Fertility, mortality, migration, and population scenarios for 195 countries and territories from 2017 to 2100: a forecasting analysis for the Global Burden of Disease Study.
Understanding potential patterns in future population levels is crucial for anticipating and planning for changing age structures, resource and health-care needs, and environmental and economic landscapes. Future fertility patterns are a key input to estimation of future population size, but they are surrounded by substantial uncertainty and diverging methodologies of estimation and forecasting, leading to important differences in global population projections. Changing population size and age structure might have profound economic, social, and geopolitical impacts in many countries. In this study, we developed novel methods for forecasting mortality, fertility, migration, and population. We also assessed potential economic and geopolitical effects of future demographic shifts. We modelled future population in reference and alternative scenarios as a function of fertility, migration, and mortality rates. We developed statistical models for completed cohort fertility at age 50 years (CCF50). Completed cohort fertility is much more stable over time than the period measure of the total fertility rate (TFR). We modelled CCF50 as a time-series random walk function of educational attainment and contraceptive met need. Age-specific fertility rates were modelled as a function of CCF50 and covariates. We modelled age-specific mortality to 2100 using underlying mortality, a risk factor scalar, and an autoregressive integrated moving average (ARIMA) model. Net migration was modelled as a function of the Socio-demographic Index, crude population growth rate, and deaths from war and natural disasters; and use of an ARIMA model. The model framework was used to develop a reference scenario and alternative scenarios based on the pace of change in educational attainment and contraceptive met need. We estimated the size of gross domestic product for each country and territory in the reference scenario. Forecast uncertainty intervals (UIs) incorporated uncertainty propagated from past data inputs, model estimation, and forecast data distributions. The global TFR in the reference scenario was forecasted to be 1·66 (95% UI 1·33-2·08) in 2100. In the reference scenario, the global population was projected to peak in 2064 at 9·73 billion (8·84-10·9) people and decline to 8·79 billion (6·83-11·8) in 2100. The reference projections for the five largest countries in 2100 were India (1·09 billion [0·72-1·71], Nigeria (791 million [594-1056]), China (732 million [456-1499]), the USA (336 million [248-456]), and Pakistan (248 million [151-427]). Findings also suggest a shifting age structure in many parts of the world, with 2·37 billion (1·91-2·87) individuals older than 65 years and 1·70 billion (1·11-2·81) individuals younger than 20 years, forecasted globally in 2100. By 2050, 151 countries were forecasted to have a TFR lower than the replacement level (TFR <2·1), and 183 were forecasted to have a TFR lower than replacement by 2100. 23 countries in the reference scenario, including Japan, Thailand, and Spain, were forecasted to have population declines greater than 50% from 2017 to 2100; China's population was forecasted to decline by 48·0% (-6·1 to 68·4). China was forecasted to become the largest economy by 2035 but in the reference scenario, the USA was forecasted to once again become the largest economy in 2098. Our alternative scenarios suggest that meeting the Sustainable Development Goals targets for education and contraceptive met need would result in a global population of 6·29 billion (4·82-8·73) in 2100 and a population of 6·88 billion (5·27-9·51) when assuming 99th percentile rates of change in these drivers. Our findings suggest that continued trends in female educational attainment and access to contraception will hasten declines in fertility and slow population growth. A sustained TFR lower than the replacement level in many countries, including China and India, would have economic, social, environmental, and geopolitical consequences. Policy options to adapt to continued low fertility, while sustaining and enhancing female reproductive health, will be crucial in the years to come. Bill & Melinda Gates Foundation.


Supplementation with Lactobacillus kefiranofaciens ZW3 from Tibetan Kefir improves depression-like behavior in stressed mice by modulating the gut microbiota.
Increasing evidence indicates that probiotics can effectively improve depression-like behavior. However, the underlying mechanism is still unclear. In this study, the antidepressant effect of Lactobacillus kefiranofaciens CGMCC2809 (ZW3) isolated from Tibetan Kefir grains was investigated using a mouse model of chronic unpredictable mild stress (CUMS). ZW3 improved depression-like behavior and independent exploration ability in the CUMS group. Moreover, ZW3 regulated biochemical disorders in the hypothalamic-pituitary-adrenal axis, immune system and tryptophan metabolism caused by stress. Furthermore, ZW3 could modulate the composition of the gut microbiota, and alleviate constipation by improving the fecal water content in stressed mice. We found that the probiotic strain was present in the whole intestine, even 7 days after its administration was stopped. These results suggest that L. kefiranofaciens ZW3 might improve depression by regulating the gut microbiota as a probiotic food.


Terrestrial invasion of pomatiopsid gastropods in the heavy-snow region of the Japanese Archipelago.
Gastropod mollusks are one of the most successful animals that have diversified in the fully terrestrial habitat. They have evolved terrestrial taxa in more than nine lineages, most of which originated during the Paleozoic or Mesozoic. The rissooidean gastropod family Pomatiopsidae is one of the few groups that have evolved fully terrestrial taxa during the late Cenozoic. The pomatiopsine diversity is particularly high in the Japanese Archipelago and the terrestrial taxa occur only in this region. In this study, we conducted thorough samplings of Japanese pomatiopsid species and performed molecular phylogenetic analyses to explore the patterns of diversification and terrestrial invasion. Molecular phylogenetic analyses revealed that Japanese Pomatiopsinae derived from multiple colonization of the Eurasian Continent and that subsequent habitat shifts from aquatic to terrestrial life occurred at least twice within two Japanese endemic lineages. Each lineage comprises amphibious and terrestrial species, both of which are confined to the mountains in heavy-snow regions facing the Japan Sea. The estimated divergence time suggested that diversification of these terrestrial lineages started in the Late Miocene, when active orogenesis of the Japanese landmass and establishment of snowy conditions began. The terrestrial invasion of Japanese Pomatiopsinae occurred at least twice beside the mountain streamlets of heavy-snow regions, which is considered the first case of this event in the area. Because snow coverage maintains stable temperatures and high humidity on the ground surface, heavy-snow conditions may have paved the way for these organisms from freshwater to land via mountain streamlets by preventing winter desiccation in mountain valleys. The fact that the terrestrialization of Pomatiopsidae occurred only in year-round wet environments, but not in seasonally dried regions, provides new insight into ancient molluscan terrestrialization.


Effects of caffeine on the detection of ischemia in patients undergoing adenosine stress cardiovascular magnetic resonance imaging.
Adenosine stress cardiovascular magnetic resonance (CMR) can detect significant coronary artery stenoses with high diagnostic accuracy. Caffeine is a nonselective competitive inhibitor of adenosine2A-receptors, which might hamper the vasodilator effect of adenosine stress, potentially yielding false-negative results. Much controversy exists about the influence of caffeine on adenosine myocardial perfusion imaging. Our study sought to investigate the effects of caffeine on ischemia detection in patients with suspected or known coronary artery disease (CAD) undergoing adenosine stress CMR. Thirty patients with evidence of myocardial ischemia on caffeine-naïve adenosine stress CMR were prospectively enrolled and underwent repeat adenosine stress CMR after intake of 200 mg caffeine. Both CMR exams were then compared for evaluation of ischemic burden. Despite intake of caffeine, no conversion of a positive to a negative stress study occurred on a per patient basis. Although we found significant lower ischemic burden in CMR exams with caffeine compared to caffeine-naïve CMR exams, absolute differences varied only slightly (1 segment based on a 16-segment model, 3 segments on a 60-segment model, and 1 ml in total ischemic myocardial volume, p < 0.001 each). Moreover, no relevant ischemia (≥2 segments in a 16-segment model) was missed by prior ingestion of caffeine. Although differences were small and no relevant myocardial ischemia had been missed, prior consumption of caffeine led to significant reduction of ischemic burden, and might lower the high diagnostic and prognostic value of adenosine stress CMR. Therefore, we suggest that patients should still refrain from caffeine prior adenosine stress CMR tests.


Anatomical variations and morphometric study of the optic strut and the anterior clinoid process.
The optic strut and the anterior clinoid process represent bony structures that are closely related to anatomically and clinically significant elements such as the cavernous sinus, the internal carotid artery, the optic nerve and the pituitary gland. The objective of our study was to quantify dimensions of the optic strut and anterior clinoid process, and to determine variations in positions and forms of these structures. A descriptive anatomical study was performed on 200 dry human skulls. We analyzed dimensions and variations in position of the optic strut, dimensions of the anterior clinoid process as well as the incidence and forms of the caroticoclinoid foramen. The average thickness of the optic strut on skulls belonging to males was 3 mm and 2.8 mm on those belonging to females. The optic strut was most commonly attached to the anterior two fifths on the lower side of the anterior clinoid process. On the male skulls the average width of the anterior clinoid process was 9.4 mm (right) and 9.1 mm (left). Its length was 9.9 and 9.3 mm. On female skulls the average width of the process was 8.7 mm (right) and 8.3 mm (left), while the length measured 9.3 mm on the right and 8.9 mm on the opposite side. In our sample, a complete caroticoclinoid foramen appeared in 4.25%, a contact form in 2.75%. At last, an incomplete form of the foramen was observed in 9.75%. The anatomic variations of the investigated structures must be considered during the approaches to the cavernous sinus and neurovascular elements of the sellar region.


