Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice.
Previous studies have shown that GIRK2 channel function is enhanced by ethanol and that GIRK2 null mutant mice are less sensitive to some of ethanol's effects, including anxiolysis, habituated locomotor stimulation, and acute handling-induced convulsions than wild types. Under some conditions, GIRK2 knockout mice consume more ethanol than wild types, but it is unclear whether they do so because they are more sensitive to ethanol's rewarding effects or less sensitive to its aversive effects. To further assess the role of GIRK2 in ethanol action, GIRK2 null mutant and wild type mice were tested in conditioning models that measure the motivational effects of ethanol. In a conditioned taste aversion (CTA) procedure, knockout and wild type mice were given ethanol (0.0, 2.0, 2.5, or 3.5 g/kg, IP) following 1-h access to saccharin every 48 h over a 10 day period. In a conditioned place preference (CPP) procedure, knockout and wild type mice were given ethanol (2.0 or 3.0 g/kg, IP) paired with one stimulus (grid or hole floor) and saline paired with the other. After four 5-min trials with each stimulus, a 60-min choice test was done. The results demonstrated a genotypic difference in both paradigms. In CTA, there was no difference between genotypes at 0.0 or 3.5 g/kg ethanol, but at the 2.0 and 2.5 g/kg doses, wild types developed a stronger aversion to saccharin than knockouts. In CPP, wild types developed place preference, but knockouts did not. These studies show that GIRK2 deletion reduced ethanol's impact in tasks that are commonly used to index the drug's rewarding and aversive effects. These findings could reflect either a learning/memory deficit or decreased sensitivity to ethanol's motivational effects in null mutant mice. The latter interpretation is more consistent with previous data showing that knockout mice consume higher doses of ethanol than wild type mice.


Inflammatory mechanisms underlying the effects of everyday discrimination on age-related memory decline.
Previous research suggests that everyday discrimination is associated with worse episodic memory and partially mediates Black-White disparities in memory aging. The biological mechanisms underlying the link between everyday discrimination and memory are unclear but may involve inflammatory processes. This study aimed to determine whether systemic inflammation, indexed by blood levels of C-reactive protein (CRP), mediates associations between everyday discrimination and episodic memory over 6 years. A longitudinal mediation model quantified associations between baseline everyday discrimination, 4-year change in CRP, and 6-year change in episodic memory. The Health and Retirement Study (HRS). 12,624 HRS participants aged 51 and older. Everyday Discrimination Scale, high-sensitivity CRP assays of dried blood spots, composite scores of immediate and delayed recall of a word list. Black participants reported greater everyday discrimination. Greater discrimination was associated with lower baseline memory and faster memory decline. Higher CRP at baseline partially mediated the negative association between discrimination and baseline memory, but CRP change did not mediate the association between discrimination and memory decline. This U.S.-representative longitudinal study provides evidence for deleterious effects of discrimination on subsequent episodic memory. The fact that elevated CRP only partially explained the concurrent association between discrimination and memory highlights the need for more comprehensive investigations of biological mechanisms underlying the link between social stress and age-related memory decline in order to better characterize potential intervention targets to reduce racial inequalities in memory aging.


Evaluation of 12 strategies for obtaining second opinions to improve interpretation of breast histopathology: simulation study.
To evaluate the potential effect of second opinions on improving the accuracy of diagnostic interpretation of breast histopathology. Simulation study. 12 different strategies for acquiring independent second opinions. Interpretations of 240 breast biopsy specimens by 115 pathologists, one slide for each case, compared with reference diagnoses derived by expert consensus. Misclassification rates for individual pathologists and for 12 simulated strategies for second opinions. Simulations compared accuracy of diagnoses from single pathologists with that of diagnoses based on pairing interpretations from first and second independent pathologists, where resolution of disagreements was by an independent third pathologist. 12 strategies were evaluated in which acquisition of second opinions depended on initial diagnoses, assessment of case difficulty or borderline characteristics, pathologists' clinical volumes, or whether a second opinion was required by policy or desired by the pathologists. The 240 cases included benign without atypia (10% non-proliferative, 20% proliferative without atypia), atypia (30%), ductal carcinoma in situ (DCIS, 30%), and invasive cancer (10%). Overall misclassification rates and agreement statistics depended on the composition of the test set, which included a higher prevalence of difficult cases than in typical practice. Misclassification rates significantly decreased (P<0.001) with all second opinion strategies except for the strategy limiting second opinions only to cases of invasive cancer. The overall misclassification rate decreased from 24.7% to 18.1% when all cases received second opinions (P<0.001). Obtaining both first and second opinions from pathologists with a high volume (≥10 breast biopsy specimens weekly) resulted in the lowest misclassification rate in this test set (14.3%, 95% confidence interval 10.9% to 18.0%). Obtaining second opinions only for cases with initial interpretations of atypia, DCIS, or invasive cancer decreased the over-interpretation of benign cases without atypia from 12.9% to 6.0%. Atypia cases had the highest misclassification rate after single interpretation (52.2%), remaining at more than 34% in all second opinion scenarios. Second opinions can statistically significantly improve diagnostic agreement for pathologists' interpretations of breast biopsy specimens; however, variability in diagnosis will not be completely eliminated, especially for breast specimens with atypia.


Alcohol-induced bone disease: impact of ethanol on osteoblast proliferation.
The habitual consumption of even moderate quantities of alcohol (1 to 2 drinks/day) is clearly linked with reduced bone mass (osteopenia). Biochemical and histological evaluation of patients with alcoholic bone disease reveal a marked impairment in bone formation in the face of relatively normal bone resorption. Experiments using well-defined osteoblastic model systems indicate that the observed reductions in bone formation result from a direct, antiproliferative effect of ethanol on the osteoblast itself. As bone remodeling and mineralization are dependent on osteoblasts, it follows that the deleterious effect of alcohol on these cells would result in slowed bone formation, aberrant remodeling of skeletal tissue and, ultimately, osteopenia and fractures. The skeletal consequences of alcohol intake during adolescence, when the rapid skeletal growth ultimately responsible for achieving peak bone mass is occurring, may be especially harmful. The specific subcellular mechanisms whereby ethanol inhibits cell proliferation are, as yet, unknown. During the last few years, attention has shifted from nonspecific membrane perturbation effects to actions on certain signaling proteins. Specifically, there is increasing evidence that ethanol may exert significant effects on transmembrane signal transduction processes that constitute major branches of cellular control mechanisms. At present, abstinence is the only effective therapy for alcohol-induced bone disease. An improved understanding of the pathogenesis of alcohol-induced bone disease may eventually result in alternative therapeutic avenues for those who are unable to abstain.


Medical school performance of initially rejected students.
At the University of Texas Medical School at Houston we had a unique opportunity to examine performance through the medical curriculum and one year of postgraduate training of 50 students initially rejected for medical school. Each had been interviewed by the same Admissions Committee, which earlier had selected 150 students through the traditional process. In contrasting the initially accepted and initially rejected groups, academic and demographic variables accounted for only 28% of group difference. The 72% of group difference not accounted for by the variables examined was presumed to relate to Admissions Committee preference. In attrition and in both preclinical and clinical performance through medical school and one year of postgraduate training, there were no meaningful differences between the groups. The observations suggest that the traditional interview process probably does not enhance the ability to predict performance of medical school applicants.


Intent-to-treat analysis of a simultaneous multisite telehealth diabetes prevention program.
Determine the effectiveness of a 16-week modified diabetes prevention program (DPP) administered simultaneously to multiple rural communities from a single urban site, as compared with a similar face-to-face intervention. A 12-week intervention was evaluated to consider minimization of staff costs in communities where resources are limited. A prospective cohort study compared DPP interventions implemented in rural (via telehealth technology) and urban (face-to-face) communities using an intent-to-treat analysis. Primary outcome measures included 5% and 7% body weight loss. Logistic regression analyses were used to determine predictors of intervention success and included a variable for treatment effect. Between 2010 and 2015, up to 667 participants were enrolled in the study representing one urban and 15 rural communities across Montana. The 16-week urban and rural interventions were comparable; 33.5% and 34.6% of participants lost 7% body weight, respectively; 50% and 47% lost 5% (p=0.22). Participants who were male (OR=2.41; 95% CI 1.32 to 4.40), had lower baseline body mass index (OR=1.03; 95% CI 1.01 to 1.07), attended more sessions (OR=1.33; 95% CI 1.11 to 1.58), and more frequently reported (OR=3.84; 95% CI 1.05 to 14.13) and met daily fat gram (OR=4.26; 95% CI 1.7 to 10.6) and weekly activity goals (OR=2.46; 95% CI 1.06 to 5.71) were more likely to meet their 7% weight loss goal. Predictors of meeting weight loss goals were similar for participants enrolled in the 12-week intervention. Using telehealth technology to administer a modified DPP to multiple rural communities simultaneously demonstrated weight loss results comparable to those in a face-to-face intervention. Given the limitation of resources, linking rural areas to urban centers using telemedicine may increase access to much needed services to prevent or delay progression to diabetes.


Patient Blood Management: An International Perspective.
This article describes practices in patient blood management (PBM) in 4 countries on different continents that may provide insights for anesthesiologists and other physicians working in global settings. The article has its foundation in the proceedings of a session at the 2014 AABB annual meeting during which international experts from England, Uganda, China, and Brazil presented the programs and implementation strategies in PBM developed in their respective countries. To systematize the review and enhance the comparability between these countries on different continents, authors were requested to respond to the same set of 6 key questions with respect to their country's PBM program(s). Considerable variation exists between these country regions that is driven both by differences in health contexts and by disparities in resources. Comparing PBM strategies from low-, middle-, and high-income countries, as described in this article, allows them to learn bidirectionally from one another and to work toward implementing innovative and preferably evidence-based strategies for improvement. Sharing and distributing knowledge from such programs will ultimately also improve transfusion outcomes and patient safety.


