized with RLBA-ZipNeo cells. Thus, the expression of melanoma-associated antigens rather than IL-2-secretion correlated with deficient MHC class I expression by the persistent melanomas. This point was substantiated by the expression of MHC class I antigens by melanomas persisting in mice treated with IL-2-secreting, melanoma-antigen-negative LM cells (LM-IL-2); it was equivalent to that of melanomas in untreated mice. The involvement of MHC class I antigens in the immune resistance of persistent melanoma cells from mice treated with the melanoma-antigen-positive immunogens was indicated by the effect of interferon gamma (IFN gamma) or N-methyl-N'-nitro- N-nitrosoguanidine (MNNG) on the susceptibility of the cells to anti-melanoma CTL. Treatment of the resistant melanomas with IFN gamma or MNNG stimulated MHC class I antigen expression and restored the cells' sensitivity to CTL from mice immunized with IL-2-secreting or nonsecreting, melanoma-antigen-positive cellular immunogens. Prior treatment of the treated cells with antibodies to MHC class I determinants inhibited the cells' susceptibility to CTL from mice immunized with RLBA-IL-2 cells.


Precessation treatment with nicotine skin patch facilitates smoking cessation.
Nicotine replacement therapy (NRT) is a well-established treatment to aid smoking cessation, and current products recommend using NRT only after quitting smoking. However, theoretical arguments and previous data support the hypothesis that precessation use of NRT might be useful in reducing dependence on inhaled nicotine and serve as a helpful prelude to smoking cessation. The present study explored the use of NRT for 2 weeks before a target quit-smoking date, during which subjects continued to smoke ad libitum. Three experimental conditions varied the nicotine delivery of the cigarettes smoked during these 2 weeks so that we could examine the effects of concurrent nicotine administration on compensatory smoking of low tar and nicotine cigarettes. Subjects smoked (a) their usual brands of cigarettes, (b) conventional low tar and nicotine cigarettes, or (c) denicotinized cigarettes. After the quit date, subjects received pharmacotherapy consisting of various doses of NRT (0, 21, or 42 mg/24-hr) in combination with the nicotinic antagonist mecamylamine (10 mg/day). Results showed that precessation nicotine patch treatment was associated with a significantly higher rate of continuous smoking abstinence at 4 weeks, regardless of cigarette condition. Ad libitum smoking before the target quit date was modulated by nicotine patch treatment, and compensatory increases in smoking low tar and nicotine cigarettes were prevented by concurrent use of nicotine patches. These results suggest that use of NRT before a target quit-smoking date deserves further evaluation as a possible smoking cessation treatment. Moreover, while nicotine patches were well tolerated when subjects smoked nicotine-containing cigarettes, the use of nicotine skin patches with reduced-nicotine cigarettes potentially offers the advantage of increased efficacy without introducing concern about toxic effects of excessive nicotine intake.


Index of convexity: A novel method for assessing liver functional reserve using technetium-99m-galactosyl human serum albumin liver scintigraphy.
Preoperative evaluation of liver functional reserve is important in hepatobiliary surgery. Although the indocyanine green retention rate at 15 minutes (ICG-R15) is the gold standard for this purpose, a new method without technical complexity would be preferable. We assessed the usefulness of the previously established index of convexity (IOC). In total, 159 consecutive patients who underwent both technetium-99m-galactosyl human serum albumin (99mTc-GSA) scintigraphy and the ICG-R15 were included. Correlation coefficients between indices from 99mTc-GSA scintigraphy and blood examinations including ICG-R15 were evaluated, and a conversion formula from the IOC to the ICG-R15 was established. The IOC was calculated as [L(15) × 2 - L(3) - L(27)] / [L(27) - L(3)], where L(t) indicates the radiation counts within the whole liver at t minutes after 99mTc-GSA injection. The IOC showed a significantly stronger correlation with the ICG-R15 (r = -0.532, p < 0.001) than the index of blood clearance (HH15) and the receptor index (LHL15). A formula for estimating ICG-R15 from IOC was "ICG-R15 = -31.0 × IOC + 30.1". In conclusion, the IOC is a better index for evaluating preoperative liver functional reserve than the conventional indices. A formula for estimating ICG-R15 from the IOC will be useful.


