Preservation of viral genomes in 700-y-old caribou feces from a subarctic ice patch.
Viruses preserved in ancient materials provide snapshots of past viral diversity and a means to trace viral evolution through time. Here, we use a metagenomics approach to identify filterable and nuclease-resistant nucleic acids preserved in 700-y-old caribou feces frozen in a permanent ice patch. We were able to recover and characterize two viruses in replicated experiments performed in two different laboratories: a small circular DNA viral genome (ancient caribou feces associated virus, or aCFV) and a partial RNA viral genome (Ancient Northwest Territories cripavirus, or aNCV). Phylogenetic analysis identifies aCFV as distantly related to the plant-infecting geminiviruses and the fungi-infecting Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1 and aNCV as within the insect-infecting Cripavirus genus. We hypothesize that these viruses originate from plant material ingested by caribou or from flying insects and that their preservation can be attributed to protection within viral capsids maintained at cold temperatures. To investigate the tropism of aCFV, we used the geminiviral reverse genetic system and introduced a multimeric clone into the laboratory model plant Nicotiana benthamiana. Evidence for infectivity came from the detection of viral DNA in newly emerged leaves and the precise excision of the viral genome from the multimeric clones in inoculated leaves. Our findings indicate that viral genomes may in some circumstances be protected from degradation for centuries.


Tick-Borne Encephalitis: An Update for the Special Operations Forces Provider.
Tick-borne encephalitis (TBE) is a severe disease caused by the tick-borne encephalitis virus (TBEV). TBEV is endemic throughout Eurasia and can cause persistent neurologic deficits and death. Special Operations Forces (SOF) participating in field exercises or operations in TBE-endemic countries are at significantly increased risk of infection. Unlike Lyme disease and other tick-borne illnesses, transmission of TBEV can be immediate, and early tick removal does not reduce the risk of infection. While there are no virus-specific treatments available, the US Food and Drug Administration (FDA) recently approved a TBE vaccine that has yet to be incorporated into formal Department of Defense (DoD) recommendations. SOF medical providers should be aware of this disease entity and consider the TBE vaccine when planning exercises and operations in areas of responsibility (AORs) with TBE-endemic countries. This review serves as a refresher and update on the epidemiology, transmission, and management of TBE for the SOF provider.


Aflatoxin-albumin adducts: a basis for comparative carcinogenesis between animals and humans.
The study objectives were (a) to correlate AFB1 serum albumin adduct levels with AFB1-DNA adduct levels in liver in different rodent species to determine whether the former could serve as a marker of hepatic DNA adduct levels irrespective of species, and (b) to relate the levels of both adducts to differences in susceptibility to tumor induction by AFB1 in the different species. Finally, an attempt was made to compare the dose response for AFB1-albumin adduct formation in the rodent species with that in human populations exposed environmentally to AFB1. Three strains of rat (Fischer 344, Wistar, and Sprague-Dawley), and one strain each of guinea pig (Hartley), hamster (Syrian golden), and mouse (C57BL) were treated by gavage with up to 14 daily doses of between 1 and 80 mug AFB1/kg body weight. Animals were killed 24 h after 1, 3, 7, or 14 days treatment. A dose response in both AFB1-albumin and AFB1-DNA adducts was seen for all species and strains with steady-state adduct levels at 14 days. In rat strains at 14 days after treatment with 20 mu g/kg, the mean AFB1-albumin levels were between 24 and 26 pg AFB1-lysine equivalent/mg albumin, and the mean AFB1-DNA adduct levels were between 1.5 and 2.5 pmol (8, 9-dihydro-8- (2, 6-diamino-4-oxo-3, 4-dihydro-pyrimid-5-ylforamido-)- 9-hydroxy) AFB1/mg DNA. The level of both adducts was in the following order: rat > guinea pig > hamster > mouse. In the case of AFB1-albumin, the mean adduct level at 14 days in the three rat strains was approximately 1.5, 3.0, and 8-fold higher than in the guinea pig, hamster, and mouse, respectively. When the levels of the albumin and DNA adducts at 14 days were plotted against each other for all species and strains, a correlation was observed (r = 0.83; P = < 0.0001; n = 57; two-tailed test) suggesting a constant relationship between the level of binding of AFB1 to serum albumin and liver DNA. The levels of AFB1-albumin adduct also reflect at least qualitatively the relative susceptibility of the different species to AFB1 carcinogenesis; the rat is sensitive and the hamster and mouse are resistant. The level of AFB1-albumin adduct formed as a function of a single dose of AFB1 in rodents was compared to data from humans exposed environmentally to AFB1. This comparison yielded a value for the three rat strains of between 0.3 and 0.51 pg AFB1-lysine equivalent/mg albumin/1 mu g AFB1/kg body weight and a value for the mouse of <0.025. The best estimate for people from The Gambia and southern China was 1.56 pg/mg albumin for the same exposure. These data suggest that humans exposed to AFB1 form amounts of albumin addducts, and by extrapolation amounts of DNA adducts, closer to those observed in AFB1-sensitive species and 1-2 orders of magnitude higher levels than the AFB1-resistant species.


Projections of future extreme weather losses under changes in climate and exposure.
Many attempts are made to assess future changes in extreme weather events due to anthropogenic climate change, but few studies have estimated the potential change in economic losses from such events. Projecting losses is more complex as it requires insight into the change in the weather hazard but also into exposure and vulnerability of assets. This article discusses the issues involved as well as a framework for projecting future losses, and provides an overview of some state-of-the-art projections. Estimates of changes in losses from cyclones and floods are given, and particular attention is paid to the different approaches and assumptions. All projections show increases in extreme weather losses due to climate change. Flood losses are generally projected to increase more rapidly than losses from tropical and extra-tropical cyclones. However, for the period until the year 2040, the contribution from increasing exposure and value of capital at risk to future losses is likely to be equal or larger than the contribution from anthropogenic climate change. Given the fact that the occurrence of loss events also varies over time due to natural climate variability, the signal from anthropogenic climate change is likely to be lost among the other causes for changes in risk, at least during the period until 2040. More efforts are needed to arrive at a comprehensive approach that includes quantification of changes in hazard, exposure, and vulnerability, as well as adaptation effects.


Documenting best practices for maintaining access to HIV prevention, care and treatment in an era of shifting immigration policy and discourse.
Changes in the United States federal-level political landscape have been felt within immigrant communities, and the public health clinics that serve them. We sought to document how HIV prevention and care clinics are reaching and retaining their immigrant community patients during a period of retrenchment of accessible public resources and immigrant rights. From May 2018 through January 2019, we conducted 20 in-depth interviews with clinicians, case workers, advocates, legal experts, and peer navigators in Northern and Central California. Interviews were recorded and transcribed. Several themes emerged which can be grouped into three primary areas: changes post-election, challenges meeting the needs of patients, and best practices for maintaining access to prevention and care services. Post-election, providers reported some of their patients skipping clinic appointments due to fear of Immigration and Customs Enforcement (ICE) raids and deportation while other patients had moved to locations that they felt were less policed. Challenges emerged around linguistic competency, meeting basic needs such as housing stability and employment, and treating mental health sequelae resulting from trauma experienced in home countries or during migration itself. Best practices included hiring bi-lingual and bi-cultural staff, linking to legal services to assist with immigration status, holding trainings around immigrant rights and responses to ICE raids, and building trust with immigrant patients by assuring them that their status would not be collected or reported. In light of adverse policy changes affecting immigrants, agencies have begun to institute best practices to mitigate the negative impact of those policies on their clients and patients.


Congenital heart disease in the Niger Delta region of Nigeria: a four-year prospective echocardiographic analysis.
Echocardiographic evaluation remains the gold standard for the diagnosis of structural cardiac disease. No previous prospective studies have been done on the prevalence of congenital heart disease (CHD) in the Niger Delta area. This study was done to determine the frequency and pattern of congenital heart disease, using echocardiography as a diagnostic tool. All patients presenting to the Paediatric Cardiology clinics of two centres, the University of Port Harcourt Teaching Hospital and the Paediatric Care Hospital between April 2009 and March 2013, were recruited and all had echocardiography performed. Prevalence of CHD in this study was 14.4 per 1 000 children; 277 (83.4%) of the patients had acyanotic CHD and 55 (16.6%) had cyanotic CHD. Ventricular septal defect and tetralogy of Fallot were the commonest acyanotic and cyanotic heart defects, respectively. The high prevalence of CHD in this study is the highest in the country and Africa, and may be attributable to the increased oil spillage and gas flaring from petroleum exploitation in this region.


Context-bound communication skills training: development of a new method.
To examine how communication skills training might be integrated into everyday clinical practice in a manner that is acceptable to clinicians. General practitioners from 3 group practices agreed to take part, in turn, in a study of how to manage difficult consultations about antibiotic prescribing for acute respiratory infections. This provided the opportunity to conduct communication skills training in which lessons learned from one practice were taken into the next. United Kingdom general practices. Three groups of general practitioners. Difficulties with the acceptability of a traditional off-site workshop approach, using role play as the main teaching method, led to the development of a new training method (context-bound training), which proved to be practical and acceptable to experienced clinicians. The main features of the method were the delivery of training in the clinicians' place of work, and the transformation of their reported difficult cases into scenarios which they then encountered with a standardized simulated patient before and after brief seminars. Everyday clinical experience was kept in the foreground and 'communication skills' in the background. The method is acceptable to clinicians and adaptable to a range of clinical situations. It offers potential for improving the communication skills of clinicians both in hospital and primary care settings.