Evaluation of potential reference genes in real-time RT-PCR studies of Atlantic salmon.
Salmonid fishes are among the most widely studied model fish species but reports on systematic evaluation of reference genes in qRT-PCR studies is lacking. The stability of six potential reference genes was examined in eight tissues of Atlantic salmon (Salmo salar), to determine the most suitable genes to be used in quantitative real-time RT-PCR analyses. The relative transcription levels of genes encoding 18S rRNA, S20 ribosomal protein, beta-actin, glyceraldehyde-3P-dehydrogenase (GAPDH), and two paralog genes encoding elongation factor 1A (EF1AA and EF1AB) were quantified in gills, liver, head kidney, spleen, thymus, brain, muscle, and posterior intestine in six untreated adult fish, in addition to a group of individuals that went through smoltification. Based on calculations performed with the geNorm VBA applet, which determines the most stable genes from a set of tested genes in a given cDNA sample, the ranking of the examined genes in adult Atlantic salmon was EF1AB>EF1AA>beta-actin>18S rRNA>S20>GAPDH. When the same calculations were done on a total of 24 individuals from four stages in the smoltification process (presmolt, smolt, smoltified seawater and desmoltified freshwater), the gene ranking was EF1AB>EF1AA>S20>beta-actin>18S rRNA>GAPDH. Overall, this work suggests that the EF1AA and EF1AB genes can be useful as reference genes in qRT-PCR examination of gene expression in the Atlantic salmon.


The evolutionary origination and diversification of a dimorphic gene regulatory network through parallel innovations in cis and trans.
The origination and diversification of morphological characteristics represents a key problem in understanding the evolution of development. Morphological traits result from gene regulatory networks (GRNs) that form a web of transcription factors, which regulate multiple cis-regulatory element (CRE) sequences to control the coordinated expression of differentiation genes. The formation and modification of GRNs must ultimately be understood at the level of individual regulatory linkages (i.e., transcription factor binding sites within CREs) that constitute the network. Here, we investigate how elements within a network originated and diversified to generate a broad range of abdominal pigmentation phenotypes among Sophophora fruit flies. Our data indicates that the coordinated expression of two melanin synthesis enzymes, Yellow and Tan, recently evolved through novel CRE activities that respond to the spatial patterning inputs of Hox proteins and the sex-specific input of Bric-à-brac transcription factors. Once established, it seems that these newly evolved activities were repeatedly modified by evolutionary changes in the network's trans-regulators to generate large-scale changes in pigment pattern. By elucidating how yellow and tan are connected to the web of abdominal trans-regulators, we discovered that the yellow and tan abdominal CREs are composed of distinct regulatory inputs that exhibit contrasting responses to the same Hox proteins and Hox cofactors. These results provide an example in which CRE origination underlies a recently evolved novel trait, and highlights how coordinated expression patterns can evolve in parallel through the generation of unique regulatory linkages.


Effect of oral administration of electrolyte pastes on rehydration of horses.
To determine whether the composition of electrolyte pastes formulated for oral administration influences voluntary water intake (WI) by horses recovering from furosemide-induced dehydration. 6 horses. Voluntary WI, body weight, and blood and urine constituents were measured before and after induction of dehydration by furosemide administration and overnight withholding of water; these same variables also were measured during a 36-hour rehydration period. Each horse was evaluated 4 times with random application of 4 treatments (electrolyte pastes) that provided 0.5 g of KCl/kg of body weight, 0.5 g of NaCl/kg, 0.25 g of NaCl and 0.25 g of KCl/kg, or no electrolytes (control treatment). Electrolyte pastes were administered 3 times (4, 8, and 12 hours after start of the rehydration period). Administration of all electrolyte pastes resulted in significantly greater voluntarily WI, compared with the control treatment, and was accompanied by significantly greater recovery of body weight when NaCl was a component of the paste. Administration of NaCl and NaCl-KCl pastes tended to produce a state of transient hyperhydration; however, electrolyte administration also resulted in significantly greater urine production and electrolyte excretion during the final 24 hours of the rehydration period. Adverse effects of oral administration of hypertonic electrolyte pastes were not observed. Oral administration of electrolyte pastes to dehydrated horses increases voluntary WI and improves rehydration during the rehydration period. Rehydration is more rapid and complete when NaCl is a component of the electrolyte paste.


The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A.
Germline missense mutations of the RET protooncogene cause a clinical spectrum called multiple endocrine neoplasia (MEN) type 2. A strong genotype-phenotype correlation results in major implications for the clinical approach. More information on less common mutations is needed to advance specific guidance. We report individualized patient information on 36 carriers of the intracellular RET gene mutation S891A from three centers and clustered data of 38 former patients reported in the literature in nine additional studies. S891A mutation accounts for up to 5% of all patients to date reported with RET mutations and 16% of those hitherto reported with intracellular mutations. S891A mutation caused medullary thyroid cancer (MTC) in 69.4%, pheochromocytoma in 2.8%, and parathyroid hyperplasia in 8.3% of the 36 patients of this case series and in 63.5, 4.1, and 4.1%, respectively, for the entire groups of 74 patients. The youngest age of onset for MTC in this group was 17 yr (median, 46 yr; range, 17-80 yr), for pheochromocytoma 46 yr (median, 46 yr), and for parathyroid hyperplasia 17 yr (median, 20 yr, range, 17-46 yr). Persistence of MTC was described in 14.3% of patients with available follow-up. Additional findings included corneal nerve thickening in three of 74 patients (4.1%). This intracellular mutation can initiate the full spectrum of MEN2a, initiates MTC at an early age, and causes recurrence and death if undertreated. We recommend stringent adherence to established guidance in MEN2a in this rare mutation.


HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C.
A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.


Experimental evidence on the impact of food advertising on children's knowledge about and preferences for healthful food.
To understand the rising prevalence of childhood obesity in affluent societies, it is necessary to take into account the growing obesity infrastructure, which over past decades has developed into an obesogenic environment. This study examines the effects of one of the constituent factors of consumer societies and a potential contributory factor to childhood obesity: commercial food communication targeted to children. Specifically, it investigates the impact of TV advertising on children's food knowledge and food preferences and correlates these findings with their weight status. Evaluations of traditional information- and education-based interventions suggest that they may not sustainably change food patterns. Based on prior consumer research, we propose five hypotheses, which we then test using a subsample from the IDEFICS study, a large-scale pan-European intervention study on childhood obesity. The results indicate that advertising has divergent effects on children's food knowledge and preferences and that food knowledge is unrelated to food preferences. This finding has important implications for both future research and public policy.


Emergence of domains and nonlinear transport in the zero-resistance state.
We study transport in the domain state, the so-called zero-resistance state, that emerges in a two-dimensional electron system in which the combined action of microwave radiation and magnetic field produces a negative absolute conductivity. We show that the voltage-biased system has a rich phase diagram in the system size and voltage plane, with second- and first-order transitions between the domain and homogeneous states for small and large voltages, respectively. We find the residual negative dissipative resistance in the stable domain state.


Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways.
Melanoma is one of the most aggressive cancers, and its incidence is increasing. These tumors derive from the melanocyte lineage and remain incurable after metastasis. Here we report that SONIC HEDGEHOG (SHH)-GLI signaling is active in the matrix of human hair follicles, and that it is required for the normal proliferation of human melanocytes in culture. SHH-GLI signaling also regulates the proliferation and survival of human melanomas: the growth, recurrence, and metastasis of melanoma xenografts in mice are prevented by local or systemic interference of HH-GLI function. Moreover, we show that oncogenic RAS-induced melanomas in transgenic mice express Gli1 and require Hh-Gli signaling in vitro and in vivo. Finally, we provide evidence that endogenous RAS-MEK and AKT signaling regulate the nuclear localization and transcriptional activity of GLI1 in melanoma and other cancer cells. Our data uncover an unsuspected role of HH-GLI signaling in melanocytes and melanomas, demonstrate a role for this pathway in RAS-induced tumors, suggest a general integration of the RAS/AKT and HH-GLI pathways, and open a therapeutic approach for human melanomas.


Role of whole grains versus fruits and vegetables in reducing subclinical inflammation and promoting gastrointestinal health in individuals affected by overweight and obesity: a randomized controlled trial.
Whole grains (WG) and fruits and vegetables (FV) have been shown to reduce the risk of metabolic disease, possibly via modulation of the gut microbiota. The purpose of this study was to determine the impact of increasing intake of either WG or FV on inflammatory markers and gut microbiota composition. A randomized parallel arm feeding trial was completed on forty-nine subjects with overweight or obesity and low intakes of FV and WG. Individuals were randomized into three groups (3 servings/d provided): WG, FV, and a control (refined grains). Stool and blood samples were collected at the beginning of the study and after 6 weeks. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP), and high sensitivity C-reactive protein (hs-CRP)] were measured. Stool sample analysis included short/branched chain fatty acids (S/BCFA) and microbiota composition. There was a significant decrease in LBP for participants on the WG (- 0.2 μg/mL, p = 0.02) and FV (- 0.2 μg/mL, p = 0.005) diets, with no change in those on the control diet (0.1 μg/mL, p = 0.08). The FV diet induced a significant change in IL-6 (- 1.5 pg/mL, p = 0.006), but no significant change was observed for the other treatments (control, - 0.009 pg/mL, p = 0.99; WG, - 0.29, p = 0.68). The WG diet resulted in a significant decrease in TNF-α (- 3.7 pg/mL; p < 0.001), whereas no significant effects were found for those on the other diets (control, - 0.6 pg/mL, p = 0.6; FV, - 1.4 pg/mL, p = 0.2). The treatments induced individualized changes in microbiota composition such that treatment group differences were not identified, except for a significant increase in α-diversity in the FV group. The proportions of Clostridiales (Firmicutes phylum) at baseline were correlated with the magnitude of change in LBP during the study. These data demonstrate that WG and FV intake can have positive effects on metabolic health; however, different markers of inflammation were reduced on each diet suggesting that the anti-inflammatory effects were facilitated via different mechanisms. The anti-inflammatory effects were not related to changes in gut microbiota composition during the intervention, but were correlated with microbiota composition at baseline. ClinicalTrials.gov , NCT02602496 , Nov 4, 2017.