Variation revealed by SNP genotyping and morphology provides insight into the origin of the tomato.
Tomato, Solanum lycopersicum, is divided into two widely distributed varieties: the cultivated S. lycopersicum var. lycopersicum, and the weedy S. lycopersicum var. cerasiforme. Solanum pimpinellifolium is the most closely related wild species of tomato.The roles of S. pimpinellifolium and S. l. cerasiforme during the domestication of tomato are still under debate. Some authors consider S. l. cerasiforme to be the ancestor, whereas others think that S. l. cerasiforme is an admixture of S. pimpinellifolium and the cultivated S. l. lycopersicum. It is also not clear whether the domestication occurred in the Andean region or in Mesoamerica. We characterized 272 accessions (63 S. pimpinellifolium, 106 S. l. cerasiforme, 95 S. l. lycopersicum and 8 derived from hybridization processes) were morphologically and genetically using the SolCap platform (7,414 SNPs). The two species were distinguished in a PCA analysis and displayed a rich geographic structure. Solanum lycopersicum var. cerasiforme and S. l. lycopersicum were also differentiated in the PCA and Structure analyses, which supports maintaining them as different varieties. Solanum pimpinellifolium and the Andean S. l. cerasiforme were more diverse than the non-Andean S. lycopersicum. Solanum lycopersicum var. cerasiforme was morphologically and molecularly intermediate between S. pimpinellifolium and tomato. Solanum lycopersicum var. cerasiforme, with the exception of several Ecuadorian and Mexican accessions, is composed of the products of admixture processes according to the Structure analysis. The non-admixtured S. l. cerasiforme might be similar to the ancestral cultivars from which the cultivated tomato originated, and presents remarkable morphological diversity, including fruits of up to 6 cm in diameter. The data obtained would fit a model in which a pre-domestication took place in the Andean region, with the domestication being completed in Mesoamerica. Subsequently, the Spaniards took plants from Mesoamerica to Spain and from there they were exported to the rest of the world.


Mechanisms of long-term potentiation: EPSP/spike dissociation, intradendritic recordings, and glutamate sensitivity.
Synaptic efficacy is modified following a brief train of high-frequency stimulation (HFS) to a cell's afferent fibers (long-term potentiation; LTP). An alteration in the postsynaptic response to endogenous neurotransmitter, as a result of an increase in the number of postsynaptic receptors, has been proposed (Baudry and Lynch, 1980). We tested this hypothesis in the CA1 hippocampus by intracellularly recording the postsynaptic response to localized application of glutamate before and after induction of LTP. When LTP was produced, there was no corresponding change in neuronal sensitivity to glutamate application. These findings are not consistent with the hypothesis that HFS of fibers in CA1 stratum radiatum induces an increase in the number of postsynaptic glutamate receptors in CA1 pyramidal cells. Previous reports concerning LTP have indicated a dissociation between the degree of potentiation in the population EPSP and population spike. Simultaneous recordings of the CA 1 population EPSP and population spike in hippocampal slices confirmed that the degree of potentiation of the population spike was not predicted by the degree of potentiation in the population EPSP. Intradendritic impalements were obtained to more accurately assess changes in the intracellular EPSP following HFS. When the population EPSP was potentiated, there was also a potentiated intradendritic EPSP. When the population spike was potentiated following HFS, however, the intradendritic EPSP was often unchanged; in the same cell, there was an increased probability of action potential discharge to stimulation which was originally (i.e., pre-HFS) subthreshold for spike initiation. These results indicate that the EPSP (intracellular or extracellular) may be potentiated following HFS, but this potentiation is not a prerequisite for, or a correlation of, potentiation in the population spike. Furthermore, these findings suggest that LTP is composed of 2 independent components--a synaptic component and an EPSP-to-spike coupling component.


Marital status, intergenerational co-residence and cardiovascular and all-cause mortality among middle-aged and older men and women during wartime in Beirut: gains and liabilities.
Studies from the West have shown an increased risk of mortality with various indicators of social isolation. In this study, we examine associations of marital status and intergenerational co-residence with mortality in Lebanon, a country that suffered wars and atrocities for almost 16 years. Using data from a retrospective 10-year follow-up study (1984-1994) among 1567 adults aged 50 years and older in Beirut, cardiovascular disease and all-cause mortality rates (per 1000 person-years) were computed for men and women separately. Age-adjusted Mantel-Haenszel rate ratios (RR) and their 95% confidence intervals (CI) were estimated, and associations were examined using multivariate Poisson regression analysis. Most men (91.3%) were married at baseline, in contrast to only 55.4% of women. Compared to men, women were more likely to be living in one- and three-generation households and with a married child at baseline. While widowhood was associated with an increased risk of all-cause mortality among men only, being never married was associated with a higher CVD mortality risk among men and women. The presence of an adult married child was associated with a significantly higher mortality risk for men and women, even after adjusting for household socioeconomic indicators, marital status, lifestyle variables or pre-existing health-related conditions (hypertension, cholesterol, and diabetes) at baseline. The popular belief that co-residence with adult children reflects greater support networks and an avenue for old age security may not be a valid presumption in the Lebanese context during times of war.