An Hsp70 antisense gene affects the expression of HSP70/HSC70, the regulation of HSF, and the acquisition of thermotolerance in transgenic Arabidopsis thaliana.
The genes and proteins of the HSP70 family, are involved in important processes in cells and organelles at normal temperature and after heat stress. Constitutive Hsc70 and heat-inducible Hsp70 genes are known in all organisms including plants. The goal of our present investigation was to generate an Hsp70 mutation in Arabidopsis thaliana. In a transgenic approach a heat-inducible antisense Hsp70 gene was constructed, plants were transformed and screened for lack of heat-inducible HSP70 mRNA; two such lines were further investigated. In these plants the Hsp70 gene was not induced by heat shock, and the level of HSC70 RNA was also greatly reduced. This negative antisense effect was specific for genes of the HSP70 family and the induction of mRNAs encoding the small HSP18 class of heat shock protein (HSP) was not affected. The level of HSP70/HSC70 proteins was significantly reduced in transgenic plants, but HSP18 was induced to the same level in different transgenic lines and in untransformed plants. The acquisition of thermotolerance was negatively affected in artisense plants, the survival temperature being 2 degrees C below the survival temperature of the wild type and other transgenic lines. Another major effect concerning the regulation of the endogenous heat shock transcription factor HSF was detected by testing the ability to form heterotrimers between authentic HSF and recombinant HSF-GUS (beta-glucuronidase) proteins. The shut-off time, required to turn of HSF activity during recovery from heat stress, was significantly prolonged in antisense plants compared with wild-type and other transgenic lines. Our results imply a dual role of HSP70 in plants, a protective role in thermotolerance and a regulatory effect on HSF activity and hence the autoregulation of the heat shock response.


Crosstalk between the circadian clock circuitry and the immune system.
Various features, components, and functions of the immune system present daily variations. Immunocompetent cell counts and cytokine levels present variations according to the time of day and the sleep-wake cycle. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwork. The biological clocks intrinsic to immune cells and lymphoid organs, together with inputs from the central pacemaker of the suprachiasmatic nuclei via humoral and neural pathways, regulate the function of cells of the immune system, including their response to signals and their effector functions. Consequences of this include, for example, the daily variation in the response to an immune challenge (e.g., bacterial endotoxin injection) and the circadian control of allergic reactions. The circadian-immune connection is bidirectional, because in addition to this circadian control of immune functions, immune challenges and immune mediators (e.g., cytokines) were shown to have strong effects on circadian rhythms at the molecular, cellular, and behavioral levels. This tight crosstalk between the circadian and immune systems has wide-ranging implications for disease, as shown by the higher incidence of cancer and the exacerbation of autoimmune symptoms upon circadian disruption.


Comparison of BEAMing and Droplet Digital PCR for Circulating Tumor DNA Analysis.
Circulating tumor DNA (ctDNA) assays are increasingly used for clinical decision-making, but it is unknown how well different assays agree. We aimed to assess the agreement in ctDNA mutation calling between BEAMing (beads, emulsion, amplification, and magnetics) and droplet digital PCR (ddPCR), 2 of the most commonly used digital PCR techniques for detecting mutations in ctDNA. Baseline plasma samples from patients with advanced breast cancer enrolled in the phase 3 PALOMA-3 trial were assessed for ESR1 and PIK3CA mutations in ctDNA with both BEAMing and ddPCR. Concordance between the 2 approaches was assessed, with exploratory analyses to estimate the importance of sampling effects. Of the 521 patients enrolled, 363 had paired baseline ctDNA analysis. ESR1 mutation detection was 24.2% (88/363) for BEAMing and 25.3% (92/363) for ddPCR, with good agreement between the 2 techniques (κ = 0.9l; 95% CI, 0.85-0.95). PIK3CA mutation detection rates were 26.2% (95/363) for BEAMing and 22.9% (83/363) for ddPCR, with good agreement (κ = 0.87; 95% CI, 0.81-0.93). Discordancy was observed for 3.9% patients with ESR1 mutations and 5.0% with PIK3CA mutations. Assessment of individual mutations suggested higher rates of discordancy for less common mutations (P = 0.019). The majority of discordant calls occurred at allele frequency <1%, predominantly resulting from stochastic sampling effects. This large, clinically relevant comparison showed good agreement between BEAMing and ddPCR, suggesting sufficient reproducibility for clinical use. Much of the observed discordancy may be related to sampling effects, potentially explaining many of the differences in the currently available ctDNA literature.


Comparing the accuracy of brief versus long depression screening instruments which have been validated in low and middle income countries: a systematic review.
Given the high prevalence of depression in primary health care (PHC), the use of screening instruments has been recommended. Both brief and long depression screening instruments have been validated in low and middle income countries (LMIC), including within HIV care settings. However, it remains unknown whether the brief instruments validated in LMIC are as accurate as the long ones. We conducted a search of PUBMED, the COCHRANE library, AIDSLINE, and PSYCH-Info from their inception up to July 2011, for studies that validated depression screening instruments in LMIC. Data were extracted into tables and analyzed using RevMan 5.0 and STATA 11.2 for the presence of heterogeneity. Nineteen studies met our inclusion criteria. The reported prevalence of depression in LMIC ranged from 11.1 to 53%. The area under curve (AUC) scores of the validated instruments ranged from 0.69-0.99. Brief as well as long screening instruments showed acceptable accuracy (AUC≥0.7). Five of the 19 instruments were validated within HIV settings. There was statistically significant heterogeneity between the studies, and hence a meta-analysis could not be conducted to completion. Heterogeneity chi-squared = 189.23 (d.f. = 18) p<.001. Brief depression screening instruments in both general and HIV-PHC are as accurate as the long ones. Brief scales may have an edge over the longer instruments since they can be administered in a much shorter time. However, because the ultra brief scales do not include the whole spectrum of depression symptoms including suicide, their use should be followed by a detailed diagnostic interview.


Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity.
We have recently demonstrated that the proteasome inhibitor, bortezomib, administered immediately following murine allogeneic bone marrow transplantation (BMT) resulted in marked inhibition of acute graft-versus-host disease (GVHD) with retention of graft-versus-tumor effects. We now assessed the effects of delayed bortezomib administration (5 or more days after BMT) on GVHD. Recipient C57BL/6 (H2b) mice were lethally irradiated and given transplants of bone marrow cells and splenocytes from major histocompatibility complex (MHC)-disparate BALB/c (H2d) donors. In marked contrast to the effects of bortezomib on GVHD prevention when administered immediately after BMT, delayed bortezomib administration resulted in significant acceleration of GVHD-dependent morbidity. No toxicity was observed following delayed bortezomib administration in models where donor T cells were not coadministered, indicating that these deleterious effects were critically dependent on GVHD induction. The increase in GVHD susceptibility even occurred when late administration of bortezomib was preceded by early administration. Pathologic assessment revealed that significant increases in gastrointestinal lesions occurred following delayed bortezomib administration during GVHD. This pathology correlated with significant increases of type 1 tumor necrosis factor alpha (TNF-alpha) receptor transcription in gastrointestinal cells and with significant increases of TNF-alpha, interleukin 1beta (IL-1beta), and IL-6 levels in the serum. These results indicate that the differential effects of proteasome inhibition with bortezomib on GVHD are critically dependent on the timing of bortezomib administration.


Transciptome analysis of the gill and swimbladder of Takifugu rubripes by RNA-Seq.
The fish gill, as one of the mucosal barriers, plays an important role in mucosal immune response. The fish swimbladder functions for regulating buoyancy. The fish swimbladder has long been postulated as a homologous organ of the tetrapod lung, but the molecular evidence is scarce. In order to provide new information that is complementary to gill immune genes, initiate new research directions concerning the genetic basis of the gill immune response and understand the molecular function of swimbladder as well as its relationship with lungs, transcriptome analysis of the fugu Takifugu rubripes gill and swimbladder was carried out by RNA-Seq. Approximately 55,061,524 and 44,736,850 raw sequence reads from gill and swimbladder were generated, respectively. Gene ontology (GO) and KEGG pathway analysis revealed diverse biological functions and processes. Transcriptome comparison between gill and swimbladder resulted in 3,790 differentially expressed genes, of which 1,520 were up-regulated in the swimbladder while 2,270 were down-regulated. In addition, 406 up regulated isoforms and 296 down regulated isoforms were observed in swimbladder in comparison to gill. By the gene enrichment analysis, the three immune-related pathways and 32 immune-related genes in gill were identified. In swimbladder, five pathways including 43 swimbladder-enriched genes were identified. This work should set the foundation for studying immune-related genes for the mucosal immunity and provide genomic resources to study the relatedness of the fish swimbladder and mammalian lung.


Impact of increasing fruit and vegetables and flavonoid intake on the human gut microbiota.
Epidemiological studies have shown protective effects of fruits and vegetables (F&V) in lowering the risk of developing cardiovascular diseases (CVD) and cancers. Plant-derived dietary fibre (non-digestible polysaccharides) and/or flavonoids may mediate the observed protective effects particularly through their interaction with the gut microbiota. The aim of this study was to assess the impact of fruit and vegetable (F&V) intake on gut microbiota, with an emphasis on the role of flavonoids, and further to explore relationships between microbiota and factors associated with CVD risk. In the study, a parallel design with 3 study groups, participants in the two intervention groups representing high-flavonoid (HF) and low flavonoid (LF) intakes were asked to increase their daily F&V intake by 2, 4 and 6 portions for a duration of 6 weeks each, while a third (control) group continued with their habitual diet. Faecal samples were collected at baseline and after each dose from 122 subjects. Faecal bacteria enumeration was performed by fluorescence in situ hybridisation (FISH). Correlations of dietary components, flavonoid intake and markers of CVD with bacterial numbers were also performed. A significant dose X treatment interaction was only found for Clostidium leptum-Ruminococcus bromii/flavefaciens with a significant increase after intake of 6 additional portions in the LF group. Correlation analysis of the data from all 122 subjects independent from dietary intervention indicated an inhibitory role of F&V intake, flavonoid content and sugars against the growth of potentially pathogenic clostridia. Additionally, we observed associations between certain bacterial populations and CVD risk factors including plasma TNF-α, plasma lipids and BMI/waist circumference.


