Prospective case-control study of premenopausal serum estradiol and testosterone levels and breast cancer risk.
Breast cancer is frequently a hormonally dependent cancer, and associations of circulating estrogens and androgens with subsequent breast cancer risk are well established in postmenopausal women. Associations of serum estrogens and androgens with breast cancer risk in premenopausal women are less well studied. The objective of this study was to determine whether estradiol and testosterone levels in serum collected before menopause are associated with subsequent breast cancer risk. We conducted a prospective case-control study of 266 participants who were registered in the Columbia, Missouri, Serum Bank and not using exogenous hormones at the time of blood collection. Each of 98 in situ or invasive breast cancer cases with prediagnostic serum collected before menopause was matched to two controls by age, date, menstrual cycle day, and time of day of blood collection. Estradiol and testosterone concentrations were quantified by using specific radioimmunoassays, and sex hormone-binding globulin (SHBG) was quantified with a chemiluminescent immunoassay to allow calculation of the non-SHBG bound hormone fractions. Data were analyzed by using conditional logistic regression. All tests of statistical significance were two-sided. Serum testosterone was strongly and significantly associated with breast cancer risk. The relative odds (OR) for increasing quartiles of total testosterone were 1.0, 2.1 (95% confidence interval (CI) 0.9 to 4.8), 1.5 (95% CI, 0.6 to 3.4), and 3.3 (95% CI, 1.5 to 7.5, P(trend) = 0.006). Comparable ORs for the non-SHBG bound fraction of testosterone that is bioavailable were 1.0, 1.7 (95% CI, 0.7 to 4.2), 1.7 (95% CI, 0.7 to 4.0), and 4.2 (95% CI, 1.6 to 10.9, P(trend) = 0.002). Total and non-SHBG-bound estradiol were not associated with breast cancer, but extreme variation in levels across the menstrual cycle coupled with relatively small numbers, particularly for analyses stratified by cycle phase, limited the power to detect associations. Results suggest that premenopausal women with elevated serum testosterone levels are at an increased risk of breast cancer.


Chronic neurosteroid treatment produces functional heterologous uncoupling at the gamma-aminobutyric acid type A/benzodiazepine receptor complex in mammalian cortical neurons.
We have investigated the effects of chronic treatment with the neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha) on the gamma-aminobutyric acid (GABA)A receptor complex in cultured mammalian cortical neurons. Chronic 5 alpha 3 alpha treatment (up to 2 microM, 5 days) did not produce any changes in the morphological appearance or the cell protein content of cortical neurons. The basal binding of [3H]flunitrazepam, [3H]Ro15-1788, and [3H]Ro15-4513 was not altered after the chronic treatment. Chronic 5 alpha 3 alpha treatment did not alter the Kd or Bmax values of [3H]flunitrazepam binding to intact cortical neurons. However, chronic 5 alpha 3 alpha treatment produced uncoupling between GABA, barbiturate, and neurosteroid sites and the benzodiazepine site. The EC50 values of these ligands were not significantly altered; however, their Emax values were decreased after chronic 5 alpha 3 alpha treatment. The 5 alpha 3 alpha-induced uncoupling was time and concentration dependent. The binding of [3H]GABA and t-[35S]butylbicyclophosphorothionate was also decreased after chronic 5 alpha 3 alpha treatment. Chronic 5 alpha 3 alpha treatment decreased the Bmax of the low affinity GABAA receptor sites, without affecting the high affinity sites, and decreased the Bmax of t-butylbicyclophosphorothionate binding sites. The EC50 value for GABA-induced 36Cl- influx was not altered, whereas the Emax value was decreased after chronic 5 alpha 3 alpha treatment. Furthermore, the 5 alpha 3 alpha-induced uncoupling was reversed by concomitant exposure of the cortical neurons to 5 alpha-pregnan-3 beta-ol-20-one or R5135, suggesting an involvement of the neurosteroid and GABA recognition sites in the observed uncoupling. Taken together, these results suggest that chronic 5 alpha 3 alpha treatment produces heterologous uncoupling at the GABAA receptor complex.


Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents.
Drugs that inhibit the cardiac rapid delayed rectifier potassium ion current (I(Kr)) can be proarrhythmic and their clinical use has been associated with sudden unexpected death (SUD) due to cardiac arrhythmia. SUD is 20-40 times more common among people with epilepsy than in the general population and case-control studies have identified polytherapy with antiepileptic drugs (AEDs) as a risk factor. In a previous study, it was described that the old AEDs phenytoin and phenobarbital had the potential to inhibit the I(Kr) channel and it was suggested that this could contribute to the increased risk for SUD in patients with epilepsy. In this study, we have investigated the I(Kr) blocking potential of some more recently introduced AEDs, lamotrigine (LTG), topiramate (TPM) and gapapentin (GBP). The whole cell patch-clamp recording technique was used to study the effects on I(Kr) channels expressed by the human ether-a-go-go related gene (hERG) stably expressed in human embryo kidney (HEK) 293 cells. Tail currents, which are purely related to hERG currents, were blocked with IC50 and IC20 (the concentrations when 50% and 20% inhibition was obtained compared to control values) of 229 and 21 microM, respectively, for LTG. A 40% inhibition of tail currents was obtained at GBP concentrations of 100 mM and a 20% inhibition at 54 mM. A 35% inhibition of tail currents was obtained at TPM concentrations of 1000 microM and a 20% inhibition at 87 microM, respectively. Collective data show that drugs with the same margins (ratio hERG IC50/unbound therapeutic concentration) as LTG, may have arrhythmogenic potential. The risk for arrhythmia may be clinically significant in the presence of predisposing factors such as seizure-induced acidosis and in the case of concurrent treatment with other I(Kr) blocking drugs, or in case of pharmacokinetic drug-drug interactions resulting in excessively high concentrations of LTG.


Epstein-Barr virus infection of human gastric carcinoma cells: implication of the existence of a new virus receptor different from CD21.
Recombinant Epstein-Barr virus (EBV) with a selectable marker successfully infected the human gastric carcinoma cell lines AGS, MKN28, and MKN74. Following incubation in selective media, drug-resistant cell clones were isolated and proved to be infected with EBV. All gastric carcinoma cell clones were positive for EBNA 1 but negative for EBNA 2. LMP 1 expression was negative in most clones, but there were a few exceptions. Gastric carcinoma cells were negative for the EBV receptor CD21, and infection was not inhibited by pretreatment of cells with the anti-CD21 monoclonal antibody OKB7. The results indicate that gastric carcinoma cells are susceptible to EBV infection and that infection is mediated via a new receptor different from CD21.