Silver ring splints improve dexterity in patients with rheumatoid arthritis.
To study the effect of Silver Ring Splints (SRSs) on hand function in patients with rheumatoid arthritis (RA). RA patients with stable disease and finger deformities eligible for splinting received 1 or more SRSs. Primary outcome was dexterity, which was measured with the Sequential Occupational Dexterity Assessment (SODA). Secondary outcome measures were self-reported hand function (Dutch Arthritis Impact Measurement Scales 2), hand pain, grip and pinch strength, Disease Activity Score in 28 joints (DAS28), and patient satisfaction. Seventeen patients (median age 65 years; median disease duration 21 years) received a total of 72 SRSs. After 1 year, 48 SRSs were regularly used. Two patients dropped out because of adverse events related to SRSs. In the remaining 15 patients, SODA dexterity scores increased significantly (median 71 at baseline, 81 at 3 months, and 85 at 12 months), Wilcoxon signed ranks test P=0.005 and P=0.026. DAS28 scores did not change at 3 months and improved slightly after 12 months (-0.5; P=0.019). Grip strength, self-reported hand function, and hand pain showed no significant changes. Eleven patients stated they would continue using their splints. SRSs can improve dexterity in selected patients with rheumatoid hand deformities. For a satisfactory result, careful patient preassessment and optimal adjustment of SRSs are essential.


Interleukin-1 receptor-associated kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress signaling.
Endoplasmic reticulum (ER) stress occurs when unfolded proteins accumulate in the lumen of the organelle, triggering signal transduction events that contribute either to cellular adaptation and recovery or alternatively to cellular dysfunction and death. ER stress has been implicated in numerous diseases. To identify novel modulators of ER stress, we undertook a siRNA library screen of the kinome, revealing Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) as a contributor to unfolded protein response (UPR) signaling and ER stress-induced cell death. Knocking down expression of IRAK2 (but not IRAK1) in cultured mammalian cells suppresses ER stress-induced expression of the pro-apoptotic transcription factor CHOP and activation of stress kinases. Similarly, RNAi-mediated silencing of the IRAK family member Tube (but not Pelle) suppresses activation of stress kinase signaling induced by ER stress in Drosophila cells. The action of IRAK2 maps to the IRE1 pathway, rather than the PERK or ATF6 components of the UPR. Interestingly, ER stress also induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, suggesting a mutually supporting amplification loop involving IRAK2 and IRE1. In vivo, ER stress induces Irak2 expression in mice. Moreover, Irak2 gene knockout mice display defects in ER stress-induced CHOP expression and IRE1 pathway signaling. These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway.


A comprehensive anesthesia simulation environment: re-creating the operating room for research and training.
Simulation is used extensively in industries that involve routine, but risky activities. The authors describe an anesthesia simulation environment that provides a re-creation of the anesthesiologist's task environment in a real operating room. The system provides appropriate inputs to standard monitoring equipment in common use during anesthesia, including ECG (with arrhythmias); invasive systemic arterial, pulmonary arterial, and central venous pressures (all coupled to ECG arrhythmias); automated cuff blood pressure; pulse oximetry; mass spectrometry; breathing circuit spirometry; and oxygen analysis. An intubation/thorax mannequin allows tracheal intubation and tube manipulation, and provides for simulation of occlusion, malposition, or disconnection of the tracheal tube, as well as regurgitation of gastric contents. The simulation is comprehensive in that it is "hands-on" and requires actual performance of most interventions using actual equipment. The simulation is conducted by a systems operator and a simulation director; the latter also acts in the roles of surgeon and circulating nurse. The simulator outputs are determined by a "script" that defines the consequences of routine anesthetic actions and pre-established critical incidents. Decisions about timing and override of the script are made by the simulation director. This control system offers maximum flexibility while maintaining clinical realism. The simulator experiences were judged as highly realistic by 21 subjects. Limitations in this version have centered on the mannequin (e.g., no patient movement, minimal or confusing physical signs) and will be addressed in future versions of the system. The authors suggest that anesthesia simulation can be accomplished at nominal expense and has major potential for training, continuing education, certification, and research.


The locus C11orf30 increases susceptibility to poly-sensitization.
A number of genetic variants have been associated with allergic sensitization, but whether these are allergen specific or increase susceptibility to poly-sensitization is unknown. Using data from the large multicentre population-based European Community Respiratory Health Survey, we assessed the association between 10 loci and specific IgE and skin prick tests to individual allergens and poly-sensitization. We found that the 10 loci associate with sensitization to different allergens in a nonspecific manner and that one in particular, C11orf30-rs2155219, doubles the risk of poly-sensitization (specific IgE/4 allergens: OR = 1.81, 95% CI 0.80-4.24; skin prick test/4+ allergens: OR = 2.27, 95% CI 1.34-3.95). The association of rs2155219 with higher levels of expression of C11orf30, which may be involved in transcription repression of interferon-stimulated genes, and its association with sensitization to multiple allergens suggest that this locus is highly relevant for atopy.


Assessment of Portal Venous and Hepatic Artery Haemodynamic Variation in Non-Alcoholic Fatty Liver Disease (NAFLD) Patients.
Non-Alcoholic Fatty Liver Disease (NAFLD) has various spectrums of liver diseases like isolated fatty liver, steatohepatitis and cirrhosis usually progressing in a linear fashion. In this process they are known to cause certain haemodynamic changes in the portal flow and hepatic artery flow. The aim of the study was to study these haemodynamic changes in patients with NAFLD and to correlate it with the disease severity. Ninety patients diagnosed to have NAFLD based on ultrasound abdomen (30 each in grade1, grade2 and grade3 NAFLD) and 30 controls (Normal liver on ultrasound abdomen) were subjected to portal vein and hepatic artery Doppler study. Peak maximum velocity (Vmax), Peak minimum velocity (Vmin), Mean flow velocity (MFV), and Vein pulsality index (VPI) of the portal vein and hepatic artery resistivity index (HARI) of the hepatic artery were the doppler parameters which were assessed. Liver span was also assessed both for the fatty liver and controls. The mean Vmax, Vmin, MFV and VPI of the portal vein in patients with NAFLD was 12.23±1.74cm/sec, 9.31±1.45cm/sec, 10.76±1.48cm/sec, and 0.24±0.04 as compared to 14.05±2.43cm/sec, 10.01±2.27cm/sec, 12.23±2.47cm/sec, 0.3±0.08 in controls respectively. All these differences were statistically significant except for Vmin. The Mean HARI in patients with fatty liver was 0.65±0.06 when compared to controls of 0.75±0.06 (p=0.001). HARI (r-value of -0.517) had a better negative correlation followed by VPI (r-value of -0.44) and Vmax (r-value of -0.293) with the severity of NAFLD. MFV had a very weak negative correlation (r-value of -0.182) with the severity of NAFLD. The Vmax, MFV, VPI and HARI were significantly less when compared to controls suggesting a reduced portal flow and an increased hepatic arterial flow in patients with NAFLD. Among the parameters, HARI correlated better with the severity of NAFLD followed by VPI.


Critical influence of chloride ions on silver ion-mediated acute toxicity of silver nanoparticles to zebrafish embryos.
The toxicity of silver nanoparticles (AgNP) to aquatic organisms, including zebrafish (Danio rerio), has been demonstrated, but differing opinions exist on the contribution of the physical properties of the particles themselves and the free dissolved silver ions (Ag(+)) to the observed effects. High concentrations of chloride ions (Cl(-)) in the routinely used exposure media can cause precipitation of Ag(+) as AgCl, as well as complexation of silver in diverse soluble chlorocomplexes, thus masking the contribution of dissolved silver to AgNP toxicity. In the present study, we formulated a zebrafish exposure medium with a low chloride content and exposed zebrafish embryos to AgNO3 or carbonate-coated AgNP. The severity of toxicity caused by both silver forms depended on the time of exposure start, with younger embryos being most sensitive. Toxicity caused by both AgNO3 and AgNP was of the same order of magnitude when compared based on the total dissolved silver concentration and could be prevented by addition of the Ag(+) chelator cysteine. Further, we have analyzed the data from several previous studies to evaluate the influence of interactions between Ag(+) and Cl(-) on silver toxicity to zebrafish embryos. Our analysis demonstrates that the acute toxicity of AgNP to zebrafish embryos is largely mediated by Ag(+). The influence of particle size and coating can at least partially be explained by the differences in Ag(+) dissolution. High Cl(-) levels in the exposure medium indeed have a pivotal influence on the resulting toxicity of AgNP, appearing to significantly attenuate toxicity in several studies. This consideration should influence the choice of exposure medium to be used when evaluating and comparing AgNP toxicity.


Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma.
The combination of carmustine, etoposide, cytarabine and melphalan (BEAM) is an effective autologous transplantation preparative regimen for lymphoma and has little toxicity, but the feasibility and tolerance of BEAM as a preparative regimen for allogeneic transplantation has not been established. Thirty adults with primary refractory or recurrent intermediate- or low-grade lymphoma were treated on a prospective phase II study with carmustine 300 mg/m2 i.v. day -6, etoposide 200 mg/m2 i.v. followed by cytarabine 200 mg/m2 i.v. twice daily days -5 to -2, melphalan 140 mg/m2 i.v. day -1, and marrow or blood stem cells from an HLA-identical donor on day 0. Tacrolimus and methotrexate were used to prevent graft-vs.-host disease (GVHD). Median time from transplantation was 20 mos (range 6-32 months). Median maximal regimen-related toxicity grade was 2, and four patients (13%) had a grade 3-4 regimen-related toxicity. Two patients had idiopathic interstitial pneumonitis. One patient had primary graft failure, and a second had autologous reconstitution documented at three months posttransplant. Grades 2-4 acute GVHD occurred in 31%, grades 3-4 in 16%, and chronic GVHD in 54%. Day-100 survival was 70%. Twenty-three patients achieved a complete response. The two-year relapse rate was 23%, survival was 48%, and disease-free survival (DFS) was 42%. BEAM supports engraftment of allogeneic transplants and is a tolerable preparative regimen for allogeneic transplantation for lymphoma.