Dovitinib (TKI258), a multi-target angiokinase inhibitor, is effective regardless of KRAS or BRAF mutation status in colorectal cancer.
We aimed to determine whether KRAS and BRAF mutant colorectal cancer (CRC) cells exhibit distinct sensitivities to the multi-target angiokinase inhibitor, TKI258 (dovitinib). We screened 10 CRC cell lines by using receptor tyrosine kinase (RTK) array to identify activated RTKs. MTT assays, anchorage-independent colony-formation assays, and immunoblotting assays were performed to evaluate the in vitro anti-tumor effects of TKI258. In vivo efficacy study followed by pharmacodynamic evaluation was done. Fibroblast Growth Factor Receptor 1 (FGFR1) and FGFR3 were among the most highly activated RTKs in CRC cell lines. In in vitro assays, the BRAF mutant HT-29 cells were more resistant to the TKI258 than the KRAS mutant LoVo cells. However, in xenograft assays, TKI258 equally delayed the growth of tumors induced by both cell lines. TUNEL assays showed that the apoptotic index was unchanged following TKI258 treatment, but staining for Ki-67 and CD31 was substantially reduced in both xenografts, implying an anti-angiogenic effect of the drug. TKI258 treatment was effective in delaying CRC tumor growth in vivo regardless of the KRAS and BRAF mutation status. Our results identify FGFRs as potential targets in CRC treatment and suggest that combined targeting of multiple RTKs with TKI258 might serve as a novel approach to improve outcome of patients with CRC.


Do protection gradients explain patterns in herbivore densities? An example with ungulates in Zambia's Luangwa Valley.
Ungulate populations face declines across the globe, and populations are commonly conserved by using protected areas. However, assessing the effectiveness of protected areas in conserving ungulate populations has remained difficult. Using herd size data from four years of line transect surveys and distance sampling models, we modeled population densities of four important herbivore species across a gradient of protection on the edge of Zambia's South Luangwa National Park (SLNP) while accounting for the role of various ecological and anthropogenic variables. Our goal was to test whether protection was responsible for density dynamics in this protection gradient, and whether a hunting moratorium impacted herbivore densities during the studies. For all four species, we estimated lower densities in partially protected buffer areas adjacent to SLNP (ranging from 4.5-fold to 13.2-fold lower) compared to protected parklands. Density trends through the study period were species-specific, with some species increasing, decreasing, or remaining stable in all or some regions of the protection gradient. Surprisingly, when controlling for other covariates, we found that these observed differences were not always detectably related to the level of protection or year. Our findings highlight the importance of accounting for variables beyond strata of interest in evaluating the effectiveness of a protected area. This study highlights the importance of comprehensively modeling ungulate population density across protection gradients, identifies lands within an important protection gradient for targeted conservation and monitoring, documents prey depletion and expands our understanding on the drivers in a critical buffer area in Zambia.


Meta-analysis of multiple microarray datasets reveals a common gene signature of metastasis in solid tumors.
Metastasis is the number one cause of cancer deaths. Expression microarrays have been widely used to study metastasis in various types of cancer. We hypothesize that a meta-analysis of publicly available gene expression datasets in various tumor types can identify a signature of metastasis that is common to multiple tumor types. This common signature of metastasis may help us to understand the shared steps in the metastatic process and identify useful biomarkers that could predict metastatic risk. We identified 18 publicly available gene expression datasets in the Oncomine database comparing distant metastases to primary tumors in various solid tumors which met our eligibility criteria. We performed a meta-analysis using a modified permutation counting method in order to obtain a common gene signature of metastasis. We then validated this signature in independent datasets using gene set expression comparison analysis with the LS-statistic. A common metastatic signature of 79 genes was identified in the metastatic lesions compared with primaries with a False Discovery Proportion of less than 0.1. Interestingly, all the genes in the signature, except one, were significantly down-regulated, suggesting that overcoming metastatic suppression may be a key feature common to all metastatic tumors. Pathway analysis of the significant genes showed that the genes were involved in known metastasis-associated pathways, such as integrin signaling, calcium signaling, and VEGF signaling. To validate the signature, we used an additional six expression datasets that were not used in the discovery study. Our results showed that the signature was significantly enriched in four validation sets with p-values less than 0.05. We have modified a previously published meta-analysis method and identified a common metastatic signature by comparing primary tumors versus metastases in various tumor types. This approach, as well as the gene signature identified, provides important insights to the common metastatic process and a foundation for future discoveries that could have broad application, such as drug discovery, metastasis prediction, and mechanistic studies.


Altered Gut Microbiota in a Fragile X Syndrome Mouse Model.
The human gut microbiome is the ecosystem of microorganisms that live in the human digestive system. Several studies have related gut microbiome variants to metabolic, immune and nervous system disorders. Fragile X syndrome (FXS) is a neurodevelopmental disorder considered the most common cause of inherited intellectual disability and the leading monogenetic cause of autism. The role of the gut microbiome in FXS remains largely unexplored. Here, we report the results of a gut microbiome analysis using a FXS mouse model and 16S ribosomal RNA gene sequencing. We identified alterations in the fmr1 KO2 gut microbiome associated with different bacterial species, including those in the genera Akkermansia, Sutterella, Allobaculum, Bifidobacterium, Odoribacter, Turicibacter, Flexispira, Bacteroides, and Oscillospira. Several gut bacterial metabolic pathways were significantly altered in fmr1 KO2 mice, including menaquinone degradation, catechol degradation, vitamin B6 biosynthesis, fatty acid biosynthesis, and nucleotide metabolism. Several of these metabolic pathways, including catechol degradation, nucleotide metabolism and fatty acid biosynthesis, were previously reported to be altered in children and adults with autism. The present study reports a potential association of the gut microbiome with FXS, thereby opening new possibilities for exploring reliable treatments and non-invasive biomarkers.


Enrichment of low penetrance susceptibility loci in a Dutch familial colorectal cancer cohort.
Recent genome-wide association studies have identified several loci that confer an increased risk of colorectal cancer (CRC). We studied the role of the 8q24.21 (rs6983267), 18q21.1 (rs12953717), 15q13.3 (rs4779584), 11q23.1 (rs3802842), 8q23.3 (rs16892766), and 10p14 (rs10795668) risk variants in a series of 995 Dutch CRC cases and 1340 controls. The CRC cases were selected on basis of having a family history of CRC and/or early-onset disease. The detailed clinical and molecular data available on the cases allowed us to examine the relationship between risk variants and clinicopathologic characteristics. We replicated the association with an increased risk of CRC cancer for all loci, except 10p14. The association with the variant on chromosome 15q13.3 was confirmed for the first time. The risks associated with variants in our series were higher (not significant) than those previously reported, consistent with our series reflecting genetic enrichment. Moreover, we show that familial CRC cases possess an increased number of risk alleles compared with solitary CRC cases (early-onset; mean age at diagnosis of 48.5 years). We also identified a significant increase in the number of risk alleles in families with early-onset disease (<or=50 years) compared with late-onset families (>50 years). In solitary CRC patients, enrichment for risk alleles was not observed, suggesting that other causes of increased CRC risk play a role in these cases. Overall, our results suggest that clustering of low-risk variants may explain part of the excess risk in CRC families.


Highly sensitive graphene-Pt nanocomposites amperometric biosensor and its application in living cell H2O2 detection.
A sensitive hydrogen peroxide (H2O2) sensor was constructed based on graphene-Pt (RGO-Pt) nanocomposites and used to measure the release of H2O2 from living cells. The graphene and Pt nanoparticles (Pt NPs) were modified on glassy carbon electrode (GCE) by the physical adsorption and electrodeposition of K2PtCl6 solution, respectively. Through characterization by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS), it was observed that the electrodeposited Pt NPs were densely covered and well distributed on the entire graphene surface. Electrochemical study demonstrates that the RGO-Pt nanocomposites modified glassy carbon electrode exhibited a high peak current and low overpotential toward the reduction of H2O2. The relevant detection limit of H2O2 is ∼0.2 μM with a wide linear range from 0.5 μM to 3.475 mM, displaying a much higher sensitivity (459 ± 3 mA M(-1) cm(-2), n = 5) than that of Pt nanoparticles or graphene modified electrode. This novel biosensor can measure the H2O2 release from living cells because of its low detection limit, wide linear range, and higher sensitivity.


Determinants of Influenza and Pertussis Vaccination Uptake in Pregnancy: A Multicenter Questionnaire Study of Pregnant Women and Healthcare Professionals.
Uptake rates of antenatal vaccination remain suboptimal. Our aims were to determine (1) the acceptability of routine vaccination among pregnant women, (2) the confidence of maternity healthcare professionals (HCPs) discussing vaccination and (3) HCP opinion regarding the optimum healthcare site for vaccine administration. Separate questionnaires for pregnant women and HCPs were distributed within 4 national health service (NHS) trusts in South England (July 2017 to January 2018). Responses from 314 pregnant women and 204 HCPs (18% obstetricians, 75% midwives, 7% unidentified) were analyzed. Previous/intended uptake of influenza and pertussis vaccination was 78% and 92%, respectively. The commonest reason for declining vaccination was feared side effects for their child. White British women (79%) were significantly more accepting of influenza [85% vs. 61%; odds ratio (OR) 3.25; 95% confidence interval [CI], 1.67-6.32] and pertussis vaccination (96% vs. 83%; OR 4.83; 95% CI: 1.77-13.19) compared with nonwhite British women. Among HCPs, 25% were slightly or not at all confident discussing vaccination. Obstetricians felt significantly more confident discussing pertussis vaccination than midwives (68% vs. 55% were very/moderately confident; OR 2.05; 95% CI: 1.02-4.12). Among HCPs, 53%, 25% and 16% thought vaccines should be administered in primary care (general practice), community midwifery and in hospital, respectively. Misconceptions exist regarding safety/efficacy of antenatal vaccination, and framing information towards the child's safety may increase uptake. Education of HCPs is essential, and vaccine promotion should be incorporated into routine antenatal care, with an emphasis on women from ethnic minorities. Administration of vaccines in primary care presents logistical barriers; however, support for alternative sites appears low among HCPs.