Computerized counseling reduces HIV-1 viral load and sexual transmission risk: findings from a randomized controlled trial.
Evaluate a computerized intervention supporting antiretroviral therapy (ART) adherence and HIV transmission prevention. Longitudinal randomized controlled trial. An academic HIV clinic and a community-based organization in Seattle. In a total of 240 HIV-positive adults on ART, 209 completed 9-month follow-up (87% retention). Randomization to computerized counseling or assessment only, 4 sessions over 9 months. HIV-1 viral suppression, and self-reported ART adherence and transmission risks, compared using generalized estimating equations. Overall, intervention participants had reduced viral load: mean 0.17 log10 decline, versus 0.13 increase in controls, P = 0.053, and significant difference in ART adherence baseline to 9 months (P = 0.046). Their sexual transmission risk behaviors decreased (odds ratio = 0.55, P = 0.020), a reduction not seen among controls (odds ratio = 1.1, P = 0.664), and a significant difference in change (P = 0.040). Intervention effect was driven by those most in need; among those with detectable virus at baseline (>30 copies/mL, n = 89), intervention effect was mean 0.60 log10 viral load decline versus 0.15 increase in controls, P = 0.034. ART adherence at the final follow-up was 13 points higher among intervention participants versus controls, P = 0.038. Computerized counseling is promising for integrated ART adherence and safer sex, especially for individuals with problems in these areas. This is the first intervention to report improved ART adherence, viral suppression, and reduced secondary sexual transmission risk behavior.


A common substrate for prefrontal and hippocampal inhibition of the neuroendocrine stress response.
A network of interconnected limbic forebrain cell groups, including the medial prefrontal cortex (mPFC) and hippocampal formation (HF), is known to shape adaptive responses to emotionally stressful experiences, including output of the hypothalamo-pituitary-adrenal (HPA) axis. While disruption of limbic HPA-inhibitory systems is implicated in stress-related psychiatric and systemic illnesses, progress in the field has been hampered by a lack of a systems-level understanding of the organization that provides for this regulation. Using rats, we first localized cell groups afferent to the paraventricular hypothalamic nucleus (PVH) (the initiator of HPA responses to stress) whose engagement following acute (30 min) restraint was diminished by excitotoxin lesions of the ventral subiculum, a component of the HF. This identified a candidate relay for imparting HF influences in a circumscribed portion of the anterior bed nucleus of the stria terminalis (aBST), which we previously identified as a GABAergic relay subserving mPFC inhibition of the stress axis. Anatomical tracing experiments then indicated that extrinsic projections from HF and mPFC converge onto regions of aBST that contain neurons that are both stress sensitive and PVH projecting. Two final experiments provided evidence that (1) HPA-inhibitory influences of mPFC and HF are additive and (2) aBST plays a more prominent inhibitory role than ventral subiculum over stress-induced HPA endpoints. These findings support the view that stress-inhibitory influences of mPFC and HF are exerted principally via convergence onto a common relay, as opposed to a serial, parallel, or more complex multisynaptic network.


Why are some dimensions integral? Testing two hypotheses through causal learning experiments.
Compound generalization and dimensional generalization are traditionally studied independently by different groups of researchers, who have proposed separate theories to explain results from each area. A recent extension of Shepard's rational theory of dimensional generalization allows an explanation of data from both areas within a single framework. However, the conceptualization of dimensional integrality in this theory (the direction hypothesis) is different from that favored by Shepard in his original theory (the correlation hypothesis). Here, we report two experiments that test differential predictions of these two notions of integrality. Each experiment takes a design from compound generalization and translates it into a design for dimensional generalization by replacing discrete stimulus components with dimensional values. Experiment 1 showed that an effect analogous to summation is found in dimensional generalization with separable dimensions, but the opposite effect is found with integral dimensions. Experiment 2 showed that the analogue of a biconditional discrimination is solved faster when stimuli vary in integral dimensions than when stimuli vary in separable dimensions. These results, which are analogous to more "non-linear" processing with integral than with separable dimensions, were predicted by the direction hypothesis, but not by the correlation hypothesis. This confirms the assumptions of the unified rational theory of stimulus generalization and reveals interesting links between compound and dimensional generalization phenomena.


The Incidence of Parkinson's Disease: A Systematic Review and Meta-Analysis.
Parkinson's disease (PD) is a common neurodegenerative disorder. Epidemiological studies on the incidence of PD are important to better understand the risk factors for PD and determine the condition's natural history. This systematic review and meta-analysis examine the incidence of PD and its variation by age and gender. We searched MEDLINE and EMBASE for epidemiologic studies of PD from 2001 to 2014, as a previously published systematic review included studies published until 2001. Data were analyzed separately for age group and gender, and meta-regression was used to determine whether a significant difference was present between groups. Twenty-seven studies were included in the analysis. Meta-analysis of international studies showed rising incidence with age in both men and women. Significant heterogeneity was observed in the 80+ group, which may be explained by methodological differences between studies. While males had a higher incidence of PD in all age groups, this difference was only statistically significant for those in the age range 60-69 and 70-79 (p < 0.05). PD incidence generally increases with age, although it may stabilize in those who are 80+.


Dietary fiber, glycemic load, and risk of NIDDM in men.
Intake of carbohydrates that provide a large glycemic response has been hypothesized to increase the risk of NIDDM, whereas dietary fiber is suspected to reduce incidence. These hypotheses have not been evaluated prospectively. We examined the relationship between diet and risk of NIDDM in a cohort of 42,759 men without NIDDM or cardiovascular disease, who were 40-75 years of age in 1986. Diet was assessed at baseline by a validated semiquantitative food frequency questionnaire. During 6-years of follow-up, 523 incident cases of NIDDM were documented. The dietary glycemic index (an indicator of carbohydrate's ability to raise blood glucose levels) was positively associated with risk of NIDDM after adjustment for age, BMI, smoking, physical activity, family history of diabetes, alcohol consumption, cereal fiber, and total energy intake. Comparing the highest and lowest quintiles, the relative risk (RR) of NIDDM was 1.37 (95% CI, 1.02-1.83, P trend = 0.03). Cereal fiber was inversely associated with risk of NIDDM (RR = 0.70; 95% CI, 0.51-0.96, P trend = 0.007; for > 8.1 g/day vs. < 3.2 g/day). The combination of a high glycemic load and a low cereal fiber intake further increased the risk of NIDDM (RR = 2.17, 95% CI, 1.04-4.54) when compared with a low glycemic load and high cereal fiber intake. These findings support the hypothesis that diets with a high glycemic load and a low cereal fiber content increase risk of NIDDM in men. Further, they suggest that grains should be consumed in a minimally refined form to reduce the incidence of NIDDM.


Analysis of the relationship between PM2.5 and lung cancer based on protein-protein interactions.
Lung cancer, characterized by uncontrolled cell growth in tissues of the lung, is one of the leading causes of cancer mortality worldwide. Many etiologic factors for lung cancer tumorigenesis have been identified to date, such as smoking and exposure to radon, cooking fumes and asbestos. Atmospheric pollution has become increasingly heavy in China in recent years. Accordingly, greater numbers of people are paying attention to the air quality around them. PM2.5 (particulate matter with a diameter of 2.5 micrometers or less), which is one of the most important indicators for measuring air quality, can penetrate and be retained in lung tissue. It is believed that PM2.5 may represent a new type of etiological factor for lung cancer. This study constitutes the analysis of the association between PM2.5 and lung cancer. Genes related to small/nonsmall cell lung cancer were evaluated by assigning scores to measure the impact caused by PM2.5. Analyses of small/nonsmall cell lung cancer genes with high scores revealed that it is theoretically possible that PM2.5 is an etiologic factor for lung cancer. Our results provided new insights of the relationship between lung cancers and air pollution.


Regeneration of the ear after wounding in different mouse strains is dependent on the severity of wound trauma.
The replacement and restoration of tissue mass after organ damage or injury in adult higher vertebrates is critical to the architecture and function of the organ. If replacement occurs with scar tissue, this often results in adverse effects on function and growth as well as an undesirable cosmetic appearance. However, certain mammals, such as the MRL/MpJ mouse, have shown a restricted capacity for regeneration, rather than scar tissue formation, after an excisional ear punch wound. To investigate the changes in tissue architecture leading to ear wound closure, initial ear wounding studies with a 2-mm clinical biopsy punch were performed on MRL/MpJ mice, by using C57BL/6 mice as a nonregenerative control strain. In contrast to previously reported studies on mouse ear regeneration, we observed that C57BL/6 mice in fact showed a limited regenerative capacity. One explanation for this difference could be attributed to the method of wounding used; both previous studies on mouse ear regeneration used a thumb punch, whereas our approach was to use a clinical biopsy punch. This approach led us to further investigate whether the severity of trauma applied influenced the rate of wound healing. We, therefore, compared the effects of the sharp clinical biopsy punch with that of a cruder thumb punch, and introduced a third strain of mouse, Balb/c, known to be a slow-healing strain. A new method to quantify ear punch hole closure was developed and a histologic investigation conducted up to 4 months after wounding. Image analysis data showed a reduction in original ear wound area of 85% in MRL/MpJ mice at 4 weeks and of 91.7% over 4 months by using a biopsy punch. In contrast, the crude thumb punch methodology resulted in an increase in wound area of up to 58% in Balb/c ears; thought to be due to increased necrosis of the wound site. All biopsy-punched wound areas plateaued in healing between days 28 and 112. Only 5 of 80 MRL/MpJ mouse ears showed no residual holes macroscopically after 28 days. Histologically, all strains of mice healed their ear wounds in a similar manner involving re-epithelialization, blastema-like formation, dermal extension, blood vessel formation, chondrogenesis, folliculogenesis, and skeletal muscle and fat differentiation. However, all regenerative features were more pronounced and accelerated in MRL/MpJ mice when compared with C57BL/6 and Balb/c biopsy-punched mouse ears.


