Climate change and waterborne disease risk in the Great Lakes region of the U.S.
Extremes of the hydrologic cycle will accompany global warming, causing precipitation intensity to increase, particularly in middle and high latitudes. During the twentieth century, the frequency of major storms has already increased, and the total precipitation increase over this time period has primarily come from the greater number of heavy events. The Great Lakes region is projected to experience a rise these extreme precipitation events. For southern Wisconsin, the precipitation rate of the 10 wettest days was simulated using a suite of seven global climate models from the UN Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report. For each ranking, the precipitation rate of these very heavy events increases in the future. Overall, the models project that extreme precipitation events will become 10% to 40% stronger in southern Wisconsin, resulting in greater potential for flooding, and for the waterborne diseases that often accompany high discharge into Lake Michigan. Using 6.4 cm (2.5 in) of daily precipitation as the threshold for initiating combined sewer overflow into Lake Michigan, the frequency of these events is expected to rise by 50% to 120% by the end of this century. The combination of future thermal and hydrologic changes may affect the usability of recreational beaches. Chicago beach closures are dependent on the magnitude of recent precipitation (within the past 24 hours), lake temperature, and lake stage. Projected increases in heavy rainfall, warmer lake waters, and lowered lake levels would all be expected to contribute to beach contamination in the future. The Great Lakes serve as a drinking water source for more than 40 million people. Ongoing studies and past events illustrate a strong connection between rain events and the amount of pollutants entering the Great Lakes. Extreme precipitation under global warming projections may overwhelm the combined sewer systems and lead to overflow events that can threaten both human health and recreation in the region.


Five-Factor Prognostic Model for Survival of Post-Platinum Patients with Metastatic Urothelial Carcinoma Receiving PD-L1 Inhibitors.
A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting. Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets. The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors. A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.


Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome.
Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers. We included 1858 participants in the Colon Cancer Family Registry who had been found to have a pathogenic germline mutation in a MMR gene (carriers). We used weighted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. A total of 714 carriers (38%) were diagnosed with colorectal cancer at a mean age of 42.4 (standard deviation 10.6) years. A reduced risk of colorectal cancer was associated with aspirin use (for 1 month to 4.9 years: HR = 0.49, 95% CI = 0.27 to 0.90, P = .02; for ≥5 years: HR = 0.25, 95% CI = 0.10 to 0.62, P = .003) and ibuprofen use (for 1 month to 4.9 years: HR = 0.38, 95% CI = 0.18 to 0.79, P = .009; for ≥5 years: HR = 0.26, 95% CI = 0.10 to 0.69, P = .007), compared with less than one month of use. Our results provide additional evidence that, for MMR gene mutation carriers, use of aspirin and ibuprofen might be effective in reducing their high risk of colorectal cancer.


Fibroblast-collagen interactions in the formation of the secondary stroma of the chick cornea.
Fibroblasts invade the primary corneal stroma of the 6-day-old chick embryo eye. The way in which these cells build the secondary stroma has been studied by microscope examination of the stroma during the subsequent 8 Days. Eyes were embedded in low viscosity nitrocellulose, and 30-micrometer tangential sections of cornea were cut and stained with azan (giving blue collagen and red cells). These sections were sufficiently thick to include enough cells and collagen for stromal organization to be visible under Nomarski optics. Three days after invasion, the fibroblasts extend along collagen bundles in the posterior region of the stroma; surprisingly, fibroblasts near the epithelium are more rounded. The collagen itself is organized in orthogonal bundles rather than in sheets. Measurements show that posterior bundles increase in size with time while anterior stroma si similar in diameter to primary stroma. These observations confirm that the epithelium continues to deposit primary stroma up to at least the 14th day. They show, moreover, that fibroblasts deposit collagen fibrils on extant stroma and that the farther a bundle is from the epithelium, and hence the longer the period since it was first laid down, the wider it is likely to be. Analysis of the results and existing data on hyaluronic acid levels in the stroma suggests that Bowman's membrane, the region of anterior stroma that remains uncolonized by cells, is, during this period at least, primary stroma laid down but as yet unswollen.


β-Nb9VO25.
The title compound, nona-niobium vanadium penta-cosa-oxide, was prepared by a solid-state reaction at 1198 K. It is isotypic with Nb9AsO25, Nb9PO25 and Ta9VO25. The structure consists of NbO6 octa-hedra (one with 4/m.. and two with m.. symmetry) and VO4 tetra-hedra (-4.. symmetry) sharing corners and edges to form a three-dimensional framework. This framework can be considered as a junction between ribbons made up from NbO6 octa-hedra and chains of NbO6 octa-hedra and chains of VO4 tetra-hedra. The V site shows half-occupancy, hence one half of the VO4 tetra-hedra is unoccupied. The structural differences with α-Nb9VO25, VOSO4, SbOPO4 and NbOPO4 oxides are discussed.


Deletion of Plasmodium falciparum ubc13 increases parasite sensitivity to the mutagen, methyl methanesulfonate and dihydroartemisinin.
The inducible Di-Cre system was used to delete the putative ubiquitin-conjugating enzyme 13 gene (ubc13) of Plasmodium falciparum to study its role in ubiquitylation and the functional consequence during the parasite asexual blood stage. Deletion resulted in a significant reduction of parasite growth in vitro, reduced ubiquitylation of the Lys63 residue of ubiquitin attached to protein substrates, and an increased sensitivity of the parasite to both the mutagen, methyl methanesulfonate and the antimalarial drug dihydroartemisinin (DHA), but not chloroquine. The parasite was also sensitive to the UBC13 inhibitor NSC697923. The data suggest that this gene does code for an ubiquitin conjugating enzyme responsible for K63 ubiquitylation, which is important in DNA repair pathways as was previously demonstrated in other organisms. The increased parasite sensitivity to DHA in the absence of ubc13 function indicates that DHA may act primarily through this pathway and that inhibitors of UBC13 may both enhance the efficacy of this antimalarial drug and directly inhibit parasite growth.


A comparison of folic acid deficiency-induced genomic instability in lymphocytes of breast cancer patients and normal non-cancer controls from a Chinese population in Yunnan.
We hypothesized that the genomic response to folate deficiency might be different between breast cancer cases and healthy subjects. To test this hypothesis, we performed a comprehensive study on the genotoxic and cytotoxic effects of in vitro folic acid (FA) deficiency on primary human lymphocytes from 19 breast cancer patients and 20 age-matched healthy females from Yunnan, China using the cytokinesis-block micronucleus assay. Lymphocytes from the volunteers were cultured in RPMI1640 medium containing 30, 120 or 240 nM FA for 9 days. The results showed that 30 nM FA was associated with increased frequencies of micronucleated binucleated cell (MNed BNC), nucleoplasmic bridges (NPB), nuclear buds (BUD), apoptosis (APO) and necrosis (NEC) relative to 120 and 240 nM FA (P<0.001) in lymphocytes of case and control groups in vitro, however there were no significant differences between the 120 and 240 nM FA within each sampling group. The case group showed significantly higher frequencies of MNed BNC than control at 120 and 240 nM FA (P<0.05-0.001) but not at 30 nM FA (P=0.052). NEC was significantly higher in breast cancer group than control at all concentrations of FA (P<0.005). FA concentration explained 60, 39, 39, 52 and 71% of the variance of MNed BNC, NPB, BUD, APO and NEC, respectively compared with breast cancer status which only explained 6 and 7% of the variance of MNed BNC and NEC(Two way ANOVA, P<0.0001). Difference of difference analysis showed that breast cancer cases were not abnormally sensitive to the genome-damaging effect of folate deficiency. We concluded that (i) increased concentrations of FA abolished the genome-damaging effect of FA deficiency in lymphocytes of both breast cancer patients and controls to a similar extent and (ii) FA concentration is much more important than breast cancer status in determining genomic instability and cell death.


Foxk1 promotes cell proliferation and represses myogenic differentiation by regulating Foxo4 and Mef2.
In response to severe injury, adult skeletal muscle exhibits a remarkable regenerative capacity due to a resident muscle stem/progenitor cell population. While a number of factors are expressed in the muscle progenitor cell (MPC) population, the molecular networks that govern this cell population remain an area of active investigation. In this study, utilizing knockdown techniques and overexpression of Foxk1 in the myogenic lineage, we observed dysregulation of Foxo and Mef2 downstream targets. Utilizing an array of technologies, we establish that Foxk1 represses the transcriptional activity of Foxo4 and Mef2 and physically interacts with Foxo4 and Mef2, thus promoting MPC proliferation and antagonizing the myogenic lineage differentiation program, respectively. Correspondingly, knockdown of Foxk1 in C2C12 myoblasts results in cell cycle arrest, and Foxk1 overexpression in C2C12CAR myoblasts retards muscle differentiation. Collectively, we have established that Foxk1 promotes MPC proliferation by repressing Foxo4 transcriptional activity and inhibits myogenic differentiation by repressing Mef2 activity. These studies enhance our understanding of the transcriptional networks that regulate the MPC population and muscle regeneration.