Functional heterogeneity of type 1 fimbriae of Escherichia coli.
Escherichia coli and other members of the family Enterobacteriaceae express surface fibrillar structures, fimbriae, that promote bacterial adhesion to host receptors. Type 1 fimbriae possess a lectinlike component, FimH, that is commonly thought to cause binding to mannose-containing oligosaccharides of host receptors. Since adhesion of type 1 fimbriated organisms are inhibited by mannose, the reactions are described as mannose sensitive (MS). We have studied the adhesion of the type 1 fimbriated CSH-50 strain of E. coli (which expresses only type 1 fimbriae) to fibronectin (FN). E. coli CSH-50 does not bind detectable amounts of soluble FN but adheres well to immobilized plasma or cellular FN. This adhesion was inhibited by mannose-containing saccharides. By using purified domains of FN, it was found that E. coli CSH-50 adheres primarily to the amino-terminal and gelatin-binding domains, only one of which is glycosylated, in an MS fashion. Binding of the mannose-specific lectin concanavalin A to FN and ovalbumin was eliminated or reduced, respectively, by incubation with periodate or endoglycosidase. Adhesion of E. coli CSH-50 to ovalbumin was reduced by these treatments, but adhesion to FN was unaffected. E. coli CSH-50 also adheres to a synthetic peptide copying a portion of the amino-terminal FN domain (FNsp1) in an MS fashion. Purified CSH-50 fimbriae bound to immobilized FN and FNsp1 in an MS fashion and inhibited adhesion of intact organisms. However, fimbriae purified from HB101 (pPKL4), a recombinant strain harboring the entire type 1 fim gene locus and expressing functional type 1 fimbriae, neither bound to FN or FNsp1 nor inhibited E. coli adhesion to immobilized FN or FNsp1. These novel findings suggest that there are two forms of type 1 MS fimbriae. One form exhibits only the well-known MS lectinlike activity that requires a substratum of mannose-containing glycoproteins. The other form exhibits not only the MS lectinlike activity but also binds to nonglycosylated regions of proteins in an MS manner.


Guidelines for the medical surveillance of shift workers.
Occupational health physicians should evaluate workers' fitness for shift and night work before their assignment, at regular intervals, and in cases of health problems connected with night work. The evaluation should be accompanied by a careful job analysis to ensure that shift schedules are arranged according to ergonomic criteria. This arrangement can reduce health problems and make coping with irregular workhours possible, even for people suffering from contraindicative illnesses. Both health disorders representing absolute or relative contraindication and actual work conditions should be taken into account. Health checks should be aimed at detecting early signs of intolerance, such as sleeping and digestive trouble, drug consumption, accidents, and reproductive function. Their periodicity should be set in relation to specific work conditions, individual characteristics, and social factors known to influence tolerance to shift work. Shift workers should receive clear information on the possible negative effect of shift work, and also counseling for coping with shift and night work.


Structures of the Toxoplasma gliding motility adhesin.
Micronemal protein 2 (MIC2) is the key adhesin that supports gliding motility and host cell invasion by Toxoplasma gondii. With a von Willebrand factor A (VWA) domain and six thrombospondin repeat domains (TSR1-6) in its ectodomain, MIC2 connects to the parasite actomyosin system through its cytoplasmic tail. MIC2-associated protein (M2AP) binds noncovalently to the MIC2 ectodomain. MIC2 and M2AP are stored in micronemes as proforms. We find that the MIC2-M2AP ectodomain complex is a highly elongated 1:1 monomer with M2AP bound to the TSR6 domain. Crystal structures of N-terminal fragments containing the VWA and TSR1 domains for proMIC2 and MIC2 reveal a closed conformation of the VWA domain and how it associates with the TSR1 domain. A long, proline-rich, disulfide-bonded pigtail loop in TSR1 overlaps the VWA domain. Mannose α-C-linked to Trp-276 in TSR1 has an unusual (1)C4 chair conformation. The MIC2 VWA domain includes a mobile α5-helix and a 22-residue disordered region containing two disulfide bonds in place of an α6-helix. A hydrophobic residue in the prodomain binds to a pocket adjacent to the α7-helix that pistons in opening of the VWA domain to a putative high-affinity state.


Effect of Oral Vitamin C Supplementation on High-Altitude Hyperuricemia in Young Men Initially Migrating to High Altitude: A Pilot Study.
Clinical studies have shown that oral vitamin C supplementation can reduce serum uric acid levels in multiple populations and may also improve acute mountain sickness. However, it is unclear whether this protocol can improve high-altitude hyperuricemia. Therefore, we aimed to evaluate the role of vitamin C supplementation on high-altitude hyperuricemia. A preliminary prospective control study was performed in 2015. Young male army recruits (n = 66), who had recently arrived on the Tibetan Plateau for the first time, were recruited for study I. Subjects were assigned to either the vitamin C group, who took an oral daily dose of 500 mg vitamin C for 1 month, or the blank control group, who had no intervention. The levels of serum uric acid, serum creatinine, and blood urea nitrogen were monitored at baseline and at the end of 1 month. In a second study II in 2016 (n = 120), the effect of 500 mg/d vitamin C on high-altitude hyperuricemia was compared with 75 IU/d of vitamin E. In study I, the level of serum uric acid at 1 month was significantly higher than at baseline (436.1 ± 79.3 μmol/L vs. 358.0 ± 79.8 μmol/L, p < 0.001) and the prevalence of hyperuricemia was also significantly higher (63.6% [95% confidence interval, CI: 52.0%-75.2%] vs. 19.7% [95% CI: 10.1%-29.3%], p < 0.001). Both the level of serum uric acid (411.5 ± 74.2 μmol/L vs. 460.8 ± 54.8 μmol/L, p = 0.003) and the prevalence of hyperuricemia (48.5% [95% CI: 31.4%-65.6%] vs. 78.8% [95% CI: 64.9%-92.7%], p = 0.020) were significantly lower in the vitamin C group than in the blank control group. In study II, the levels of serum uric acid and the frequency of hyperuricemia also increased over 1 month and were similar in the vitamin C and the vitamin E groups at both baseline and 1 month (p > 0.05). The change in serum uric acid was positively correlated with both the changes in serum creatinine (r = 0.599, p < 0.001) and blood urea nitrogen (r = 0.207, p = 0.005). These findings indicate that healthy young men develop an increase in serum uric acid within a month of moving from low to high altitude. Oral vitamin C supplementation can safely reduce this increase at a low cost.


The double burden of malnutrition: aetiological pathways and consequences for health.
Malnutrition has historically been researched and addressed within two distinct silos, focusing either on undernutrition, food insecurity, and micronutrient deficiencies, or on overweight, obesity, and dietary excess. However, through rapid global nutrition transition, an increasing proportion of individuals are exposed to different forms of malnutrition during the life course and have the double burden of malnutrition (DBM) directly. Long-lasting effects of malnutrition in early life can be attributed to interconnected biological pathways, involving imbalance of the gut microbiome, inflammation, metabolic dysregulation, and impaired insulin signalling. Life-course exposure to early undernutrition followed by later overweight increases the risk of non-communicable disease, by imposing a high metabolic load on a depleted capacity for homoeostasis, and in women increases the risk of childbirth complications. These life-course trajectories are shaped both by societal driving factors-ie, rapidly changing diets, norms of eating, and physical activity patterns-and by broader ecological factors such as pathogen burden and extrinsic mortality risk. Mitigation of the DBM will require major societal shifts regarding nutrition and public health, to implement comprehensive change that is sustained over decades, and scaled up into the entire global food system.