B-type natriuretic peptide as a predictor of ischemia/reperfusion injury immediately after myocardial reperfusion in patients with ST-segment elevation acute myocardial infarction.
In animal models of acute myocardial infarction (AMI), B-type natriuretic peptide (BNP) administered before and during coronary occlusion limits infarct size. However, the relation between plasma BNP levels and ischemia/reperfusion injury remains unclear. 302 patients with ST-segment elevation AMI (STEMI) received emergency percutaneous coronary intervention within six hours from the onset. The patients were divided into two groups according to the plasma BNP level before angiography: group L (n=151), BNP ≤ 32.2 pg/ml; group H (n=151), BNP >32.2 pg/ml. The Selvester QRS-scoring system was used to estimate infarct size. The rate of ischemia/reperfusion injury immediately after reperfusion, defined as reperfusion ventricular arrhythmias (26% vs. 11%, p=0.001) and ST-segment re-elevation (44% vs. 22%, p=0.008), was higher in group L than in group H. Group L had a greater increase in the QRS score during percutaneous coronary intervention (3.55 ± 0.17 vs. 2.09 ± 0.17, p<0.001) and a higher QRS score 1 h after percutaneous coronary intervention (5.77 ± 0.28 vs. 4.51 ± 0.28, p=0.002). On multivariate analysis, plasma BNP levels in the lower 50th percentile were an independent predictor of reperfusion injury (odds ratio, 2.620; p<0.001). The odds ratios of reperfusion injury according to decreasing quartiles of BNP level, as compared with the highest quartile, were 1.536, 3.692 and 4.964, respectively (p trend=0.002). Plasma BNP level before percutaneous coronary intervention may be a predictor of ischemia/reperfusion injury and the resultant extent of myocardial damage. Our findings suggest that high plasma BNP levels might have a clinically important protective effect on ischemic myocardium in patients with STEMI who receive percutaneous coronary intervention.


On the cross-streamline lift of microswimmers in viscoelastic flows.
The current work studies the dynamics of a microswimmer in pressure-driven flow of a weakly viscoelastic fluid. Employing a second-order fluid model, we show that a self-propelling swimmer experiences a viscoelastic swimming lift in addition to the well-known passive lift that arises from its resistance to shear flow. Using the reciprocal theorem, we evaluate analytical expressions for the swimming lift experienced by neutral and pusher/puller-type swimmers and show that they depend on the hydrodynamic signature associated with the swimming mechanism. We find that, in comparison to passive particles, the focusing of neutral swimmers towards the centerline can be significantly accelerated, while for force-dipole swimmers no net modification in cross-streamline migration occurs.


Does weight status influence associations between children's fundamental movement skills and physical activity?
This study sought to determine whether weight status influences the association among children's fundamental movement skills (FMS) and physical activity (PA). Two hundred forty-eight children ages 9-12 years participated. Proficiency in three object-control skills and two locomotor skills was examined. Accelerometers objectively assessed physical activity. Body mass index was calculated to determine weight status. Correlations between physical activity and FMS proficiency were evident among boys and girls. No significant interaction was apparent when examining FMS proficiency scores, PA variables, and weight status. Future studies should examine a broader range of skills and types of activities to better characterize this relationship and to inform the promotion of movement skill proficiency and PA.


Talking Circles to Improve Diabetes Self-care Management.
Purpose The purpose of this study was to determine if the use of both the Talking Circles (TCs) and diabetes self-management education (DSME) results in better adherence and outcomes for diabetes self-management than DSME alone in American Indians (AIs) with type 2 diabetes mellitus (T2DM). Methods A quasiexperimental, mixed-methods approach was used for AIs with uncontrolled T2DM, defined by an A1C > 7.0%. The experimental group (n = 20) participated in a TC and received DSME. The control group (n = 19) received only DSME. Talking Circles were audio-taped and analyzed qualitatively. Quantitative data were analyzed using the generalized estimating equation and Fisher exact test for all study participants every 3 months for 1 year. Results Themes identified by TC participants were spirituality, gratitude, and sharing. Major topics of discussion were the experiences of living with T2DM, including challenges and coping. Evidence of positive trends for the experimental group who received the TC intervention included lower systolic blood pressure, lower A1C, lower weight over time, and increased adherence without incentives. Conclusion Talking Circles may have utility in improving adherence in AI adults with uncontrolled T2DM. Further studies are warranted, including extending the use of the TCs after completion of DSME sessions.


Acute stress throughout the memory cycle: Diverging effects on associative and item memory.
Acute stress can modulate memory for individual parts of an event (items), but whether it similarly influences memory for associations between items remains unclear. We used a within-subjects design to explore the influence of acute stress on item and associative memory in humans. Participants associated negative words with neutral objects, rated their subjective arousal for each pair, and completed delayed item and paired associative recognition tasks. We found strikingly different patterns of acute stress effects on item and associative memory: for high-arousal pairs, preencoding stress enhanced associative memory, whereas postencoding stress enhanced item memory. Preretrieval stress consistently impaired both forms of memory. We found that the influence of stress-induced cortisol also varied, with a linear relationship between cortisol and item memory but a quadratic relationship between cortisol and associative memory. These findings reveal key differences in how stress, throughout the memory cycle, shapes our memories for items and associations. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Thymidine phosphorylase expression in Kaposi sarcoma.
To examine the immunohistochemical distribution of thymidine phosphorylase (TP) in all clinicopathological subtypes of Kaposi sarcoma. Thirty two biopsy specimens of Kaposi sarcoma (29 patients) were studied. Six of these patients represented classic, six endemic, eight HIV associated, seven post-immunosuppression/transplant related, and two unclassified variants of Kaposi sarcoma. The average age was 49 years (range 22-83 years) and the male: female ratio 24:5. Four samples of angiosarcoma and one of spindle cell haemangio-endothelioma were stained in parallel. All specimens were fixed in formalin, embedded in paraffin wax and processed routinely. Immunohistochemistry was carried out using an antibody directed against CD31 (JC70) and the monoclonal antibody P-GF.44C against TP. All biopsy specimens showed immunoexpression for TP. The spindle cell component stained more strongly than newly formed endothelium lined vessels and normal, resident vessels at a distance from the lesions. The strong immunoexpression of TP suggests up-regulation of TP and a role for TP in angiogensis in Kaposi sarcoma. The mechanism for the up-regulation of TP remains unknown, but viral infections may trigger it. The differential staining of the various cell components of Kaposi sarcoma also suggest that TP either plays a role in the differentiation and maturation of Kaposi sarcoma or is a reflection of such changes.


Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study.
Although the association between menopause and cardiovascular disease (CVD) risk has been studied extensively, the simultaneous role of chronological aging herein remains underexposed. This study aims to disentangle the relationships of menopausal status and chronological aging with CVD risk factors in the largest study population to date. In this cross-sectional study, CVD risk factors were compared between women with a different menopausal status within the same yearly age strata. The study population comprised female participants of the baseline visit of the population-based LifeLines Cohort Study. A total of 63,466 women, aged between 18 and 65 years, was included. Of them, 39,379 women were considered to be premenopausal, 8669 were perimenopausal, 14,514 were naturally postmenopausal, and 904 were surgically postmenopausal. Compared to postmenopausal women aged 45 years, average total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) were 0.5 and 0.4 mmol/L higher, respectively, in postmenopausal women aged 50. Systolic and diastolic blood pressure levels were 4 and 1 mmHg higher, respectively. At all ages between 46 and 55 years, and after adjustment for confounders, naturally postmenopausal women had 0.2 to 0.4 mmol/L higher TC and 0.1 to 0.3 mmol/L higher LDL-c levels compared to premenopausal women in the same age range. Systolic blood pressure levels were up to 4 mmHg lower in naturally post- compared to premenopausal women at all ages between 29 and 52 years. Body mass index levels were up to 3.2 kg/m2 higher in women with surgical menopause compared to all other women between the ages 32 and 52 years. All aforementioned results were statistically significant. Chronological age and menopausal status are both independently associated with CVD risk factors. Based on the comparatively smaller observed differences associated with menopausal status than with chronological aging, the significance of a more unfavorable lipid profile in a later reproductive stage may be less obvious than previously thought.


Changes in hip fracture rate before and after total knee replacement due to osteoarthritis: a population-based cohort study.
Patients with knee osteoarthritis have an increase in bone mass but no corresponding decrease in risk of fracture. This study describes the rates of hip fracture in subjects with knee osteoarthritis before and after having a total knee replacement (TKR), compared with matched controls. A population-based prospective cohort study was conducted. The study population included, from the General Practice Research Database (UK), patients 40 years and older, undergoing TKR between 1986 and end-2006 for knee osteoarthritis as 'cases' (n=20,033). Five disease-free controls (n=100,165) were randomly selected, and matched for age, gender and practice. Hip fractures were ascertained using READ codes, and yearly rates of hip fracture and rate differences were calculated for the 5 years before and after surgery, using Poisson regression. Stratified analyses were performed by age and history of fracture. Hip fracture rates were non-significantly reduced compared with controls before the operation. In the year after TKR, risk increased significantly (RR 1.58; 95% CI 1.14 to 2.19). Rates then declined to equal those of controls by 3 years, and continued decreasing until the end of follow-up; corresponding RR were not significant. The increased risk is greatest in younger ages and in those without previous fracture. The association between knee osteoarthritis and fractures is time-dependent, which may explain the current controversy in the literature. The association is also modified by TKR: subjects have a higher rate of hip fracture than matched controls after TKR, although the rates may eventually decrease.


Relation between phenotype and banal melanocytic naevi.
In a study of risk factors for the development of melanocytic naevi in relation to the pathogenesis of malignant melanoma 197 white adults were examined by four dermatologists and naevus counts correlated with several other features. Highly significant associations were found between large numbers of banal acquired melanocytic naevi and the ability to tan easily without burning (skin types 3 and 4; relative risk 4.6), brown or hazel eyes (relative risk 3.5), green or grey eyes (relative risk 3.5) and brown or black hair (relative risk 3.7). No significant associations with numbers of naevi were shown for parity or use of oral contraceptives or other steroid hormones. This is the first study to find any relation between melanocytic naevi and phenotypic factors in a white population.


Beware of the hot swollen calf following knee replacement surgery: it might not be a deep vein thrombosis.
We report the case of a 77-year-old woman who presented with a 10-day history of increasing swelling and erythema of her right calf and popliteal areas 12 years after bilateral total knee replacements. Deep venous thrombosis (DVT), cellulitis or possible deep sepsis as a result of the knee replacement were the initial differential diagnoses. Due to clinical deterioration, exploration and radical debridement were performed and a 1.5 L collection of pus was identified through a small posteromedial proximal tibial bone defect adjacent to the tibial component, extending between gastrocnemius, soleus and into the distal calf. The procedure was extended to a first stage revision (complete implant and cement removal). Although leg swelling is common in joint infections secondary to knee swelling as a result of the inflammation, synovitis and/or knee effusion response, this case highlights the need to consider additional pathology such as deep abscess formation or DVT in these types of presentations.