Distortions of the posterior surface in optical coherence tomography images of the isolated crystalline lens: effect of the lens index gradient.
We quantify the posterior surface distortions in optical coherence tomography (OCT) images of isolated crystalline lenses. The posterior radius of curvature and asphericity obtained from OCT images acquired with the beam incident first on the anterior, and then the posterior, surface were compared. The results were compared with predictions of a ray-tracing model which includes the index gradient. The results show that the error in the radius of curvature is within the measurement reproducibility and that it can be corrected by assuming a uniform refractive index. However, accurate asphericity values require a correction algorithm that takes into account the gradient.


Forget-me-some: General versus special purpose models in a hierarchical probabilistic task.
Humans build models of their environments and act according to what they have learnt. In simple experimental environments, such model-based behaviour is often well accounted for as if subjects are ideal Bayesian observers. However, more complex probabilistic tasks require more sophisticated forms of inference that are sufficiently computationally and statistically taxing as to demand approximation. Here, we study properties of two approximation schemes in the context of a serial reaction time task in which stimuli were generated from a hierarchical Markov chain. One, pre-existing, scheme was a generically powerful variational method for hierarchical inference which has recently become popular as an account of psychological and neural data across a wide swathe of probabilistic tasks. A second, novel, scheme was more specifically tailored to the task at hand. We show that the latter model fit significantly better than the former. This suggests that our subjects were sensitive to many of the particular constraints of a complex behavioural task. Further, the tailored model provided a different perspective on the effects of cholinergic manipulations in the task. Neither model fit the behaviour on more complex contingencies that competently. These results illustrate the benefits and challenges that come with the general and special purpose modelling approaches and raise important questions of how they can advance our current understanding of learning mechanisms in the brain.


Adaptation of health systems to climate-related migration in Sub-Saharan Africa: Closing the gap.
Health systems worldwide need to be adapted to cope with growing numbers of migrants and to climate-exacerbated morbidity. Heatwaves, water stress, desertification, flooding, and sea level rise are environmental stressors that increase morbidity, mortality, and poor mental health in Sub-Saharan Africa. While most migration is intra-African, climate change is also affecting migration patterns outside the continent. To tackle the health challenges induced by these events, such as infectious diseases and malnutrition, health care providers in Sub-Saharan Africa and in receiving countries in Europe must adapt their systems to provide appropriate health services to these communities. While health systems differ greatly across the global north and south, adaptation measures are similar and should be integrated. We present recommendations for adaptation of health systems to climate-related migration, including strengthening health systems, providing access to healthcare, culturally-appropriate services, policy-oriented research and training, and inter-sectoral collaboration.


Recent developments in smart antibacterial surfaces to inhibit biofilm formation and bacterial infections.
Since their development over 70 years, antibiotics are still the most effective strategy to treat bacterial biofilms and infections. However, the overuse of antibiotics in human healthcare and industrial applications has resulted in the development of serious antibiotic-resistant bacteria. Therefore, alternative ways to prevent bacteria attachment and biofilm formation are urgently needed. Recently, mediated biofilm formation processes and smart antibacterial surfaces have emerged as promising strategies to prevent and treat bacterial infections. This review discusses the recent progress in biofilm interference and smart antibacterial surfaces. Smart antibacterial and anti-biofilm surfaces should be responsive to the bacterial infection environment, switchable between various antibacterial functions and have a special bio-inspired structure and function. The major topics discussed are: (i) smart anti-biofilm surfaces via the prevention of biofilm formation or promoting mature biofilm dissolution, (ii) smart materials for reversible killing and/or release of bacteria, (iii) smart surfaces responsive to bacterial infection microenvironments or external stimuli and (iv) bio-inspired surfaces with antifouling and bactericidal properties.


Spinal cord trauma in a cat caused by ingestion of a splinter.
A 5-month-old male Abyssinian presented with right hemiplegia. Cervical radiographs, haematology and serum biochemistry were normal. A foreign body was identified on computed tomography (CT) and magnetic resonance imaging (MRI). Removal of the foreign body was carried out via a dorsal approach between the occipital bone and the C1 vertebral body using intra-operative CT. No complications were encountered. Thirty days after surgery, the cat was ambulatory.


Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus.
Human genetic variation is a determinant of recovery from acute hepatitis C virus (HCV) infection; however, to date, single-nucleotide polymorphisms (SNPs) in only a limited number of genes have been studied with respect to HCV clearance. We determined whether SNPs in 112 selected immune response genes are important for HCV clearance, by genotyping 1536 SNPs in a cohort of 343 persons with natural HCV clearance and 547 persons with HCV persistence. PLINK (version 1.05) and Haploview (version 4.1) software packages were used to perform association, permutation, and haplotype analyses stratified by African American and European American race. Of the 1536 SNPs tested, 1426 (92.8%) were successfully genotyped. In African Americans, we identified 18 SNPs located in 11 gene regions that were associated with HCV infection outcome (empirical P value, < .01). In European Americans, there were 20 SNPs located in 8 gene regions associated with HCV infection outcome. Four of the gene regions studied (TNFSF18, TANK, HAVCR1, and IL18BP) contained SNPs for which the empirical P value was <.01 in both of the race groups. In this large-scale analysis of 1426 genotyped SNPs in 112 candidate genes, we identified 4 gene regions that are likely candidates for a role in HCV clearance or persistence in both African Americans and European Americans.


Treatment plan optimization incorporating respiratory motion.
Similar to conventional conformal radiotherapy, during lung tomotherapy, a motion margin has to be set for respiratory motion. Consequently, large volume of normal tissue is irradiated by intensive radiation. To solve this problem, we have developed a new motion mitigation method by incorporating target motion into treatment optimization. In this method, the delivery-breathing correlation is determined prior to treatment plan optimization. Beamlets are calculated by using the CT images at the corresponding breathing phases from a dynamic (four-dimensional) image sequence. With the displacement vector fields at different breathing phases, a set of deformed beamlets is obtained by mapping the dose to the primary phase. Optimization incorporating motion is then performed by using the deformed beamlets obtained by dose mapping. During treatment delivery, the same breathing-delivery correlation can be reproduced by instructing the patient to breathe following a visually displayed guiding cycle. This method was tested using a computer-simulated deformable phantom and a real lung case. Results show that treatment optimization incorporating motion achieved similar high dose conformality on a mobile target compared with static delivery. The residual motion effects due to imperfect breathing tracking were also analyzed.


Extracapsular cataract extraction with posterior chamber lens implantation in capsular glaucoma.
To evaluate intraocular pressure (IOP) control after extracapsular cataract extraction (ECCE) with posterior chamber intraocular lens (PCIOL) implantation in patients with capsular glaucoma (CG) and coexisting cataract. This prospective study included 20 patients (20 eyes) having CG and cataract whose IOPs were under 22 mm Hg and controlled with antiglaucoma medication. All patients had ECCE with PCIOL implantation and the follow-up period was at least 18 months. IOP was measured postoperatively at 3, 6, 9, 12 and 18 months and compared with preoperative IOP. Following the cataract extraction, PCIOL implantation produced a statistically significant reduction in IOP at all time points compared with the preoperative IOP during the study period (p < 0. 001). The mean preoperative IOP was 18.25 +/- 1.83 mm Hg; postoperatively at 1 month, it was 13.45 +/- 2.06 mm Hg; at 3 months 14.80 +/- 2.50 mm Hg; at 6 months 15.35 +/- 1.27 mm Hg, at 12 months 14.85 +/- 1.87 mm Hg and at 18 months 15.15 +/- 1.42 mm Hg (p < 0. 0008). The mean reduction in IOP was 16.98% from baseline at 18 months postoperatively. The mean number of antiglaucoma medication was reduced from 1.35/eye preoperatively to 0.60/eye postoperatively at 18 months (p < 0.0007). The result of our study revealed that ECCE with PCIOL implantation may be a reliable choice in controlling IOP in patients with CG.


Complete temporal pulse characterization based on phase reconstruction using optical ultrafast differentiation (PROUD).
A simple and general technique for recovering the phase profile of a given optical waveform from temporal intensity measurements is introduced and experimentally demonstrated. The proposed method involves the measurement of the temporal intensity profiles at the input and output of a linear optical time differentiator. The signal phase profile can be unambiguously recovered from these intensity measurements using a direct and noniterative algorithm. Given that ultrafast optical differentiators can be readily implemented in all-fiber or free-space platforms, the proposed technique could be applied over time waveforms with durations ranging from the subpicosecond to the nanosecond regime.