Rational design of antisense oligomers to induce dystrophin exon skipping.
Duchenne muscular dystrophy (DMD), one of the most severe neuromuscular disorders of childhood, is caused by the absence of a functional dystrophin. Antisense oligomer (AO) induced exon skipping is being investigated to restore functional dystrophin expression in models of muscular dystrophy and DMD patients. One of the major challenges will be in the development of clinically relevant oligomers and exon skipping strategies to address many different mutations. Various models, including cell-free extracts, cells transfected with artificial constructs, or mice with a human transgene, have been proposed as tools to facilitate oligomer design. Despite strong sequence homology between the human and mouse dystrophin genes, directing an oligomer to the same motifs in both species does not always induce comparable exon skipping. We report substantially different levels of exon skipping induced in normal and dystrophic human myogenic cell lines and propose that animal models or artificial assay systems useful in initial studies may be of limited relevance in designing the most efficient compounds to induce targeted skipping of human dystrophin exons for therapeutic outcomes.


Transcriptome research of human amniocytes identifies hub genes associated with developmental dysplasia in down syndrome.
Trisomy 21, or Down syndrome (DS), is the most frequent human autosomal chromosome aneuploidy, which leads to multiple developmental disorders, especially mental retardation in individuals. The presence of an additional human chromosome 21 (HSA21) could account for the pathological manifestations in DS. In this study, we analyzed the mRNA gene expression profile of DS-derived amniocytes compared with normal amniocytes, aiming to evaluate the relationship between candidate dysregulated HSA21 genes and DS developmental phenotypes. Differentially expressed genes (DEGs) included 1794 upregulated genes and 1411 downregulated genes, which are mainly involved in cell adhesion, inflammation, cell proliferation and thus may play an important role in inducing multiple dysplasia during DS fetal development. Furthermore, STRING protein network studies demonstrated 7 candidate HSA21 genes participated Gene Ontology (GO) terms: cell adhesion and extracellular matrix remodeling (COL6A1, COL6A2, COL18A1, ADAMTS5, JAM2, and POFUT2), inflammation and virus infection response (MX1 and MX2), histone modification and chromatin remodeling (NRIP1), glycerolipid and glycerophospholipid metabolism (AGPAT3), mitochondrial function (ATP5PF and ATP5PO), synaptic vesicle endocytosis (ITSN1 and SYNJ1) and amyloid metabolism (APP). Meanwhile, GSEA enrichment identified several transcription factors and miRNAs, which may target gene expression in the DS group. Our study established connections between dysregulated genes, especially HSA21 genes, and DS-associated phenotypes. The alteration of multiple pathways and biological processes may contribute to DS developmental disorders, providing potential pathogenesis and therapeutic targets for DS.


Pediatric firearm-related traumatic brain injury in United States trauma centers.
Pediatric firearm injury is a leading cause of death and disability in the youth of the United States. The epidemiology of and outcomes following gunshot wounds to the head (GSWHs) are in need of systematic characterization. Here, the authors analyzed pediatric GSWHs from a population-based sample to identify predictors of prolonged hospitalization, morbidity, and death. All patients younger than 18 years of age and diagnosed with a GSWH in the National Sample Program (NSP) of the National Trauma Data Bank (NTDB) in 2003-2012 were eligible for inclusion in this study. Variables of interest included injury intent, firearm type, site of incident, age, sex, race, health insurance, geographic region, trauma center level, isolated traumatic brain injury (TBI), hypotension in the emergency department, Glasgow Coma Scale (GCS) score, and Injury Severity Score (ISS). Risk predictors for a prolonged hospital stay, morbidity, and mortality were identified. Odds ratios, mean increases or decreases (B), and 95% confidence intervals were reported. Statistical significance was assessed at α < 0.001 accounting for multiple comparisons. In a weighted sample of 2847 pediatric patients with GSWHs, the mean age was 14.8 ± 3.3 years, 79.2% were male, and 59.0% had severe TBI (GCS score 3-8). The mechanism of assault (63.0%), the handgun as firearm (45.6%), and an injury incurred in a residential area (40.6%) were most common. The mean hospital length of stay was 11.6 ± 14.4 days for the survivors, for whom suicide injuries involved longer hospitalizations (B = 5.9-day increase, 95% CI 3.3-8.6, p < 0.001) relative to those for accidental injuries. Mortality was 45.1% overall but was greater with injury due to suicidal intent (mortality 71.5%, p < 0.001) or caused by a shotgun (mortality 56.5%, p < 0.001). Lower GCS scores, higher ISSs, and emergency room hypotension predicted poorer outcomes. Patients with private insurance had lower mortality odds than those with Medicare/Medicaid (OR 2.4, 95% CI 1.7-3.4, p < 0.001) or government insurance (OR 3.6, 95% CI 2.2-5.8, p < 0.001). Management at level II centers, compared to level I, was associated with lower odds of returning home (OR 0.3, 95% CI 0.2-0.5, p < 0.001). From 2003 to 2012, with regard to pediatric TBI hospitalizations due to GSWHs, their proportion remained stable, those caused by accidental injuries decreased, and those attributable to suicide increased. Overall mortality was 45%. Hypotension, cranial and overall injury severity, and suicidal intent were associated with poor prognoses. Patients treated at level II trauma centers had lower odds of being discharged home. Given the spectrum of risk factors that predispose children to GSWHs, emphasis on screening, parental education, and standardization of critical care management is needed to improve outcomes.


ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance.
Overexpression or amplification of ACTR (also named AIB1, RAC3, p/CIP, TRAM-1, and SRC-3), a member of the p160 family of coactivators for nuclear hormone receptors, has been frequently detected in multiple types of human tumors, including breast cancer. However, its role in cancer cell proliferation and the underlying mechanism are unclear. Here, we show that overexpression of ACTR not only enhances estrogen-stimulated cell proliferation but also, more strikingly, completely negates the cell cycle arrest effect by tamoxifen and pure antiestrogens. Unexpectedly, we found that ACTR directly interacts, through its N-terminal domain, with E2F1 and is recruited to E2F target gene promoters. Elevation of ACTR in quiescent cells strongly stimulates the transcription of a subset of E2F-responsive genes that are associated with the G(1)/S transition. We also demonstrated, by adenovirus vector-mediated RNA interference, that ACTR is required for E2F1-mediated gene expression and the proliferation of estrogen receptor (ER)-negative breast cancer cells. Moreover, the ability of elevated ACTR to promote estrogen-independent cell proliferation depends on the function of E2F1 and the association between ACTR and E2F1, but not ER. Thus, our results reveal an essential role of ACTR in control of breast cancer cell proliferation and implicate the ACTR-E2F1 pathway as a novel mechanism in antiestrogen resistance.


Validation of risk stratification models in acute myeloid leukemia using sequencing-based molecular profiling.
Risk stratification of acute myeloid leukemia (AML) patients needs improvement. Several AML risk classification models based on somatic mutations or gene-expression profiling have been proposed. However, systematic and independent validation of these models is required for future clinical implementation. We performed whole-transcriptome RNA-sequencing and panel-based deep DNA sequencing of 23 genes in 274 intensively treated AML patients (Clinseq-AML). We also utilized the The Cancer Genome Atlas (TCGA)-AML study (N=142) as a second validation cohort. We evaluated six previously proposed molecular-based models for AML risk stratification and two revised risk classification systems combining molecular- and clinical data. Risk groups stratified by five out of six models showed different overall survival in cytogenetic normal-AML patients in the Clinseq-AML cohort (P-value<0.05; concordance index >0.5). Risk classification systems integrating mutational or gene-expression data were found to add prognostic value to the current European Leukemia Net (ELN) risk classification. The prognostic value varied between models and across cohorts, highlighting the importance of independent validation to establish evidence of efficacy and general applicability. All but one model replicated in the Clinseq-AML cohort, indicating the potential for molecular-based AML risk models. Risk classification based on a combination of molecular and clinical data holds promise for improved AML patient stratification in the future.


The effects of honey compared to silver sulfadiazine for the treatment of burns: A systematic review of randomized controlled trials.
Evidence from animal studies and trials suggests that honey may accelerate wound healing. The objective of this review was to assess the effects of honey compared with silver dressings on the healing of burn wounds. Relevant databases for randomized controlled trials (RCTs) of honey compared with silver sulfadiazine (SSD) were searched. The quality of the selected trials was assessed using the Cochrane Risk of Bias Assessment Tool. The primary endpoints considered were wound healing time and the number of infected wounds rendered sterile. Nine RCTs met the inclusion criteria. Based on moderate quality evidence there was a statistically significant difference between the two groups, favoring honey in healing time (MD -5.76days, 95% CI -8.14 to -3.39) and the proportions of infected wounds rendered sterile (RR 2.59; 95% CI 1.58-2.88). The available evidence suggests that honey dressings promote better wound healing than silver sulfadiazine for burns.


Labor mobility of the direct care workforce: implications for the provision of long-term care.
This study provides the first comprehensive analysis of the dynamics of labor supply of direct care workers, the lower-skill nursing workers who provide the bulk of long-term care for the elderly in the USA. Our estimates from the 1996 and 2001 panels of the Survey of Income and Program Participation (SIPP) show that the mean (median) duration of employment spells for the same direct care employer is only 9.7 (5.0) months. We find that fewer than one-third of direct care workers leave a job to take another job in the direct care field. There is also little indication of upward mobility in the health sector; direct care workers are approximately equally likely to transition to working as Registered Nurses as they are to working in household service jobs. Additionally, the rate at which spells end in work-limiting disability (5.4%) is very high compared with rates in similar occupations. We estimate duration models of direct care job spell length and find that, after correcting for the endogenous relationship between wages and tenure, wages appear to have a modest effect in preventing turnover; this effect is concentrated among the shortest spells.