High-intensity interval training on an aquatic treadmill in adults with osteoarthritis: effect on pain, balance, function, and mobility.
Although aquatic exercise is considered a potentially effective treatment intervention for people with osteoarthritis (OA), previous research has focused primarily on calisthenics in a shallow pool with the inherent limitations on regulating exercise intensity. The purpose of this study was to quantify the efficacy of a 6-week aquatic treadmill exercise program on measures of pain, balance, function, and mobility. Eighteen participants (age = 64.5 ± 10.2 years) with knee OA completed a non-exercise control period followed by a 6-week exercise period. Outcome measures included visual analog scales for pain, posturography for balance, sit-to-stand test for function, and a 10-m walk test for mobility. The exercise protocol included balance training and high-intensity interval training (HIT) in an aquatic treadmill using water jets to destabilize while standing and achieve high ratings of perceived exertion (14-19) while walking. In comparison with pretests, participants displayed reduced joint pain (pre = 50.3 ± 24.8 mm vs. post = 15.8 ± 10.6 mm), improved balance (equilibrium pre = 66.6 ± 11.0 vs. post = 73.5 ± 7.1), function (rising index pre = 0.49 ± 0.19% vs. post = 0.33 ± 0.11%), and mobility (walk pre = 8.6 ± 1.4 s vs. post = 7.8 ± 1.1 s) after participating in the exercise protocol (p = 0.03-0.001). The same benefits were not observed after the non-exercise control period. Adherence to the exercise protocol was exceptional and no participants reported adverse effects, suggesting that aquatic treadmill exercise that incorporates balance and HIT training was well tolerated by patients with OA and may be effective at managing symptoms of OA.


Early dysautonomia detected by heart rate variability predicts late depression in female patients following mild traumatic brain injury.
Depression is one of the frequent complications following a mild traumatic brain injury (mTBI). Recent research indicated that abnormalities in the autonomic nervous system (ANS) can be evaluated by a noninvasive power spectral analysis of the heart rate variability (HRV). In this study, we investigated whether a frequency-domain analysis of HRV was correlated with late depression in mTBI patients. In total, 181 patients diagnosed with mTBI and 83 volunteers as healthy controls were recruited in 2010-2014. Beck Depression Inventory (BDI) scores were used to evaluate depression in the 1st week of assessment and at 1.5-, 3-, 6-, 12-, and 18-month follow-ups. Correlation and logistic regression analyses of the 1st week HRV parameters with BDI scores at 18 months were performed in individual female mTBI patients. Female mTBI patients were more vulnerable to depression accompanied by reduced HRV compared to healthy controls. Over time, depression was aggravated in female mTBI patients but was alleviated in male mTBI patients. A significantly lower parasympathetic proportion of the ANS was noted at 18 months with respect to the 1st week in female mTBI patients. In addition, depression in female mTBI patients at 18 months after injury was significantly correlated with a decrease in the parasympathetic proportion of the ANS in the 1st week (ρ = -0.411; p < .05). Dysautonomia resulted in higher risks of depression in female mTBI patients. We concluded that early dysautonomia following an mTBI contributes to late depression in female mTBI patients.


Prevalence of Botrytis spp. in Onion Seed Crops in the Columbia Basin of Washington.
Of 12 onion seed lots harvested in the semi-arid Columbia Basin of Washington in 1999 or 2000, 8 were infected and 10 infested with Botrytis aclada at incidences of 1 to 10% and 2 to 26%, respectively. Twenty to forty plants were sampled from each of nine direct-seeded, biennial seed crops in April, June, and July 2001 and assayed for Botrytis spp. Six direct-seeded crops were sampled in October and November 2001 and April, June, and July 2002. One bulb-to-seed crop was sampled in April, June, and July 2002. The incidence of B. aclada increased through each season, reaching 100% in most fields by July. Infections were primarily asymptomatic, with no apparent relationship between plant infection and infection of harvested seed. B, cinerea, B. squamosa, and B. porri were detected in 16, 4, and 4% of the fields, respectively, at lower incidences than B. aclada. Harvested seed from 15 of the fields were infected with B. aclada at <1 to 28%. B, cinerea, B. porri, and B. squamosa were detected in three, three, and none of the harvested lots, respectively.


In Vitro Modeling of Bile Acid Processing by the Human Fecal Microbiota.
Bile acids, the products of concerted host and gut bacterial metabolism, have important signaling functions within the mammalian metabolic system and a key role in digestion. Given the complexity of the mega-variate bacterial community residing in the gastrointestinal tract, studying associations between individual bacterial genera and bile acid processing remains a challenge. Here, we present a novel in vitro approach to determine the bacterial genera associated with the metabolism of different primary bile acids and their potential to contribute to inter-individual variation in this processing. Anaerobic, pH-controlled batch cultures were inoculated with human fecal microbiota and treated with individual conjugated primary bile acids (500 μg/ml) to serve as the sole substrate for 24 h. Samples were collected throughout the experiment (0, 5, 10, and 24 h) and the bacterial composition was determined by 16S rRNA gene sequencing and the bile acid signatures were characterized using a targeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) approach. Data fusion techniques were used to identify statistical bacterial-metabolic linkages. An increase in gut bacteria associated bile acids was observed over 24 h with variation in the rate of bile acid metabolism across the volunteers (n = 7). Correlation analysis identified a significant association between the Gemmiger genus and the deconjugation of glycine conjugated bile acids while the deconjugation of taurocholic acid was associated with bacteria from the Eubacterium and Ruminococcus genera. A positive correlation between Dorea and deoxycholic acid production suggest a potential role for this genus in cholic acid dehydroxylation. A slower deconjugation of taurocholic acid was observed in individuals with a greater abundance of Parasutterella and Akkermansia. This work demonstrates the utility of integrating compositional (metataxonomics) and functional (metabonomics) systems biology approaches, coupled to in vitro model systems, to study the biochemical capabilities of bacteria within complex ecosystems. Characterizing the dynamic interactions between the gut microbiota and the bile acid pool enables a greater understanding of how variation in the gut microbiota influences host bile acid signatures, their associated functions and their implications for health.


Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide.
Despite optimal current therapies, cardiovascular disease remains the leading cause for death worldwide. Importantly, advances in peptide engineering have accelerated the development of innovative therapeutics for diverse human disease states. Additionally, the advancement of bispecific therapeutics targeting >1 signaling pathway represents a highly innovative strategy for the treatment of cardiovascular disease. We, therefore, engineered a novel, designer peptide, which simultaneously targets the pGC-A (particulate guanylyl cyclase A) receptor and the MasR (Mas receptor), potentially representing an attractive cardiorenoprotective therapeutic for cardiovascular disease. We engineered a novel, bispecific receptor activator, NPA7, that represents the fusion of a 22-amino acid sequence of BNP (B-type natriuretic peptide; an endogenous ligand of pGC-A) with Ang 1-7 (angiotensin 1-7)-the 7-amino acid endogenous activator of MasR. We assessed NPA7's dual receptor activating actions in vitro (second messenger production and receptor interaction). Further, we performed an intravenous peptide infusion comparison study in normal canines to study its biological actions in vivo, including in the presence of an MasR antagonist. Our in vivo and in vitro studies demonstrate the successful synthesis of NPA7 as a bispecific receptor activator targeting pGC-A and MasR. In normal canines, NPA7 possesses enhanced natriuretic, diuretic, systemic, and renal vasorelaxing and cardiac unloading properties. Importantly, NPA7's actions are superior to that of the individual native pGC-A or MasR ligands. These studies advance NPA7 as a novel, bispecific designer peptide with potential cardiorenal therapeutic benefit for the treatment of cardiovascular disease, such as hypertension and heart failure.


The potential scientist's dilemma: How the Masculinization of Science Shapes Friendships and Science Job Preferences.
In the United States, girls and boys have similar science achievement, yet fewer girls aspire to science careers than boys. This paradox emerges in middle school, when peers begin to play a stronger role in shaping adolescent identities. We use complete network data from a single middle school and theories of gender, identity, and social distance to explore how friendship patterns might influence this gender and science paradox. Three patterns highlight the social dimensions of gendered science persistence: (1) boys and girls do not differ in self-perceived science potential and science career aspirations; (2) consistent with gender-based norms, both middle school boys and girls report that the majority of their female friends are not science kinds of people; and (3) youth with gender-inconsistent science aspirations are more likely to be friends with each other than youth with gender normative science aspirations. Together, this evidence suggests that friendship dynamics contribute to gendered patterns in science career aspirations.


Glucocorticoids and TNFalpha interact cooperatively to mediate sepsis-induced leucine resistance in skeletal muscle.
Sepsis blunts the ability of nutrient signaling by leucine to stimulate skeletal muscle protein synthesis by impairing translation initiation. The present study tested the hypothesis that overproduction of either tumor necrosis factor (TNF)-alpha or glucocorticoids mediate the sepsis-induced leucine resistance. Prior to producing peritonitis, rats received either vehicle, TNF binding protein (TNF(BP)) to inhibit endogenous TNFalpha action, and/or the glucocorticoid receptor antagonist RU486. Leucine was orally administered to all rats 24 h thereafter and the gastrocnemius removed 20 min later to assess protein synthesis and signaling components important in controlling peptide-chain initiation. Muscle protein synthesis was 65% lower in septic rats administered leucine than in leucine-treated control animals. This reduction was not prevented by either TNF(BP) or RU486 alone, but was completely reversed by the combination. This sepsis-induced leucine resistance was associated with an 80% reduction in the amount of active eIF4E.eIF4G complex, a 5-fold increase in the formation of the inactive eIF4E.4E-BP1 complex as well as markedly reduced (at least 70%) phosphorylation of 4E-BP1, eIF4G, S6K1, S6, and mTOR. Pretreatment of septic rats with either TNF(BP) or RU486 individually only nominally improved the leucine action as assessed by the above-mentioned endpoints. In contrast, when TNF(BP) and RU486 were co-administered, the ability of sepsis to impair the leucine-stimulated phosphorylation of 4E-BP1, eIF4G, S6K1, and S6 as well as the redistribution of eIF4E was essentially prevented. No differences in the total amount or phosphorylation of eIF2alpha and eIF2Bepsilon were detected between the different groups, and changes could not be attributed to differences in the prevailing plasma concentration of insulin or leucine. Our data demonstrate the sepsis-induced leucine resistance in skeletal muscle results from the cooperative interaction of both TNFalpha and glucocorticoids.


Service Delivery Transformation for UHC in Asia and the Pacific.
This article was drafted as part of a review of strategies for making progress toward universal health coverage in the countries of Asia and the Pacific. It focuses on strengthening the delivery of services, in the context of population aging. It argues that it is important to take into account big differences in development contexts and also the rapid, interconnected changes that many countries are experiencing. The article focuses especially on countries with relatively undeveloped institutions and pluralistic and highly segmented health sectors. It argues that attempts by these countries to import institutional arrangements from outside are likely to be complicated. It argues that government needs to focus on both short-term measures to meet immediate needs and the longer-term aim of establishing effective institutional arrangements. This means that they need to take into account the political factors that influence the direction of health system change. The article emphasizes the need to strengthen the capacity of the health system to address the growing challenge of chronic noncommunicable diseases to avoid heavy political pressure to expand hospital services. It then explores the opportunities and challenges associated with the rapid expansion of digital health services. It concludes with a discussion of government stewardship and management of health system transformation to address the major challenges associated with population aging.


Genetic variability and social structure of Colonies in Acromyrmex heyeri and A. striatus (Hymenoptera: Formicidae).
The breeding structure of both colony and population of social insects can be examined by genetic analysis. Colonies of the leaf-cutting ants Acromyrmex heyeri and A. striatus (Myrmicinae, Attini) were thus analyzed for isoenzyme systems MDH, a-GPDH, and AMY to describe genotype variability and social structure. A total of five loci were investigated (three for amylase and one for each other system). Ninety-seven colonies of A. heyeri and 103 of A. striatus were sampled in different localities in Southern Brazil (State of Rio Grande do Sul). The genotypes found show the occurrence of monogyny and polygyny associated or not with polyandry, which indicates that the social organization is colony-specific. The polygyny and polyandry observed are likely to be responsible for the great genotypic diversity of the colonies. The average inbreeding coefficient per colony was higher in A. striatus than in A. heyeri, which may reflect the different patterns of production of sexual individuals and nuptial flight of those two species.


Efficient soft tissue deformation using charged particles.
As the power of personal computing increases, there is a greater demand for high fidelity virtual environments for medical training simulators. However, it is still a challenge to provide realistic soft tissue deformation especially when haptic feedback is also required. This paper presents a new approach to soft tissue deformation using a novel Charged Particle method to efficiently model both the structure and haptic properties of anatomy in real time.