Microbial players involved in the decline of filamentous and colonial cyanobacterial blooms with a focus on fungal parasitism.
In the forthcoming decades, it is widely believed that the dominance of colonial and filamentous bloom-forming cyanobacteria (e.g. Microcystis, Planktothrix, Anabaena and Cylindrospermopsis) will increase in freshwater systems as a combined result of anthropogenic nutrient input into freshwater bodies and climate change. While the physicochemical parameters controlling bloom dynamics are well known, the role of biotic factors remains comparatively poorly studied. Morphology and toxicity often - but not always - limit the availability of cyanobacteria to filter feeding zooplankton (e.g. cladocerans). Filamentous and colonial cyanobacteria are widely regarded as trophic dead-ends mostly inedible for zooplankton, but substantial evidence shows that some grazers (e.g. copepods) can bypass this size constraint by breaking down filaments, making the bloom biomass available to other zooplankton species. A wide range of algicidal bacteria (mostly from the Alcaligenes, Flavobacterium/Cytophaga group and Pseudomonas) and viruses (Podoviridae, Siphoviridae and Myoviridae) may also contribute to bloom control, via their lytic activity underpinned by a diverse array of mechanisms. Fungal parasitism by the Chytridiomycota remains the least studied. While each of these biotic factors has traditionally been studied in isolation, emerging research consistently point to complex interwoven interactions between biotic and environmental factors.


History of 7,093 patients with lower urinary tract symptoms related to benign prostatic hyperplasia treated with alfuzosin in general practice up to 3 years.
As we have previously published 4 articles reporting the treatment of 7,093 clinical benign prostatic hyperplasia (BPH) patients treated with alfuzosin in a 3-month open-labelled study which was subsequently extended to 12, 24, and 36 months, the objective of this article is to provide additional data on dropouts, acute urinary retention (AUR), progression to surgery, and safety under the natural conditions of general practice, paying special attention to the predictive factors. 7,093 patients were initially enrolled by 1,812 centers for up to 3 months. Subsequently 1,508, 1,325, and 812 general practitioners agreed to extend the study up to 12, 24, and 36 months, respectively, which corresponds to 4 patient populations. The baseline symptom profile of patients who completed the study was identical to that of patients who dropped out (because the center resigned or during treatment). In the 4 patient populations, the percentage of patients per month who dropped out, experienced adverse effects, AUR and surgery were 0. 6-1.6, 0.1-0.5, 0.01-0.03, and 0.1-0.3%, respectively. The classes of symptom severity were not predictive for dropouts: 3.5, 12.6, 20, and 14.3% of the severe patients dropped out during treatment versus 4.2, 13.7, 22.9, and 14.0% of the moderate patients who dropped out up to 3, 12, 24, and 36 months, respectively. Safety was satisfactory regarding the number of adverse events and blood pressure measurement. No retrograde ejaculation was reported. Under the natural conditions of general practice the reasons for dropping out were not correlated with symptom severity.


Adherence to a low-fat vs. low-carbohydrate diet differs by insulin resistance status.
Previous research shows diminished weight loss success in insulin-resistant (IR) women assigned to a low-fat (LF) diet compared to those assigned to a low-carbohydrate (LC) diet. These secondary analyses examined the relationship between insulin-resistance status and dietary adherence to either a LF-diet or LC-diet among 81 free-living, overweight/obese women [age = 41.9 ± 5.7 years; body mass index (BMI) = 32.6 ± 3.6 kg/m(2)]. This study found differential adherence by insulin-resistance status only to a LF-diet, not a LC-diet. IR participants were less likely to adhere and lose weight on a LF-diet compared to insulin-sensitive (IS) participants assigned to the same diet. There were no significant differences between IR and IS participants assigned to LC-diet in relative adherence or weight loss. These results suggest that insulin resistance status may affect dietary adherence to weight loss diets, resulting in higher recidivism and diminished weight loss success of IR participants advised to follow LF-diets for weight loss.


Permutation testing in the presence of polygenic variation.
This article discusses problems with and solutions to performing valid permutation tests for quantitative trait loci in the presence of polygenic effects. Although permutation testing is a popular approach for determining statistical significance of a test statistic with an unknown distribution--for instance, the maximum of multiple correlated statistics or some omnibus test statistic for a gene, gene-set, or pathway--naive application of permutations may result in an invalid test. The risk of performing an invalid permutation test is particularly acute in complex trait mapping where polygenicity may combine with a structured population resulting from the presence of families, cryptic relatedness, admixture, or population stratification. I give both analytical derivations and a conceptual understanding of why typical permutation procedures fail and suggest an alternative permutation-based algorithm, MVNpermute, that succeeds. In particular, I examine the case where a linear mixed model is used to analyze a quantitative trait and show that both phenotype and genotype permutations may result in an invalid permutation test. I provide a formula that predicts the amount of inflation of the type 1 error rate depending on the degree of misspecification of the covariance structure of the polygenic effect and the heritability of the trait. I validate this formula by doing simulations, showing that the permutation distribution matches the theoretical expectation, and that my suggested permutation-based test obtains the correct null distribution. Finally, I discuss situations where naive permutations of the phenotype or genotype are valid and the applicability of the results to other test statistics.


Reinforcement learning neural-network-based controller for nonlinear discrete-time systems with input constraints.
A novel adaptive-critic-based neural network (NN) controller in discrete time is designed to deliver a desired tracking performance for a class of nonlinear systems in the presence of actuator constraints. The constraints of the actuator are treated in the controller design as the saturation nonlinearity. The adaptive critic NN controller architecture based on state feedback includes two NNs: the critic NN is used to approximate the "strategic" utility function, whereas the action NN is employed to minimize both the strategic utility function and the unknown nonlinear dynamic estimation errors. The critic and action NN weight updates are derived by minimizing certain quadratic performance indexes. Using the Lyapunov approach and with novel weight updates, the uniformly ultimate boundedness of the closed-loop tracking error and weight estimates is shown in the presence of NN approximation errors and bounded unknown disturbances. The proposed NN controller works in the presence of multiple nonlinearities, unlike other schemes that normally approximate one nonlinearity. Moreover, the adaptive critic NN controller does not require an explicit offline training phase, and the NN weights can be initialized at zero or random. Simulation results justify the theoretical analysis.


Developmental Ethanol Exposure Causes Reduced Feeding and Reveals a Critical Role for Neuropeptide F in Survival.
Food intake is necessary for survival, and natural reward circuitry has evolved to help ensure that animals ingest sufficient food to maintain development, growth, and survival. Drugs of abuse, including alcohol, co-opt the natural reward circuitry in the brain, and this is a major factor in the reinforcement of drug behaviors leading to addiction. At the junction of these two aspects of reward are alterations in feeding behavior due to alcohol consumption. In particular, developmental alcohol exposure (DAE) results in a collection of physical and neurobehavioral disorders collectively referred to as Fetal Alcohol Spectrum Disorder (FASD). The deleterious effects of DAE include intellectual disabilities and other neurobehavioral changes, including altered feeding behaviors. Here we use Drosophila melanogaster as a genetic model organism to study the effects of DAE on feeding behavior and the expression and function of Neuropeptide F. We show that addition of a defined concentration of ethanol to food leads to reduced feeding at all stages of development. Further, genetic conditions that reduce or eliminate NPF signaling combine with ethanol exposure to further reduce feeding, and the distribution of NPF is altered in the brains of ethanol-supplemented larvae. Most strikingly, we find that the vast majority of flies with a null mutation in the NPF receptor die early in larval development when reared in ethanol, and provide evidence that this lethality is due to voluntary starvation. Collectively, we find a critical role for NPF signaling in protecting against altered feeding behavior induced by developmental ethanol exposure.


Abdominal compartment syndrome and open abdomen management with negative pressure devices.
Abdominal compartment syndrome (ACS) is defined as an increase of intra-abdominal pressure (IAH) to values higher than 20 mmHg, associated with reduced perfusion and organ dysfunction. There is a classification of open abdomen which stratifies patients according to the natural history of improvement or clinical deterioration. The aim of treatment is to maintain the open abdomen at the lowest level and to prevent progression to a more complex level. Surgical treatment essentially consists in abdominal decompression by leaving the abdomen open. Analysis of the literature shows that negative pressure increases the rate of primary fascial closure; entero-cutaneous fistulas are seen in a minority of cases, without seeming consequence of the application of the dressing. Open abdomen management consists of three treatment stages: acute (24-48 hours), intermediate (from 48 hours to 10 days) and late or reconstruction (from 10 days to the final closure). It's important to recognize patients at risk of IAH and the first signs of ACS and intervene early with abdominal decompression if this will establish itself. Management of the open abdomen is now facilitated by negative pressure devices, which positively affect the morbidity and mortality of patients with ACS.


Introducing the National Headache Fellowship Opportunities Website.
To build a national Headache Medicine fellowship opportunities website that promotes a unified application timeline and a more transparent application process. In July 2019, the Consortium of Academic Headache Program Directors unanimously accepted the recommendations of the American Academy of Neurology Fellowship Application Timing Position Statement. To implement the unified application timeline, the American Headache Society agreed to host a fellowship opportunities website with information on the application process and resources for each fellowship program. We designed a main landing page that features the unified timeline for applications and offers. The page also features icons for all participating US fellowship programs (identified using the United Council for Neurologic Subspecialties certification database). The icons serve as links to each fellowship program's individual webpage. We sent an electronic form to each fellowship program director, asking them to submit program information to be included on each fellowship program's individual webpage. Key contents on each program webpage include an image of the program, brief program description, names of applicants who have filled positions, and open positions. Each institution webpage also includes an electronic form that allows applicants to directly send their name, contact, and a brief message to the program director. We launched the website on May 15, 2020. As of June 19, 2020, the website featured 24 participating headache fellowship programs, including 5 pediatric programs and 19 adult training programs, from all regions of the US. The website serves as a central resource for Headache Medicine fellowship applicants and promotes a unified application timeline and a more transparent application process.


SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.
Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.