Complete Genome Sequence Analysis of Enterobacter sp. SA187, a Plant Multi-Stress Tolerance Promoting Endophytic Bacterium.
Enterobacter sp. SA187 is an endophytic bacterium that has been isolated from root nodules of the indigenous desert plant Indigofera argentea. SA187 could survive in the rhizosphere as well as in association with different plant species, and was able to provide abiotic stress tolerance to Arabidopsis thaliana. The genome sequence of SA187 was obtained by using Pacific BioScience (PacBio) single-molecule sequencing technology, with average coverage of 275X. The genome of SA187 consists of one single 4,429,597 bp chromosome, with an average 56% GC content and 4,347 predicted protein coding DNA sequences (CDS), 153 ncRNA, 7 rRNA, and 84 tRNA. Functional analysis of the SA187 genome revealed a large number of genes involved in uptake and exchange of nutrients, chemotaxis, mobilization and plant colonization. A high number of genes were also found to be involved in survival, defense against oxidative stress and production of antimicrobial compounds and toxins. Moreover, different metabolic pathways were identified that potentially contribute to plant growth promotion. The information encoded in the genome of SA187 reveals the characteristics of a dualistic lifestyle of a bacterium that can adapt to different environments and promote the growth of plants. This information provides a better understanding of the mechanisms involved in plant-microbe interaction and could be further exploited to develop SA187 as a biological agent to improve agricultural practices in marginal and arid lands.


Paramyosin in invertebrate muscles. II. Content in relation to structure and function.
By quantitative sodium dodecyl sulfate-polyacrylamide gel electrophoresis, paramyosin:myosin heavy chain molecular ratios were calculated for three molluscan muscles:Aequipecten striated adductor, Mercenaria opaque adductor, and Mytilus anterior byssus retractor; and four arthropodan muscles:Limulus telson, Homarus slow claw. Balanus scutal depressor, and Lethocerus air tube retractor. These ratios correlate positively with both thick filament dimensions and maximum active tension development in these tissues. The role of paramyosin in these muscles is discussed with respect to the following characteristics: force development, "catch," and extreme reversible changes in length.


Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice.
Secondary malignancies are a serious adverse consequence of alkylator chemotherapy. The risk of developing an alkylator-associated malignancy is influenced by genetic background, although the relevant genetic factors are poorly understood. To screen for novel susceptibility factors, we established a mouse model of alkylator-induced malignancy. We exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared with a background incidence of 8% spontaneous tumors in 240 strain-, age-, and sex-matched control mice (relative risk, 8.4; P < 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H(2) = 0.25), T cell lymphoma (H(2) = 0.19), and myeloid malignancies (H(2) = 0.10). Quantitative trait locus mapping identified regions on chromosomes 3, 6, 9, and 15 containing candidate genes associated with lung adenoma, lung carcinoma, and lymphoma susceptibility. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to make informed clinical treatment decisions.


An altered rpoS allele contributes to the avirulence of Salmonella typhimurium LT2.
Virulent Salmonella typhimurium strains differ from the attenuated laboratory strain LT2 at the rpoS locus. It was previously shown that the rpoS gene in strain LT2 contains a rare UUG start codon (I. S. Lee, J. Lin, H. K. Hall, B. Bearson, and J. W. Foster, Mol. Microbiol. 17:155-167, 1995). This difference is responsible for the inability of LT2 to display a sustained log-phase acid tolerance response. We show that the altered rpoS allele (rpoS(LT2)) also affects the stationary-phase acid tolerance response in Salmonella. By transducing the rpoS(LT2) allele into virulent strain backgrounds and crossing wild-type rpoS allele into strain LT2, we demonstrate that the rpoS(LT2) allele contributes to the attenuation of strain LT2. We examined the effect of the rpoS allele on invasion and found that the rpoS status of the cell had no effect on the ability of the strains to invade intestinal epithelial cells in tissue culture. Enumeration of bacteria from tissues of infected mice indicated that the presence of the rpoS(LT2) allele affected the ability of S. typhimurium to reach the liver and spleen and to persist in several tissues at 6 days postinfection. This is likely due, at least in part, to a decrease in spv gene expression in these mutants. We demonstrate that strains containing the rpoS(LT2) allele are not only sensitive to pH 3.0 (acid stress) but are also sensitive to the DNA-damaging agent methyl methanesulfonate. However, these strains appear to survive stationary-phase and oxidative stresses as well as strains containing a wild-type rpoS allele. Despite an increased sensitivity to acid stress and DNA damage, strains containing either an rpoS-null mutation or the rpoS(LT2) allele survived in J774 cells and bone marrow-derived macrophages as well as did otherwise isogenic strains with a wild-type rpoS allele.


Nutrition and health issues in the general Hong Kong population.
In Hong Kong, the chronic diseases that lead to mortality and morbidity, and contribute to disability include cardiovascular diseases, cancer, hypertension, osteoporosis, and diabetes mellitus. The role of nutrition as a risk factor for the development of these diseases has been described elsewhere. For the older population, adequate nutrition is important to maintain health, particularly with regard to the effect of nutrition on immunocompetence. Nutritional surveys of the general adult population show that although the intake pattern for cardiovascular health is good, follow-up surveys to monitor the pattern are needed. In the context of chronic disease prevention, decreasing salt consumption, increasing calcium intake, and increasing the awareness of the health value of fibre may all be beneficial actions. Educational efforts should be directed particularly at those with lower levels of education, since the poorly educated have been shown to have a less healthy diet and a greater prevalence of overweight individuals. Among the elderly, evidence of undernutrition has been documented in institutional settings and is associated with increased mortality. The diet of those residing in vegetarian homes has been shown to be deficient in many B vitamins, which results in a high frequency of nutritional anaemias. To help achieve an optimal nutritional status, nutrition screening programmes should become an integral part of the development of quality care programmes for institutions responsible for care of the elderly.


Concrete fictions and hegemonic methodologies: doing policy research in government.
Faced with having to justify programs to offices of management and budget, government agencies generate numbers which describe expected program impacts. But the assumptions or data on which these numbers are based are frequently suspect, as is the utility of relying on counts and modeling techniques for evaluating the achievement of program aims. The result is that agencies often create "concrete fictions," hard numbers with feet of (soft) clay. Offices of management and budget are able to make their methodology "hegemonic" because agencies usually have to secure their approval to get funding. But imposing this methodology encourages agencies to use research staffs more to defend against the budget office than to help create effective programs, creates differences between the expectations of government and the public, and fosters the overrepresentation of particular interests.


Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages.
Endothelial and hematopoietic cells appear synchronously on the extra-embryonic membranes of amniotes in structures known as blood islands. This observation has led to the suggestion that these two ventral lineages share a common progenitor. Recently, we have shown in the zebrafish, Danio rerio, that a single cell in the ventral marginal zone of the early blastula can give rise to both endothelial and blood cells as well as to other mesodermal cells (Stainier, D. Y. R., Lee, R. K. and Fishman, M. C. (1993). Development 119, 31-40; Lee, R. K. K., Stainier, D. Y. R., Weinstein, B. M. and Fishman, M. C. (1994). Development 120, 3361-3366). Here we describe a zebrafish mutation, cloche, that affects both the endothelial and hematopoietic lineages at a very early stage. The endocardium, the endothelial lining of the heart, is missing in mutant embryos. This deletion is selective as evidenced by the presence of other endothelial cells, for example those lining the main vessels of the trunk. Early cardiac morphogenesis proceeds normally even in the absence of the endocardium. The myocardial cells form a tube that is demarcated into chambers, beats rhythmically, but exhibits a reduced contractility. This functional deficit is likely due to the absence of the endocardial cells, although it may be a direct effect of the mutation on the myocardial cells. Cell transplantation studies reveal that the endothelial defect, i.e. the endocardial deletion, is a cell-autonomous lesion, consistent with the possibility that cloche is part of a signal transduction pathway. In addition, the number of blood cells is greatly reduced in cloche mutants and the hematopoietic tissues show no expression of GATA-1 or GATA-2, two key hematopoietic transcription factors that are first expressed during early embryogenesis. These results show that cloche is involved in the genesis and early diversification of the endothelial and blood lineages, possibly by affecting a common progenitor cell population.


Interaction of ascorbate peroxidase with substrates: a mechanistic and structural analysis.
Previous work [Sharp, K. H., et al. (2003) Nat. Struct. Biol. 10, 303-307] has revealed the location of the ascorbate binding site in ascorbate peroxidase and has identified hydrogen-bonding interactions to Arg172, Lys30, and the heme 6-propionate as important in formation of the enzyme-substrate complex. In this work, the individual and collective contributions of these hydrogen bond interactions have been dissected using site-directed mutagenesis, steady-state and pre-steady-state kinetics, X-ray crystallography, and modified substrate analogues. Steady-state and pre-steady-state kinetic data reveal that the hydrogen bonds to Arg172 and the heme 6-propionate play a major part in stabilization of the bound ascorbate but that the interaction with Lys30 plays only a minor role. Binding of aromatic substrates is not affected by substitutions at Arg172/Lys30. Neutralization or removal of electrostatic charge at (Lys30) or adjacent to (Lys31) the ascorbate site does not substantially disrupt the binding interaction. Substrate oxidation and reduction of Compounds I and II is still possible in the absence of Arg172, but at a much reduced level. Crystallographic data (to 1.8 A) for the R172A variant indicate that the molecular structure of the proposed [Sharp, K. H., et al. (2004) Biochemistry 43, 8644-8651] proton transfer pathway from the ascorbate to the heme is conserved, which accounts for the residual activity. The results are discussed in terms of our wider understanding of the structural features that control substrate binding specificity in other peroxidase enzymes.