Grasping the Agent's Perspective: A Kinematics Investigation of Linguistic Perspective in Italian and German.
Every day, we primarily experience actions as agents, by having a concrete perspective on our actions, their means and goals. This peculiar perspective is what allows us to successfully plan and execute our actions in a dense social environment. Nevertheless, in this environment actions are also perceived from an observer's perspective. Adopting such a perspective helps us to understand and respond to other's people actions and their outcomes. Importantly, similar experiences of being agent and observer occur also when actions are not physically acted/perceived but are merely linguistically shared. In this paper we present two exploratory studies, one in Italian and one in German, in which we applied a direct comparison of three singular perspectives in combination with different verb categories. First, second and third person pronouns were combined with action and interaction verbs, i.e., verbs implying an interaction with an object - e.g., grasp - or an interaction with an object and another person - e.g., give. By means of kinematics recording, we analyzed participants' reaching-grasping responses to a mouse while they were presented with the different combinations of linguistic stimuli (pronouns and verb type). Results of Experiment 1 on reaching show that, when they are preceded by YOU, interaction verbs reached the velocity peak earlier than action verbs, since a further motor act will follow. Thus pronouns influence perspective taking and while comprehending language we are sensitive to the motor chain organization of verbs. The absence of the same effects in Experiment 2 is likely due to the fact that, being the pronoun in German mandatory, it is perceived as less salient than in Italian. Overall our result supports the idea that language is grounded in the motor system in a flexible way, and highlights the need for cross-linguistic studies in the field of embodied language processing.


The optical and biological properties of glacial meltwater in an Antarctic fjord.
As the Western Antarctic Peninsula (WAP) region responds to a warmer climate, the impacts of glacial meltwater on the Southern Ocean are expected to intensify. The Antarctic Peninsula fjord system offers an ideal system to understand meltwater's properties, providing an extreme in the meltwater's spatial gradient from the glacio-marine boundary to the WAP continental shelf. Glacial meltwater discharge in Arctic and Greenland fjords is typically characterized as relatively lower temperature, fresh and with high turbidity. During two cruises conducted in December 2015 and April 2016 in Andvord Bay, we found a water lens of low salinity and low temperature along the glacio-marine interface. Oxygen isotope ratios identified this water lens as a mixture of glacial ice and deep water in Gerlache Strait suggesting this is glacial meltwater. Conventional hydrographic measurements were combined with optical properties to effectively quantify its spatial extent. Fine suspended sediments associated with meltwater (nanoparticles of ~ 5nm) had a significant impact on the underwater light field and enabled the detection of meltwater characteristics and spatial distribution. In this study, we illustrate that glacial meltwater in Andvord Bay alters the inherent and apparent optical properties of the water column, and develop statistical models to predict the meltwater content from hydrographic and optical measurements. The predicted meltwater fraction is in good agreement with in-situ values. These models offer a potential for remote sensing and high-resolution detection of glacial meltwater in Antarctic waters. Furthermore, the possible influence of meltwater on phytoplankton abundance in the surface is highlighted; a significant correlation is found between meltwater fraction and chlorophyll concentration.


First Report of Shallot virus X in Onion in Sudan.
Onion (Alium cepa L.) is among the most important vegetable field crops in Sudan. During a disease survey in crops (cvs. Kamleen Yellow and Abu-freua) conducted in 2010, samples showing mild mottling symptoms were collected from Shambat Research Station Farm, Khartoum North, Sudan. A CF-11 cellulose chromatography dsRNA preparation (4) of a mixed onion leaf sample of five plants (20 g) resulted, apart from smaller dsRNAs up to 3 kbp, in a high molecular weight dsRNA of approximately 9 kbp. This dsRNA was used as a template for a random reverse transcriptase (RT)-PCR followed by cloning (4) and sequencing of two randomly selected clones by the ABI BigDye Terminator v3.1 Cycle Sequencing Kit. Comparison with sequences available at GenBank revealed high identities to Shallot virus X (ShVX). ShVX is the type member of the genus Allexivirus (Alphaflexiviridae). One sequence obtained showed 84% nt and 98% aa sequence identity (genome position 414 to 1,285 of Accession No. M97264) to the replicase, whereas the other sequence partially covered the ORF4 and coat protein (CP) coding region (7,127 to 7,998). This sequence showed 80% nt (entire sequence) and 80/89% aa sequence identity to the ORF4 encoded protein/coat protein of a Russian ShVX isolate, respectively. ShVX was first reported in shallot in Russia (2) and subsequently in the Netherlands, Germany, India (3), and New Zealand (1). To confirm the presence of ShVX in Sudan, 32 symptomatic leaf samples were collected in 2011 from different onion fields in Khartoum North, with a similar disease incidence compared to 2010. Thirty-one of these onion samples reacted positively in a double antibody sandwich-ELISA with a ShVX-specific antiserum (DSMZ AS-1042). Total RNA was extracted from five ShVX-ELISA positive onion samples using the RNeasy Plant Mini Kit (QIAGEN, Hilden, Germany) according to the manufacturer's protocol. Two primer pairs were also designed on the basis of sequences obtained in the random RT-PCR approach, targeting a 659-bp fragment of the coat protein region (ShVX-CPs 5'GTTGAATGTGGCGAGCGCAA3' and ShVX-CPas 5'AGTGCAGAAGCCTTCCACA3') or a 686-bp fragment of the replicase (ShVX-Rs 5'ATGTACTTCGGTACGGCATCA3' and ShVX-R-as 5'TAATCGAATGAGGTCGGCCA3'). Fragments of the expected sizes were obtained for all positive samples. One RT-PCR product of each primer pair was directly sequenced, showing high sequence identities to those previously obtained (>98%). The random RT-PCR sequences obtained in this study were submitted to GenBank (JQ751056 and JQ751057). On the basis of the nucleotide sequences obtained with the dsRNA template, ShVX specific RT-PCR, and ELISA, the presence of ShVX in Sudan was confirmed in two consecutive years. To our knowledge, this is the first report of ShVX in Sudan and Africa, indicating this virus is more widespread than previously reported. The presence of ShVX also suggests the presence of its only known vector, the mite Aceria tulipae. The virus may have been introduced to Sudan by infected onion sets. Even if the impact of ShVX on onion production has not been determined, its identification and the availability of a diagnostic antiserum may be helpful to select virus-free propagation material in order to achieve sustainable onion production in Sudan. References: (1) Z. Egusquiza et al. New Disease Reports 18:29, 2008. (2) K. V. Kanyuka et al. J. Gen. Virol. 73:2553, 1992. (3) S. Majumder et al. New Disease Reports 15:52, 2007. (4) W. Menzel et al. Arch. Virol. 154:1343, 2009.


Personalized medicine: motivation, challenges, and progress.
There is a great deal of hype surrounding the concept of personalized medicine. Personalized medicine is rooted in the belief that since individuals possess nuanced and unique characteristics at the molecular, physiological, environmental exposure, and behavioral levels, they may need to have interventions provided to them for diseases they possess that are tailored to these nuanced and unique characteristics. This belief has been verified to some degree through the application of emerging technologies such as DNA sequencing, proteomics, imaging protocols, and wireless health monitoring devices, which have revealed great inter-individual variation in disease processes. In this review, we consider the motivation for personalized medicine, its historical precedents, the emerging technologies that are enabling it, some recent experiences including successes and setbacks, ways of vetting and deploying personalized medicines, and future directions, including potential ways of treating individuals with fertility and sterility issues. We also consider current limitations of personalized medicine. We ultimately argue that since aspects of personalized medicine are rooted in biological realities, personalized medicine practices in certain contexts are likely to be inevitable, especially as relevant assays and deployment strategies become more efficient and cost-effective.