A randomized controlled trial on 2 simulation-based training methods in radiology: effects on radiologic technology student skill in assessing image quality.
A simulator for virtual radiographic examinations was developed. In the virtual environment, the user can perform and analyze radiographic examinations of patient models without the use of ionizing radiation. We investigated if this simulation technique could improve education of radiology technology students. We compared student performance in the assessment of radiographic image quality after training with a conventional manikin or with the virtual radiography simulator. A randomized controlled experimental study involving 31 first-year radiology technology students was performed. It was organized in 4 phases as follows: (I) randomization to control or experimental group based on the results of an anatomy examination; (II) proficiency testing before training; (III) intervention (control group, exposure and analysis of radiographic images of the cervical spine of a manikin; experimental group, exposure and analysis of the cervical spine images in the virtual radiography simulator); and (IV) proficiency testing after training. The experimental group showed significantly higher scores after training compared with those before training (P < 0.01). A linear mixed-effect analysis revealed a significant difference between the control and experimental groups regarding proficiency change (P = 0.01). Virtual radiographic simulation is an effective tool for learning image quality assessment. Simulation can therefore be a valuable adjunct to traditional educational methods and reduce exposure to x-rays and tutoring time.


Review: Assessment of completeness of reporting in intervention studies using livestock: an example from pain mitigation interventions in neonatal piglets.
Accurate and complete reporting of study methods, results and interpretation are essential components for any scientific process, allowing end-users to evaluate the internal and external validity of a study. When animals are used in research, excellence in reporting is expected as a matter of continued ethical acceptability of animal use in the sciences. Our primary objective was to assess completeness of reporting for a series of studies relevant to mitigation of pain in neonatal piglets undergoing routine management procedures. Our second objective was to illustrate how authors can report the items in the Reporting guidElines For randomized controLled trials for livEstoCk and food safety (REFLECT) statement using examples from the animal welfare science literature. A total of 52 studies from 40 articles were evaluated using a modified REFLECT statement. No single study reported all REFLECT checklist items. Seven studies reported specific objectives with testable hypotheses. Six studies identified primary or secondary outcomes. Randomization and blinding were considered to be partially reported in 21 and 18 studies, respectively. No studies reported the rationale for sample sizes. Several studies failed to report key design features such as units for measurement, means, standard deviations, standard errors for continuous outcomes or comparative characteristics for categorical outcomes expressed as either rates or proportions. In the discipline of animal welfare science, authors, reviewers and editors are encouraged to use available reporting guidelines to ensure that scientific methods and results are adequately described and free of misrepresentations and inaccuracies. Complete and accurate reporting increases the ability to apply the results of studies to the decision-making process and prevent wastage of financial and animal resources.


Novel Self-assembled Organic Nanoprobe for Molecular Imaging and Treatment of Gram-positive Bacterial Infection.
Background: Increasing bacterial infections as well as a rise in bacterial resistance call for the development of novel and safe antimicrobial agents without inducing bacterial resistance. Nanoparticles (NPs) present some advantages in treating bacterial infections and provide an alternative strategy to discover new antibiotics. Here, we report the development of novel self-assembled fluorescent organic nanoparticles (FONs) with excellent antibacterial efficacy and good biocompatibility. Methods: Self-assembly of 1-(12-(pyridin-1-ium-1-yl)dodecyl)-4-(1,4,5-triphenyl-1H-imidazol-2-yl)pyridin-1-ium (TPIP) in aqueous solution was investigated using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The bacteria were imaged under a laser scanning confocal microscope. We evaluated the antibacterial efficacy of TPIP-FONsin vitro using sugar plate test. The antimicrobial mechanism was explored by SEM. The biocompatibility of the nanoparticles was examined using cytotoxicity test, hemolysis assay, and histological staining. We further tested the antibacterial efficacy of TPIP-FONsin vivo using the S. aureus-infected rats. Results: In aqueous solution, TPIP could self-assemble into nanoparticles (TPIP-FONs) with characteristic aggregation-induced emission (AIE). TPIP-FONs could simultaneously image gram-positive bacteria without the washing process. In vitro antimicrobial activity suggested that TPIP-FONs had excellent antibacterial activity against S. aureus (MIC = 2.0 µg mL-1). Furthermore, TPIP-FONs exhibited intrinsic biocompatibility with mammalian cells, in particular, red blood cells. In vivo studies further demonstrated that TPIP-FONs had excellent antibacterial efficacy and significantly reduced bacterial load in the infectious sites. Conclusion: The integrated design of bacterial imaging and antibacterial functions in the self-assembled small molecules provides a promising strategy for the development of novel antimicrobial nanomaterials.


Surface-stabilized nonferromagnetic ordering of a layered ferromagnetic manganite.
An outstanding question regarding the probing or possible device applications of correlated electronic materials (CEMs) with layered structure is the extent to which their bulk and surface properties differ or not. The broken translational symmetry at the surface can lead to distinct functionality due to the charge, lattice, orbital, and spin coupling. Here we report on the case of bilayered manganites with hole doping levels corresponding to bulk ferromagnetic order. We find that, although the hole doping level is measured to be the same as in the bulk, the surface layer is not ferromagnetic. Further, our low-energy electron diffraction and x-ray measurements show that there is a c-axis collapse in the outermost layer. Bulk theoretical calculations reveal that, even at fixed doping level, the relaxation of the Jahn-Teller distortion at the surface is consistent with the stabilization of an A-type antiferromagnetic state.


Markers of hydration status in a 3-day trail running event.
To examine the relationships between changes in static prestage and poststage measures of commonly used hematological and urinary markers of hydration status and body mass (BM) in participants in a 3-day trail run. Descriptive field study. Three Cranes Challenge trail run, South Africa. Twenty (6 men and 14 women) amateur runners. In stage 1 (S1), 29.3 km and 37.9 km in stage 2 (S2), and 27.8 km in stage 3 (S3). Prestage and poststage individual changes in serum osmolality (S osm), serum sodium (s[Na]), plasma volume (PV), urine osmolality (U osm), urine specific gravity (U sg), and BM. Consistently, mild environmental conditions were experienced on the 3 days of the race (ambient temperature range, 11.5-22.8°C). Mean S osm increased by 5 ± 6, 7 ± 9, and 3 ± 4 mOsm/kg during S1, S2, and S3, respectively, and returned to baseline pre-S2 and pre-S3. The correlation between individual prestage and poststage changes in S osm, Uosm, and U sg (n = 60) were nonsignificant (P > 0.05; r = 0.0047, r = 0.0074). There was a significant, but relatively low correlation between changes in S osm and percentage reduction in BM (r = 0.35; P < 0.01) and prechange and postchange in s[Na] (r = 0.45; P < 0.001). Serum osmality values confirm appropriate interstage rehydration. Changes in U osm, U sg, BM, s[Na+], and PV are not closely related to changes in S osm as markers of hydration assessment in multiday events in which single static measures of hydration status are required. These measures of hydration station status are therefore not recommended in this field setting.


The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein.
The Nogo-66 receptor (NgR1) is a promiscuous receptor for the myelin inhibitory proteins Nogo/Nogo-66, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp). NgR1, an axonal glycoprotein, is the founding member of a protein family composed of the structurally related molecules NgR1, NgR2, and NgR3. Here we show that NgR2 is a novel receptor for MAG and acts selectively to mediate MAG inhibitory responses. MAG binds NgR2 directly and with greater affinity than NgR1. In neurons NgR1 and NgR2 support MAG binding in a sialic acid-dependent Vibrio cholerae neuraminidase-sensitive manner. Forced expression of NgR2 is sufficient to impart MAG inhibition to neonatal sensory neurons. Soluble NgR2 has MAG antagonistic capacity and promotes neuronal growth on MAG and CNS myelin substrate in vitro. Structural studies have revealed that the NgR2 leucine-rich repeat cluster and the NgR2 "unique" domain are necessary for high-affinity MAG binding. Consistent with its role as a neuronal MAG receptor, NgR2 is an axonassociated glycoprotein. In postnatal brain NgR1 and NgR2 are strongly enriched in Triton X-100-insoluble lipid rafts. Neural expression studies of NgR1 and NgR2 have revealed broad and overlapping, yet distinct, distribution in the mature CNS. Taken together, our studies identify NgRs as a family of receptors (or components of receptors) for myelin inhibitors and provide insights into how interactions between MAG and members of the Nogo receptor family function to coordinate myelin inhibitory responses.


Responses to Mineral Supplementation and Salmon Lice (Lepeophtheirus salmonis) Infestation in Skin Layers of Atlantic Salmon (Salmo salar L.).
The crustacean ectoparasite salmon louse (Lepeophtheirus salmonis), which severely affects Atlantic salmon health and welfare is one of the main problems of commercial aquaculture. In the present study, fish were fed a diet supplemented with extra minerals through the inclusion of a commercial additive (Biofeed Forte Salmon), substituting wheat in the control diet, before experimental infestation with salmon lice. Lice counts reduced with time but with no apparent effect of the diets. Further, fish fed the mineral diet had an overall higher number of blue (acidic) mucous cells, while the ratio of purple mucous cells was higher in the mineral diet. The transcriptional response in skin was enhanced at 7 dpc (copepodite life stage) in fish fed the mineral diet including immune and stress responses, while at 21 dpc (pre-adult life stage), the difference disappeared, or reversed with stronger induction in the control diet. Overall, 9.3% of the genes affected with lice also responded to the feed, with marked differences in outer (scale + epidermis) and inner (dermis) skin layers. A comparison of transcriptome data with five datasets from previous trials revealed common features and gene markers of responses to lice, stress, and mechanically induced wounds. Results suggested a prevalence of generic responses in wounded skin and lice-infected salmon.