Probabilistic Evaluation of Drought in CMIP6 Simulations.
As droughts have widespread social and ecological impacts, it is critical to develop long-term adaptation and mitigation strategies to reduce drought vulnerability. Climate models are important in quantifying drought changes. Here, we assess the ability of 285 CMIP6 historical simulations, from 17 models, to reproduce drought duration and severity in three observational data sets using the Standardized Precipitation Index (SPI). We used summary statistics beyond the mean and standard deviation, and devised a novel probabilistic framework, based on the Hellinger distance, to quantify the difference between observed and simulated drought characteristics. Results show that many simulations have less than ± 10 % error in reproducing the observed drought summary statistics. The hypothesis that simulations and observations are described by the same distribution cannot be rejected for more than 80 % of the grids based on our H distance framework. No single model stood out as demonstrating consistently better performance over large regions of the globe. The variance in drought statistics among the simulations is higher in the tropics compared to other latitudinal zones. Though the models capture the characteristics of dry spells well, there is considerable bias in low precipitation values. Good model performance in terms of SPI does not imply good performance in simulating low precipitation. Our study emphasizes the need to probabilistically evaluate climate model simulations in order to both pinpoint model weaknesses and identify a subset of best-performing models that are useful for impact assessments.


Joint Associations of Prevalent Radiographic Vertebral Fracture and Abdominal Aortic Calcification With Incident Hip, Major Osteoporotic, and Clinical Vertebral Fractures.
Prevalent vertebral fractures (PVFx) and abdominal aortic calcification (AAC) are both associated with incident fractures and can be ascertained on the same lateral spine images, but their joint association with incident fractures is unclear. Our objective was to estimate the individual and joint associations of PVFx and AAC with incident major osteoporotic, hip, and clinical vertebral fractures in 5365 older men enrolled in the Osteoporotic Fractures in Men (MrOS) Study, using Cox proportional hazards and Fine and Gray subdistribution hazards models to account for competing mortality. PVFx (Genant SQ grade 2 or 3) and 24-point AAC score were ascertained on baseline lateral spine radiographs. Self-reports of incident fractures were solicited every 4 months and confirmed by review of clinical radiographic reports. Compared with men without PVFx and AAC-24 score 0 or 1, the subdistribution hazard ratio (SHR) for incident major osteoporotic fracture was 1.38 (95% confidence interval [CI] 1.13-1.69) among men with AAC-24 score ≥2 alone, 1.71 (95% CI 1.37-2.14) for men with PVFx alone, and 2.35 (95% CI 1.75-3.16) for men with both risk factors, after accounting for conventional risk factors and competing mortality. Wald statistics showed improved prediction model performance by including both risk factors compared with including only AAC (chi-square = 17.3, p < .001) or including only PVFx (chi-square = 8.5, p = .036). Older men with both PVFx and a high level of AAC are at higher risk of incident major osteoporotic fracture than men with either risk factor alone. Assessing prevalent radiographic vertebral fracture and AAC on the same lateral spine images may improve prediction of older men who will have an incident major osteoporotic fracture, even after accounting for traditional fracture risk factors and competing mortality. © 2021 American Society for Bone and Mineral Research (ASBMR).


Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease.
Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation. We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis. Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point. In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.


Prospective study of risk factors for hepatitis C virus acquisition by Caucasian, Hispanic, and Asian American patients.
Commonly known risk factors for infection with hepatitis C virus (HCV) include blood transfusion, injection drug use, intranasal cocaine use, and body tattoos. We hypothesized that Asian Americans infected with HCV may not identify with these established risk factors present in Caucasians and Hispanics, and our aim was to conduct a survey of risk factors in HCV-infected patients in these ethnic groups. In this prospective study, 494 patients infected with HCV completed a detailed risk assessment questionnaire at a liver centre in Northern California from 2001 to 2008. Among subjects participating in this study, 55% identified themselves as Caucasian, 20% as Hispanic, and 25% as Asian. Asian Americans were older, less likely to smoke or consume alcohol, and have a family history of cancer compared with Caucasians and Hispanics. The laboratory profiles were similar, and genotype 1 was the most common infection in all groups (74-75%). The great majority of Caucasians (94%) and Hispanics (86%) identified with commonly known risk factors, which was in contrast to 67% of Asians (P < 0.0001). The most common risk factors in Asians were blood transfusions (50%) and acupuncture (50%). Furthermore, 74% of Caucasians and 66% of Hispanics identified more than one major risk factor, while only 20% of Asians reported having more than one risk factor (P < 0.0001). Survey for established risk factors for acquisition of HCV may be more appropriate for risk assessment of Caucasians and Hispanics, but not for Asian Americans. These findings may guide the development of HCV screening in our increasingly diverse population.


Optimal control of charge transfer for slow H+ + D collisions with shaped laser pulses.
We show that optimally shaped laser pulses can beneficially influence charge transfer in slow H(+)+D collisions. Time-dependent wave packet optimal control simulations are performed based on a two-state adiabatic Hamiltonian. Optimal control is performed using either an adaptive or a fixed target to obtain the desired laser control field. In the adaptive target scheme, the target state is updated according to the renormalized fragmentary yield in the exit channel throughout the optimization process. In the fixed target scheme, the target state in the exit channel is a normalized outgoing Gaussian wave packet located at a large internuclear separation. Both approaches produced excellent optimal outcomes, far exceeding that achieved in the field-free collisional charge transfer. The adaptive target scheme proves to be more efficient, and often with complex final wave packet. In contrast, the fixed target scheme, although more slowly convergent, is found to produce high fidelity for the desired target wave packet. The control mechanism in both cases utilizes bound vibrational states of the transient HD(+) complex.


Maternal exposure to arsenic in drinking water and risk of congenital heart disease in the offspring.
Prenatal exposure to arsenic is suspected to impair fetal health, including congenital malformations. Few studies investigated an association between maternal exposure to arsenic and congenital heart disease. To examine the association between maternal exposure to arsenic through drinking water and congenital heart disease among offspring. This nationwide cohort study included all liveborn children in Denmark, 1997-2014. Maternal addresses at fetal age 4 weeks were linked to drinking water supply areas. Exposure was arsenic concentration in drinking water in first trimester in four categories (<0.5 μg/L, 0.5-0.9 μg/L, 1.0-4.9 μg/L, ≥5.0 μg/L). Outcomes were defined as congenital heart disease diagnosed within the first year of life, with sub-categorization of severe, septal defects and valvular heart defect. Associations between arsenic levels and congenital heart disease were analysed using logistic regression, presented as odds ratios (OR) with 95% confidence interval (CI), and adjusted for year of birth, mother's educational level and ethnicity. A total of 1,042,413 liveborn children were included of whom 1.0% had a congenital heart disease. The OR of congenital heart disease was higher among children exposed to all levels of arsenic above 0.5 μg/L; the OR was 1.13 (95% CI: 1.08-1.19) for exposure of 0.5-0.9 μg/L, 1.33 (95% CI: 1.27-1.39) for 1.0-4.9 μg/L and 1.42 (95% CI: 1.24-1.63) for ≥5.0 μg/L. Similar associations were observed for congenital septal defects. The OR was also higher for severe congenital heart disease but at the same level among all exposure levels ≥0.5 μg/L. The OR of congenital valvular heart defects was only higher among children with maternal exposure to arsenic in drinking water ≥5.0 μg/L. The associations were similar for boys and girls. The findings indicate that maternal exposure to arsenic in drinking water even at low concentrations (i.e., 0.5-0.9 μg/L) increased the risk of congenital heart disease in the offspring.


The reproducibility of 31-phosphorus MRS measures of muscle energetics at 3 Tesla in trained men.
Magnetic resonance spectroscopy (MRS) provides an exceptional opportunity for the study of in vivo metabolism. MRS is widely used to measure phosphorus metabolites in trained muscle, although there are no published data regarding its reproducibility in this specialized cohort. Thus, the aim of this study was to assess the reproducibility of (31)P-MRS in trained skeletal muscle. We recruited fifteen trained men (VO(2)peak = 4.7±0.8 L min(-1)/58±8 mL kg(-1) min(-1)) and performed duplicate MR experiments during plantar flexion exercise, three weeks apart. Measures of resting phosphorus metabolites were reproducible, with 1.7 mM the smallest detectable difference in phosphocreatine (PCr). Measures of metabolites during exercise were less reliable: exercising PCr had a coefficient of variation (CV) of 27% during exercise, compared with 8% at rest. Estimates of mitochondrial function were variable, but experimentally useful. The CV of PCr(1/2t) was 40%, yet much of this variance was inter-subject such that differences of <20% were detectable with n = 15, given a significance threshold of p<0.05. 31-phosphorus MRS provides reproducible and experimentally useful measures of phosphorus metabolites and mitochondrial function in trained human skeletal muscle.


Vascular endothelial growth factor (VEGF) and melanoma. N-acetylcysteine downregulates VEGF production in vitro.
Vascular endothelial growth factor (VEGF), the most potent angiogenic factor identified to date, is associated with growth and metastasis of solid tumours, including melanoma. It has been shown in vitro that melanoma cells produce raised concentrations of VEGF. We examined the VEGF concentrations in plasma of 20 patients with primary melanoma, local recurrence and metastatic melanoma. We also studied the inhibiting effect of one antioxidant, N-acetylcysteine, on VEGF production in three human melanoma cell lines. We found elevated levels of VEGF (median 205 pg ml; 95 percent confidence interval, 80-414) in metastatic melanoma, with respect to primary and locally recurrent melanoma (75 pg/ml; 95 percent confidence interval, 35-130). The health control patients had levels of 25 pg/ml (95 percent confidence interval, 10-35). Human melanoma cell lines secreted VEGF in basal conditions (550-963 +/- 125 pg/ml) and N-acetylcysteine (0.5-20 mM) significantly decreased the VEGF production in a dose-dependent manner. VEGF concentrations were found to be raised in patients with primary melanoma, local recurrence, and above all, metastatic melanoma (P=0.008). N-acetylcysteine inhibits VEGF production in three human melanoma cell lines. This antioxidant might have therapeutic applications in metastatic melanoma in combination with other cytotoxic drugs.