A valid method for comparing rational and empirical heat stress indices.
No single heat stress index has gained universal acceptance within the past 20 years, despite extensive research. It is currently difficult to directly and quantitatively compare the many rational and empirical indices that are available, which results in confusion and a reluctance to change to a different index. A method is developed using the concept of limiting metabolic rate, which allows virtually all heat stress indices to be compared with one another. Because all occupational heat stress indices are based, explicitly or implicitly, on the human heat balance equation, a unique value of metabolic rate can be found that just allows an unrestricted work/rest cycle in particular environmental conditions. A comparison using this methodology shows that there are very large differences between the recommended limits under the various indices, even for similar populations of acclimatized workers.


Molecular evolution and functional relevance of the chalcone synthase genes of pea.
We have isolated seven genomic chalcone synthase (CHS) genes and six classes of CHS cDNA from elicitor-treated pea tissues. Comparison of the nucleotide sequences of the coding regions revealed the existence of eight members of the CHS gene family in pea. These can essentially be divided into three groups (PSCHS1, 2 and 8; PSCHS3, 4 and 5; and PSCHS6 and 7) on the basis of nucleotide and or amino acid sequence comparisons of the coding regions, introns and promoter regions. We previously reported that the accumulation of CHS mRNAs is induced by elicitor treatment. Accumulation of CHS mRNA was observed mainly in roots and very little was found in floral organs. To specifically detect expression of each CHS gene in various types of pea cells. S1 nuclease protection assays were performed. Interestingly, the classification of the eight members of the CHS gene family based on the sequence identity was found to reflect their expression patterns as determined by the S1 nuclease protection assay. The first group of CHS genes, PSCHS1, 2 and 8, was strongly induced not only by elicitor treatment and UV irradiation but is also constitutively expressed in root and flower tissues. The second group, PSCHS3, 4 and 5, was also strongly induced by elicitor treatment and UV irradiation but is constitutively expressed only in root. Expression of the third group, PSCHS6 and 7 was barely detectable in any of the organs tested and was not influenced by environmental stimuli such as elicitor or UV. Furthermore, sequence analysis of the promoter region of each member of the CHS gene family revealed that putative cis-regulatory elements, such as Box-I. Box-II and G-Box, were conserved only in PSCHS1, 2, 3, 4 and 5. From these results we propose that an ancestral CHS gene might have given rise to defense response-related (UV irradiation- and elicitor-responsive) and -unrelated (unresponsive) genes at an early stage of evolution, followed by divergence within these subclasses based upon the developmental program in pea.


Dietary Intake and Biomarkers of Folate and Cobalamin Status in Norwegian Preschool Children: The FINS-KIDS Study.
Folate and cobalamin (vitamin B-12) are essential for growth and development. However, few population-based studies have investigated B-vitamin status in children. This study aimed to assess biomarkers of folate and vitamin B-12 status and to explore their dietary determinants in healthy Norwegian children. Using baseline data obtained from a randomized controlled trial on the effect of fish intake on neurodevelopment in children aged 4-6 y, we measured the plasma concentrations of folate, cobalamin, total plasma homocysteine (tHcy), and methylmalonic acid (MMA). Food-frequency questionnaires (FFQs) were used to assess dietary intake. We used unadjusted and multiple linear regression models to explore the determinants of biomarker concentrations. The median (IQR) of plasma folate (n = 197) and plasma cobalamin (n = 195) concentrations were 15.2 (12.2-21.1) nmol/L and 785 (632-905) pmol/L, respectively. Plasma folate concentrations of <10 nmol/L were observed in 13% of the children. No child had a cobalamin concentration <148 pmol/L. Two children were identified with elevated plasma MMA concentrations (>0.26 μmol/L) and 8 children had elevated tHcy concentrations (>6.5 μmol/L). Plasma folate concentration was inversely correlated with tHcy (ρ = -0.24, P < 0.001); we found no correlation between tHcy and cobalamin (ρ = -0.075, P = 0.30). Children who consumed vitamin supplements had 51% higher plasma folate concentrations (P < 0.0001) than those who did not. Consumption of red meat for dinner more than twice a week was associated with 23% lower plasma folate (P < 0.01). No other significant associations between dietary intake and the biomarkers were observed. The Norwegian preschool children from this cohort had adequate vitamin B-12 status. Poor folate status was common and associated with elevated tHcy. The implications of poor folate status during childhood should be a prioritized research question. This trial was registered at ClinicalTrials.gov as NCT02331667.


Direct interaction between protein kinase C theta (PKC theta) and 14-3-3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta translocation and function.
Recent studies have documented direct interactions between 14-3-3 proteins and several oncogene and proto-oncogene products involved in signal transduction pathways. Studies on the effects of 14-3-3 proteins on protein kinase C (PKC) activity in vitro have reported conflicting results, and previous attempts to demonstrate a direct association between PKC and 14-3-3 were unsuccessful. Here, we examined potential physical and functional interactions between PKC theta, a Ca(2+)-independent PKC enzyme which is expressed selectively in T lymphocytes, and the 14-3-3 tau isoform in vitro and in intact T cells. PKC theta and 14-3-3 tau coimmunoprecipitated from Jurkat T cells, and recombinant 14-3-3 tau interacted directly with purified PKC theta in vitro. Transient overexpression of 14-3-3 tau suppressed stimulation of the interleukin 2 (IL-2) promoter mediated by cotransfected wild-type or constitutively active PKC theta, as well as by endogenous PKC in ionomycin- and/or phorbol ester-stimulated cells. This did not represent a general inhibition of activation events, since PKC-independent (but Ca(2+)-dependent) activation of an IL-4 promoter element was not inhibited by 14-3-3 tau under similar conditions. Overexpression of wild-type 14-3-3 tau also inhibited phorbol ester-induced PKC theta translocation from the cytosol to the membrane in Jurkat cells, while a membrane-targeted form of 14-3-3 tau caused increased localization of PKC theta in the particulate fraction in unstimulated cells. Membrane-targeted 14-3-3 tau was more effective than wild-type 14-3-3 tau in suppressing PKC theta-dependent IL-2 promoter activity, suggesting that 14-3-3 tau inhibits the function of PKC theta not only by preventing its translocation to the membrane but also by associating with it. The interaction between 14-3-3 and PKC theta may represent an important general mechanism for regulating PKC-dependent signals and, more specifically, PKC theta-mediated functions during T-cell activation.


Iron and mitochondria in the susceptibility, pathogenesis and progression of COPD.
Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterised by airflow limitation, chronic bronchitis, emphysema and airway remodelling. Cigarette smoke is considered the primary risk factor for the development of COPD; however, genetic factors, host responses and infection also play an important role. Accumulating evidence highlights a role for iron dyshomeostasis and cellular iron accumulation in the lung as a key contributing factor in the development and pathogenesis of COPD. Recent studies have also shown that mitochondria, the central players in cellular iron utilisation, are dysfunctional in respiratory cells in individuals with COPD, with alterations in mitochondrial bioenergetics and dynamics driving disease progression. Understanding the molecular mechanisms underlying the dysfunction of mitochondria and cellular iron metabolism in the lung may unveil potential novel investigational avenues and therapeutic targets to aid in the treatment of COPD.