Development and Validation of a New Short-Form Health Literacy Instrument (HLS-SF12) for the General Public in Six Asian Countries.
No comprehensive short-form health literacy (HL) survey tool has been available for general use across Asia. This study aimed to develop and validate a short-form HL instrument derived from the 47-item European Health Literacy Questionnaire (HLS-EU-Q47). A population survey (N = 10,024) was conducted from 2013 to 2015 using the HLS-EU-Q47 in 1,029 participants from Indonesia, 1,845 from Kazakhstan, 462 from Malaysia, 1,600 from Myanmar, 3,015 from Taiwan, and 2,073 from Vietnam. Validation of the short form was evaluated by principle component analysis, internal consistency, Pearson correlation, and regression analysis. Based on responses from six countries, a 12-item short-form HL questionnaire (HLS-SF12) was developed, retaining the conceptual framework of the HLS-EU-Q47 and accounting for the high variance of the full-form (i.e., 90% in Indonesia, 91% in Myanmar, 93% in Malaysia, 94% in Taiwan, and 95% in both Kazakhstan and Vietnam). The HLS-SF12 was demonstrated to have adequate psychometric properties, including high reliability (Cronbach's alpha = .85), good criterion-related validity, a moderate and high level of item-scale convergent validity, no floor or ceiling effect, and good model-data-fit throughout the populations in these countries. The HLS-SF12 was shown to be a valid and reliable tool for HL surveys in the general public in six Asian countries. [HLRP: Health Literacy Research and Practice. 2019;3(2):e90-e102.]. A health literacy survey was conducted from 2013 to 2015 in six Asian countries using the European Health Literacy Questionnaire (HLS-EU-Q47). The collected data were used to develop and validate a comprehensive short-form questionnaire. A health literacy questionnaire with 12 items (HLS-SF12) that retains the original conceptual framework of the HLS-EU-Q47 was demonstrated to be reliable and valid.


Feeding practices and child weight: is the association bidirectional in preschool children?
Parental feeding practices are associated with children's body mass index (BMI). It has been generally assumed that parental feeding determines children's eating behaviors and weight gain, but feeding practices could equally be a parent's response to child weight. In longitudinal analyses, we assessed the directionality in the relation between selected controlling feeding practices and BMI in early childhood. Participants were 4166 children from the population-based Generation R Study. BMI was measured at ages 2 and 6 y. With the use of the Child Feeding Questionnaire, parents reported on restriction, monitoring, and pressure to eat (child age: 4 y). BMI and feeding-behavior scales were transformed to SD scores. With the use of linear regression analyses, there was an indication that a higher BMI at age 2 y predicted higher levels of parental restriction (adjusted β = 0.07; 95% CI: 0.04, 0.10) and lower levels of pressure to eat (adjusted β = -0.20; 95% CI: -0.23, -0.17) 2 y later. Restriction at age 4 y positively predicted child BMI at 6 y of age, although this association attenuated to statistical nonsignificance after accounting for BMI at age 4 y (β = 0.01; 95% CI: -0.01, 0.03). Pressure to eat predicted lower BMI independently of BMI at age 4 y (β = -0.02; 95% CI: -0.04, -0.01). For both restriction and pressure to eat, the relation from BMI to parenting was stronger than the reverse (Wald's test for comparison: P = 0.03 and < 0.001, respectively). Monitoring predicted a lower child BMI, but this relation was explained by confounding factors. Although the feeding-BMI relation is bidirectional, the main direction of observed effects suggests that parents tend to adapt their controlling feeding practices in response to their child's BMI rather than the reverse. Therefore, some components of current programs aimed at preventing or treating unhealthy child weight may need to be carefully scrutinized, especially those targeting parental food-related restriction and pressure to eat.


T Cell Responses and Regulation and the Impact of In Vitro IL-10 and TGF-β Modulation During Treatment of Active Tuberculosis.
Mycobacterium tuberculosis (Mtb) is particularly challenging for the immune system being an intracellular pathogen, and a variety of T cell subpopulations are activated by the host defence mechanism. In this study, we investigated T cell responses and regulation in active TB patients with drug-sensitive Mtb (N = 18) during 24 weeks of efficient anti-TB therapy. T cell activation, differentiation, regulatory T cell (Treg) subsets, Mtb-induced T cell proliferation and in vitro IL-10 and TGF-β modulation were analysed by flow cytometry at baseline and after 8 and 24 weeks of therapy, while soluble cytokines in culture supernatants were analysed by a 9-plex Luminex assay. Successful treatment resulted in significantly reduced co-expression of HLA-DR/CD38 and PD-1/CD38 on both CD4+ and CD8+ T cells, while the fraction of CD4+ CD25high CD127low Tregs (P = 0.017) and CD4+ CD25high CD127low CD147+ Tregs (P = 0.029) showed significant transient increase at week 8. In vitro blockade of IL-10/TGF-β upon Mtb antigen stimulation significantly lowered the fraction of ESAT-6-specific CD4+ CD25high CD127low Tregs at baseline (P = 0.047), while T cell proliferation and cytokine production were unaffected. Phenotypical and Mtb-specific T cell signatures may serve as markers of effective therapy, while the IL-10/TGF-β pathway could be a target for early inhibition to facilitate Mtb clearance. However, larger clinical studies are needed for verification before concluding.


The modulation of motor contagion by intrapersonal sensorimotor experience.
Sensorimotor experiences can modify the internal models for action. These modifications can govern the discrepancies between predicted and actual sensory consequences, such as distinguishing self- and other-generated actions. This distinction may also contribute toward the inhibition of movement interference, which is strongly associated with the coupling of observed and executed actions. Therefore, movement interference could be mediated by the sensorimotor experiences underlying the self-other distinction. The present study examined the impact of sensorimotor experiences on involuntary movement interference (motor contagion). Participants were required to complete a motor contagion paradigm in which they executed horizontal arm movements while observing congruent (horizontal) or incongruent (vertical) arm movements of a model. This task was completed before and after a training protocol in which participants executed the same horizontal arm movements in the absence of the model stimuli. Different groups of participants trained with or without vision of their moving limb. Analysis of participants who were predisposed to motor contagion (involuntary movement interference during the observation of incongruent movements) revealed that the no vision group continued to demonstrate contagion at post-training, although the vision group did not. We propose that the vision group were able to integrate the visual afferent information with an internal model for action, which effectively refines the ability to match self-produced afferent and efferent sources of information during response-execution. This enhanced matching allows for a better distinction between self and other, which in turn, mediates the inhibition of motor contagion.


Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission.
The monitoring of BCR-ABL transcript levels by real-time quantitative polymerase chain reaction (RT-qPCR) has become important to assess minimal residual disease (MRD) and standard of care in the treatment of chronic myeloid leukemia (CML). In this study, we performed a prospective, sequential analysis using RT-qPCR monitoring of BCR-ABL gene rearrangements in blood samples from 91 CML patients in chronic phase (CP) who achieved complete cytogenetic remission (CCyR) and major molecular remission (MMR) throughout imatinib treatment. The absolute level of BCR-ABL transcript from peripheral blood was serially measured every 4 to 12 weeks by RT-qPCR. Only level variations > 0.5%, according to the international scale, was considered positive. Sequential cytogenetic analysis was also performed in bone marrow samples from all patients using standard protocols. Based on sequential analysis of BCR-ABL transcripts, the 91 patients were divided into three categories: (A) 57 (62.6%) had no variation on sequential analysis; (B) 30 (32.9%) had a single positive variation result obtained in a single sample; and (C) 4 (4.39%) had variations of BCR-ABL transcripts in at least two consecutive samples. Of the 34 patients who had elevated levels of transcripts (group B and C), 19 (55.8%) had a < 1% of BCR-ABL/BCR ratio, 13 (38.2%) patients had a 1% to 10% increase and 2 patients had a >10% increase of RT-qPCR. The last two patients had lost a CCyR, and none of them showed mutations in the ABL gene. Transient cytogenetic alterations in Ph-negative cells were observed in five (5.5%) patients, and none of whom lost CCyR. Despite an increase levels of BCR-ABL/BCR ratio variations by RT-qPCR, the majority of CML patients with MMR remained in CCyR. Thus, such single variations should neither be considered predictive of subsequent failure and nor an indication for altering imatinib dose or switching to second generation therapy. Changing of imatinib on the basis of BCR-ABL/BCR% sustained increase and mutational studies is a prudent approach for preserving other therapeutic options in imatinib-resistant patients.


Recapture of patients with an incomplete diagnosis of hepatitis C virus infection.
hepatitis C virus (HCV) antibody tests have been performed since the 90s, although HCV-RNA (viral load) determination was not always performed. Some of these patients may be actively infected and not be aware of it. Here, we describe a procedure to capture these subjects and complete their diagnosis. the historical laboratory results of Navarra were reviewed and individuals who were positive for antibodies against HCV (anti-HCV) and had not undergone HCV-RNA testing were identified. In September 2018, each general practitioner (GP) was informed about their patients and given precise instructions for completing the diagnosis. The procedure was assessed until December 2019. two hundred and eighty-nine anti-HCV positive patients were detected for whom active infection had not been discarded. Two were HIV-positive and six had already died. GPs were asked to assess the remaining 281 subjects. By the end of 2019, a new blood test had been performed in 187 (67 %) patients, 5 % decided not to do it, 4 % were living outside of Navarra, 3 % could not be contacted and the GP considered that it was not justified in 2 % of cases. Thus, 19 % remained to be contacted. From the 187 assessed patients, active infection was confirmed in 52 (28 %) individuals, 40 % were false positives and HCV-RNA was undetectable in 31 %. Regarding the 52 actively infected subjects, 34 had already initiated antiviral therapy and three were hospitalized due to decompensated cirrhosis, from which one patient died. the strategy to recapture individuals with an incomplete HCV infection diagnosis was effective to detect active infections and subsequent initiation of antiviral therapy.


Genistein suppresses tumor necrosis factor-alpha-induced proliferation via the apoptotic signaling pathway in human aortic smooth muscle cells.
The proliferation of vascular smooth muscle cells (VSMCs) plays a key role in the development of atherosclerosis. Abnormal VSMC proliferation induces vascular dysfunction and several other pathological processes. The present study investigated the apoptotic effects of genistein on tumor necrosis factor-alpha (TNF-alpha)-induced proliferation in human aortic smooth muscle cells (HASMCs). The apoptotic effects of genistein were assessed to determine the mechanism(s) of its antiproliferative activity, including MTT, LDH assay, morphological change of cell, DNA fragmentation, and expression levels of pro- or anti-apoptotic molecules by RT-PCR and Western blots. The results show that genistein significantly reduced cell proliferation in TNF-alpha-induced HASMCs. Genistein also reduced intracellular nuclei staining with DAPI in a dose-dependent manner. In addition, genistein increased nucleosomal DNA fragmentation, increased the expression levels of Bax and c-Myc, and decreased the expression levels of Bcl-2 and Bcl-xL in TNF-alpha-induced HASMCs. Taken together, these findings indicate that genistein regulates the activation of apoptosis-related molecules in TNF-alpha-induced HASMCs, leading to the suppression of proliferation and induction of apoptosis.


AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC's 9th AML trial.
The outcome of treatment with standard first line therapy of 66 patients with acute myeloid leukaemia (AML) secondary to preceding chemotherapy (Group 1), a myelodysplastic state (Group 2) or a myeloproliferative disorder (Group 3) was analysed in relation to the preceding disorder, the cytogenetic pattern where available, and the cytology and cytochemistry of blood and bone marrow. The complete remission (CR) rate for the secondary AMLs was 36% (24/66), with 24% (16/66) dying in the induction period and 39% (26/66) having resistant disease. The CR rate was 25% (5/20) for Group 1, 42% (15/36) for Group 2, and 40% (4/10) for Group 3. Even after allowance for the generally older age of the secondary AML patients, they still had a significantly poorer CR rate than the de novo AMLs (P = 0.0004). The lower CR rate was chiefly due to resistant disease. Despite this, overall survival was not significantly worse for the secondary AML patients (P = 0.15). For the 36% that achieved remission, remission duration appeared similar to that of de novo cases. Of 62 cases with adequate cytology, 38 (61%) had evidence of erythroid and/or megakaryocytic dysplasia with a CR rate of 32% (12/38). The CR rate of these multineage leukaemias was not significantly different from that of the 24 (39%) who showed granulocyte/monocyte precursor involvement only, 42% (10) of whom achieved CR. The presence of features of differentiation within blast cells such as Auer rods or sudanophilia (greater than 50% positive blasts) was associated with a higher remission rate 47% (18/38) than that of poorly differentiated cases 17% (3/18) (P = 0.04) and thus appeared to be a more important determinant of CR achievement than was lineage involvement. Cases with a normal karyotype had a 33% (7/21) CR rate, while those with chromosomal abnormalities had a 37% (9/24) CR rate. Only 12 of the 45 cases with adequate cytogenetic analysis showed deletions or monosomies involving chromosomes 5 or 7, and seven of these were in Group 1.


Chromophoric dissolved organic matter in inland waters: Present knowledge and future challenges.
Chromophoric dissolved organic matter (CDOM) plays an important role in the biogeochemical cycle and energy flow of aquatic ecosystems. Thus, systematic and comprehensive understanding of CDOM dynamics is critically important for aquatic ecosystem management. CDOM spans multiple study fields, including analytical chemistry, biogeochemistry, water color remote sensing, and global environmental change. Here, we thoroughly summarize the progresses of recent studies focusing on the characterization, distribution, sources, composition, and fate of CDOM in inland waters. Characterization methods, remote sensing estimation, and biogeochemistry cycle processes were the hotspots of CDOM studies. Specifically, optical, isotope, and mass spectrometric techniques have been widely used to characterize CDOM abundance, composition, and sources. Remote sensing is an effective tool to map CDOM distribution with high temporal and spatial resolutions. CDOM dynamics are mainly determined by watershed-related processes, including rainfall discharge, groundwater, wastewater discharges/effluents, and biogeochemical cycling occurring in soil and water bodies. We highlight the underlying mechanisms of the photochemical degradation and microbial decomposition of CDOM, and emphasize that photochemical and microbial processes of CDOM in inland waters accelerate nutrient cycling and regeneration in the water column and also exacerbate global warming by releasing greenhouse gases. Future study directions to improve the understanding of CDOM dynamics in inland waters are proposed. This review provides an interdisciplinary view and new insights on CDOM dynamics in inland waters.


DNA polymerase kappa deficiency does not affect somatic hypermutation in mice.
Somatic hypermutation (SH) in B cells undergoing T cell-dependent immune responses generates high-affinity antibodies that provide protective immunity. Most current models of SH postulate the introduction of a nick into the DNA and subsequent replication-independent, error-prone short-patch synthesis by one or more DNA polymerases. The Pol kappa (DinB1) gene encodes a specialized mammalian DNA polymerase called DNA polymerase kappa (pol kappa), a member of the recently discovered Y family of DNA polymerases. The mouse PolK gene is expressed at high levels in the seminiferous tubules of the testis and in the adrenal cortex, and at lower levels in most other cells of the body including B lymphocytes. In vitro studies showed that pol kappa can act as an error-prone polymerase, although they failed to ascribe a clear function to this enzyme. The ability of pol kappa to generate mutations when extending primers on undamaged DNA templates identifies this enzyme as a potential candidate for the introduction of nucleotide changes in the immunoglobulin (Ig) genes during the process of SH. Here we show that pol kappa-deficient mice are viable, fertile and able to mount a normal immune response to the antigen (4-hydroxy-3-nitrophenyl)acetyl-chicken gamma-globulin (NP-GC). They also mutate their Ig genes normally. However, pol kappa-deficient embryonic fibroblasts are abnormally sensitive to killing following exposure to ultraviolet (UV) radiation, suggesting a role of pol kappa in translesion DNA synthesis.