Modulation of the mobility of a key region in human galactokinase: Impacts on catalysis and stability.
Galactokinase catalyses the phosphorylation of α-d-galactose and some structurally related monosaccharides. The enzyme is of interest due to its potential as a biocatalyst for the production of sugar 1-phosphates and due to its involvement in the inherited metabolic disease type II galactosemia. It has been previously shown that a region (residues 231-245) in human galactokinase often has altered mobility when active site residues are varied. We hypothesised that the reverse may be true and that designing changes to this region might affect the functioning of the active site of the enzyme. Focussing on four residues (Leu-231, Gln-242, Glu-244 and Glu-245) we conducted molecular dynamics simulations to explore the effects of changing these residues to glycine or serine. In most cases the variations resulted in local changes to the 231-245 region and global changes to the root mean squared fluctuation (RMSF) of the protein. The four serine variants were expressed as recombinant proteins. All had altered steady state enzyme kinetic parameters with α-d-galactose as a substrate. However, these changes were generally less than ten-fold in magnitude. Changes were also observed with 2-deoxy-α-d-galactose, α-d-galactosamine and α-d-talose as substrates, including (in some cases) loss of detectable activity, suggesting that these variations can tune the specificity of the enzyme. This study demonstrates that activity and specificity of human galactokinase can be modulated by variations designed to affect active site flexibility. It is likely that this principle can be generalised to other enzymes.


Production, Collection, and Purification of 47Ca for the Generation of 47Sc through Isotope Harvesting at the National Superconducting Cyclotron Laboratory.
An experiment was performed at the National Superconducting Cyclotron Laboratory using a 140 MeV/nucleon 48Ca beam and a flowing-water target to produce 47Ca for the first time with this production route. A production rate of 0.020 ± 0.004 47Ca nuclei per incoming beam particle was measured. An isotope harvesting system attached to the target was used to collect radioactive cationic products, including 47Ca, from the water on a cation-exchange resin. The 47Ca collected was purified using three separation methods optimized for this work: (1) DGA extraction chromatography resin with HNO3 and HCl, (2) AG MP-50 cation-exchange resin with an increasing concentration gradient of HCl, and (3) AG MP-50 cation-exchange resin with a methanolic HCl gradient. These methods resulted in ≥99 ± 2% separation yield of 47Ca with 100% radionuclidic purity within the limits of detection for HPGe measurements. Inductively coupled plasma-optical emission spectrometry (ICP-OES) was used to identify low levels of stable ions in the water of the isotope harvesting system during the irradiation and in the final purified solution of 47Ca. For the first time, this experiment demonstrated the feasibility of the production, collection, and purification of 47Ca through isotope harvesting for the generation of 47Sc for nuclear medicine applications.


Physical Activity for Symptom Management in Women With Metastatic Breast Cancer: A Randomized Feasibility Trial on Physical Activity and Breast Metastases.
Physical activity for women with early-stage breast cancer is well recognized for managing cancer-related symptoms and improving quality of life. While typically excluded from interventions, women with metastatic breast cancer may also benefit from physical activity. To 1) determine the safety and feasibility of a physical activity program for women with metastatic breast cancer and 2) explore the efficacy of the program. Fourteen women with metastatic breast cancer were randomized to either a control group or an 8-week home-based physical activity intervention comprising twice weekly supervised resistance training and an unsupervized walking program. The recruitment rate was 93%. Adherence to the resistance and walking components of the program was 100% and 25%, respectively. No adverse events were reported. When mean change scores from baseline to postintervention were compared, trends in favor of the exercise group over the control group were observed for the Functional Assessment of Chronic Illness Therapy-Fatigue score (+5.6 ± 3.2 vs. -1.8 ± 3.9, respectively), VO2max (+1.6 ml/kg/minute ±1.8 mL/kg/minute vs. -0.2 mL/kg/minute ±0.1 mL/kg/minute, respectively) and six-minute walk test (+40 m ± 23 m vs. -46 m ± 56 m, respectively). A partially supervised home-based physical activity program for women with metastatic breast cancer is feasible and safe. The dose of the resistance training component was well tolerated and achievable in this population. In contrast, adherence and compliance to the walking program were poor. Preliminary data suggest a physical activity program, comprising predominantly resistance training, may lead to improvements in physical capacity and may help women to live well with their disease.


Normalisation of gait EMGs: a re-examination.
The purpose of this study was to compare four different methods of normalising electromyograms (EMGs) recorded during normal gait. Comparisons were made between the amplitude, intra-individual variability and inter-individual variability of EMGs. Surface EMGs were recorded from the biceps femoris, semitendinosus, vastus lateralis and vastus medialis of ten males and two females while they walked on a treadmill at a self-selected speed. EMGs from the same muscles were subsequently recorded during isometric maximal voluntary contractions (MVCs) and concentric, isokinetic MVCs that were performed between 0.52 and 7.85 rad x s(-1) on a BIODEX dynamometer. EMGs were also recorded during eccentric, isokinetic MVCs between 0.52 and 2.62 rad x s(-1). Gait EMGs were then normalised at 2% intervals of the gait cycle by expressing them as a percentage of the following reference values: the mean (mean dynamic method) and the peak (peak dynamic method) EMG from the intra-individual ensemble average; the EMG from an isometric MVC (isometric MVC method); and the EMG from an isokinetic MVC that occurred with the same muscle action, length and velocity of musculotendinous unit as the gait EMGs (isokinetic MVC method). The isokinetic MVC method produced significantly greater (P<0.05) intra-individual variability compared to the other methods when it was measured using the variance ratio. Inter-individual variability of gait EMGs, again measured using the variance ratio, was also greatest when they were normalised using the isokinetic MVC method. The pattern and amplitude of EMGs normalised using the isometric MVC method and the isokinetic MVC method were very similar (root mean square difference and absolute difference both less than 3%). It was concluded that the isokinetic MVC method should not be adopted by gait researchers or clinicians as it does not reduce intra- or inter-individual variability anymore than existing normalisation methods, nor does it provide a more representative measure of muscle activation during gait than the isometric MVC method.


Only patients with dysplasia progress to adenocarcinoma in Barrett's oesophagus.
Columnar lined oesophagus (Barrett's oesophagus) carries a risk for the development of adenocarcinoma. Epithelial dysplasia appears to be a precursor but the utility of this marker for predicting subsequent adenocarcinoma is unsettled. We therefore prospectively studied 81 patients with histologically proven columnar epithelium of at least the distal 3 cm of the tubular oesophagus with regular endoscopic biopsies for a total of 289.2 patient years (mean 3.6 years, range 0.5-8). Twenty three patients (28%) had epithelial dysplasia detected during follow up. Both patients with persistent high grade dysplasia present on initial biopsies developed adenocarcinoma after 2.6-4.5 years, despite the absence of gross macroscopic change. The initial single layer pleomorphic high grade dysplasia in one patient regressed to low grade dysplasia which has persisted for 1.5 years. Of 10 patients with initial low grade dysplasia, one progressed to adenocarcinoma in 4.3 years. The low grade dysplasia persisted unchanged in seven patients for 1.5-7 years and appears to have regressed in two patients after three to five years. Ten patients developed low grade dysplasia during the surveillance period. This has persisted unchanged in six patients from 0.5-5 years, regressed in three for 0.5-5 years and has appeared after the first yearly biopsy in one patient. No patient without dysplasia has developed adenocarcinoma. The incidence of adenocarcinoma in Barrett's oesophagus in this study is one case per 96 patient years. This is 61 times (95% confidence limits 12-176) the age adjusted incidence of oesophageal cancer in Australia. Persistent high grade dysplasia appears to be a sensitive indicator for the development of subsequent adenocarcinoma.


Trajectories of Acute Antidepressant Efficacy: How Long to Wait for Response? A Systematic Review and Meta-Analysis of Long-Term, Placebo-Controlled Acute Treatment Trials.
In patients who are not responding to antidepressant pharmacotherapy, information regarding the future probability of response with the same treatment is scarce. Specifically, it is unclear at what point in time the probability to respond or remit ceases to increase, because few studies report data on response or remission at repeated time points beyond 4 or 8 weeks of treatment. Consequently, treatment recommendations in clinical practice guidelines differ widely. We systematically searched MEDLINE, Embase, PsycINFO, and CENTRAL databases through March 2014 using generic terms for depressive or affective disorders, individual drug names, and placebo (Prospero Registration: CRD42014010105). We identified double-blind, randomized studies with continuous outcome reporting from 4 weeks up to at least 12 weeks that compared antidepressant monotherapy to placebo in adult patients suffering from acute depressive disorder. Data extraction and synthesis followed Cochrane Collaboration guidelines. Primary outcome was response; secondary outcomes were remission and changes in rating scale scores in previously unresponsive patients, respectively. Of 6,043 articles screened, we selected 9 studies including 3,466 patients. Altogether, 21.6% (18.6%, 24.9%) of previously nonresponsive patients achieved response with ongoing antidepressant treatment between weeks 5 and 8, and 9.9% (7.5%, 12.7%), between weeks 9 and 12. Probability of response when taking placebo was 13.0% (9.9%, 16.5%) between weeks 5 and 8 and 2.4% (1.2%, 4.6%) between weeks 9 and 12. Differences in the probability of response between antidepressant and placebo translated into a number needed to treat of 11 after 4 weeks and 17 after 8 weeks. Heterogeneity was low to moderate, and results remained stable across subgroup and sensitivity analyses. In patients unresponsive to antidepressant pharmacotherapy, improvements in psychopathology can be expected with ongoing antidepressant treatment for up to 3 months. After 8 weeks of treatment, improvement with ongoing monotherapy is relatively small.