The influence of modeling separate neuromuscular compartments on the force and moment generating capacities of muscles of the feline hindlimb.
Functional electrical stimulation (FES) has the capacity to regenerate motion for individuals with spinal cord injuries. However, it is not straightforward to determine the stimulation parameters to generate a coordinated movement. Musculoskeletal models can provide a noninvasive simulation environment to estimate muscle force and activation timing sequences for a variety of tasks. Therefore, the purpose of this study was to develop a musculoskeletal model of the feline hindlimb for simulations to determine stimulation parameters for intrafascicular multielectrode stimulation (a method of FES). Additionally, we aimed to explore the differences in modeling neuromuscular compartments compared with representing these muscles as a single line of action. When comparing the modeled neuromuscular compartments of biceps femoris, sartorius, and semimembranosus to representations of these muscles as a single line of action, we observed that modeling the neuromuscular compartments of these three muscles generated different force and moment generating capacities when compared with single muscle representations. Differences as large as 4 N m (approximately 400% in biceps femoris) were computed between the summed moments of the neuromuscular compartments and the single muscle representations. Therefore, modeling neuromuscular compartments may be necessary to represent physiologically reasonable force and moment generating capacities of the feline hindlimb.


Return to Sport Following Adolescent Concussion: Epidemiologic Findings From a High School Population.
High school athletes sustaining a concussion require careful attention when determining return-to-sport (RTS) readiness. The purpose of this study was to determine epidemiological and RTS data of a large cohort of high school athletes who sustained 1 or more concussions. Records of 357 consecutive youth patients who sustained concussions and presented to a single health care system between September 2013 and December 2016 were reviewed. Demographic data, RTS, and concussion-related variables were obtained via chart review. Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) scores at baseline and following concussions were performed by neuropsychologists. The average age at injury was 15.5 years (range, 14-18 years), 61.9% of patients were male, 6.7% reported a loss of consciousness, and 14.3% reported amnesia, requiring 30.4±23.3 days of recovery prior to RTS. The most common sport of injury was football (27.7%). There was a high incidence of previous concussion (33.1%), and 32 athletes sustained a recurrent concussion. A multivariate model demonstrated that females, players with a history of concussion, and those diagnosed in-clinic rather than in-game required increased time to RTS. Memory ImPACT scores were found to increase as players had recurrent concussions. Visual motor speed and reaction time scores decreased with recurrent concussions. [Orthopedics. 2020;43(4):e306-e310.].


Insulin-mediated hypoglycaemia secondary to recurrent clear cell renal carcinoma.
Renal cell carcinoma has previously been associated with hypoglycaemia in the setting of non-islet cell tumours, caused by a paraneoplastic phenomenon relating to the production of insulin-like growth factor type II. We present a case of recurrent clear cell renal cell carcinoma, leading to an insulin-mediated paraneoplastic phenomenon causing severe recurrent hypoglycaemia. Hypoglycaemina was managed successfully using diazoxide therapy, in conjunction with pazopanib and radiotherapy to reduce tumour burden.


Label-free Bacteria Quantification in Blood Plasma by a Bioprinted Microarray Based Interferometric Point-of-Care Device.
Existing clinical methods for bacteria detection lack speed, sensitivity, and, importantly, point-of-care (PoC) applicability. Thus, finding ways to push the sensitivity of clinical PoC biosensing technologies is crucial. Here we report a portable PoC device based on lens-free interferometric microscopy (LIM). The device employs high performance nanoplasmonics and custom bioprinted microarrays and is capable of direct label-free bacteria ( E. coli) quantification. With only one-step sample handling we offer a sample-to-data turnaround time of 40 min. Our technology features detection sensitivity of a single bacterial cell both in buffer and in diluted blood plasma and is intrinsically limited by the number of cells present in the detection volume. When employed in a hospital setting, the device has enabled accurate categorization of sepsis patients (infectious SIRS) from control groups (healthy individuals and noninfectious SIRS patients) without false positives/negatives. User-friendly on-site bacterial clinical diagnosis can thus become a reality.


Behavior change intervention research in community settings: how generalizable are the results?
This review examines the extent to which recent behavioral intervention studies conducted in community settings reported on elements of internal and external validity, with an emphasis on whether research has been conducted in representative settings with representative populations. A targeted review was conducted on community-based intervention studies that promoted good nutrition, physical activity or smoking cessation/prevention, and were published in 11 leading health behavior journals between 1996 and 2000. The RE-AIM framework (reach, efficacy, adoption, implementation and maintenance) was used to evaluate the extent to which each paper reported on elements of reach, efficacy/effectiveness, adoption, implementation and maintenance. A total of 27 publications were reviewed. Although most studies (88%) reported participation rates among eligible members of the target audience ('reach'), only 11% of studies reported the participation rate ('adoption') among eligible community-based organizations or settings. Few studies reported if participating individuals or settings were representative of those found in the broader population. Although a majority of studies (59%) reported whether the intervention was delivered ('implementation'), few reported whether individuals maintained behavior change (30%) or whether organizations maintained or institutionalized interventions (0%). To increase the potential to translate community research findings to practice, studies should place a greater emphasis on obtaining and reporting external validity information, such as representativeness. The lack of external validity information limits researchers' and practitioners' ability to judge the generalizability of effects and the comparative utility of interventions. Improved reporting will facilitate implementation of proven and broadly applicable intervention strategies in communities. To make significant progress, all parties, including researchers, reviewers, editors and funders, need to take responsibility for increased emphasis on external validity information and ask what role they can best play to facilitate this process.


Effective area of photonic crystal fibers.
We consider the effective area Ae. of photonic crystal fibers (PCFs) with a triangular air-hole lattice in the cladding. It is first of all an important quantity in the context of non-linearities, but it also has connections to leakage loss, macro-bending loss, and numerical aperture. Single-mode versus multi-mode operation in PCFs can also be studied by comparing effective areas of the different modes. We report extensive numerical studies of PCFs with varying air hole size. Our results can be scaled to a given pitch and thus provide a general map of the effective area. We also use the concept of effective area to calculate the "phase" boundary between the regimes with single-mode and multi-mode operation.