The effect of oral sodium acetate administration on plasma acetate concentration and acid-base state in horses.
Sodium acetate (NaAcetate) has received some attention as an alkalinizing agent and possible alternative energy source for the horse, however the effects of oral administration remain largely unknown. The present study used the physicochemical approach to characterize the changes in acid-base status occurring after oral NaAcetate/acetic acid (NAA) administration in horses. Jugular venous blood was sampled from 9 exercise-conditioned horses on 2 separate occasions, at rest and for 24 h following a competition exercise test (CET) designed to simulate the speed and endurance test of 3-day event. Immediately after the CETs horses were allowed water ad libitum and either: 1) 8 L of a hypertonic NaAcetate/acetic acid solution via nasogastric tube followed by a typical hay/grain meal (NAA trial); or 2) a hay/grain meal alone (Control trial). Oral NAA resulted in a profound plasma alkalosis marked by decreased plasma [H+] and increased plasma [TCO2] and [HCO3-] compared to Control. The primary contributor to the plasma alkalosis was an increased [SID], as a result of increased plasma [Na+] and decreased plasma [Cl-]. An increased [Atot], due to increased [PP] and a sustained increase in plasma [acetate], contributed a minor acidifying effect. It is concluded that oral NaAcetate could be used as both an alkalinizing agent and an alternative energy source in the horse.


Epigenetic silencing of a proapoptotic cell adhesion molecule, the immunoglobulin superfamily member IGSF4, by promoter CpG methylation protects Hodgkin lymphoma cells from apoptosis.
The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) are believed to derive from germinal center (GC) B cells, but lack expression of a functional B cell receptor. As apoptosis is the normal fate of B-cell receptor-negative GC B cells, mechanisms that abrogate apoptosis are thus critical in HL development, such as epigenetic disruption of certain pro-apoptotic cancer genes including tumor suppressor genes. Identifying methylated genes elucidates oncogenic mechanisms and provides valuable biomarkers; therefore, we performed a chemical epigenetic screening for methylated genes in HL through pharmacological demethylation and expression profiling. IGSF4/CADM1/TSLC1, a pro-apoptotic cell adhesion molecule of the immunoglobulin superfamily, was identified together with other methylated targets. In contrast to its expression in normal GC B cells, IGSF4 was down-regulated and methylated in HL cell lines, most primary HL, and microdissected HRS cells of 3/5 cases, but not in normal peripheral blood mononuclear cells and seldom in normal lymph nodes. We also detected IGSF4 methylation in sera of 14/18 (78%) HL patients but seldom in normal sera. Ectopic IGSF4 expression decreased HL cells survival and increased their sensitivity to apoptosis. IGSF4 induction that normally follows heat shock stress treatment was also abrogated in methylated lymphoma cells. Thus, our data demonstrate that IGSF4 silencing by CpG methylation provides an anti-apoptotic signal to HRS cells important in HL pathogenesis.


SCPP genes in the coelacanth: tissue mineralization genes shared by sarcopterygians.
The coelacanth is the basal-most extant sarcopterygian that has teeth and tooth-like structures, comprising bone, dentin, and enamel or enameloid. Formation of these tissues involves many members of the secretory calcium-binding protein (SCPP) family. In tetrapods, acidic-residue-rich SCPPs are used in mineralization of bone and dentin, whereas Pro/Gln-rich SCPPs participate in enamel formation. Teleosts also employ many SCPPs for tissue mineralization. Nevertheless, the repertoire of SCPPs is largely different in teleosts and tetrapods; hence, filling this gap would be critical to elucidate early evolution of mineralized tissues in osteichthyans. In the present study, we searched for SCPP genes in the coelacanth genome and identified 11, of which two have clear orthologs in both tetrapods and teleosts, seven only in tetrapods, and two in neither of them. Given the divergence times of these vertebrate lineages, our discovery of this many SCPP genes shared between the coelacanth and tetrapods, but not with teleosts, suggests a complicated evolutionary scheme of SCPP genes in early osteichthyans. Our investigation also revealed both conserved and derived characteristics of SCPPs in the coelacanth and other vertebrates. Notably, acidic SCPPs independently evolved various acidic repeats in different lineages, while maintaining high acidity, presumably important for interactions with calcium. Furthermore, the three Pro/Gln-rich SCPP genes, required for mineralizing enamel matrix and confirmed only in tetrapods, were all identified in the coelacanth, strongly suggesting that enamel is equivalent in the coelacanth and tetrapods. This finding corroborates the previous proposition that true enamel evolved much earlier than the origin of tetrapods.


Clinically apparent eating disorders in young diabetic women: associations with painful neuropathy and other complications.
Of 208 young women with insulin dependent diabetes, 15 (7%) had a clinically apparent eating disorder (anorexia nervosa or bulimia), a much higher prevalence than reported in non-diabetic women. Most, but not all, of these patients had a long history of poor glycaemic control. In contrast with previous suggestions, control did not deteriorate after the onset of the eating disorder. There was a high incidence and an early onset of diabetic complications. Eleven of the 15 patients had retinopathy, six with proliferative changes; six had nephropathy; and six neuropathy. Most strikingly, four patients with anorexia nervosa developed acute painful polyneuropathy. In each case pain started when the eating disorder developed, almost coinciding with the peak of weight reduction. Remission of pain occurred as weight was regained. The symptoms were accompanied by abnormalities in peripheral nerve electrophysiology and autonomic nerve function, some improvements in which accompanied weight recovery. It is suggested that nutritional factors may contribute to the high rate of early onset diabetic complications, particularly neuropathy.