Azathioprine hypersensitivity presenting as septic shock with encephalopathy.
We present a case of azathioprine hypersensitivity presenting as septic shock with associated encephalopathy. The patient was presented with rapid onset of fever, hypotension, confusion and a rapidly declining conscious level. He was admitted to the intensive care unit where he received numerous invasive investigations and treatments with broad-spectrum antibiotics, antivirals and antifungals. All microbial cultures were negative. The patient-consistent with azathioprine hypersensitivity-made a spontaneous recovery after 7 days. The case shows that a time line of drug initiation is a key part of the medical history and consideration of azathioprine hypersensitivity could avoid unnecessary interventions and excessive antimicrobial use.


Influence of a Confined Methanol Solvent on the Reactivity of Active Sites in UiO-66.
UiO-66, composed of Zr-oxide bricks and terephthalate linkers, is currently one of the most studied metal-organic frameworks due to its exceptional stability. Defects can be introduced in the structure, creating undercoordinated Zr atoms which are Lewis acid sites. Here, additional Brønsted sites can be generated by coordinated protic species from the solvent. In this Article, a multilevel modeling approach was applied to unravel the effect of a confined methanol solvent on the active sites in UiO-66. First, active sites were explored with static periodic density functional theory calculations to investigate adsorption of water and methanol. Solvent was then introduced in the pores with grand canonical Monte Carlo simulations, followed by a series of molecular dynamics simulations at operating conditions. A hydrogen-bonded network of methanol molecules is formed, allowing the protons to shuttle between solvent methanol, adsorbed water, and the inorganic brick. Upon deprotonation of an active site, the methanol solvent aids the transfer of protons and stabilizes charged configurations via hydrogen bonding, which could be crucial in stabilizing reactive intermediates. The multilevel modeling approach adopted here sheds light on the important role of a confined solvent on the active sites in the UiO-66 material, introducing dynamic acidity in the system at finite temperatures by which protons may be easily shuttled from various positions at the active sites.


Delivering at home or in a health facility? health-seeking behaviour of women and the role of traditional birth attendants in Tanzania.
Traditional birth attendants retain an important role in reproductive and maternal health in Tanzania. The Tanzanian Government promotes TBAs in order to provide maternal and neonatal health counselling and initiating timely referral, however, their role officially does not include delivery attendance. Yet, experience illustrates that most TBAs still often handle complicated deliveries. Therefore, the objectives of this research were to describe (1) women's health-seeking behaviour and experiences regarding their use of antenatal (ANC) and postnatal care (PNC); (2) their rationale behind the choice of place and delivery; and to learn (3) about the use of traditional practices and resources applied by traditional birth attendants (TBAs) and how they can be linked to the bio-medical health system. Qualitative and quantitative interviews were conducted with over 270 individuals in Masasi District, Mtwara Region and Ilala Municipality, Dar es Salaam, Tanzania. The results from the urban site show that significant achievements have been made in terms of promoting pregnancy- and delivery-related services through skilled health workers. Pregnant women have a high level of awareness and clearly prefer to deliver at a health facility. The scenario is different in the rural site (Masasi District), where an adequately trained health workforce and well-equipped health facilities are not yet a reality, resulting in home deliveries with the assistance of either a TBA or a relative. Instead of focusing on the traditional sector, it is argued that more attention should be paid towards (1) improving access to as well as strengthening the health system to guarantee delivery by skilled health personnel; and (2) bridging the gaps between communities and the formal health sector through community-based counselling and health education, which is provided by well-trained and supervised village health workers who inform villagers about promotive and preventive health services, including maternal and neonatal health.


Knockout of αA-crystallin inhibits ocular neovascularization.
The present study aimed to investigate the effects of αA-crystallin on pathologic ocular neovascularization. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study, and αA-crystallin-knockout (CRYAA[-/-]) mice were used for the in vivo study. αA-crystallin was knocked down in HUVECs by using a specific small interfering RNA (siRNA), and the effects of αA-crystallin knockdown on proliferation, migration, tube formation, and apoptosis were evaluated. Enzyme-linked immunosorbent assays were performed to investigate extracellular concentrations of vascular endothelial growth factor (VEGF). In vivo mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) were generated by using CRYAA(-/-) mice. The nonperfused area in the OIR model was measured in flat-mounted retinas, and angiogenesis resulting in CNV was evaluated in retinal sections. Western blot analysis was performed to investigate the phosphorylation status of vascular endothelial growth factor receptor 2 (VEGFR2, high affinity receptor for VEGF), AKT, PLCγ1, FAK, Src, p42/p44MAPK, p38MAPK, caspase-3, and caspase-9 in cultured HUVECs, as well as in the OIR and CNV models. The CRYAA siRNA not only induced HUVEC apoptosis but also inhibited exogenous and endogenous VEGF-induced cell activities, including proliferation, migration, and tube formation. Pathologic neovascularization was attenuated in the CRYAA(-/-) murine OIR and CNV models. Both in vitro and in vivo, the inhibition of angiogenesis was mediated by the suppression of VEGF secretion and the inhibition of the VEGFR2 signaling pathway; VEGFR2, AKT, PLCγ1, FAK, Src, p42/p44 MAPK, and p38 MAPK all showed reduced phosphorylation levels. In addition, CRYAA knockout led to increased levels of cleaved caspase-9 and caspase-3. Knockout of αA-crystallin inhibited pathologic neovascularization through the VEGF and VEGFR2 signaling pathways both in vitro and in vivo. These results suggest that αA-crystallin could be a novel pharmaceutical target for the prevention of ocular neovascularization.


Assessing water-assisted UV-C light and its combination with peroxyacetic acid and Pseudomonas graminis CPA-7 for the inactivation and inhibition of Listeria monocytogenes and Salmonella enterica in fresh-cut 'Iceberg' lettuce and baby spinach leaves.
The effectiveness of ultraviolet C light (UV-C) delivered in water (WUV) or in peroxyacetic acid (PAA) for the inactivation and inhibition of L. monocytogenes and S. enterica in ready-to-eat 'Iceberg lettuce' and baby spinach leaves, was evaluated throughout chilled storage in modified atmosphere packaging (MAP). The inhibition of pathogen's growth by sequential pretreatments with UV-C in PAA and then biocontrol using Pseudomonas graminis CPA-7 was assessed during MAP storage at 5 °C and upon a breakage of the cold-storage chain. In fresh-cut lettuce, 0 1 kJ/m2 UV-C, in water or in 40 mg/L PAA, inactivated both pathogens by up to 2.1 ± 0.7 log10, which improved the efficacy of water-washing by up to 1.9 log10 and showed bacteriostatic effects on both pathogens. In baby spinach leaves, the combination of 0 3 kJ/m2 UV-C and 40 mg/L PAA reduced S. enterica and L. monocytogenes populations by 1.4 ± 0.2 and 2.2 ± 0.3 log10 respectively, which improved water-washing by 0.8 ± 0.2 log10. Combined treatments (0.1 or 0 3 kJ/m2 WUV and 40 mg/L PAA) inactivated both pathogens in the process solution from lettuce or spinach single sanitation, respectively. Pretreating lettuce with UV-C in PAA reduced L. monocytogenes and S. enterica's growth by up to 0.9 ± 0.1 log10 with respect to the PAA-pretreated control after 6 d at 5 °C in MAP. Upon a cold-chain breakage, CPA-7 prevented S. enterica growth in PAA-pretreated lettuce, whereas showed no effect on L. monocytogenes in any of both matrices. Low-dose UV-C in PAA is a suitable preservation strategy for improving the safety of ready-to-eat leafy greens and reducing the risk of cross contamination.


A remnant planetary core in the hot-Neptune desert.
The interiors of giant planets remain poorly understood. Even for the planets in the Solar System, difficulties in observation lead to large uncertainties in the properties of planetary cores. Exoplanets that have undergone rare evolutionary processes provide a route to understanding planetary interiors. Planets found in and near the typically barren hot-Neptune 'desert'1,2 (a region in mass-radius space that contains few planets) have proved to be particularly valuable in this regard. These planets include HD149026b3, which is thought to have an unusually massive core, and recent discoveries such as LTT9779b4 and NGTS-4b5, on which photoevaporation has removed a substantial part of their outer atmospheres. Here we report observations of the planet TOI-849b, which has a radius smaller than Neptune's but an anomalously large mass of [Formula: see text] Earth masses and a density of [Formula: see text] grams per cubic centimetre, similar to Earth's. Interior-structure models suggest that any gaseous envelope of pure hydrogen and helium consists of no more than [Formula: see text] per cent of the total planetary mass. The planet could have been a gas giant before undergoing extreme mass loss via thermal self-disruption or giant planet collisions, or it could have avoided substantial gas accretion, perhaps through gap opening or late formation6. Although photoevaporation rates cannot account for the mass loss required to reduce a Jupiter-like gas giant, they can remove a small (a few Earth masses) hydrogen and helium envelope on timescales of several billion years, implying that any remaining atmosphere on TOI-849b is likely to be enriched by water or other volatiles from the planetary interior. We conclude that TOI-849b is the remnant core of a giant planet.