Trends in concussion incidence in high school sports: a prospective 11-year study.
Understanding the risk and trends of sports-related concussion among 12 scholastic sports may contribute to concussion detection, treatment, and prevention. To examine the incidence and relative risk of concussion in 12 high school boys' and girls' sports between academic years 1997-1998 and 2007-2008. Descriptive epidemiology study. Data were prospectively gathered for 25 schools in a large public high school system. All schools used an electronic medical record-keeping program. A certified athletic trainer was on-site for games and practices and electronically recorded all injuries daily. In sum, 2651 concussions were observed in 10 926 892 athlete-exposures, with an incidence rate of 0.24 per 1000. Boys' sports accounted for 53% of athlete-exposures and 75% of all concussions. Football accounted for more than half of all concussions, and it had the highest incidence rate (0.60). Girls' soccer had the most concussions among the girls' sports and the second-highest incidence rate of all 12 sports (0.35). Concussion rate increased 4.2-fold (95% confidence interval, 3.4-5.2) over the 11 years (15.5% annual increase). In similar boys' and girls' sports (baseball/softball, basketball, and soccer), girls had roughly twice the concussion risk of boys. Concussion rate increased over time in all 12 sports. Although the collision sports of football and boys' lacrosse had the highest number of concussions and football the highest concussion rate, concussion occurred in all other sports and was observed in girls' sports at rates similar to or higher than those of boys' sports. The increase over time in all sports may reflect actual increased occurrence or greater coding sensitivity with widely disseminated guidance on concussion detection and treatment. The high-participation collision sports of football and boys' lacrosse warrant continued vigilance, but the findings suggest that focus on concussion detection, treatment, and prevention should not be limited to those sports traditionally associated with concussion risk.


Impaired Functional Connectivity Unmasked by Simple Repetitive Motor Task in Early Relapsing-Remitting Multiple Sclerosis.
Resting brain activity can be modulated by motor tasks to adapt to function. In multiple sclerosis (MS) patients, altered resting-state functional connectivity (RS-FC) has been reported and associated with impaired function and disability; little is known on how RS-FC is modulated by a simple repetitive motor task. To assess changes in RS-FC in early relapsing-remitting MS (RRMS) patients associated with repetitive thumb flexions (RTFs). A total of 20 right-handed patients with early RRMS and 14 healthy controls underwent a resting functional magnetic resonance imaging (fMRI) scan, before and after 25 minutes of alternate 30-s blocks of right RTF and rest. Dual-regression analysis of resting fMRI data followed the independent component analysis. Individual spatial maps of coherence between brain areas for 2 networks of interest, sensorimotor and cerebellar, were compared at the group level and correlated with measures of both clinical impairment and brain damage. Significant RTF-induced differences in RS-FC were observed between groups in the cerebellar network because of increased RS-FC in patients but not in controls. In the sensorimotor network, the RS-FC after RTF increased in both groups, with no significant between-group differences. The sensorimotor and the cerebellar RS-FC were intercorrelated only in patients and only after the RTF. The sensorimotor RS-FC increase in patients correlated with structural MRI alterations. Our study unmasked RS-FC changes of motor-related networks occurring after a simple repetitive motor task in early RRMS patients only. Evaluation of altered RSN dynamics might prove useful for anticipating neuroplasticity and for MRI-informed neurorehabilitation.


Chediak-Higashi syndrome.
Chediak-Higashi syndrome, a rare autosomal recessive disorder, was described over 50 years ago. Patients show hypopigmentation, recurrent infections, mild coagulation defects and varying neurologic problems. Treatment is bone marrow transplant, which is effective in treating the hematologic and immune defects, however the neurologic problems persist. The CHS1/LYST gene was identified over 10 years ago and homologous CHS1/LYST genes are present in all eukaryotes. This review will discuss the advances made in understanding the clinical aspects of the syndrome and the function of CHS1/LYST/Beige. Clinical reports of Chediak-Higashi syndrome have identified mutations throughout the CHS1/LYST gene. The nature of the mutation can be a predictor of the severity of the disease. Over the past decade the CHS1/LYST family of proteins has been analyzed using model organisms, two-hybrid analysis, overexpression phenotypes and dominant negatives. These studies suggest that the CHS1/LYST protein is involved in either vesicle fusion or fission. Although CHS is a rare disease, the Chediak-like family of proteins is providing insight into the regulation of vesicle trafficking. Understanding the basic mechanisms that govern vesicle trafficking will provide essential information regarding how loss of CHS1/LYST affects hematologic, immunologic and neurologic processes.


A multifaceted biomimetic interface to improve the longevity of orthopedic implants.
The rise of additive manufacturing has provided a paradigm shift in the fabrication of precise, patient-specific implants that replicate the physical properties of native bone. However, eliciting an optimal biological response from such materials for rapid bone integration remains a challenge. Here we propose for the first time a one-step ion-assisted plasma polymerization process to create bio-functional 3D printed titanium (Ti) implants that offer rapid bone integration. Using selective laser melting, porous Ti implants with enhanced bone-mimicking mechanical properties were fabricated. The implants were functionalized uniformly with a highly reactive, radical-rich polymeric coating generated using a unique combination of plasma polymerization and plasma immersion ion implantation. We demonstrated the performance of such activated Ti implants with a focus on the coating's homogeneity, stability, and biological functionality. It was shown that the optimized coating was highly robust and possessed superb physico-chemical stability in a corrosive physiological solution. The plasma activated coating was cytocompatible and non-immunogenic; and through its high reactivity, it allowed for easy, one-step covalent immobilization of functional biomolecules in the absence of solvents or chemicals. The activated Ti implants bio-functionalized with bone morphogenetic protein 2 (BMP-2) showed a reduced protein desorption and a more sustained osteoblast response both in vitro and in vivo compared to implants modified through conventional physisorption of BMP-2. The versatile new approach presented here will enable the development of bio-functionalized additively manufactured implants that are patient-specific and offer improved integration with host tissue. STATEMENT OF SIGNIFICANCE: Additive manufacturing has revolutionized the fabrication of patient-specific orthopedic implants. Although such 3D printed implants can show desirable mechanical and mass transport properties, they often require surface bio-functionalities to enable control over the biological response. Surface covalent immobilization of bioactive molecules is a viable approach to achieve this. Here we report the development of additively manufactured titanium implants that precisely replicate the physical properties of native bone and are bio-functionalized in a simple, reagent-free step. Our results show that covalent attachment of bone-related growth factors through ion-assisted plasma polymerized interlayers circumvents their desorption in physiological solution and significantly improves the bone induction by the implants both in vitro and in vivo.


The Economic Impact of Space Weather: Where Do We Stand?
Space weather describes the way in which the Sun, and conditions in space more generally, impact human activity and technology both in space and on the ground. It is now well understood that space weather represents a significant threat to infrastructure resilience, and is a source of risk that is wide-ranging in its impact and the pathways by which this impact may occur. Although space weather is growing rapidly as a field, work rigorously assessing the overall economic cost of space weather appears to be in its infancy. Here, we provide an initial literature review to gather and assess the quality of any published assessments of space weather impacts and socioeconomic studies. Generally speaking, there is a good volume of scientific peer-reviewed literature detailing the likelihood and statistics of different types of space weather phenomena. These phenomena all typically exhibit "power-law" behavior in their severity. The literature on documented impacts is not as extensive, with many case studies, but few statistical studies. The literature on the economic impacts of space weather is rather sparse and not as well developed when compared to the other sections, most probably due to the somewhat limited data that are available from end-users. The major risk is attached to power distribution systems and there is disagreement as to the severity of the technological footprint. This strongly controls the economic impact. Consequently, urgent work is required to better quantify the risk of future space weather events.


Compound stutter in D2S1338 and D12S391.
Compound repeats provide a testing ground for evaluating hypotheses on the causes and consequences of stutter. As compound repeats have two repeating motifs, each motif may produce stutter variants; thus as the repeat within the locus is compound, so is the resultant stutter. Further, the rates of stutter formation between these motifs may not be independent. This lack of independence may complicate modeling strategies, thus contributing to the challenges of mixture interpretation that rely on nucleotide sequence. This study evaluates compound stutter in two STR loci: D2S1338 and D12S391. The effects of flanking variation, as well as possible interactions between the two different uninterrupted stretches (US) and their respective stutter variants are assessed. Multivariate multiple linear regression (MMLR) was used to show that, as with simple repeats, the rate of stutter product formation of a particular repeating motif is not solely a function of the US of that repeat. The nucleotides adjacent to the repeating motif also appear to influence the rate of stutter formation of that motif, with those nucleotides sometimes including the other motif. MMLR was used to estimate the size of these effects and to construct an example of a two-dimensional (thus, a compound) stutter prediction. This example may merit further investigation in the application of massively parallel sequencing data to mixture interpretation and probabilistic genotyping.


Effects of walnut consumption on blood lipids and other cardiovascular risk factors: an updated meta-analysis and systematic review of controlled trials.
Intervention studies suggest that incorporating walnuts into the diet may improve blood lipids without promoting weight gain. We conducted a systematic review and meta-analysis of controlled trials evaluating the effects of walnut consumption on blood lipids and other cardiovascular risk factors. We conducted a comprehensive search of PubMed and EMBASE databases (from database inception to January 2018) of clinical trials comparing walnut-enriched diets with control diets. We performed random-effects meta-analyses comparing walnut-enriched and control diets for changes in pre-post intervention in blood lipids (mmol/L), apolipoproteins (mg/dL), body weight (kg), and blood pressure (mm Hg). Twenty-six clinical trials with a total of 1059 participants were included. The following weighted mean differences (WMDs) in reductions were obtained for walnut-enriched diets compared with control groups: -6.99 mg/dL (95% CI: -9.39, -4.58 mg/dL; P < 0.001) (3.25% greater reduction) for total blood cholesterol (TC) and -5.51 mg/dL (95% CI: -7.72, -3.29 mg/dL; P < 0.001) (3.73% greater reduction) for low-density lipoprotein (LDL) cholesterol. Triglyceride concentrations were also reduced in walnut-enriched diets compared with control [WMD = -4.69 (95% CI: -8.93, -0.45); P = 0.03; 5.52% greater reduction]. More pronounced reductions in blood lipids were observed when walnut interventions were compared with American and Western diets [WMD for TC = -12.30 (95% CI: -23.17, -1.43) and for LDL = -8.28 (95% CI: -13.04, -3.51); P < 0.001]. Apolipoprotein B (mg/dL) was also reduced significantly more on walnut-enriched diets compared with control groups [WMD = -3.74 (95% CI: -6.51, -0.97); P = 0.008] and a trend towards a reduction was observed for apolipoprotein A [WMD = -2.91 (95% CI: -5.98, 0.08); P = 0.057]. Walnut-enriched diets did not lead to significant differences in weight change (kg) compared with control diets [WMD = -0.12 (95% CI: -2.12, 1.88); P = 0.90], systolic blood pressure (mm Hg) [WMD = -0.72 (95% CI: -2.75, 1.30); P = 0.48], or diastolic blood pressure (mm Hg) [WMD = -0.10 (95% CI: -1.49, 1.30); P = 0.88]. Incorporating walnuts into the diet improved blood lipid profile without adversely affecting body weight or blood pressure.