Patterning vascular networks in vivo for tissue engineering applications.
The ultimate design of functionally therapeutic engineered tissues and organs will rely on our ability to engineer vasculature that can meet tissue-specific metabolic needs. We recently introduced an approach for patterning the formation of functional spatially organized vascular architectures within engineered tissues in vivo. Here, we now explore the design parameters of this approach and how they impact the vascularization of an engineered tissue construct after implantation. We used micropatterning techniques to organize endothelial cells (ECs) into geometrically defined "cords," which in turn acted as a template after implantation for the guided formation of patterned capillaries integrated with the host tissue. We demonstrated that the diameter of the cords before implantation impacts the location and density of the resultant capillary network. Inclusion of mural cells to the vascularization response appears primarily to impact the dynamics of vascularization. We established that clinically relevant endothelial sources such as induced pluripotent stem cell-derived ECs and human microvascular endothelial cells can drive vascularization within this system. Finally, we demonstrated the ability to control the juxtaposition of parenchyma with perfused vasculature by implanting cords containing a mixture of both a parenchymal cell type (hepatocytes) and ECs. These findings define important characteristics that will ultimately impact the design of vasculature structures that meet tissue-specific needs.


The genetic theory of adaptation: a brief history.
Theoretical studies of adaptation have exploded over the past decade. This work has been inspired by recent, surprising findings in the experimental study of adaptation. For example, morphological evolution sometimes involves a modest number of genetic changes, with some individual changes having a large effect on the phenotype or fitness. Here I survey the history of adaptation theory, focusing on the rise and fall of various views over the past century and the reasons for the slow development of a mature theory of adaptation. I also discuss the challenges that face contemporary theories of adaptation.


One-step hydrothermal synthesis of fluorescence carbon quantum dots with high product yield and quantum yield.
A one-step hydrothermal synthesis of nitrogen and silicon co-doped fluorescence carbon quantum dots (N,Si-CQDs), from citric acid monohydrate and silane coupling agent KH-792 with a high product yield (PY) of 52.56% and high quantum yield (QY) of 97.32%, was developed. This greatly improves both the PY and QY of CQDs and provides a new approach for a large-scale production of high-quality CQDs. Furthermore, N,Si-CQDs were employed as phosphors without dispersants to fabricate white light-emitting diodes (WLEDs) with the color coordinates at (0.29, 0.32). It is suggested that N,Si-CQDs have great potential as promising fluorescent materials to be applied in WLEDs.


Interactive use of on-line portal imaging in pelvic radiation.
We have evaluated a fluoroscopic on-line portal imaging system in routine clinical radiotherapy, involving the treatment of 566 pelvic fields on 13 patients. The image was typically generated by delivering a radiation dose of 6-8 cGy. Comparison between portal image and simulator film was done by eye and all visible errors were corrected before continuing irradiation. If possible, these corrections were performed from outside the treatment room by moving the patient couch by remote control or by changing collimator parameters. Adjustments were performed on 289/530 (54.5%) evaluable fields or 229/278 (82.4%) evaluable patient set-ups. The lateral couch position was most frequently adjusted (n = 254). The absolute values of the adjustments were 6.8 mm mean (SD 6.6 mm) with a maximum of 40 mm. All absolute values of adjustments exceeding 25 mm were recorded in one patient and those exceeding 15 mm were observed in two patients. Both patients were obese females. Adjustments exceeding 5 mm were observed in all 13 patients. Related to the use of on-line portal imaging, treatment time was increased by a median of 36.5% (mean 45.8%; SD 42.1%). The range was 7.7 to 442%. The fraction of the total treatment time to perform corrections was 22.7% median (mean: 26.0; SD: 11.8%). Statistically significant systematic in-plane errors were found in 7/13 patients. A systematic error was detected on the lateral position of the field in five patients. In one patient a systematic error of the longitudinal field position and in one patient a rotational error was detected. For adjustments in the lateral direction the present method does not allow to detect lateral shifts of less than 2 mm. For adjustments in the longitudinal direction the sensitivity could not be estimated but the available data suggest that 80% of errors < or = 5 mm were not adjusted. In obese patients, random errors may be surprisingly large.