Chromosomal mapping of repetitive DNAs in Triportheus trifurcatus (Characidae, Characiformes): insights into the differentiation of the Z and W chromosomes.
Repetitive DNA sequences play an important role in the structural and functional organization of chromosomes, especially in sex chromosome differentiation. The genus Triportheus represents an interesting model for such studies because all of its species analyzed so far contain a ZZ/ZW sex chromosome system. A close relationship has been found between the differentiation of the W chromosome and heterochromatinization, with the involvement of different types of repetitive DNA in this process. This study investigated several aspects of this association in the W chromosome of Triportheus trifurcatus (2 n = 52 chromosomes), including the cytogenetic mapping of repetitive DNAs such as telomeric sequences (TTAGGG)n, microsatellites and retrotransposons. A remarkable heterochromatic segment on the W chromosome was observed with a preferential accumulation of (CAC)10, (CAG)10, (CGG)10, (GAA)10 and (TA)15. The retrotransposons Rex1 and Rex3 showed a general distribution pattern in the chromosomes, and Rex6 showed a different distribution on the W chromosome. The telomeric repeat (TTAGGG)n was highly evident in both telomeres of all chromosomes without the occurrence of ITS. Thus, the differentiation of the W chromosome of T. trifurcatus is clearly associated with the formation of heterochromatin and different types of repetitive DNA, suggesting that these elements had a prominent role in this evolutionary process.


First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity.
IMP321 is a recombinant soluble LAG-3Ig fusion protein that binds to MHC class II with high avidity and mediates APC and then antigen-experienced memory CD8+ T cell activation. We report clinical and biological results of a phase I/II in patients with metastatic breast carcinoma (MBC) receiving first-line paclitaxel weekly, 3 weeks out of 4. MBC patients were administered one dose of IMP321 s.c. every two weeks for a total of 24 weeks (12 injections). The repeated single doses were administered the day after chemotherapy at D2 and D16 of the 28-day cycles of paclitaxel (80 mg/m2 at D1, D8 and D15, for 6 cycles). Blood samples were taken 13 days after the sixth and the twelfth IMP321 injections to determine sustained APC, NK and memory CD8 T cell responses. Thirty MBC patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). IMP321 induced both a sustained increase in the number and activation of APC (monocytes and dendritic cells) and an increase in the percentage of NK and long-lived cytotoxic effector-memory CD8 T cells. Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Also, the objective tumor response rate of 50% compared favorably to the 25% rate reported in the historical control group. The absence of toxicity and the demonstration of activity strongly support the future development of this agent for clinical use in combined first-line regimens. ClinicalTrials.gov NCT00349934.


Plasma radiation dynamics with the upgraded Absolute Extreme Ultraviolet tomographical system in the Tokamak à Configuration Variable.
We introduce an upgraded version of a tomographical system which is built up from Absolute Extreme Ultraviolet-type (AXUV) detectors and has been installed on the Tokamak à Configuration Variable (TCV). The system is suitable for the investigation of fast radiative processes usually observed in magnetically confined high-temperature plasmas. The upgrade consists in the detector protection by movable shutters, some modifications to correct original design errors and the improvement in the data evaluation techniques. The short-term sensitivity degradation of the detectors, which is caused by the plasma radiation itself, has been monitored and found to be severe. The results provided by the system are consistent with the measurements obtained with the usual plasma radiation diagnostics installed on TCV. Additionally, the coupling between core plasma radiation and plasma-wall interaction is revealed. This was impossible with other available diagnostics on TCV.


Mock Drills: Implementation for Emergency Scenarios in the Outpatient Setting.
Oncology care has made the shift to the outpatient setting. The authors' cancer center is a basic life support-certified facility using an affiliated hospital for emergent transfers. A nurse-led initiative was developed in response to expressed anxieties and lack of comfort by staff related to their role in emergency management. Mock drills help staff retain knowledge and skills necessary during an emergency. This project aimed to create simulation-based scenarios to practice outpatient emergency management skills. Targeted objectives for each scenario were developed by the team with staff input. An evaluation form following the mock drill is used to assess comfort level and attained knowledge. Practicing an emergency scenario in a controlled and simulated environment improves provider confidence, communication, teamwork, and patient safety. It is an adaptable strategy that fosters team cohesiveness during actual emergencies. A successful mock drill team encompasses organization, clearly identified roles, and frequent team practice.


Changes in practitioners' attitudes, perceived training needs and self-efficacy over the implementation process of an evidence-based parenting program.
Evidence-based family support programs such as the Triple P - Positive Parenting Program have the potential to enhance the well-being of children and families. However, they cannot achieve their expected outcomes if insufficient attention is paid to the implementation process. It has been demonstrated that practitioners' attitudes towards evidence-based programs (EBPs), perceived training needs and self-efficacy for working with parents influence implementation outcomes (e.g., program acceptability, adoption, adherence and sustainability). At the same time, the experience of being involved in the implementation process of an EBP could enhance practitioners' perceptions of the initiative. This study aimed to assess changes in practitioner's attitudes, perceived training needs and self-efficacy over a two-year EBP implementation process, in interaction with their appraisal of their organization's capacity to implement the EPB. In the province of Quebec, Canada, Triple P was implemented and evaluated in two communities. Ninety-nine practitioners from various organizations completed questionnaires shortly before their training in Triple P and two years later. Findings show that practitioners who displayed more initial skepticism regarding their organization's capacity to implement the program reported greater improvements in attitudes over time, while practitioners who showed more optimism at baseline reported a greater decrease in their perceived training needs. Practitioners' self-efficacy increased moderately regardless of perceived organizational capacity. These results are encouraging given that more positive perceptions of EBPs could foster the systematic use of these programs in communities, for the potential benefit of a greater number of families.


Clinical characteristics of a large cohort of US participants enrolled in the National Amyotrophic Lateral Sclerosis (ALS) Registry, 2010-2015.
Background: Amyotrophic lateral sclerosis (ALS) is a progressive fatal disease with a varying range of clinical characteristics. Objective: To describe the clinical characteristics in a large cohort of ALS participants enrolled in the National ALS Registry. Methods: Data from ALS participants who completed the Registry's online clinical survey module during 2010-2015 were analyzed to determine characteristics, such as site of onset, associated symptoms, time of symptom onset to diagnosis, time of diagnosis to hospice referral, and pharmacological and non-pharmacological interventions. Results: Of the 1758 participants who completed the survey, 60.9% were male, 62.1% were 50-69 years old, and 95.5% white. Approximately, 72.0% reported initial limb weakness onset of disease, followed by bulbar (22.1%), and trunk/global onset (6.1%). Other symptoms ever experienced included cramps (56.7%), fasciculations (56.3%), and dysarthria (33.0%). The median time between an increase of muscle cramps until an ALS diagnosis was 12 months; limb onset participants had cramps longer preceding diagnosis versus those with bulbar onset. The most frequent interventions used included riluzole (48.3% currently using), wheelchairs/scooters (32.8%), and noninvasive breathing equipment (30.0%). Participants with trunk/global onset were referred to hospice almost four times earlier than others. Conclusions: These data show how ALS clinical characteristics differ widely in a large cohort of participants preceding diagnosis and reflect variations in disease onset, progression, and prognosis. Better characterization of symptom onset may assist clinicians in diagnosing ALS sooner, which could lead to earlier therapeutic interventions.


Experimental infection of chickens with Nocardia asteroides and Nocardia transvalensis.
Ten-day-old cockerels were infected with N. asteroides or N. transvalensis by the oral or intraperitoneal routes. Clinical signs included depression, gasping and emaciation. Grey nodules or foci were observed in the lungs, air sacs, liver and breast muscles. These organs showed necrosis, granulomas, lymphoid follicles and infiltration of lymphocytes, heterophils and macrophages. Intraperitoneal infection resulted in a more severe disease with either organism. N. transvalensis appeared more pathogenic than N. asteroides intraperitoneally and vice versa with the oral route.


Whole-Genome Sequencing of Invasion-Resistant Cells Identifies Laminin α2 as a Host Factor for Bacterial Invasion.
To understand the role of glycosaminoglycans in bacterial cellular invasion, xylosyltransferase-deficient mutants of Chinese hamster ovary (CHO) cells were created using clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated gene 9 (CRISPR-cas9) gene targeting. When these mutants were compared to the pgsA745 cell line, a CHO xylosyltransferase mutant generated previously using chemical mutagenesis, an unexpected result was obtained. Bacterial invasion of pgsA745 cells by group B Streptococcus (GBS), group A Streptococcus, and Staphylococcus aureus was markedly reduced compared to the invasion of wild-type cells, but newly generated CRISPR-cas9 mutants were only resistant to GBS. Invasion of pgsA745 cells was not restored by transfection with xylosyltransferase, suggesting that an additional mutation conferring panresistance to multiple bacteria was present in pgsA745 cells. Whole-genome sequencing and transcriptome sequencing (RNA-Seq) uncovered a deletion in the gene encoding the laminin subunit α2 (Lama2) that eliminated much of domain L4a. Silencing of the long Lama2 isoform in wild-type cells strongly reduced bacterial invasion, whereas transfection with human LAMA2 cDNA significantly enhanced invasion in pgsA745 cells. The addition of exogenous laminin-α2β1γ1/laminin-α2β2γ1 strongly increased bacterial invasion in CHO cells, as well as in human alveolar basal epithelial and human brain microvascular endothelial cells. Thus, the L4a domain in laminin α2 is important for cellular invasion by a number of bacterial pathogens. Pathogenic bacteria penetrate host cellular barriers by attachment to extracellular matrix molecules, such as proteoglycans, laminins, and collagens, leading to invasion of epithelial and endothelial cells. Here, we show that cellular invasion by the human pathogens group B Streptococcus, group A Streptococcus, and Staphylococcus aureus depends on a specific domain of the laminin α2 subunit. This finding may provide new leads for the molecular pathogenesis of these bacteria and the development of novel antimicrobial drugs.