Eating breakfast and avoiding late-evening snacking sustains lipid oxidation.
Circadian (daily) regulation of metabolic pathways implies that food may be metabolized differentially over the daily cycle. To test that hypothesis, we monitored the metabolism of older subjects in a whole-room respiratory chamber over two separate 56-h sessions in a random crossover design. In one session, one of the 3 daily meals was presented as breakfast, whereas in the other session, a nutritionally equivalent meal was presented as a late-evening snack. The duration of the overnight fast was the same for both sessions. Whereas the two sessions did not differ in overall energy expenditure, the respiratory exchange ratio (RER) was different during sleep between the two sessions. Unexpectedly, this difference in RER due to daily meal timing was not due to daily differences in physical activity, sleep disruption, or core body temperature (CBT). Rather, we found that the daily timing of nutrient availability coupled with daily/circadian control of metabolism drives a switch in substrate preference such that the late-evening Snack Session resulted in significantly lower lipid oxidation (LO) compared to the Breakfast Session. Therefore, the timing of meals during the day/night cycle affects how ingested food is oxidized or stored in humans, with important implications for optimal eating habits.


Long-Read Single-Cell Sequencing Using scCOLOR-seq.
Single-cell sequencing allows for the measurement of sequence information from individual cells with next-generation sequencing (NGS). However, its application to third-generation sequencing platforms such as Oxford Nanopore has been challenging because of its lower basecalling accuracy. Here we describe the method to perform highly accurate single-cell COrrected Long-Read sequencing (scCOLOR-seq) by droplet-based encapsulation of cells and sequencing using the Oxford Nanopore Sequencing system.


Divergent synthesis of indoles, oxindoles, isocoumarins and isoquinolinones by general Pd-catalyzed retro-aldol/α-arylation.
Divergent synthesis of indoles, oxindoles, isocoumarins and isoquinolinones is described in this report by using a general Pd-catalyzed tandem reaction of β-hydroxy carbonyl compounds with aryl halides bearing an ortho-nitro, -ester or -cyano substituent. A key retro-aldol/α-arylation reaction is involved that merges classic Pd cross-coupling chemistry with novel Pd-promoted retro-aldol C-C activation to produce α-arylated ketones or esters. Subsequent intramolecular condensation of the carbonyl with the ortho-synthon gives target heterocycles. The use of common, commercially available and cheap substrates and catalyst system adds additional synthetic advantages to the conceptual significance.


Social Workers' Perceptions of Job Satisfaction, Interdisciplinary Collaboration, and Organizational Leadership.
To address job satisfaction, and therefore employment retention, of hospice social workers, this study examined how relationships with other members of the interdisciplinary hospice team and perceptions of hospice leadership may be associated with job satisfaction of hospice social workers. The sample of 203 hospice social workers was recruited by e-mailing invitations to hospice social workers identified by hospice directors in three states, use of online social media sites accessed by hospice social workers, and snowball sampling. Study measures included professional experience, hospice characteristics, interdisciplinary collaboration, perception of servant leadership, and intrinsic and extrinsic job satisfaction. Variables significant in the model for intrinsic satisfaction were perception of servant leadership, interdisciplinary collaboration, and feeling valued by the hospice physician. Variables significant in the model for extrinsic satisfaction were perception of servant leadership, interdisciplinary collaboration, feeling valued by the hospice physician, and number of social workers at the hospice. Interdisciplinary collaboration was more important for intrinsic job satisfaction and leadership style was more important for extrinsic job satisfaction. Profit status of the hospice, experience of the social worker, caseload size, and other variables were not significant in either model. These results support previous findings that leadership style of the hospice director and relationships with hospice colleagues are important for hospice social workers' job satisfaction. Such low-cost modifications to the hospice work environment, albeit not simple, may improve job satisfaction of hospice social workers.


Risk Analysis for Invasive Fungal Infection after Living Donor Liver Transplantation: Which Patient Needs Potent Prophylaxis?
Invasive fungal infection (IFI) is associated with high mortality after living donor liver transplant (LDLT). The aim of this study was to identify the risk factors for post-LDLT IFI for early diagnosis and improvement of antifungal treatment outcome. Risk analysis data were available for all 153 patients who underwent LDLT between January 2005 and April 2012. During the follow-up period (1,553 ± 73 days, range 20-2,946 days), 15 patients (9.8%) developed IFI classified as "proven" (n = 8) and "probable" (n = 7) with fungal pathogens including Candida spp. (n = 10), Aspergillus spp. (n = 4), and Trichosporon (n = 2). Of these patients, 7 patients with IFI died despite treatment. The 1-, 3-, and 5-year survival rates were lower in patients with IFI than those without IFI (66.7/59.3/44.4 vs. 90.4/85.7/81.8%, respectively; p = 0.0026). Multivariate analysis identified model for end-stage liver disease score of ≥26 (OR 16.0, p = 0.0012) and post-transplant acute kidney injury (RIFLE criteria I- or F-class; OR 4.87, p = 0.047) as independent risk factors for IFI. Preoperative recipients' status and postoperative kidney dysfunction can affect an occurrence of post-transplant IFI. These risk factors would be taken into consideration for designation of proper antifungal therapy.


Synthesis and sequence optimization of GFP mutants containing aromatic non-natural amino acids at the Tyr66 position.
In order to alter the fluorescence properties of green fluorescent protein (GFP), aromatic non-natural amino acids were introduced into the Tyr66 position of GFP in a cell-free translation system using a four-base codon method. Two non-natural mutants (O-methyltyrosine and p-aminophenylalanine mutants) out of 18 mutants showed blue-shifted but weak fluorescence compared with wild-type GFP. Then the aminophenylalanine mutant was sequence optimized by introducing random mutations around the Tyr66 site. For this purpose, a method for random mutation of non-natural proteins in a cell-free system was developed. Three aminophenylalanine mutants with Y145F, Y145L and Y145 M mutations were obtained, which exhibited increased fluorescence by 1.5-, 3- and 4-fold, respectively. These results indicate that random mutation around non-natural amino acids is useful strategy in order to improve protein functions that are reduced by non-natural amino acid incorporation. The method described here will be applicable to other non-natural mutant proteins in a high-throughput manner.


High precision NMR structure of YhhP, a novel Escherichia coli protein implicated in cell division.
YhhP, a small protein of 81 amino acid residues encoded by the yhhP gene in the Escherichia coli database, is implicated in cell division although the precise biological function of this protein has not been yet identified. A variety of microorganisms have similar proteins, all of which contain a common CPxP sequence motif in the N-terminal region. We have determined the three-dimensional solution structure of YhhP by NMR spectroscopy in order to obtain insight into its biological function. It folds into a two-layered alpha/beta-sandwich structure with a betaalphabetaalphabetabeta fold, comprising a mixed four-stranded beta-sheet stacked against two alpha-helices, both of which are nearly parallel to the strands of the beta-sheet. The CPxP motif plays a significant structural role in stabilizing the first helix as a part of the new type N-capping box where the Cys-Pro peptide bond adopts a cis configuration. The structure of YhhP displays a striking resemblance to the C-terminal ribosome-binding domain of translation initiation factor IF3 (IF3C). In addition, the surface charge distribution of the RNA-recognition helix of IF3C is nearly the same as that of the corresponding helix of YhhP. These results suggest a structure-based hypothesis in which binding to an RNA target plays an essential role in the function of this ubiquitous protein.


Mental health training and the hospice community: a national survey.
This article summarizes a national survey of the hospice community. Respondents provided detailed information in the following areas: (a) What formal mental health training is provided for staff members? (b) Who conducts this training? (c) What areas are covered and where would more training be useful? (d) How is the training conducted--what formats and teaching materials are used? and (e) How much training do staff members receive? The results of the survey indicate that the hospice community is making a concerted effort to meet the mental health training needs of its paid staff members and volunteers. However, more than half of the hospices surveyed expressed a need for further training in 26 of the 33 issues and skills covered in the questionnaire, and many reported a need for a more systematic and comprehensive mental health curriculum. The findings point to several areas of particularly great need and provide a basis for the development of future mental health training in the hospice community.


Tennessee smiles: the UT grassroots oral health outreach initiative.
Access to and awareness of oral healthcare in the United States have been highlighted in the mass media and discussed among diverse populations. The current surge to provide access to oral healthcare for citizens springs from this quagmire of oral healthcare issues which affects global to local (grassroots) communities. Publications by the World Health Organization's (WHO) Health for All and the United States' Healthy People have set into motion an agenda by which institutions, healthcare professionals and governments can develop action plans to foster and nurture grassroots organizations to address these issues. An initiative has been undertaken by members of the faculty, student doctors and staff of the University of Tennessee Health Science Center, College of Dentistry (UTHSC CoD) and its partners. This cadre of volunteers has implemented grassroots efforts for the citizens of western Tennessee to date as the flagship of Tennessee Smiles: UT Grassroots Oral Health Outreach Initiative (Tennessee Smiles). By participation in health fairs, school programs and other cultural events, these volunteers have made a difference in the lives of thousands of Tennessee citizens who need exposure to information regarding their oral health care needs. The authors discuss the basis for the Tennessee Smiles organization, their successes and challenges. Future plans and the need for support of the organization are emphasized.


Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy.
This prospective multicenter study assessed the prognostic influence of the extent of resection when compared with biopsy only in a contemporary patient population with newly diagnosed glioblastoma. Histology, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and clinical data were centrally analyzed. Survival analyses were carried out with the Kaplan-Meier method. Prognostic factors were assessed with proportional hazard models. Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31). The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy.


Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer.
Although androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer, incurable castration-resistant prostate cancer (CRPC) inevitably develops. Importantly, androgen receptor (AR) continues to be critical for prostate cancer growth and progression after ADT. One of the underlying molecular mechanisms is derepression of AR-repressed genes involved in cell cycle and proliferation after ADT. Here, the data demonstrate that C-X-C chemokine receptor type 7 (CXCR7), a seven-transmembrane G-protein-coupled chemokine receptor, is an AR-repressed gene and is upregulated after ADT. AR directly regulates CXCR7 using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Macrophage migration inhibitory factor (MIF) was identified as a ligand for CXCR7, which induces expression of cell-cycle genes through activating AKT signaling pathway. Previous studies have been focused on chemokine CXCL12 and its receptor CXCR4 in mediating metastasis of various cancer types, including prostate cancer. The critical roles of CXCL12/CXCR4 axis in the interaction between cancer cells and their microenvironment render it a promising therapeutic target in cancer treatment. The data suggest that the MIF/CXCR7/AKT pathway drives CRPC growth and metastasis independent of the CXCL12/CXCR4 axis. Furthermore, CXCR7 blockade in combination with anti-androgen enzalutamide inhibits CRPC tumor growth and potentially prevents metastasis. Notably, both MIF and CXCR7 are overexpressed in CRPC patient specimens and therefore are attractive therapeutic targets for these patients. IMPLICATIONS: This work suggests that CXCR7 plays more important roles than CXCR4 in CRPC progression; thus, targeting CXCR7 in combination with anti-androgen is a promising therapeutic approach for metastatic CRPC.


Prevalence of autism spectrum disorders in Hispanic and non-Hispanic white children.
The number of individuals diagnosed with autism spectrum disorders (ASDs) continues to increase in the United States and other developed countries; however, ASD is diagnosed less commonly in Hispanic than in non-Hispanic white individuals. This report analyzes differences in ASD prevalence between Hispanic and non-Hispanic whites in a large, population-based sample of 8-year-old children, and explores how prevalence has changed over time. Population-based surveillance of ASD was conducted on 142 717 8-year-old children. Evaluation of clinical and educational records resulted in 1212 children meeting the case definition criteria in 4 study years between 2000 and 2006. ASD prevalence in Hispanic children was lower than in non-Hispanic white children (P < .005) for all study years. More Hispanic than non-Hispanic white children met the case definition for intellectual disability (P < .05) in study years 2004 and 2006. Prevalence of ASD diagnosis increased in both groups; the Hispanic prevalence almost tripled, from 2.7 per 1000 in 2000 to 7.9 per 1000 in 2006. A comparison of prevalence ratios found that Hispanic and non-Hispanic white ASD prevalence became significantly more similar from 2000 to 2006 (χ(2) = 124.89, P < .001). The ASD prevalence for Hispanic individuals in this population-based sample is substantially higher than previously reported. Nonetheless, Hispanic children continue to have a significantly lower ASD prevalence in comparison with non-Hispanic whites. The prevalence of ASD is increasing in both populations, and results indicate that the gap in prevalence between groups is decreasing.


Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE.
Enoxaparin treatment is associated with a 20% reduction in clinical events during the acute phase of management of patients with unstable angina/non ST elevation myocardial infarction. Interest in the use of enoxaparin would be enhanced further if evidence of a durable treatment benefit over the long term could be provided. Event rates at 1 year for the composite end-point of death/non-fatal myocardial infarction/urgent revascularization and its individual components were ascertained from the TIMI 11B and ESSENCE databases. There was no evidence of heterogeneity between TIMI 11B and ESSENCE in tests for interactions between treatment and trial. A significant treatment benefit of enoxaparin on the rate of death/non-fatal myocardial infarction/urgent revascularization was observed at 1 year (hazard ratio 0.88;P=0.008). The event rate was 25.8% in the unfractionated heparin group and 23.3% in the enoxaparin group, an absolute difference of 2.5%. A progressively greater treatment benefit of enoxaparin was observed as the level of patient risk at baseline increased. Treatment effects for the individual end-point elements ranged from 9-14%, favouring enoxaparin. The stable absolute difference in event rates of 2.5% seen at 8 days and again at 1 year favouring enoxaparin may be due to more effective control of the thrombotic process surrounding the index event. Once the pharmacological effect of enoxaparin had dissipated there was no rebound increase in events. Thus, those patients who had received enoxaparin acutely were protected from experiencing a deterioration of the original therapeutic benefit. These findings regarding enoxaparin add to the data to be considered by clinicians when selecting an antithrombin for the acute phase of management of unstable angina/non-ST elevation myocardial infarction.


Stress detection in computer users based on digital signal processing of noninvasive physiological variables.
A stress detection system is developed based on the physiological signals monitored by non-invasive and non-intrusive sensors. The development of this emotion recognition system involved three stages: experiment setup for physiological sensing, signal preprocessing for the extraction of affective features and affective recognition using a learning system. Four signals: galvanic skin response (GSR), blood volume pulse (BVP), pupil diameter (PD) and skin temperature (ST) are monitored and analyzed to differentiate affective states in a computer user. A support vector machine is used to perform the supervised classification of affective states between "stress" and "relaxed". Results indicate that the physiological signals monitored do, in fact, have a strong correlation with the changes in emotional state of our experimental subjects when stress stimuli are applied to the interaction environment. It was also found that the pupil diameter was the most significant affective state indicator, compared to the other three physiological signals monitored.


Natural history of human immunodeficiency virus disease in perinatally infected children: an analysis from the Pediatric Spectrum of Disease Project.
To describe the progression of human immunodeficiency virus (HIV) disease through clinical stages from birth to death among a large number of perinatally infected children. The Pediatric Spectrum of Disease (PSD) project, coordinated by the Centers for Disease Control and Prevention (CDC), has conducted active surveillance for HIV disease since 1988 in seven geographic regions. PSD data are collected from medical and social service records every 6 months through practitioners at each participating hospital clinic. We analyzed data from perinatally HIV-infected children born between 1982 and 1993. The natural history of HIV disease was divided into five progressive stages using the clinical categories in the CDC 1994 pediatric HIV classification system: stage N, no signs or symptoms; stage A, mild signs or symptoms; stage B, moderate signs or symptoms; stage C, severe signs or symptoms; and stage D, death. A five-stage Markov model was fitted to the PSD data. To compare the estimates from the PSD project with the published estimates, we also fitted an alternative Markov model using acquired immunodeficiency syndrome (AIDS; 1987 case definition) in place of stage C and also calculated standard Kaplan-Meier estimates. A total of 2148 perinatally HIV-infected children were included in the analysis. The estimated mean times spent in each stage were: N, 10 months; A, 4 months; B, 65 months; and C, 34 months. We estimated that a child born with HIV infection has a 50% (95% confidence interval [CI], 40%-60%) chance of severe signs or symptoms developing by 5 years of age and a 75% (95% CI, 68%-82%) chance of surviving to 5 years of age. For a child in stage B, there is a 60% (95% CI, 49%-71%) chance of severe signs or symptoms developing within the next 5 years and a 65% (95% CI, 56%-73%) chance of surviving 5 more years. The estimated mean time from birth to stage C was 6.6 (95% CI, 5.7-7.5) years, and the estimated mean survival time from birth was 9.4 (95% CI, 8.1-10.7) years. From the alternative Markov model, the estimated mean time from birth to AIDS was 4.8 (95% CI, 4.5-5.2) years. Markov modeling using the revised pediatric classification system allowed us to describe the natural history of HIV disease in children before diagnosis of AIDS. On average, children progress to moderate symptoms in the second year of life and then remain moderately symptomatic for more than half of their expected lives, underscoring their need for clinical care before the onset of AIDS. The results from the Markov model are useful in family counseling, health care planning, and clinical trial designs.


Perinodular and Intranodular Radiomic Features on Lung CT Images Distinguish Adenocarcinomas from Granulomas.
Purpose To evaluate ability of radiomic (computer-extracted imaging) features to distinguish non-small cell lung cancer adenocarcinomas from granulomas at noncontrast CT. Materials and Methods For this retrospective study, screening or standard diagnostic noncontrast CT images were collected for 290 patients (mean age, 68 years; range, 18-92 years; 125 men [mean age, 67 years; range, 18-90 years] and 165 women [mean age, 68 years; range, 33-92 years]) from two institutions between 2007 and 2013. Histopathologic analysis was available for one nodule per patient. Corresponding nodule of interest was identified on axial CT images by a radiologist with manual annotation. Nodule shape, wavelet (Gabor), and texture-based (Haralick and Laws energy) features were extracted from intra- and perinodular regions. Features were pruned to train machine learning classifiers with 145 patients. In a test set of 145 patients, classifier results were compared against a convolutional neural network (CNN) and diagnostic readings of two radiologists. Results Support vector machine classifier with intranodular radiomic features achieved an area under the receiver operating characteristic curve (AUC) of 0.75 on the test set. Combining radiomics of intranodular with perinodular regions improved the AUC to 0.80. On the same test set, CNN resulted in an AUC of 0.76. Radiologist readers achieved AUCs of 0.61 and 0.60, respectively. Conclusion Radiomic features from intranodular and perinodular regions of nodules can distinguish non-small cell lung cancer adenocarcinomas from benign granulomas at noncontrast CT. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Nishino in this issue.