Inhibition of human immunodeficiency virus replication by the herpes simplex virus virion host shutoff protein.
The herpes simplex virus (HSV) virion host shutoff gene (vhs) encodes a protein which nonspecifically accelerates the degradation of mRNA molecules, leading to inhibition of protein synthesis. This ability to inhibit a critical cellular function suggested that vhs could be used as a suicide gene in certain gene therapy applications. To investigate whether vhs might be useful for treatment of AIDS, we tested the ability of both HSV type 1 (HSV-1) and HSV-2 vhs to inhibit replication of human immunodeficiency virus (HIV). Replication of HIV was substantially inhibited when an infectious HIV proviral clone was cotransfected into HeLa cells together with vhs under the control of the cytomegalovirus (CMV) immediate-early promoter. HSV-2 vhs was more active than HSV-1 vhs in these experiments, consistent with previously published studies on these genes. Since expression of vhs from the CMV promoter is essentially unregulated, we also tested the ability of vhs expressed from the HIV long terminal repeat (LTR) promoter to inhibit HIV replication. Wild-type HSV-1 vhs inhibited HIV replication more than 44,000-fold in comparison to a mutant vhs gene encoding a nonfunctional form of the Vhs protein. Production of Vhs in transfected cells was verified by Western blot assays. A larger amount of Vhs was observed in cells transfected with plasmids expressing vhs from the HIV LTR than from the CMV promoter, consistent with the greater inhibition of HIV replication observed with these constructs. Mutant forms of Vhs were expressed at higher levels than wild-type Vhs, most likely due to the ability of wild-type Vhs to degrade its own mRNA. The strong inhibitory activity of the vhs gene and its unique biological properties make vhs an interesting candidate for use as a suicide gene for HIV gene therapy.


Phellinus tropicalis abscesses in a patient with chronic granulomatous disease.
Chronic Granulomatous Disease (CGD), caused by genetic defects in components of the phagocyte NADPH oxidase pathway, leads to recurrent life-threatening bacterial and invasive fungal infections. While a number of unique pathogens have been associated with this disease, the causative organisms may be difficult to identify. Here, we present a 24 year old male with known X-linked CGD who concurrently developed a cervical abscess and an abscess in the subcutaneous tissues of the right hip, both of which were surgically drained. Cultures failed to identify any organisms. He was treated empirically with ertapenem but the hip abscess recurred at the original site and in contiguous dependent areas in the posterior thigh and knee. A filamentous organism was observed microscopically, initially considered a contaminant, but on culture yielded a mold growth, identified as Phellinus tropicalis (synonym: Inonotus tropicalis) based on phenotypic and molecular methods. This is the third case report of human infection with P. tropicalis, all in subjects with CGD. The patient was treated with voriconazole with resolution of his symptoms.


White-light optical implementation of the fractional fourier transform with adjustable order control.
An optical implementation of the fractional Fourier transform (FRT) with broadband illumination is proposed by use of a single imaging element, namely, a blazed diffractive lens. The setup displays an achromatized version of the FRT of order P of any two-dimensional input function. This fractional order can be tuned continuously by shifting of the input along the optical axis. Our compact and flexible configuration is tested with a chirplike input signal, and the good experimental results obtained support the theory.


Evaluation of blood-brain barrier penetration and examination of binding to human serum albumin of 7-O-arylpiperazinylcoumarins as potential antipsychotic agents.
The delivery of drugs to the brain is complicated by the multiple factors including low blood-brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT1A and 5-HT2A with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log KQ = 5.3-6.0 which corresponds to -8.12 to -7.15 kcalmol-1 of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log KQ coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow's site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket.


A Southern Indian Ocean database of hydrographic profiles obtained with instrumented elephant seals.
The instrumentation of southern elephant seals with satellite-linked CTD tags has offered unique temporal and spatial coverage of the Southern Indian Ocean since 2004. This includes extensive data from the Antarctic continental slope and shelf regions during the winter months, which is outside the conventional areas of Argo autonomous floats and ship-based studies. This landmark dataset of around 75,000 temperature and salinity profiles from 20-140 °E, concentrated on the sector between the Kerguelen Islands and Prydz Bay, continues to grow through the coordinated efforts of French and Australian marine research teams. The seal data are quality controlled and calibrated using delayed-mode techniques involving comparisons with other existing profiles as well as cross-comparisons similar to established protocols within the Argo community, with a resulting accuracy of ±0.03 °C in temperature and ±0.05 in salinity or better. The data offer invaluable new insights into the water masses, oceanographic processes and provides a vital tool for oceanographers seeking to advance our understanding of this key component of the global ocean climate.


mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn's Disease.
Crohn's disease (CD) is a chronic inflammatory condition that can affect different portions of the gastrointestinal tract. Lymphatic drainage was demonstrated to be dysfunctional in CD pathogenesis, ultimately causing the failure of the resolution of intestinal inflammation. To investigate the molecular mechanisms underlying these dysfunctions, we isolated human intestinal lymphatic endothelial cells (HILECs) from surgical specimens of patients undergoing resection for complicated CD (CD HILEC) and from a disease-free margin of surgical specimens of patients undergoing resection for cancer (healthy HILEC). Both cell types underwent transcriptomic profiling, and their barrier functionality was tested using a transwell-based co-culture system between HILEC and lamina propria mononuclear cells (LPMCs). Results showed CD HILEC displayed a peculiar transcriptomic signature that highlighted mTOR signaling as an orchestrator of leukocyte trafficking through the lymphatic barrier of CD patients. Moreover, we demonstrated that LPMC transmigration through the lymphatic endothelium of patients with CD depends on the capability of mTOR to trigger interleukin 20 receptor subunit α (IL20RA)-mediated intracellular signaling. Conclusively, our study suggests that leukocyte trafficking through the intestinal lymphatic microvasculature can be controlled by modulating IL20RA, thus leading to the resolution of chronic inflammation in patients with CD.