Hepatocyte nuclear factor 3 is a major determinant of CYP2C6 promoter activity in hepatoma cells.
Cytochrome P450 2C6 (CYP2C6) is a developmentally regulated, constitutively expressed form of rat liver microsomal cytochrome P450 that in the liver of adult male rats is induced to a limited extent by phenobarbital. The gene is not expressed at detectable levels in the lung, kidney, or brain. It is expressed and inducible by phenobarbital in differentiated Reuber hepatoma cells that express many hepatocyte-specific genes but not in dedifferentiated derivatives lacking the majority of hepatocyte-specific functions. A 505-base pair proximal segment of the CYP2C6 promoter is highly efficient in driving transcription of a linked chloramphenicol acetyltransferase reporter gene in the differentiated rat hepatoma cell line FGC4, is much less effective in a related dedifferentiated variant H5, and has no measurable activity in nonhepatic C33 human cervical carcinoma cells. The activity of the CYP2C6 promoter in the differentiated hepatoma cells is strongly dependent on hepatocyte nuclear factor (HNF)3, which acts at a complex site just upstream of the TATA motif. Transactivation experiments show that the D-site-binding protein (DBP) may also contribute to CYP2C6 promoter activity, via a site that is adjacent to the proximal HNF3 site. A substantial contribution to promoter activity by the base pair -505 to -316 segment is observed in FGC4 and H5 cells but not in HepG2 cells; deletion of this segment causes a marked diminution in promoter activity only in the former two cell lines. Although footprinting experiments have permitted the definition of three protein binding sites in this region (two HNF3 and one unidentified), mutation of these sites does not diminish promoter activity. The functionally important cis sequences in this region therefore remain to be defined. In HepG2 cells the distal region does not contribute to promoter activity. This most likely accounts for the low promoter activity in HepG2 and implies a deficiency in the relevant trans-acting factor(s).


Immunolocalization of GQ1b and related gangliosides in human extraocular neuromuscular junctions and muscle spindles.
To examine the distribution of anti-GQ1b, -GT1a, and -GD1b antibody binding in human extraocular muscles (EOMs), axial and limb muscles, and muscle spindles and thereby test the hypothesis that their distinctive ganglioside composition provides the molecular basis for selective involvement of EOMs and muscle spindles in Miller Fisher syndrome. Muscle samples from adult human EOMs, vastus lateralis, biceps brachii, lumbrical, psoas, and deep muscles of the neck were processed for immunohistochemistry, with monoclonal antibodies against ganglioside GQ1b, GT1a, and GD1b. Neuromuscular junctions (NMJs) were detected by alpha-bungarotoxin binding and by acetyl cholinesterase reaction. Most motor endplates of human EOMs richly bound anti-GQ1b, -GT1a, and -GD1b ganglioside antibodies. Anti-GQ1b, -GT1a, and -GD1b ganglioside antibody bindings to NMJs in human limb and axial muscle were scarce, but the nerve terminals inside muscle spindles and in direct contact with intrafusal fibers were labeled with anti- GQ1b, -GT1a, and -GD1b ganglioside antibodies. The abundant and synaptic-specific binding of anti-GQ1b, -GT1a, and -GD1b ganglioside antibodies and the rich capillary supply in the human EOMs may partly explain the selective paralysis of these muscles in Miller Fisher syndrome.


Temperament, character, and suicidality among Croatian war veterans with posttraumatic stress disorder.
The occurrence of suicidal thoughts and behaviors is rather frequent among war veterans, particularly those suffering from posttraumatic stress disorder (PTSD). Understanding factors present within these individuals that increase suicide risk may inform prevention efforts. The present study aimed to determine whether the dimensions of temperament and character are associated with various aspects of suicidality among Croatian war veterans with PTSD. A sample of 72 Croatian male war veterans (mean age 52.33 years) diagnosed with PTSD was gathered at the National Center for Psychotrauma between May and October 2014. The participants completed the Temperament and Character Inventory - Revised (TCI-R) and the Suicidal Behaviors Questionnaire - Revised (SBQ-R). Zero-order analyses revealed that temperament dimension Harm avoidance and character dimension Self-directedness were moderately associated with the total risk for suicide (i.e., the SBQ-R total score), while Persistence and Cooperativeness showed significant but weaker relations. Different dimensions of suicidality were associated with different personality traits. Harm Avoidance was shown to be significantly increased among the subgroup of war veterans with high suicidal risk. Notwithstanding some limitations of this study, these findings could help extend our understanding of the elevated suicide risk in war veterans with PTSD. Detection of individuals displaying high Harm Avoidance and low Self-Directedness might facilitate prevention of suicidal behaviors in this population.


Basic family budgets: working families' incomes often fail to meet living expenses around the United States.
The ability of families to meet their most basic needs is an important measure of economic stability and well-being. While poverty thresholds are used to evaluate the extent of serious economic deprivation in our society, family budgets--that is, the income a family needs to secure safe and decent-yet-modest living standards in the community in which it resides--offer a broader measure of economic welfare. Basic family budgets take into account differences in both geographic location and family type. In total, this report presents basic budgets for more than 400 U.S. communities and six family types (either one or two parents with one, two, or three children). That the budgets differ by location is important, since certain costs, such as housing, vary significantly depending on where one resides. This geographic dimension of family budget measurements offers a comparative advantage over using poverty thresholds, which only use a national baseline in their measurements.


Revised criteria for mild cognitive impairment may compromise the diagnosis of Alzheimer disease dementia.
To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD)dementia. Retrospective review of ratings of functional impairment across diagnostic categories. Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center. Individuals (N=17 535) with normal cognition,MCI, or AD dementia. The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and 2 for categorical variables. Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority(92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria,based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home.Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire. The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.


Translating the Developmental Origins of Health and Disease concept to improve the nutritional environment for our next generations: a call for a reflexive, positive, multi-level approach.
Evidence supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis indicates that improving early life environments can reduce non-communicable disease risks and improve health over the lifecourse. A widespread understanding of this evidence may help to reshape structures, guidelines and individual behaviors to better the developmental conditions for the next generations. Yet, few efforts have yet been made to translate the DOHaD concept beyond the research community. To understand why, and to identify priorities for DOHaD Knowledge Translation (KT) programs, we review here a portion of published descriptions of DOHaD KT efforts and critiques thereof. We focus on KT targeting people equipped to apply DOHaD knowledge to their everyday home or work lives. We identified 17 reports of direct-to-public DOHaD KT that met our inclusion criteria. Relevant KT programs have been or are being initiated in nine countries, most focusing on secondary school students or care-workers-in-training; few target parents-to-be. Early indicators suggest that such programs can empower participants. Main critiques of DOHaD KT suggest it may overburden mothers with responsibility for children's health and health environments, minimizing the roles of other people and institutions. Simultaneously, though, many mothers-to-be seek reliable guidance on prenatal health and nutrition, and would likely benefit from engagement with DOHaD KT. We thus recommend emphasizing solidarity, and bringing together people likely to one day become parents (youth), people planning pregnancies, expecting couples, care workers and policymakers into empowering conversation about DOHaD and about the importance and complexity of early life environments.


SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells.
RP is a retinal degeneration disorder that is caused by mutations of various genes, including semaphorin-4A (SEMA4A). A number of retinal diseases, including RP, are associated with light exposure, oxidative stress, and endoplasmic reticulum (ER) stress. In this study, we investigated whether mutant SEMA4A causes retinal dysfunction via light exposure, oxidative stress, and ER stress. Mutant SEMA4A (D345H or F350C) was overexpressed in a human retinal epithelium cell line ARPE19. Intracellular localization of mutant SEMA4A was investigated using confocal laser scanning microscopy. The ARPE-19 cells were also irradiated with white light, and expression of 78 kDa glucose-regulated protein (GRP78), a marker of ER stress, and phagocytosis were measured. The cells were treated with an ER stress inducer, tunicamycin, or an oxidative stressor, H(2)O(2), and cell death was measured. Human SEMA4A mutants were expressed in zebrafish embryos with tunicamycin and mRNA of DNA damage-inducible transcript 3 (ddit3) was measured as an ER stress marker. Mutant SEMA4A was localized in the ER, whereas wild type (WT) SEMA4A was observed in cell membranes. The expression of GRP78 was increased by mutant SEMA4A following light irradiation, and phagocytosis was suppressed in mutant SEMA4A-transfected cells. Mutant SEMA4A induced susceptibility to ER stress and oxidative stress. In zebrafish, human mutant SEMA4A increased ddit3 mRNA compared with WT under the ER stress condition. Our results suggest that mutations in SEMA4A may cause susceptibility to light exposure, oxidative stress, and ER stress, which may be involved in the progression and pathology of RP.


Science in the art of the master Bizen potter.
Bizen stoneware, with the characteristic reddish hidasuki or "fire-marked" pattern, is one of Japan's best known traditional ceramic works of art. The means of creating and controlling the various hues of the hidasuki pattern has remained a mystery to outsiders for about a thousand years; the methods were known only to master potters who served under generations of master potters before them. In this Account, we present the results of 30 years of study in which we investigated the microstructure and color-formation process in Bizen stoneware. We discovered that the hidasuki pattern results from the precipitation of corundum (alpha-Al(2)O(3)) and the subsequent epitaxial growth of hematite (alpha-Fe(2)O(3)) around it in a approximately 50-microm-thick liquid specifically formed in the ceramic surface. The epitaxial composites include hexagonal plate-like alpha-Fe(2)O(3)/alpha-Al(2)O(3)/alpha-Fe(2)O(3) sandwiched particles and also surprisingly beautiful flower-like crystals, centered by hexagonal corundum crystals and decorated by several hexagonal hematite petal crystals. Bizen stoneware is produced from a unique clay that can only be mined from the Bizen area of Okayama Prefecture, Japan. The clay has an unusually high Fe content compared with the traditional porcelain clay, as well as Si, Ca, Mg, and Na. Prior to firing, the Bizen works are wrapped in rice straw that was used originally as a separator to prevent adhesion. The hidasuki pattern only appears where the rice straw is in direct contact with the clay; the rice straw supplies potassium, which reduces the melting point of the ceramic surface, thereby converting the contact area into a site for these reactions to take place. The effect is almost accidental and is produced without the aid of any artificial glazing and enameling. An unexpected variety of substances, including metallic iron coated by graphite, Fe(3)P, and epsilon-Fe(2)O(3), were also found to appear at low oxygen partial pressures. Many of the techniques used by master potters are passed down through an apprenticeship system; an unfortunate consequence is that they are poorly documented. Moreover, the masters of these techniques are often unaware of the underlying chemical reactions that take place. Chemical studies of traditional processes can provide new inspiration to artists, allowing them to control the various factors and thus produce new works, and perhaps new functional materials. We studied the process of creating Bizen stoneware and then mimicked the color-producing process under controlled laboratory conditions, demonstrating the possibilities of the endeavor.