Epicatechin-rich cocoa polyphenol inhibits Kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model.
Activated Kras gene coupled with activation of Akt and nuclear factor-kappa B (NF-κB) triggers the development of pancreatic intraepithelial neoplasia, the precursor lesion for pancreatic ductal adenocarcinoma (PDAC) in humans. Therefore, intervention at premalignant stage of disease is considered as an ideal strategy to delay the tumor development. Pancreatic malignant tumor cell lines are widely used; however, there are not relevant cell-based models representing premalignant stages of PDAC to test intervention agents. By employing a novel Kras-driven cell-based model representing premalignant and malignant stages of PDAC, we investigated the efficacy of ACTICOA-grade cocoa polyphenol (CP) as a potent chemopreventive agent under in vitro and in vivo conditions. It is noteworthy that several human intervention/clinical trials have successfully established the pharmacological benefits of cocoa-based foods. The liquid chromatography (LC)-mass spectrometry (MS)/MS data confirmed epicatechin as the major polyphenol of CP. Normal, nontumorigenic and tumorigenic pancreatic ductal epithelial (PDE) cells (exhibiting varying Kras activity) were treated with CP and epicatechin. CP and epicatechin treatments induced no effect on normal PDE cells, however, caused a decrease in the (i) proliferation, (ii) guanosine triphosphate (GTP)-bound Ras protein, (iii) Akt phosphorylation and (iv) NF-κB transcriptional activity of premalignant and malignant Kras-activated PDE cells. Further, oral administration of CP (25 mg/kg) inhibited the growth of Kras-PDE cell-originated tumors in a xenograft mouse model. LC-MS/MS analysis of the blood showed epicatechin to be bioavailable to mice after CP consumption. We suggest that (i) Kras-driven cell-based model is an excellent model for testing intervention agents and (ii) CP is a promising chemopreventive agent for inhibiting PDAC development.


Cutaneous candidiasis caused by Candida glabrata in a HIV/AIDS patient.
Cutaneous Candida infections may occur in patients with HIV/AIDS, cancer, receiving chemotherapy and solid organ transplantation. A 32-year-old woman was admitted to the department suffering from pruritic and erythematous plaque on left side of her face for the past two months. The patient was HIV positive, diagnosed five years previously, and had been on antiretroviral therapy (tenofovir/emtricitabine and lopinavir/ritonavir) for a year. She was not compliant with the medication. Elevated HIV RNA load and decreased CD4+ lymphocyte count were observed. Fungal elements were detected from the skin scraping sample taken from the facial plaque. Fluconazole-sensitive Candida glabrata was isolated from this sample. Topical clotrimazole ointment and systemic fluconazole 400 mg/day were used. After systemic fluconazole therapy was continued for two months, the plaque was cured. C. glabrata rarely causes cutaneous infection without involving the mucous membranes. Presentation of cutaneous fungal infections in HIV patients with decreased CD4+ T lymphocyte counts can be atypical and require extensive antifungal treatment.


Clinicopathological correlation of the expression of excision repair cross complementation group 1 (ERCC1) in oral cavity squamous cell carcinomas: an immunohistochemical study.
The nucleotide excision repair pathway is a sophisticated DNA repair mechanism that reduces DNA damage caused by exogenous factors. Excision repair cross complementation group 1 (ERCC1) is a prominent member of this pathway that maintains the genomic stability. The aim of this study is to determine the association between the immunohistochemical expression of ERCC1 and the clinical and pathological features of oral cavity squamous cell carcinomas. The sections of formalin fixed paraffin embedded tissue blocks of oral squamous cell carcinomas (n = 60) were immunohistochemically stained with anti-ERCC1 antibody. The association between the nuclear expression of ERCC1 and the clinicopathological parameters of the tumors and the patient outcomes was evaluated using the chi-square test. ERCC1 expression was evident in all studied cases of the oral squamous cell carcinomas. A high ERCC1 expression was associated with smaller tumors, tumors without lymph node involvement and well-differentiated tumors (p < 0.001). Better outcomes were associated with higher expression of ERCC1 (p = 0.028). ERCC1 seems to be an efficient biomarker for prognostication of oral squamous cell carcinomas. High expression of ERCC1 indicates more favorable course of the disease.


Fc receptors in antibody-dependent enhancement of viral infections.
Sensitization of the humoral immune response to invading viruses and production of antiviral antibodies forms part of the host antiviral repertoire. Paradoxically, for a number of viral pathogens, under certain conditions, antibodies provide an attractive means of enhanced virus entry and replication in a number of cell types. Known as antibody-dependent enhancement (ADE) of infection, the phenomenon occurs when virus-antibody immunocomplexes interact with cells bearing complement or Fc receptors, promoting internalization of the virus and increasing infection. Frequently associated with exacerbation of viral disease, ADE of infection presents a major obstacle to the prevention of viral disease by vaccination and is thought to be partly responsible for the adverse effects of novel antiviral therapeutics such as intravenous immunoglobulins. There is a growing body of work examining the intracellular signaling pathways and epitopes responsible for mediating ADE, with a view to aiding rational design of antiviral strategies. With in vitro studies also confirming ADE as a feature of infection for a growing number of viruses, challenges remain in understanding the multilayered molecular mechanisms of ADE and its effect on viral pathogenesis.


Comparative performance of WANTAI ELISA for total immunoglobulin to receptor binding protein and an ELISA for IgG to spike protein in detecting SARS-CoV-2 antibodies in Kenyan populations.
Many SARS-CoV-2 antibody detection assays have been developed but their differential performance is not well described. In this study we compared an in-house (KWTRP) ELISA which has been used extensively to estimate seroprevalence in the Kenyan population with WANTAI, an ELISA which has been approved for widespread use by the WHO. Using a wide variety of sample sets including pre-pandemic samples (negative gold standard), SARS-CoV-2 PCR positive samples (positive gold standard) and COVID-19 test samples from different periods (unknowns), we compared performance characteristics of the two assays. The overall concordance between WANTAI and KWTRP was 0.97 (95% CI, 0.95-0.98). For WANTAI and KWTRP, sensitivity was 0.95 (95% CI 0.90-0.98) and 0.93 (95% CI 0.87-0.96), respectively. Specificity for WANTAI was 0.98 (95% CI, 0.96-0.99) and 0.99 (95% CI 0.96-1.00) while KWTRP specificity was 0.99 (95% CI, 0.98-1.00) and 1.00 using pre-pandemic blood donors and pre-pandemic malaria cross-sectional survey samples respectively. Both assays show excellent characteristics to detect SARS-CoV-2 antibodies.


Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly.
To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly. This is a cross-sectional study in two tertiary referral centers in The Netherlands. One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS. IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85±1.52 vs 0.25±1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44±0.72 vs SSTA-, n=44, IGF1 SDS 0.41±0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA. QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels.


Alcohol suppresses endothelium-dependent relaxation in rat mesenteric vascular beds.
The effects of prolonged infusions of ethanol on endothelium-dependent vasorelaxation induced by acetylcholine and adenosine triphosphate (ATP) and on endothelium-independent relaxation induced by papaverine were studied and compared in isolated perfused rat mesenteric artery preparations. Infusion of ethanol over 60 minutes at concentrations of 1.6, 4.7, 6.3, and 7.9 mg/ml caused concentration-related inhibition of norepinephrine-induced vasoconstriction. In preparations infused with 6.3 and 7.9 mg/ml, this effect reached a maximum after 10-20 minutes but had vanished by the end of the infusion; 1 hour after the end of the infusion, the effects of norepinephrine were potentiated by 71% and 108%, respectively. Acetylcholine-induced vasorelaxation (EC50 3.0 ng/ml in controls) was significantly reduced after 6.3 mg/ml ethanol infusion and totally abolished after 7.9 mg/ml ethanol infusion. ATP-induced vasorelaxation (EC50 180 ng/ml in controls) was also abolished after 7.9 mg/ml of ethanol infusion. By contrast, the vasorelaxant effects of papaverine were not affected by 7.9 mg/ml ethanol infusion. Light-microscopic examination revealed that the endothelial cells were present in ethanol-treated and in control mesenteric arterial beds. These observations indicate that ethanol suppresses endothelium-dependent vasorelaxation without apparent removal of the endothelial cells. The compromised relaxant capacity of the endothelium after ethanol and the resultant intensification of the vasoconstrictor response to norepinephrine may contribute to the development of vascular diseases such as hypertension and stroke.


Weight training in youth-growth, maturation, and safety: an evidence-based review.
To review the effects of resistance training programs on pre- and early-pubertal youth in the context of response, potential influence on growth and maturation, and occurrence of injury. Evidence-based review. Twenty-two reports dealing with experimental resistance training protocols, excluding isometric programs, in pre- and early-pubertal youth, were reviewed in the context of subject characteristics, training protocol, responses, and occurrence of injury. Experimental programs most often used isotonic machines and free weights, 2- and 3-day protocols, and 8- and 12-week durations, with significant improvements in muscular strength during childhood and early adolescence. Strength gains were lost during detraining. Experimental resistance training programs did not influence growth in height and weight of pre- and early-adolescent youth, and changes in estimates of body composition were variable and quite small. Only 10 studies systematically monitored injuries, and only three injuries were reported. Estimated injury rates were 0.176, 0.053, and 0.055 per 100 participant-hours in the respective programs. Experimental training protocols with weights and resistance machines and with supervision and low instructor/participant ratios are relatively safe and do not negatively impact growth and maturation of pre- and early-pubertal youth.