Homeopathic preparations to control the rosy apple aphid (Dysaphis plantaginea Pass.).
A laboratory model system with the rosy apple aphid (Dysaphis plantaginea Pass.) on apple seedlings was developed to study the effects of homeopathic preparations on this apple pest. The assessment included the substance Lycopodium clavatum and a nosode of the rosy apple aphid. Each preparation was applied on the substrate surface as aqueous solution of granules (6c, 15c, or 30c). Controls were aqueous solutions of placebo granules or pure water. In eight independent, randomized, and blinded experiments under standardized conditions in growth chambers, the development of aphids on treated and untreated apple seedlings was observed over 17 days, each. Six experiments were determined to assess the effects of a strict therapeutic treatment; two experiments were designed to determine the effects of a combined preventative and therapeutic treatment. After application of the preparations, the number of juvenile offspring and the damage on apple seedlings were assessed after 7 and 17 days, respectively. In addition, after 17 days, the seedling weight was measured. In the final evaluation of the six strictly therapeutic trials after 17 days, the number of juvenile offspring was reduced after application of L. clavatum 15c (-17%, p = 0.002) and nosode 6c (-14%, p = 0.02) compared to the pure water control. No significant effects were observed for leaf damage or fresh weight for any application. In the two experiments with combined preventative and therapeutic treatment, no significant effects were observed in any measured parameter. Homeopathic remedies may be effective in plant-pest systems. The magnitude of observed effects seems to be larger than in models with healthy plants, which renders plant-pest systems promising candidates for homeopathic basic research. For successful application in agriculture, however, the effect is not yet sufficient. This calls for further optimization concerning homeopathic remedy selection, potency level, dosage, and application routes.


Social Closure and the Evolution of Cooperation via Indirect Reciprocity.
Direct and indirect reciprocity are good candidates to explain the fundamental problem of evolution of cooperation. We explore the conditions under which different types of reciprocity gain dominance and their performances in sustaining cooperation in the PD played on simple networks. We confirm that direct reciprocity gains dominance over indirect reciprocity strategies also in larger populations, as long as it has no memory constraints. In the absence of direct reciprocity, or when its memory is flawed, different forms of indirect reciprocity strategies are able to dominate and to support cooperation. We show that indirect reciprocity relying on social capital inherent in closed triads is the best competitor among them, outperforming indirect reciprocity that uses information from any source. Results hold in a wide range of conditions with different evolutionary update rules, extent of evolutionary pressure, initial conditions, population size, and density.


Exercising in a hot environment: which T-shirt to wear?
The aim of this study was to investigate thermoregulatory, cardiorespiratory, metabolic, and perceptual responses while running in a hot environment (31.7° ± 1.0°C; 42% ± 3% relative humidity) and wearing T-shirts made from different fiber types. Eight well-trained men performed 4 tests wearing either a T-shirt made of 100% polyester with 4, 6, or 8 channels, or one made of 100% cotton. Each test consisted of 30 minutes running at 70% of peak oxygen uptake, followed by a ramp test to exhaustion and 15 minutes of recovery. There were no differences in skin, core, and body temperatures between fiber types during submaximal and high-intensity running (best P = .08). During recovery, body temperature and shivering/sweating sensations were lower when wearing 4- and 6-channel fibers (P ≤ .04) compared with cotton. The relative humidity at the chest and back were lower for all polyester T-shirts compared with cotton during and after submaximal and maximal running (P ≤ .007). Heart rate (best P = .10), oxygen uptake (P = .95), respiratory exchange ratio (best P = .93), ventilation (best P = .99), and blood lactate concentration (best P = .97) did not differ between the fiber types. Nor were any differences in time to exhaustion (best P = .76), ratings of perceived exertion (best P = .09), thermal sensation (best P = .07), or sensation of clothing wetness (best P = .36) discovered. Although statistical analysis revealed lower shivering/sweating sensations while wearing 4- and 6-channel fiber shirts during recovery, with an improved chest and back microenvironment for all polyester T-shirts, the question remains whether these differences are of any practical relevance because the performance of the well-trained men was unaffected.


Radiation therapy in the management of rectal cancer.
Substantial advances have been made in the adjuvant management of patients with resectable rectal cancer. Increasing interest in patient quality of life has promoted the use of radiation therapy to enhance sphincter-preserving surgical approaches as an alternative to the standard abdominoperineal resection. Because of the suggestion of enhanced sphincter preservation with preoperative therapy and the potential advantage of decreased acute morbidity, randomized trials comparing preoperative and postoperative adjuvant combined modality therapy are ongoing. Recent progress in adjuvant postoperative treatment regimens relates to the integration of systemic therapy to radiation, and redefining the techniques for both modalities. The incorporation of improved radiation planning may reduce treatment-related bowel toxicity. The integration of novel chemotherapeutic agents in the adjuvant therapy of rectal cancer remains an active area of investigation.


Respecting relational agency in the context of vulnerability: What can research ethics learn from the social sciences?
Despite advances in theory, often driven by feminist ethicists, research ethics struggles in practice to adequately account for and respond to the agency and autonomy of people considered vulnerable in the research context. We argue that shifts within feminist research ethics scholarship to better characterise and respond to autonomy and agency can be bolstered by further grounding in discourses from the social sciences, in work that confirms the complex nature of human agency in contexts of structural and other sources of vulnerability. We discuss some of the core concepts and critiques emerging from the literature on women and children's agency in under-resourced settings, highlighting calls to move from individualistic to relational models of agency, and to recognise the ambiguous, value-laden, and heterogeneous nature of the concept. We then draw out what these conceptual shifts might mean for research ethics obligations and guidance, illustrating our analysis using a case vignette based on research ethics work conducted in South Africa. We conclude that if research practices are to be supportive of agency, it will be crucial to scrutinise the moral judgements which underpin accounts of agency, derive more situated definitions of and responses to agency, and enable people and participants to influence these based on their own experiences and self-perceptions.


Measurement of circulating transcript levels (NETest) to detect disease recurrence and improve follow-up after curative surgical resection of well-differentiated pancreatic neuroendocrine tumors.
Recurrence of pancreatic neuroendocrine tumors (pNET) after surgery is common. Strategies to detect recurrence have limitations. We investigated the role of clinical criteria and the multigene polymerase chain reaction-based NETest during post-operative follow-up of pNET. We studied 3 groups of resections: R0 with no recurrence (n = 11), R0 with recurrence (n = 12), and R1 with no recurrence (n = 12). NETest levels (>40%) were compared with chromogranin A (CgA) and clinicopathological criteria (CC; grade, lymph node metastases, size). Nonparametric, receiver operating characteristics, logistic regression, and predictive feature importance analyses were performed. NETest was higher in R0 with recurrence (56 ± 8%) compared with R1 with no recurrence (39 ± 6%) and R0 with no recurrence (28 ± 6%, P < .005). NETest positively correlated with recurrence (area under the curve: 0.82), CgA was not (area under the curve: 0.51 ± 0.09). Multiple regression analysis defined factor impact as highest for NETest (P < .005) versus CC (P < .03) and CgA (P = .23). NETest gave false positive or negative recurrence in 18% using a 40% cutoff. Logistic regression modeling of CC was 83% accurate; it was 91% when the NETest was included. Combining CC and NETest was approximately 2× more effective than individual CC alone (increase in R 2 value from 43% to 80%). A multigene blood test facilitates effective identification of pNET recurrence, prediction of disease relapse, and outperforms CgA.


How nursing staff spend their time on activities in a nursing home: an observational study.
This article is a report of a study to examine how nursing staff spend their time on activities in a nursing home. Few studies have investigated how nursing staff spend their time on activities in a nursing home. Such information is important for nurse managers in deciding on staff deployment, and for evaluating the effects of changes in nursing practice. A work sampling study with an observational component was undertaken in 2009 with nursing staff at a nursing home. A total of 430 activities were recorded for Registered Nurses, 331 for Endorsed Enrolled Nurses, 5276 for Personal Carers, and 501 for Recreational Activity Officers. Registered Nurses spent 48·4% of their time on communication and 18·1% on medication management. Endorsed Enrolled Nurses spent 37·7% on communication and 29·0% on documentation tasks. Communication was the most time-consuming activity for Recreational Activity Officers and Personal Carers, except that Personal Carers in a high care house spent more time on direct care duties. Hygiene duties and resident interaction were more frequently multitasked by the nursing staff in high care than in low care house. Nursing staff value their face-to-face interaction for successful care delivery. There is need, however, to investigate the effects of this form of communication on quality of care given to residents. Differences in multi-tasked activities between high care and low care houses should be considered when deploying staff in a nursing home.