EWSR1-NFATC2 Translocation-associated Sarcoma Clinicopathologic Findings in a Rare Aggressive Primary Bone or Soft Tissue Tumor.
In recent years, a novel small round cell sarcoma harboring EWSR1-NFATC2 translocation with immunomorphologic overlap with Ewing sarcoma (ES), myoepithelial tumors, and extraskeletal myxoid chondrosarcoma has emerged. There has not been a case series devoted to describing its detailed clinicopathologic and immunohistochemical characteristics. Six sarcomas harboring EWSR1-NFATC2 fusion transcripts by reverse transcription polymerase chain reaction and amplification of the fusion gene by fluorescence in situ hybridization were identified. The patients were 5 adult men and 1 adult woman. Three were primary bone tumors of the radius and 3 were primary soft tissue tumors. Most tumors showed monomorphic round to epithelioid cells in anastomosing cords and abundant myxohyaline to collagenous extracellular matrix. Two tumors had large areas of a solid, matrix-poor histomorphology. All tumors stained for CD99 and NKX2.2; while EMA, dot-like cytokeratin, and focal WT-1 and SMA were present in some tumors. All but 1 tumor showed poor histologic and radiologic responses to neoadjuvant ES-specific chemotherapy. Local or distant recurrences happened in 4 cases. EWSR1-NFATC2 sarcoma is a novel translocation-associated sarcoma. It presents as either a primary bone or soft tissue tumor, usually exhibits distinctive histopathologic features, and has predilection for long bones of adult men. It consistently shows recurrent fusion gene amplification readily detectable by EWSR1 breakapart fluorescence in situ hybridization, which serves as a diagnostic surrogate. It has potential for local and distant recurrence and histologic progression, and is resistant to Ewing sarcoma-specific chemotherapy.


Definitive radiotherapy in locally advanced non-small cell lung cancer: dose and fractionation.
Definitive radiotherapy plays a major role in the treatment of locally advanced non-small cell lung cancer (LA NSCLC). After the impact of RT dose for lung cancer was established, a number of trials were structured with the aim of better local control and overall survival by either dose escalation or shortening the total treatment time through conventional/altered fractionation, even in combination with chemotherapy (CT) and other targeted agents. In spite of the increased number of these studies, the optimal dose or fractionation still remains to be determined. Another aspect questioned is the incorporation of these higher doses and shorter treatment times with chemotherapy or targeted agents. This review summarises the results of significant trials on dose and altered fractionation in the treatment of LA-NSCLC with an emphasis on possible future perspectives.


Appropriate use of nomograms to guide prostate cancer treatment selection.
For decades physicians have attempted to accurately predict post-treatment outcomes before performing prostate cancer interventions. Use of basic clinical factors, such as clinical T-stage, biopsy Gleason sum, and pretreatment prostate specific antigen, has allowed some level of prediction of pathologic and clinical outcomes. However, these basic tables and risk stratification schema provide a broad range of potential outcomes. The rapid growth of retrospective research in prostate cancer has yielded an abundance of additional potential prognostic factors that may influence outcomes of interest; however, incorporating and understanding the significance of these ever-expanding factors is difficult for even the most experienced physicians. Nomograms incorporate these factors (including treatment-specific) and assign them relative weights to provide a probability of the outcome of interest on a graphical scale. They distill large numbers of data into a manageable format and provide the probability of outcomes on a continuous scale rather than in categoric groups. However, because they require a computation to generate a probability, they are not amenable to memorization, which decreases ease of use. Furthermore, these numbers still have associated confidence intervals and the models are largely derived from retrospective data, which have inherent drawbacks. Clinicians and patients should still exercise due diligence when interpreting the results of these nomograms, and these prediction tools should not serve as a stand-alone substitute for clinical decision-making.


Physical exercise for people with Parkinson's disease: a systematic review and network meta-analysis.
Physical exercise is effective in managing Parkinson's disease (PD), but the relative benefit of different exercise types remains unclear. To compare the effects of different types of physical exercise in adults with PD on the severity of motor signs, quality of life (QoL), and the occurrence of adverse events, and to generate a clinically meaningful treatment ranking using network meta-analyses (NMAs). An experienced information specialist performed a systematic search for relevant articles in CENTRAL, MEDLINE, Embase, and five other databases to 17 May 2021. We also searched trial registries, conference proceedings, and reference lists of identified studies up to this date. We included randomized controlled trials (RCTs) comparing one type of physical exercise for adults with PD to another type of exercise, a control group, or both. Two review authors independently extracted data. A third author was involved in case of disagreements. We categorized the interventions and analyzed their effects on the severity of motor signs, QoL, freezing of gait, and functional mobility and balance up to six weeks after the intervention using NMAs. Two review authors independently assessed the risk of bias using the risk of bias 2 (RoB 2) tool and rated the confidence in the evidence using the CINeMA approach for results on the severity of motor signs and QoL. We consulted a third review author to resolve any disagreements. Due to heterogeneous reporting of adverse events, we summarized safety data narratively and rated our confidence in the evidence using the GRADE approach. We included 156 RCTs with a total of 7939 participants with mostly mild to moderate disease and no major cognitive impairment. The number of participants per study was small (mean 51, range from 10 to 474). The NMAs on the severity of motor signs and QoL included data from 71 (3196 participants), and 55 (3283 participants) trials, respectively. Eighty-five studies (5192 participants) provided safety data. Here, we present the main results. We observed evidence of beneficial effects for most types of physical exercise included in our review compared to a passive control group. The effects on the severity of motor signs and QoL are expressed as scores on the motor scale of the Unified Parkinson Disease Rating Scale (UPDRS-M) and the Parkinson's Disease Questionnaire 39 (PDQ-39), respectively. For both scales, higher scores denote higher symptom burden. Therefore, negative estimates reflect improvement (minimum clinically important difference: -2.5 for UPDRS-M and -4.72 for PDQ-39). Severity of motor signs The evidence from the NMA (71 studies; 3196 participants) suggests that dance has a moderate beneficial effect on the severity of motor signs (mean difference (MD) -10.32, 95% confidence interval (CI) -15.54 to -4.96; high confidence), and aqua-based, gait/balance/functional, and multi-domain training might have a moderate beneficial effect on the severity of motor signs (aqua-based: MD -7.77, 95% CI -13.27 to -2.28; gait/balance/functional: MD -7.37, 95% CI -11.39 to -3.35; multi-domain: MD -6.97, 95% CI -10.32 to -3.62; low confidence). The evidence also suggests that mind-body training and endurance training might have a small beneficial effect on the severity of motor signs (mind-body: MD -6.57, 95% CI -10.18 to -2.81; endurance: MD -6.43, 95% CI -10.72 to -2.28; low confidence). Flexibility training might have a trivial or no effect on the severity of motor signs (MD 2.01, 95% CI -4.82 to 8.98; low confidence). The evidence is very uncertain about the effects of strength/resistance training and "Lee Silverman Voice training BIG" (LSVT BIG) on the severity of motor signs (strength/resistance: MD -6.97, 95% CI -11.93 to -2.01; LSVT BIG: MD -5.49, 95% CI -14.74 to 3.62; very low confidence). Quality of life The evidence from the NMA (55 studies; 3283 participants) suggests that aqua-based training probably has a large beneficial effect on QoL (MD -14.98, 95% CI -23.26 to -6.52; moderate confidence). The evidence also suggests that endurance training might have a moderate beneficial effect, and that gait/balance/functional and multi-domain training might have a small beneficial effect on QoL (endurance: MD -9.16, 95% CI -15.68 to -2.82; gait/balance/functional: MD -5.64, 95% CI -10.04 to -1.23; multi-domain: MD -5.29, 95% CI -9.34 to -1.06; low confidence). The evidence is very uncertain about the effects of mind-body training, gaming, strength/resistance training, dance, LSVT BIG, and flexibility training on QoL (mind-body: MD -8.81, 95% CI -14.62 to -3.00; gaming: MD -7.05, 95% CI -18.50 to 4.41; strength/resistance: MD -6.34, 95% CI -12.33 to -0.35; dance: MD -4.05, 95% CI -11.28 to 3.00; LSVT BIG: MD 2.29, 95% CI -16.03 to 20.44; flexibility: MD 1.23, 95% CI -11.45 to 13.92; very low confidence). Adverse events Only 85 studies (5192 participants) provided some kind of safety data, mostly only for the intervention groups. No adverse events (AEs) occurred in 40 studies and no serious AEs occurred in four studies. AEs occurred in 28 studies. The most frequently reported events were falls (18 studies) and pain (10 studies). The evidence is very uncertain about the effect of physical exercise on the risk of adverse events (very low confidence). Across outcomes, we observed little evidence of differences between exercise types. We found evidence of beneficial effects on the severity of motor signs and QoL for most types of physical exercise for people with PD included in this review, but little evidence of differences between these interventions. Thus, our review highlights the importance of physical exercise regarding our primary outcomes severity of motor signs and QoL, while the exact exercise type might be secondary. Notably, this conclusion is consistent with the possibility that specific motor symptoms may be treated most effectively by PD-specific programs. Although the evidence is very uncertain about the effect of exercise on the risk of adverse events, the interventions included in our review were described as relatively safe. Larger, well-conducted studies are needed to increase confidence in the evidence. Additional studies recruiting people with advanced disease severity and cognitive impairment might help extend the generalizability of our findings to a broader range of people with PD.