Leucoselect Phytosome Modulates Serum Eicosapentaenoic Acid, Docosahexaenoic Acid, and Prostaglandin E3 in a Phase I Lung Cancer Chemoprevention Study.
Grape seed procyanidin extract (GSE) has been shown to exert antineoplastic properties in preclinical studies. Recently, we reported findings from a modified phase I, open-label, dose escalation clinical study conducted to evaluate the safety, tolerability, MTD, and potential chemopreventive effects of leucoselect phytosome, a standardized GSE complexed with soy phospholipids to enhance bioavailability, in heavy active and former smokers. Three months of leucoselect phytosome treatment significantly decreased bronchial Ki-67 labeling index (LI), a marker of cell proliferation on the bronchial epithelium. Because GSE is widely used as a supplement to support cardiovascular health, we evaluate the impact of oral leucoselect phytosome on the fasting serum complex lipid metabolomics profiles in our participants. One month of leucoselect phytosome treatment significantly increased eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the omega-3 polyunsaturated fatty acids (n-3 PUFA) with well-established anticancer properties. Leucoselect phytosome also significantly increased unsaturated phosphatidylcholines (PC), likely from soy phospolipids in the phytosome and functioning as transporters for these PUFAs. Furthermore, 3-month leucoselect phytosome treatment significantly increased serum prostaglandin (PG) E3 (PGE3), a metabolite of EPA with anti-inflammatory and antineoplastic properties. Such increases in PGE3 correlated with reductions of bronchial Ki-67 LI (r = -0.9; P = 0.0374). Moreover, posttreatment plasma samples from trial participants significantly inhibited proliferation of human lung cancer cell lines A549 (adenocarcinoma), H520 (squamous cell carcinoma), DMS114 (small cell carcinoma), and 1198 (preneoplastic cell line). Our findings further support the potential utility of leucoselect phytosome in reducing cardiovascular and neoplastic risks in heavy former and active smokers. PREVENTION RELEVANCE: In this correlative study of leucoselect phytosome for lung cancer chemoprevention in heavy active and former smokers, we demonstrate for the first time, favorable modulations of n-3PUFA and downstream PGE3 in fasting serum, further supporting the chemopreventive potential of leucoselect phytosome against lung cancer.


Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial.
Physical function and exercise capacity decline with age and are a major source of disability in older people. Recent evidence suggests a potential role for the renin-angiotensin system in modulating muscle function. We sought to examine the effect of the angiotensin-converting-enzyme (ACE) inhibitor perindopril on physical function in elderly people with functional impairment who had no heart failure or left ventricular systolic dysfunction. In this double-blind randomized controlled trial, participants aged 65 years and older who had problems with mobility or functional impairment were randomly assigned to receive either perindopril or placebo for 20 weeks. The primary outcome was the change in the 6-minute walking distance over the 20 weeks. Secondary outcomes were changes in muscle function, daily activity levels, self-reported function and health-related quality of life. A total of 130 participants were enrolled in the study (mean age 78.7, standard deviation 7.7 years); 95 completed the trial. At 20 weeks, the mean 6-minute walking distance was significantly improved in the perindopril group relative to the placebo group (mean between-group difference 31.4 m, 95% confidence interval [CI] 10.8 to 51.9 m; p = 0.003). There was a significant impact on health-related quality of life: although the mean score for part 1 of the EQ-5D questionnaire deteriorated over time in the placebo group, quality of life was maintained in the perindopril group, for a between-group difference of 0.09 (p = 0.046). There were no significant differences between the 2 groups in the other outcomes. Use of the ACE inhibitor perindopril improved exercise capacity in functionally impaired elderly people who had no heart failure and maintained health-related quality of life. The degree of improvement was equivalent to that reported after 6 months of exercise training. (International Standard Randomised Controlled Trial Register no. ISRCTN67679521).


Epithelial Sodium Channel-α Mediates the Protective Effect of the TNF-Derived TIP Peptide in Pneumolysin-Induced Endothelial Barrier Dysfunction.
Streptococcus pneumoniae is a major etiologic agent of bacterial pneumonia. Autolysis and antibiotic-mediated lysis of pneumococci induce release of the pore-forming toxin, pneumolysin (PLY), their major virulence factor, which is a prominent cause of acute lung injury. PLY inhibits alveolar liquid clearance and severely compromises alveolar-capillary barrier function, leading to permeability edema associated with pneumonia. As a consequence, alveolar flooding occurs, which can precipitate lethal hypoxemia by impairing gas exchange. The α subunit of the epithelial sodium channel (ENaC) is crucial for promoting Na+ reabsorption across Na+-transporting epithelia. However, it is not known if human lung microvascular endothelial cells (HL-MVEC) also express ENaC-α and whether this subunit is involved in the regulation of their barrier function. The presence of α, β, and γ subunits of ENaC and protein phosphorylation status in HL-MVEC were assessed in western blotting. The role of ENaC-α in monolayer resistance of HL-MVEC was examined by depletion of this subunit by specific siRNA and by employing the TNF-derived TIP peptide, a specific activator that directly binds to ENaC-α. HL-MVEC express all three subunits of ENaC, as well as acid-sensing ion channel 1a (ASIC1a), which has the capacity to form hybrid non-selective cation channels with ENaC-α. Both TIP peptide, which specifically binds to ENaC-α, and the specific ASIC1a activator MitTx significantly strengthened barrier function in PLY-treated HL-MVEC. ENaC-α depletion significantly increased sensitivity to PLY-induced hyperpermeability and in addition, blunted the protective effect of both the TIP peptide and MitTx, indicating an important role for ENaC-α and for hybrid NSC channels in barrier function of HL-MVEC. TIP peptide blunted PLY-induced phosphorylation of both calmodulin-dependent kinase II (CaMKII) and of its substrate, the actin-binding protein filamin A (FLN-A), requiring the expression of both ENaC-α and ASIC1a. Since non-phosphorylated FLN-A promotes ENaC channel open probability and blunts stress fiber formation, modulation of this activity represents an attractive target for the protective actions of ENaC-α in both barrier function and liquid clearance. Our results in cultured endothelial cells demonstrate a previously unrecognized role for ENaC-α in strengthening capillary barrier function that may apply to the human lung. Strategies aiming to activate endothelial NSC channels that contain ENaC-α should be further investigated as a novel approach to improve barrier function in the capillary endothelium during pneumonia.


Renin-angiotensin-aldosterone system inhibitors and the risk of mortality in patients with hypertension hospitalised for COVID-19: systematic review and meta-analysis.
The association between the use of renin-angiotensin-aldosterone (RAAS) inhibitors and the risk of mortality from COVID-19 is unclear. We aimed to estimate the association of RAAS inhibitors, including ACE inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) with COVID-19 mortality risk in patients with hypertension. PubMed (MEDLINE) SCOPUS, OVID, Cochrane Library databases and medrxiv.org were searched from 1 January 2020 to 1 September 2020. Studies reporting the association of RAAS inhibitors (ACEi or ARBs) and mortality in patients with hypertension, hospitalised for COVID-19 were extracted. Two reviewers independently extracted appropriate data of interest and assessed the risk of bias. All analyses were performed using random-effects models on log-transformed risk ratio (RR) estimates, and heterogeneity was quantified. Fourteen studies were included in the systematic review (n=73,073 patients with COVID-19; mean age 61 years; 53% male). Overall, the between-study heterogeneity was high (I2=80%, p<0.01). Patients with hypertension with prior use of RAAS inhibitors were 35% less likely to die from COVID-19 compared with patients with hypertension not taking RAAS inhibitors (pooled RR 0.65, 95% CI 0.45 to 0.94). The quality of evidence by Grading of Recommendations, Assessment, Development and Evaluations was graded as 'moderate' quality. In this meta-analysis, with prior use of RAAS inhibitors was associated with lower risk mortality from COVID-19 in patients with hypertension. Our findings suggest a potential protective effect of RAAS-inhibitors in COVID-19 patients with hypertension. The present study has been registered with PROSPERO (registration ID: CRD 42020187963).


A large, consistent plasma proteomics data set from prospectively collected breast cancer patient and healthy volunteer samples.
Variability of plasma sample collection and of proteomics technology platforms has been detrimental to generation of large proteomic profile datasets from human biospecimens. We carried out a clinical trial-like protocol to standardize collection of plasma from 204 healthy and 216 breast cancer patient volunteers. The breast cancer patients provided follow up samples at 3 month intervals. We generated proteomics profiles from these samples with a stable and reproducible platform for differential proteomics that employs a highly consistent nanofabricated ChipCube™ chromatography system for peptide detection and quantification with fast, single dimension mass spectrometry (LC-MS). Protein identification is achieved with subsequent LC-MS/MS analysis employing the same ChipCube™ chromatography system. With this consistent platform, over 800 LC-MS plasma proteomic profiles from prospectively collected samples of 420 individuals were obtained. Using a web-based data analysis pipeline for LC-MS profiling data, analyses of all peptide peaks from these plasma LC-MS profiles reveals an average coefficient of variability of less than 15%. Protein identification of peptide peaks of interest has been achieved with subsequent LC-MS/MS analyses and by referring to a spectral library created from about 150 discrete LC-MS/MS runs. Verification of peptide quantity and identity is demonstrated with several Multiple Reaction Monitoring analyses. These plasma proteomic profiles are publicly available through ProteomeCommons. From a large prospective cohort of healthy and breast cancer patient volunteers and using a nano-fabricated chromatography system, a consistent LC-MS proteomics dataset has been generated that includes more than 800 discrete human plasma profiles. This large proteomics dataset provides an important resource in support of breast cancer biomarker discovery and validation efforts.