Is there an association between metabolic syndrome and rotator cuff-related shoulder pain? A systematic review.
Rotator cuff-related shoulder pain (RCRSP) is a common upper limb complaint. It has been suggested that this condition is more common among people with cardiometabolic risk factors. This systematic review has synthesised evidence from case-control, cross-sectional and cohort studies on the association between metabolic syndrome (MetS) and RCRSP. Five medical databases (MEDLINE, EMBASE, SCOPUS, CINAHL and AMED) and reference checking methods were used to identify all relevant English articles that considered MetS and RCRSP. Studies were appraised using the Newcastle-Ottawa Scale (NOS). Two reviewers performed critical appraisal and data extraction. Narrative synthesis was performed via content analysis of statistically significant associations. Three cross-sectional, two case-control and one cohort study met the inclusion criteria, providing a total of 1187 individuals with RCRSP. Heterogeneity in methodology and RCRSP or MetS definition precluded a meaningful meta-analysis. Four of the included studies identified associations between the prevalence of MetS and RCRSP. Studies consistently identified independent cardiometabolic risk factors associated with RCRSP. All studies were level III evidence. The low-moderate quality evidence included in this review suggests an association between MetS and RCRSP. Most studies demonstrated moderate quality on appraisal. The direction of association and cardiometabolic factors influencing should be investigated by longitudinal and treatment studies. These preliminary conclusions and clinical utility should be treated with caution due to limitations of the evidence base.


Policy statement--Pedestrian safety.
Each year, approximately 900 pediatric pedestrians younger than 19 years are killed. In addition, 51000 children are injured as pedestrians, and 5300 of them are hospitalized because of their injuries. Parents should be warned that young children often do not have the cognitive, perceptual, and behavioral abilities to negotiate traffic independently. Parents should also be informed about the danger of vehicle back-over injuries to toddlers playing in driveways. Because posttraumatic stress syndrome commonly follows even minor pedestrian injury, pediatricians should screen and refer for this condition as necessary. The American Academy of Pediatrics supports community- and school-based strategies that minimize a child's exposure to traffic, especially to high-speed, high-volume traffic. Furthermore, the American Academy of Pediatrics supports governmental and industry action that would lead to improvements in vehicle design, driver manuals, driver education, and data collection for the purpose of reducing pediatric pedestrian injury.


Intestinal CD103+ dendritic cells are key players in the innate immune control of Cryptosporidium parvum infection in neonatal mice.
Cryptosporidium parvum is a zoonotic protozoan parasite found worldwide, that develops only in the gastrointestinal epithelium and causes profuse diarrhea. Using a mouse model of C. parvum infection, we demonstrated by conditional depletion of CD11c+ cells that these cells are essential for the control of the infection both in neonates and adults. Neonates are highly susceptible to C. parvum but the infection is self-limited, whereas adults are resistant unless immunocompromised. We investigated the contribution of DC to the age-dependent susceptibility to infection. We found that neonates presented a marked deficit in intestinal CD103+ DC during the first weeks of life, before weaning, due to weak production of chemokines by neonatal intestinal epithelial cells (IEC). Increasing the number of intestinal CD103+ DC in neonates by administering FLT3-L significantly reduced susceptibility to the infection. During infections in neonates, the clearance of the parasite was preceded by a rapid recruitment of CD103+ DC mediated by CXCR3-binding chemokines produced by IEC in response to IFNγ. In addition to this key role in CD103+ DC recruitment, IFNγ is known to inhibit intracellular parasite development. We demonstrated that during neonatal infection CD103+ DC produce IL-12 and IFNγ in the lamina propria and the draining lymph nodes. Thus, CD103+DC are key players in the innate immune control of C. parvum infection in the intestinal epithelium. The relative paucity of CD103+ DC in the neonatal intestine contributes to the high susceptibility to intestinal infection.


Recurrence of clinical chorioamnionitis in subsequent pregnancies.
To establish the role of clinical chorioamnionitis as an independent risk factor for recurrence in a subsequent pregnancy. This was a historical cohort study of pregnant women who had their first and second deliveries at our institution between January 1988 and May 2005. The index pregnancy was restricted to those who delivered vaginally. Data were collected from a continuously updated obstetric database and included demographic and labor characteristics and neonatal outcomes. Chorioamnionitis was diagnosed clinically. The study population consisted of 23,397 women. During the index pregnancy, 10% of women developed chorioamnionitis. This group was significantly different from the rest of the cohort in terms of age, ethnicity, length of labor, epidural analgesia, use of internal monitors, and incidence of prolonged rupture of membranes. In the second pregnancy, 6% of those women again developed chorioamnionitis compared with 2% of women who did not have chorioamnionitis in the first pregnancy (odds ratio 2.93, 95% confidence interval 2.40-3.57). After adjusting for the above confounders, the increased risk of recurrence persisted (odds ratio 1.85, 95% confidence interval 1.49-2.30). Women delivering vaginally who were diagnosed with chorioamnionitis during their first pregnancy are at increased risk for chorioamnionitis in a subsequent pregnancy. This supports the concept that there may be a predisposition to chorioamnionitis that should be further investigated. II-2.


Life events; their role in onset and relapse in psychosis, research utilizing semi-structured interview methods: a literature review.
This literature review explores the findings of studies that adopted semi-structured interviewing methods to assess the impact of life events on the course of psychotic illness. It begins by discussing the historical context and theoretical underpinnings of the use of semi-structured approaches to measure the role and impact of life events in the onset and course of psychotic illness. The review then focuses on the main findings of the studies commencing by focusing on causality by specifically discussing the time frame from life event to relapse and whether life events have a triggering role or cumulative effect in onset. The review examines the sample populations studied and asks whether they are homogenous and comparable or heterogeneous, therefore making comparisons between studies less valid. Issues concerning the number of episodes of illness and sensitivity to relapse are explored. The review concludes that despite a general acceptance in the literature that life events have an impact on psychotic illness the findings of life events studies provide contradictory and inconclusive results and that this is at least partly attributable to the differing methodologies utilized. Continued methodological refinements may generate a 'gold standard' methodology that with repeated use will provide consistency in findings.


The evolution of social learning rules: payoff-biased and frequency-dependent biased transmission.
Humans and other animals do not use social learning indiscriminately, rather, natural selection has favoured the evolution of social learning rules that make selective use of social learning to acquire relevant information in a changing environment. We present a gene-culture coevolutionary analysis of a small selection of such rules (unbiased social learning, payoff-biased social learning and frequency-dependent biased social learning, including conformism and anti-conformism) in a population of asocial learners where the environment is subject to a constant probability of change to a novel state. We define conditions under which each rule evolves to a genetically polymorphic equilibrium. We find that payoff-biased social learning may evolve under high levels of environmental variation if the fitness benefit associated with the acquired behaviour is either high or low but not of intermediate value. In contrast, both conformist and anti-conformist biases can become fixed when environment variation is low, whereupon the mean fitness in the population is higher than for a population of asocial learners. Our examination of the population dynamics reveals stable limit cycles under conformist and anti-conformist biases and some highly complex dynamics including chaos. Anti-conformists can out-compete conformists when conditions favour a low equilibrium frequency of the learned behaviour. We conclude that evolution, punctuated by the repeated successful invasion of different social learning rules, should continuously favour a reduction in the equilibrium frequency of asocial learning, and propose that, among competing social learning rules, the dominant rule will be the one that can persist with the lowest frequency of asocial learning.


Phonological recoding under articulatory suppression.
We report data from an experiment in which participants performed immediate serial recall of visually presented words with or without articulatory suppression, while also performing homophone or rhyme detection. The separation between homophonous or rhyming pairs in the list was varied. According to the working memory model (Baddeley, 1986; Baddeley & Hitch, 1974), suppression should prevent articulatory recoding. Nevertheless, rhyme and homophone detection was well above chance. However, with suppression, participants showed a greater tendency to false-alarm to orthographically related foils (e.g., GIVE-FIVE). This pattern is similar to that observed in short-term memory patients.


Graphenes prepared by Staudenmaier, Hofmann and Hummers methods with consequent thermal exfoliation exhibit very different electrochemical properties.
Large-scale fabrication of graphene is highly important for industrial and academic applications of this material. The most common large-scale preparation method is the oxidation of graphite to graphite oxide using concentrated acids in the presence of strong oxidants and consequent thermal exfoliation and reduction by thermal shock to produce reduced graphene. These oxidation methods typically use concentrated sulfuric acid (a) in combination with fuming nitric acid and KClO(3) (Staudenmaier method), (b) in combination with concentrated nitric acid and KClO(3) (Hofmann method) or (c) in the absence of nitric acid but in the presence of NaNO(3) and KMnO(4) (Hummers method). The evaluation of quality and applicability of the graphenes produced by these various methods is of high importance and is attempted side-by-side for the first time in this paper. Full-scale characterization of thermally reduced graphenes prepared by these standard methods was performed with techniques such as transmission and scanning electron microscopy, Raman spectroscopy and X-ray photoelectron spectroscopy. Their applicability for electrochemical devices was further evaluated by means of cyclic voltammetry techniques. We showed that while Staudenmaier and Hofmann methods (methods that do not use potassium permanganate as oxidant) generated thermally reduced graphenes with comparable electrochemical properties, the graphene prepared by the Hummers method which uses permanganate as oxidant showed higher heterogeneous electron transfer rates and lower overpotentials as compared to graphenes prepared by the Staudenmaier or Hofmann methods. This clearly shows that the methods of preparations have dramatic influences on the materials properties and, thus, such findings are of eminent importance for practical applications as well as for academic research.