Engineered albumin-functionalized nanoparticles for improved FcRn binding enhance oral delivery of insulin.
Oral delivery of biopharmaceuticals, as insulin, is hampered by rapid degradation and inefficient absorption in the gastrointestinal tract (GIT). To solve this, a new class of biodegradable poly(lactic-co-glycolic)-poly(ethylene glycol) (PLGA-PEG) mucodiffusive nanoparticles (NPs) was designed. Specifically, these were decorated with site-specific conjugated human albumin, engineered for improved pH dependent binding to the neonatal Fc receptor (FcRn), which naturally mediates transport of albumin across the intestinal epithelium. The designed NPs of monodisperse 150 nm in size were 10% loaded with insulin and their surface was successfully functionalized with human albumin. Importantly, the engineered albumin-functionalized NPs bound human FcRn favorably in a pH dependent manner and showed enhanced transport across polarized cell layers. When orally administered to human FcRn expressing mice induced with diabetes, a reduction of glycemia was measured as a function of receptor targeting, with up to around 40% reduction after 1 h post-delivery. Thus, biodegradable PLGA-PEG NPs decorated with human albumin for improved FcRn-dependent transport offer a novel attractive strategy for delivery of encapsulated biopharmaceuticals across intestinal barriers.


Feeding Stimulation Ability and Central Effects of Intraperitoneal Treatment of L-Leucine, L-Valine, and L-Proline on Amino Acid Sensing Systems in Rainbow Trout: Implication in Food Intake Control.
To continue gathering knowledge on the central regulation of food intake in response to amino acids in teleost fish, using as a model rainbow trout (Oncorhynchus mykiss), we evaluated in a first experiment the feeding attractiveness of L-leucine, L-valine, and L-proline offered as an agar gel matrix. In a second experiment, we assessed the effect of intraperitoneal (IP) treatment with the same amino acids on food intake. In a third experiment, we carried out a similar IP administration of amino acids to evaluate the response of amino acid sensing mechanisms in the hypothalamus and telencephalon. Results are discussed in conjunction with an earlier study where leucine and valine were administered intracerebroventricularly (ICV). The attractiveness of amino acids does not appear to relate to their effects on food intake, at least when administrated by-passing ingestion and luminal absorption, since two attractive amino acids resulted in an anorexigenic (Leu) or no effects (Pro) on food intake while a non-attractive amino acid (Val) induced anorexigenic (IP treatment) or orexigenic (ICV treatment) responses. The effects of Leu on food intake might relate to the expression of hypothalamic neuropeptides and result from the direct activation of amino acid sensing systems. In contrast, while valine had few effects on hypothalamic amino acid sensing systems after ICV treatment, a significant amount of parameters become affected by IP treatment suggesting that the effect of Val after IP treatment is indirect. Proline had no relevant effects on amino acid sensing systems, neuropeptide expression, and food intake, which suggest that this amino acid might not have a relevant role in the homeostatic regulation of food intake through hypothalamic mechanisms. In telencephalon, the same amino acid sensing systems operating in hypothalamus appear to be present and respond to Leu and Val, but it is still unclear how they might relate to the control of food intake.


Saltation of particles in turbulent channel flow.
This paper numerically investigates particle saltation in a turbulent channel flow having a rough bed consisting of two to three layers of densely packed spheres. The Shields function is 0.065 which is just above the sediment entrainment threshold to give a bed-load regime. The applied methodology is a combination of three technologies, i.e., the direct numerical simulation of turbulent flow; the combined finite-discrete element modeling of the deformation, movement, and collision of the particles; and the immersed boundary method for the fluid-solid interaction. It is shown that the presence of entrained particles significantly modifies the flow profiles of velocity, turbulent intensities, and shear stresses in the vicinity of a rough bed. The quasi-streamwise-aligned streaky structures are not observed in the near-wall region and the particles scatter on the rough bed owing to their large size. However, in the outer flow region, the turbulent coherent structures recover due to the weakening rough-bed effects and particle interferences. First- and second-order statistical features of particle translational and angular velocities, together with sediment concentration and volumetric flux density profiles, are presented. Several key parameters of the particle saltation trajectory are calculated and agree closely with published experimental data. Time histories of the hydrodynamic forces exerted upon a typical saltating particle, together with those of the particle's coordinates and velocities, are presented. A strong correlation is shown between the abruptly decreasing streamwise velocity and increasing vertical velocity at collision which indicates that the continuous saltation of large-grain-size particles is controlled by collision parameters such as particle incident angle, local bed packing arrangement, and particle density, etc.


An Australian survey of audiologists' preferences for patient-centredness.
Patient-centredness is becoming a core value of health services worldwide, however it remains largely unexplored in audiology. This study investigated audiologists' preferences for patient-centredness and identified factors that explain audiologists' preferences for patient-centredness. All members of the Audiological Society of Australia received two questionnaires: (1) a descriptive questionnaire (e.g. age, gender, place of residence, years in practice, employment characteristics), and (2) a modified patient-practitioner orientation scale (PPOS; Krupat et al, 2000) which measures preferences for two aspects of patient-centredness, sharing and caring. In total 663 (46%) audiologists returned both questionnaires fully completed. Mean PPOS scores indicated that audiologists prefer patient-centredness. Linear regression modelling identified that older audiologists, that had practiced longer, and who worked in community education, industrial audiology, or teaching had a significantly greater preference for patient-centredness than their peers. In contrast, audiologists who practiced in a private environment and who worked in the area of assessment of adults had a significantly lesser preference for patient-centredness than their peers. Audiologists prefer client-centredness and age, years of experience, and employment characteristics can partly explain preferences for patient-centredness. Future research should explore the relationships between patient-centredness and intervention outcomes in audiology.


Coordinated group response to nest intruders in social shrimp.
A key characteristic of highly social animals is collective group response to important stimuli such as invasion by enemies. The marine societies of social snapping shrimp share many convergences with terrestrial eusocial animals, including aggressive reaction to strangers, but no group actions have yet been observed in shrimp. Here we describe 'coordinated snapping', during which a sentinel shrimp reacts to danger by recruiting other colony members to snap in concert for several to tens of seconds. This distinctive behaviour is a specific response to intrusion by strange shrimp into the colony's sponge and is highly successful at repelling these intruders. Although coordinated snapping apparently functions analogously to alarm responses in other social animals, colony members in social shrimp do not rush to the site of the attack. Coordinated snapping appears instead to be a warning signal to would-be intruders that the sponge is occupied by a cooperative colony ready to defend it. This is the first evidence for coordinated communication in social shrimp and represents yet another remarkable convergence between social shrimp, insects and vertebrates.


Genomic characterization and phylogenetic position of two new species in Rhabdoviridae infecting the parasitic copepod, salmon louse (Lepeophtheirus salmonis).
Several new viruses have emerged during farming of salmonids in the North Atlantic causing large losses to the industry. Still the blood feeding copepod parasite, Lepeophtheirus salmonis, remains the major challenge for the industry. Histological examinations of this parasite have revealed the presence of several virus-like particles including some with morphologies similar to rhabdoviruses. This study is the first description of the genome and target tissues of two new species of rhabdoviruses associated with pathology in the salmon louse. Salmon lice were collected at different Atlantic salmon (Salmo salar) farming sites on the west coast of Norway and prepared for histology, transmission electron microscopy and Illumina sequencing of the complete RNA extracted from these lice. The nearly complete genomes, around 11,600 nucleotides encoding the five typical rhabdovirus genes N, P, M, G and L, of two new species were obtained. The genome sequences, the putative protein sequences, and predicted transcription strategies for the two viruses are presented. Phylogenetic analyses of the putative N and L proteins indicated closest similarity to the Sigmavirus/Dimarhabdoviruses cluster, however, the genomes of both new viruses are significantly diverged with no close affinity to any of the existing rhabdovirus genera. In situ hybridization, targeting the N protein genes, showed that the viruses were present in the same glandular tissues as the observed rhabdovirus-like particles. Both viruses were present in all developmental stages of the salmon louse, and associated with necrosis of glandular tissues in adult lice. As the two viruses were present in eggs and free-living planktonic stages of the salmon louse vertical, transmission of the viruses are suggested. The tissues of the lice host, Atlantic salmon, with the exception of skin at the attachment site for the salmon louse chalimi stages, were negative for these two viruses.


A 48-Year-Old Man at Low Risk for SARS-CoV-2 Infection Who Underwent Planned Elective Triple-Vessel Coronary Artery Bypass Graft Surgery at a National Heart Center in Indonesia Followed by a Fatal Case of COVID-19.
BACKGROUND This is of the first fatal case of coronavirus disease 2019 (COVID-19) pneumonia at a National Heart Center in Indonesia following planned elective triple-vessel coronary artery bypass graft (CABG) who was considered to be at low risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection when admitted for surgery. CASE REPORT A 48-year-old man was diagnosed with coronary artery disease (CAD) in 3 vessels (3VD) with an ejection fraction (EF) of 61% and chronic kidney disease (CKD) with routine hemodialysis. The patient was scheduled for a coronary artery bypass graft (CABG) surgery. He underwent surgery after COVID-19 screening using a checklist provided by the hospital. The patient's condition worsened on the 3rd postoperative day in the ward, and he was transferred back to the Intensive Care Unit (ICU), reintubated, and tested for COVID-19 with a real time-polymerase chain reaction (PCR) test. Because of the COVID-19 pandemic, we excluded the other possible pneumonia causes (e.g., influenza). An RT-PCR test performed after surgery revealed that the patient was positive for COVID-19. COVID-19 tracing was performed for all health care providers and relatives; all results were negative except for 1 family member. The patient was treated for 4 days in the isolation ICU but died due to complications of the infection. CONCLUSIONS This report shows the importance of testing patients for SARS-CoV-2 infection before hospital admission for elective surgery and during the hospital stay, and the importance of developing rapid and accurate testing methods that can be used in countries and centers with limited health resources.