Rule Perseveration during Task-Switching in Brain Tumor: A Severe Form of Task-Setting Impairment.
It has been proposed that at least two distinct processes are engaged during task-switching: reconfiguration of the currently relevant task-set and interference resolution arising from the competing task-set. Whereas in healthy individuals the two are difficult to disentangle, their disruption is thought to cause different impairments in brain-damaged patients. Yet, the observed deficits are inconsistent across studies and do not allow drawing conclusions regarding their independence. Forty-one brain tumor patients were tested on a task-switching paradigm. We compared their performance between switch and repeat trials (switch cost) to assess rule reconfiguration, and between trials requiring the same response (congruent) and a different response for the two tasks (incongruent) to assess interference control. In line with previous studies, we found the greatest proportion of errors on incongruent trials, suggesting an interference control impairment. However, a closer look at the distribution of errors between two task rules revealed a rule perseveration impairment: Patients with high error rate on incongruent trials often applied only one task rule throughout the task and less frequently switched to the alternative one. Multivariate lesion-symptom mapping analysis unveiled the relationship between lesions localized in left orbitofrontal and posterior subcortical regions and perseveration scores, measured as absolute difference in accuracy between two task rules. This finding points to a more severe task-setting impairment, not reflected as a mere switching deficit, but instead as a difficulty in creating multiple stable task representations, in line with recent accounts of OFC functions suggesting its critical role in representing task states.


A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent.
Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base. To assess whether or not augmenting symptomatic follow-up in primary care with two intensive methods of follow-up [monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging] is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent. Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up (n = 301), (2) CEA testing only (n = 300), (3) computerised tomography (CT) only (n = 299) or (4) CEA testing and CT (n = 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing-only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata). Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence. A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was ≤ 10 µg/l. Primary outcome Surgical treatment of recurrence with curative intent. Secondary outcomes Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained. Detection of recurrence During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%; p = 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%; p = 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49. Survival A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank p = 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%. Cost-effectiveness The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was £40,131 with CEA testing, £43,392 with CT and £85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was £25,951 and for CT was £246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-£208,347) and a dominated policy. Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality. Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future. Current Controlled Trials ISRCTN41458548. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 32. See the NIHR Journals Library website for further project information.


Replication and characterization of CADM2 and MSRA genes on human behavior.
Progress identifying the genetic determinants of personality has historically been slow, with candidate gene studies and small-scale genome-wide association studies yielding few reproducible results. In the UK Biobank study, genetic variants in CADM2 and MSRA were recently shown to influence risk taking behavior and irritability respectively, representing some of the first genomic loci to be associated with aspects of personality. We extend this observation by performing a personality "phenome-scan" across 16 traits in up to 140,487 participants from 23andMe for these two genes. Genome-wide heritability estimates for these traits ranged from 5-19%, with both CADM2 and MSRA demonstrating significant effects on multiple personality types. These associations covered all aspects of the big five personality domains, including specific facet traits such as compliance, altruism, anxiety and activity/energy. This study both confirms and extends the original observations, highlighting the role of genetics in aspects of mental health and behavior.


Scepticism towards insecticide treated mosquito nets for malaria control in rural community in north-western Tanzania.
Despite existence of effective tools for malaria control, malaria continues to be one of the leading killer diseases especially among under-five year children and pregnant women in poor rural populations of Sub Saharan Africa. In Tanzania Mainland the disease contributes to 39.4% of the total OPD attendances. In terms of mortality, malaria is known to be responsible for more than one third of deaths among children of age below 5 years and also contributes for up to one fifth of deaths among pregnant women. This paper is based on a study conducted in a rural community along the shores of Lake Victoria in Mwanza region, North-Western Tanzania. The study explores reasons for scepticism and low uptake of insecticide treated mosquito nets (ITNs) that were promoted through social marketing strategy for malaria control prior to the introduction of long lasting nets (LLN). The paper breaks from traditional approach that tend to study low uptake of health interventions in terms of structural practical constraints--cost, accessibility, everyday priorities--or in terms of cognition--insufficient knowledge of benefits e.g. ignorance of public health messages. This paper has shown that, the majority of people who could afford the prices of ITNs and who knew where to obtain the insecticides did not necessarily buy them. This suggests that, although people tend to report cost-related factors as a barrier against the use of ITNs, there are other critical concerns at work. Without underestimating the practical factors, our study have recommended to consider critical examinations of those other concerns that hinder optimal utilization of ITN for malaria control, and the basis for those concerns.


Effect of an Education Programme for South Asians with Asthma and Their Clinicians: A Cluster Randomised Controlled Trial (OEDIPUS).
People with asthma from ethnic minority groups experience significant morbidity. Culturally-specific interventions to reduce asthma morbidity are rare. We tested the hypothesis that a culturally-specific education programme, adapted from promising theory-based interventions developed in the USA, would reduce unscheduled care for South Asians with asthma in the UK. A cluster randomised controlled trial, set in two east London boroughs. 105 of 107 eligible general practices were randomised to usual care or the education programme. Participants were south Asians with asthma aged 3 years and older with recent unscheduled care. The programme had two components: the Physician Asthma Care Education (PACE) programme and the Chronic Disease Self Management Programme (CDSMP), targeted at clinicians and patients with asthma respectively. Both were culturally adapted for south Asians with asthma. Specialist nurses, and primary care teams from intervention practices were trained using the PACE programme. South Asian participants attended an outpatient appointment; those registered with intervention practices received self-management training from PACE-trained specialist nurses, a follow-up appointment with PACE-trained primary care practices, and an invitation to attend the CDSMP. Patients from control practices received usual care. Primary outcome was unscheduled care. 375 south Asians with asthma from 84 general practices took part, 183 registered with intervention practices and 192 with control practices. Primary outcome data were available for 358/375 (95.5%) of participants. The intervention had no effect on time to first unscheduled attendance for asthma (Adjusted Hazard Ratio AHR = 1.19 95% CI 0.92 to 1.53). Time to first review in primary care was reduced (AHR = 2.22, (1.67 to 2.95). Asthma-related quality of life and self-efficacy were improved at 3 months (adjusted mean difference -2.56, (-3.89 to -1.24); 0.44, (0.05 to 0.82) respectively. A multi-component education programme adapted for south Asians with asthma did not reduce unscheduled care but did improve follow-up in primary care, self-efficacy and quality of life. More effective interventions are needed for south Asians with asthma.


Distinct pathways for modification of the bacterial cell wall by non-canonical D-amino acids.
Production of non-canonical D-amino acids (NCDAAs) in stationary phase promotes remodelling of peptidoglycan (PG), the polymer that comprises the bacterial cell wall. Impairment of NCDAAs production leads to excessive accumulation of PG and hypersensitivity to osmotic shock; however, the mechanistic bases for these phenotypes were not previously determined. Here, we show that incorporation of NCDAAs into PG is a critical means by which NCDAAs control PG abundance and strength. We identified and reconstituted in vitro two (of at least three) distinct processes that mediate NCDAA incorporation. Diverse bacterial phyla incorporate NCDAAs into their cell walls, either through periplasmic editing of the mature PG or via incorporation into PG precursor subunits in the cytosol. Production of NCDAAs in Vibrio cholerae requires the stress response sigma factor RpoS, suggesting that NCDAAs may aid bacteria in responding to varied environmental challenges. The widespread capacity of diverse bacteria, including non-producers, to incorporate NCDAAs suggests that these amino acids may serve as both autocrine- and paracrine-like regulators of chemical and physical properties of the cell wall in microbial communities.


Audibility-Based Hearing Aid Fitting Criteria for Children With Mild Bilateral Hearing Loss.
Purpose Because of uncertainty about the level of hearing where hearing aids should be provided to children, the goal of the current study was to develop audibility-based hearing aid candidacy criteria based on the relationship between unaided hearing and language outcomes in a group of children with hearing loss who did not wear hearing aids. Method Unaided hearing and language outcomes were examined for 52 children with mild-to-severe hearing losses. A group of 52 children with typical hearing matched for age, nonverbal intelligence, and socioeconomic status was included as a comparison group representing the range of optimal language outcomes. Two audibility-based criteria were considered: (a) the level of unaided hearing where unaided children with hearing loss fell below the median for children with typical hearing and (b) the level of unaided hearing where the slope of language outcomes changed significantly based on an iterative, piecewise regression modeling approach. Results The level of unaided audibility for children with hearing loss that was associated with differences in language development from children with typical hearing or based on the modeling approach varied across outcomes and criteria but converged at an unaided speech intelligibility index of 80. Conclusions Children with hearing loss who have unaided speech intelligibility index values less than 80 may be at risk for delays in language development without hearing aids. The unaided speech intelligibility index potentially could be used as a clinical criterion for hearing aid fitting candidacy for children with hearing loss.


Vitamin E supplementation and mammalian lifespan.
Vitamin E refers to a family of several compounds that possess a similar chemical structure comprising a chromanol ring with a 16-carbon side chain. The degree of saturation of the side chain, and positions and nature of methyl groups designate the compounds as tocopherols or tocotrienols. Vitamin E compounds have antioxidant properties due to a hydroxyl group on the chromanol ring. Recently, it has been suggested that vitamin E may also regulate signal transduction and gene expression. We previously reported that lifelong dietary vitamin E (alpha-tocopherol) supplementation significantly increased median lifespan in C57BL/6 mice by 15%. This lifespan extension appeared to be independent of any antioxidant effect. Employing a transcriptional approach, we suggest that this increase in lifespan may reflect an anti-cancer effect via induction of the P21 signalling pathway, since cancer is the major cause of death in small rodents. We suggest that the role of this pathway in life span extension following supplementation of vitamin E now requires further investigation.