Outcomes, preferences for resuscitation, and physician-patient communication among patients with metastatic colorectal cancer. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.
To describe characteristics, outcomes, and decision making in patients with colorectal cancer metastatic to the liver, and to examine the relationship of doctor-patient communication with patient understanding of prognosis and physician understanding of patients' treatment preferences. The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) was a prospective cohort study conducted at five teaching hospitals in the United States between 1989 and 1994. Participants in this study were hospitalized patients 18 years of age or older with known liver metastases who had been diagnosed with colorectal cancer at least 1 month earlier. Data were collected by patient interview and chart review at study entry; patients were interviewed again at 2 and 6 months. Data collected by physician interview included estimates of survival and impressions of patients' preferences for cardiopulmonary resuscitation (CPR). Patients and physicians were also asked about discussions about prognosis and resuscitation preferences. We studied 520 patients with metastatic colorectal cancer (median age 64, 56% male, 80% white, 2-month survival 78%, 6-month survival 56%). Quality of life (62% "good" to "excellent") and functional status (median number of disabilities = 0) were high at study entry and remained so among interviewed survivors at 2 and 6 months. Of 339 patients with available information, 212 (63%) of 339 wanted CPR in the event of a cardiopulmonary arrest. Factors independently associated with preference for resuscitation included younger age, better quality of life, absence of lung metastases, and greater patient estimate of 2-month prognosis. Of the patients who preferred not to receive CPR, less than half had a do-not-resuscitate note or order written. Patients' self-assessed prognoses were less accurate than those of their physicians. Physicians incorrectly identified patient CPR preferences in 30% of cases. Neither patient prognostication nor physician understanding of preferences were significantly better when discussions were reported between doctors and patients. A majority of patients with colorectal cancer have preferences regarding end of life care. The substantial misunderstanding between patients and their physicians about prognosis and treatment preferences appears not to be improved by direct communication. Future research focused on enhancing the effectiveness of communication between patients and physicians about end of life issues is needed.


Bites by Russell's vipers (Daboia russelii siamensis) in Myanmar: effect of the snake's length and recent feeding on venom antigenaemia and severity of envenoming.
An improved enzyme immunoassay technique (EIA) was used in the diagnosis of 311 suspected Russell's viper bite cases in Myanmar [Burma], 181 of whom (58%) had systemic envenoming. Russell's viper venom was detected in the sera of 175 (56.3%), cobra or green pit viper venoms in 4 (1.3%), and no venom in the remaining 132 (42.4). Among 175 of these patients who failed to bring the dead snake, EIA achieved a specific diagnosis of Russell's viper envenoming in 101 (58%). The serum venom antigen concentration was higher in patients with systemic envenoming than in those with local or no envenoming and it increased with the development of coagulopathy. Stomach contents were examined in 101 Russell's vipers responsible for bites. The presence of prey, usually a rodent, in the snake's stomach, indicating that it had eaten recently, did not influence the severity of envenoming, the initial venom level, or the percentage circumference increase and the extent of local swelling in the bitten limb. One hundred and fifty-five Russell's vipers responsible for bites showed a bimodal distribution of total lengths. The smaller snakes had probably been born that year. Longer snakes were responsible for more severe envenoming, a shorter interval between the bite and the detection of incoagulable blood, and more extensive local swelling with a greater percentage circumference increase of the bitten limb; but their bites were not associated with higher initial venom antigenaemia or a greater risk of developing acute renal failure.


Population genetic analysis reveals a geographically limited transition zone between two genetically distinct Atlantic salmon lineages in Norway.
Atlantic salmon is characterized by a high degree of population genetic structure throughout its native range. However, while populations inhabiting rivers in Norway and Russia make up a significant proportion of salmon in the Atlantic, thus far, genetic studies in this region have only encompassed low to modest numbers of populations. Here, we provide the first "in-depth" investigation of population genetic structuring in the species in this region. Analysis of 18 microsatellites on >9,000 fish from 115 rivers revealed highly significant population genetic structure throughout, following a hierarchical pattern. The highest and clearest level of division separated populations north and south of the Lofoten region in northern Norway. In this region, only a few populations displayed intermediate genetic profiles, strongly indicating a geographically limited transition zone. This was further supported by a dedicated cline analysis. Population genetic structure was also characterized by a pattern of isolation by distance. A decline in overall genetic diversity was observed from the south to the north, and two of the microsatellites showed a clear decrease in number of alleles across the observed transition zone. Together, these analyses support results from previous studies, that salmon in Norway originate from two main genetic lineages, one from the Barents-White Sea refugium that recolonized northern Norwegian and adjacent Russian rivers, and one from the eastern Atlantic that recolonized the rest of Norway. Furthermore, our results indicate that local conditions in the limited geographic transition zone between the two observed lineages, characterized by open coastline with no obvious barriers to gene flow, are strong enough to maintain the genetic differentiation between them.


Antihypertensive and lipid lowering treatment in 70-74 year old individuals--predictors for treatment and blood-pressure control: a population based survey. The Hordaland Health Study (HUSK).
In an elderly, community based population we aimed at investigating antihypertensive and lipid lowering medication use in relation to own and familiar cardiovascular morbidity and diabetes mellitus, as well as to lifestyle factors and general health. We also examined levels of blood pressure in untreated and treated residents, to investigate factors correlating with blood pressure control. A health survey carried out in 1997-9 in the county of Hordaland, Norway included a self-administered questionnaire mailed to 4,338 persons born in 1925-7. Drug use the day prior to filling in the questionnaire was reported. A health check-up was carried out, where their systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), and serum-cholesterol level were recorded. One third of respondents used one or more antihypertensive drugs, while 13% of men and women were treated with a statin. Diabetes mellitus, own or relatives'cardiovascular disease, having quit smoking, physical inactivity, and overweight correlated with antihypertensive treatment. Mean blood pressure was lower in respondents not on treatment. Among those on treatment, 38% of men and 29% of women had reached a target BP-level of lower than 140/90 mm Hg. Own cardiovascular disease and a low BMI correlated with good BP-control. One third of 70-74 year old individuals living in the community used one or more antihypertensive drugs. Only around one third of those treated had reached a target BP-level of less than 140/90 mm Hg. Own cardiovascular disease and a low BMI correlated with good BP-control.


TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression.
Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal-regulated kinase (ERK)1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN.


Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial.
MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations. Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts. From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts. Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed.


Consensus statement on effective communication of urgent diagnoses and significant, unexpected diagnoses in surgical pathology and cytopathology from the College of American Pathologists and Association of Directors of Anatomic and Surgical Pathology.
Recognizing the difficulty in applying the concept of critical values to anatomic pathology diagnoses, the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology have chosen to reevaluate the concept of critical diagnoses. To promote effective communication of urgent and significant, unexpected diagnoses in surgical pathology and cytology. A comprehensive literature search was conducted and reviewed by an expert panel. A policy of effective communication of important results in surgical pathology and cytology is desirable to enhance patient safety and to address multiple regulatory requirements. Each institution should create its own policy regarding urgent diagnoses and significant, unexpected diagnoses in anatomic pathology. This policy should be separate from critical results or panic-value policies in clinical pathology, with the expectation of a different time frame for communication. Urgent diagnosis is defined as a medical condition that, in most cases, should be addressed as soon as possible. Significant, unexpected diagnosis is defined as a medical condition that is clinically unusual or unforeseen and should be addressed at some point in the patient's course. Further details of this statement are provided.


Civil society engagement in innovation and research through the European Public Health Association.
The European Public Health Association (EUPHA) proposed and led PHIRE (Public Health Innovation and Research in Europe), with co-financing by the European Commission, to assess public health innovation and research at national level in Europe. PHIRE was also designed to promote organizational development and capacity building of EUPHA. We assess the success and limitations of using EUPHA's participative structures. In total, 30 European countries were included-27 EU countries, Iceland, Norway and Switzerland. EUPHA thematic section presidents were asked to identify country informants to report, through a web-based questionnaire, on eight public health innovations. National public health associations (EUPHA member organizations) were requested to identify their national public health research programmes and calls, review the health research system, coordinate a stakeholder workshop and provide a national report. The section and national reports were assessed for responses and completeness. Half of the final responding CIs were members of EUPHA sections and the other half gained from other sources. Experts declined to respond for reasons including lack of time, knowledge of the innovation or funding. National public health associations held PHIRE workshops with Ministries of Health in 14 countries; information for 10 countries was gained through discussions within the national association, or country visits by PHIRE partners. Six countries provided no response. Some national associations had too weak organizational structures for the work or insufficient financial resources or criticism of the project. EUPHA is the leading civil society organization giving support to public health research in Europe. PHIRE created new knowledge and supported organizational development. EUPHA sections gained expert reports on public health innovations in European countries and national public health associations reported on national public health research systems. Significant advances could be made if the European Commission worked more directly with EUPHA's expert members and with the national public health associations.


Wild-type measles virus infection in human CD46/CD150-transgenic mice: CD11c-positive dendritic cells establish systemic viral infection.
We generated transgenic (TG) mice that constitutively express human CD46 (huCD46) and/or TLR-inducible CD150 (huCD150), which serve as receptors for measles virus (MV). These mice were used to study the spreading and pathogenicity of GFP-expressing or intact laboratory-adapted Edmonston and wild-type Ichinose (IC) strains of MV. Irrespective of the route of administration, neither type of MV was pathogenic to these TG mice. However, in ex vivo, limited replication of IC was observed in the spleen lymphocytes from huCD46/huCD150 TG and huCD150 TG, but not in huCD46 TG and non-TG mice. In huCD150-positive TG mouse cells, CD11c-positive bone marrow-derived myeloid dendritic cells (mDC) participated in MV-mediated type I IFN induction. The level and induction profile of IFN-beta was higher in mDC than the profile of IFN-alpha. Wild-type IC induced markedly high levels of IFN-beta compared with Edmonston in mDC, as opposed to human dendritic cells. We then generated huCD46/huCD150 TG mice with type I IFN receptor (IFNAR1)-/- mice. MV-bearing mDCs spreading to draining lymph nodes were clearly observed in these triple mutant mice in vivo by i.p. MV injection. Infectious lymph nodes were also detected in the double TG mice into which MV-infected CD11c-positive mDCs were i.v. transferred. This finding suggests that in the double TG mouse model mDCs once infected facilitate systemic MV spreading and infection, which depend on mDC MV permissiveness determined by the level of type I IFN generated via IFNAR1. Although these results may not simply reflect human MV infection, the huCD150/huCD46 TG mice may serve as a useful model for the analysis of MV-dependent modulation of mDC response.


Updating the Canadian obesity maps: an epidemic in progress.
Obesity is a growing problem in Canada and worldwide. While obesity maps that convey changing rates over time and geography provide a useful way to convey such information, regional obesity surveillance maps for Canada have not been published since 1998. This research provides a summary of changing Canadian obesity rates since that time. We computed estimated obesity rates for provinces and territories across Canada from 2000 to 2011. Data were based on Canadian Community Health Survey and corrected for self-report bias. Data reporting the estimated percent of the adult population who are obese were mapped over time overall and by sex according to Canadian province and territory. The data indicate that the estimated prevalence of obesity across Canada has continued to increase over the past 11 years. Current rates exceed 30% in the Maritime provinces (Newfoundland, New Brunswick, Nova Scotia, Prince Edward Island) and in two territories (Northwest Territory, Nunavut). Data for men and women are generally consistent. The major increase in obesity appears to have occurred in the first part of this period, with relatively stable rates found from 2008 to 2011. However, obesity rates are still climbing, warranting continued surveillance efforts. Maps showing changing regional obesity rates provide a compelling pan-Canadian portrait that can lead to an impetus for action for the public, health care providers, and decision makers. Such colour-coded maps offer an efficient way to convey complex data that transcends language differences and personalizes the data for the viewer.


Molecular genetic analysis of terminal steps in bacteriochlorophyll a biosynthesis: characterization of a Rhodobacter capsulatus strain that synthesizes geranylgeraniol-esterified bacteriochlorophyll a.
Site-directed mutational analysis of the Rhodobacter capsulatus photosynthesis gene cluster was undertaken in order to identify and characterize genetic loci involved in bacteriochlorophyll a biosynthesis. A mutant in orf304 was shown to accumulate the tetrapyrrole intermediate "bacteriochlorophyllide a" which is a tetrapyrrole that has a bacteriochlorophyll a ring structure without the presence of an esterifying alcohol. A mutant in orf391 is shown to synthesize bacteriochlorophyll a that is esterified with geranylgeraniol rather than the normal phytol. This latter result provides the first genetic confirmation that esterification of bacteriochlorophyllide a initially involves the addition of a geranylgeraniol group followed by sequential reduction of the geranylgeraniol moiety to phytol which is the end product of the pathway. An R. capsulatus strain synthesizing geranylgeraniol-esterified bacteriochlorophyll is shown to exhibit severely impaired photosynthetic growth capability. This is despite our observation that synthesis of geranylgeraniol-esterified bacteriochlorophyll does not affect the energy transfer rate from light harvesting to reaction center complexes nor the electron transfer function as measured by the yield of electron transfer to the primary and secondary quinones, the charge recombination rate from the quinones, and the rate of cytochrome c2 oxidation. We conclude that the observed reduction of the photosynthetic growth rate observed for R. capsulatus strains that synthesize geranylgeraniol-esterified bacteriochlorophyll is primarily a consequence of the reduced steady-state level of the photosystem.


Survivin is a negative prognostic factor in malignant pleural effusion.
Survivin is a well-known member of the inhibitor of apoptosis family, and has been related to increased tumour aggressivity, both in tissue and in pleural fluid. In patients with malignant pleural effusion, we sought to investigate the changes in pleural fluid survivin concentrations induced by talc instillation into the pleural space. Those changes were also examined in relation to pleurodesis outcome and patient survival. We investigated 84 patients with malignant pleural effusion who underwent talc pleurodesis. Of them, 32 had breast cancer, 25 lung cancer and 27 had mesothelioma. Serial samples of pleural fluid were obtained before thoracoscopy (baseline) and 24 hours thereafter. Survivin levels were successfully quantified in all pleural fluid samples, and they were significantly higher in samples obtained after thoracoscopic talc poudrage compared with baseline (P < .001). Patients with higher pleural fluid survivin levels at baseline had a significantly poorer pleurodesis outcome (P = .004). A 30 pg/mL cut-off for baseline survivin in pleural fluid predicted failure of pleurodesis with a 54% sensitivity and 79% specificity (P = .009). Moreover, median postpleurodesis survival of patients with baseline survivin levels ≥30 pg/mL was 4 months (range: 0.1-38), compared with 13 months (range: 0.1-259) in patients below that cut-off (P < .001). Elevated pleural fluid survivin concentrations are useful to predict failure of pleurodesis and are associated with shorter survival in patients with malignant pleural effusion.


Inhibition of angiogenesis and suppression of colorectal cancer metastatic to the liver using the Sleeping Beauty Transposon System.
Metastatic colon cancer is one of the leading causes of cancer-related death worldwide, with disease progression and metastatic spread being closely associated with angiogenesis. We investigated whether an antiangiogenic gene transfer approach using the Sleeping Beauty (SB) transposon system could be used to inhibit growth of colorectal tumors metastatic to the liver. Liver CT26 tumor-bearing mice were hydrodynamically injected with different doses of a plasmid containing a transposon encoding an angiostatin-endostatin fusion gene (Statin AE) along with varying amounts of SB transposase-encoding plasmid. Animals that were injected with a low dose (10 μg) of Statin AE transposon plasmid showed a significant decrease in tumor formation only when co-injected with SB transposase-encoding plasmid, while for animals injected with a higher dose (25 μg) of Statin AE transposon, co-injection of SB transposase-encoding plasmid did not significantly affect tumor load. For animals injected with 10 μg Statin AE transposon plasmid, the number of tumor nodules was inversely proportional to the amount of co-injected SB plasmid. Suppression of metastases was further evident in histological analyses, in which untreated animals showed higher levels of tumor cell proliferation and tumor vascularization than animals treated with low dose transposon plasmid. These results demonstrate that hepatic colorectal metastases can be reduced using antiangiogenic transposons, and provide evidence for the importance of the transposition process in mediating suppression of these tumors.


Social participation post stroke: a meta-ethnographic review of the experiences and views of community-dwelling stroke survivors.
There is currently no consensus on a definition of participation that describes experiences and challenges of people with stroke. This meta-synthesis aimed to identify, appraise and synthesise qualitative research on stroke survivors' views of their experiences of social participation. Ten electronic databases were searched for relevant qualitative studies in English from January 2001 and ending September 2011. Searching was extended to grey literature, hand searching journals, checking references and contacting authors of included studies. Two independent reviewers extracted data and assessed methodological study quality. A meta-ethnographic approach described by Noblit and Hare was used to synthesise findings. Eleven articles met the inclusion criteria. Five main themes were identified: (1) change and disruption; (2) perceived magnitude of individual barriers; (3) pursuing personal choices; (4) building individual confidence and (5) evaluating personal meaning. The ability of the person to accept their stroke-related problems and adapt their behaviour and attitude by using active decision-making and self-management skills are central factors to social participation post stroke. This synthesis contributes an important addition to the conceptual understanding of social participation relevant to people with stroke within the UK. Implications for Rehabilitation Social participation post stroke appears to be a dynamic, complex and continuous individual process, and a personalised longer term approach to rehabilitation would be beneficial. Rehabilitation should be focussed on what is most meaningful to the person following their stroke. Professionals can do this by using questions which explore what stroke survivors want to do; what they perceive to be the significant barriers, and what skills and supportive networks are needed. Our findings emphasise the importance of rehabilitation practitioners supporting stroke survivors' to engage with meaningful self-selected social activities and the importance of stroke survivors having the freedom and autonomy to set their own goals within rehabilitation. The person's ability to adapt their behaviour and attitude by being positive, hopeful, determined, resilient and courageous is an essential part of pursuing their self-selected valued activities. Acknowledging and encouraging the importance of these behaviours and attitudes should be promoted in rehabilitation.