Progressive renal distortion by multiple cysts in transgenic mice expressing artificial microRNAs against Pkd1.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening inherited diseases, and the PKD1 gene is responsible for most cases of this disease. Previous efforts to establish a mouse model that recapitulates the phenotypic characteristics of ADPKD, which have used conventional or conditional knockout of the mouse orthologue Pkd1, have been unsuccessful or unreliable. In a previous study, we described the generation of a novel Pkd1 hypomorphic allele, in which Pkd1 expression was significantly reduced but not totally blocked. These Pkd1 homozygous mutant mice rapidly developed renal cystic disease, supporting the hypothesis that 'haploinsufficiency' explains development of the ADPKD phenotype. In the present study, we further investigated the Pkd1 haploinsufficiency effect by generating Pkd1 knockdown transgenic mice with co-cistronic expression of two miRNA hairpins specific to Pkd1 transcript and an Emerald GFP reporter driven by a human ubiquitin B promoter. Two transgenic lines which had ∼60-70% reduction of Pkd1 expression developed severe renal cystic disease at a rate similar to that of human ADPKD. These results further support the haploinsufficiency hypothesis, and suggest that the onset and progression of the renal cystic diseases are correlated with the level of Pkd1 expression. The two novel mutant lines of mice appear to be ideal models for the study of ADPKD.


Computational fluid dynamics (CFD) investigation of impacts of an obstruction on airflow in underground mines.
Continuous airflow monitoring can improve the safety of the underground work force by ensuring the uninterrupted and controlled distribution of mine ventilation to all working areas. Air velocity measurements vary significantly and can change rapidly depending on the exact measurement location and, in particular, due to the presence of obstructions in the air stream. Air velocity must be measured at locations away from obstructions to avoid the vortices and eddies that can produce inaccurate readings. Further, an uninterrupted measurement path cannot always be guaranteed when using continuous airflow monitors due to the presence of nearby equipment, personnel, roof falls and rib rolls. Effective use of these devices requires selection of a minimum distance from an obstacle, such that an air velocity measurement can be made but not affected by the presence of that obstacle. This paper investigates the impacts of an obstruction on the behavior of downstream airflow using a numerical CFD model calibrated with experimental test results from underground testing. Factors including entry size, obstruction size and the inlet or incident velocity are examined for their effects on the distributions of airflow around an obstruction. A relationship is developed between the minimum measurement distance and the hydraulic diameters of the entry and the obstruction. A final analysis considers the impacts of continuous monitor location on the accuracy of velocity measurements and on the application of minimum measurement distance guidelines.


Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2.
Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a double mutant ofPlasmodium falciparum ATC (PfATC) revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant was employed in protein interference assays (PIAs), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in medium lacking an excess of nutrients, including aspartate. Addition of 5 or 10 mg/L of aspartate to the minimal medium restored the parasites' normal growth rate. In vitro and whole-cell assays in the presence of the compound Torin 2 showed inhibition of specific activity and parasite growth, respectively. In silico analyses revealed the potential binding mode of Torin 2 to PfATC. Furthermore, a transgenic ATC-overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared with control cultures. Taken together, our results confirm the antimalarial activity of Torin 2, suggesting PfATC as a target of this drug and a promising target for the development of novel antimalarials.


The biologic activity of mast cell granules. IV. The effect of complement depletion on rat cutaneous late phase reactions.
Cutaneous late phase reactions (LPR) in rats can be induced by the intradermal injection of anti-IgE antibody or isolated rat peritoneal mast cell granules. Rat LPR are characterized by neutrophil-rich infiltrates at 2 to 8 hr followed by mononuclear cell-rich infiltrates thereafter. Rat Arthus reactions are histologically similar and are complement (C) dependent. To determine the importance of C in the pathogenesis of rat LPR compared with its role in Arthus reactions, rats were treated with cobra venom factor (CVF) (250 U/kg i.v.), and the effects of this treatment on total hemolytic complement (CH50), C3 titers, LPR, and Arthus reactions were assessed. CVF treatment produced profound decreases in both CH50 (from 197 +/- 20 to less than 1.0 U/ml) and C3 (from 44,240 +/- 2840 to less than 5 U/ml) titers after 6 hr, which persisted through at least 30 hr. The inflammatory intensity of heterologous reverse passive Arthus reactions was significantly decreased in CVF-treated animals. In contrast, the intensity of LPR was unaffected by CVF treatment. Therefore, although LPR and Arthus reactions share certain histologic characteristics, these similarities are not due to a mutual requirement for the presence of C.


Protein biomarker discovery and validation: the long and uncertain path to clinical utility.
Better biomarkers are urgently needed to improve diagnosis, guide molecularly targeted therapy and monitor activity and therapeutic response across a wide spectrum of disease. Proteomics methods based on mass spectrometry hold special promise for the discovery of novel biomarkers that might form the foundation for new clinical blood tests, but to date their contribution to the diagnostic armamentarium has been disappointing. This is due in part to the lack of a coherent pipeline connecting marker discovery with well-established methods for validation. Advances in methods and technology now enable construction of a comprehensive biomarker pipeline from six essential process components: candidate discovery, qualification, verification, research assay optimization, biomarker validation and commercialization. Better understanding of the overall process of biomarker discovery and validation and of the challenges and strategies inherent in each phase should improve experimental study design, in turn increasing the efficiency of biomarker development and facilitating the delivery and deployment of novel clinical tests.


Anthrax toxins induce shock in rats by depressed cardiac ventricular function.
Anthrax infections are frequently associated with severe and often irreversible hypotensive shock. The isolated toxic proteins of Bacillus anthracis produce a non-cytokine-mediated hypotension in rats by unknown mechanisms. These observations suggest the anthrax toxins have direct cardiovascular effects. Here, we characterize these effects. As a first step, we administered systemically anthrax lethal toxin (LeTx) and edema toxin (EdTx) to cohorts of three to twelve rats at different doses and determined the time of onset, degree of hypotension and mortality. We measured serum concentrations of the protective antigen (PA) toxin component at various time points after infusion. Peak serum levels of PA were in the microg/mL range with half-lives of 10-20 minutes. With doses that produced hypotension with delayed lethality, we then gave bolus intravenous infusions of toxins to groups of four to six instrumented rats and continuously monitored blood pressure by telemetry. Finally, the same doses used in the telemetry experiments were given to additional groups of four rats, and echocardiography was performed pretreatment and one, two, three and twenty-four hours post-treatment. LeTx and EdTx each produced hypotension. We observed a doubling of the velocity of propagation and 20% increases in left ventricular diastolic and systolic areas in LeTx-treated rats, but not in EdTx-treated rats. EdTx-but not LeTx-treated rats showed a significant increase in heart rate. These results indicate that LeTx reduced left ventricular systolic function and EdTx reduced preload. Uptake of toxins occurs readily into tissues with biological effects occurring within minutes to hours of serum toxin concentrations in the microg/mL range. LeTx and EdTx yield an irreversible shock with subsequent death. These findings should provide a basis for the rational design of drug interventions to reduce the dismal prognosis of systemic anthrax infections.


Whole gastrointestinal transit time is associated with clinical severity and nutritional status of HIV-infected children.
Malnutrition and malabsorption are common consequences in pediatric human immunodeficiency virus (HIV) infection. The gastrointestinal tract is a major site affected by HIV Rapid gastrointestinal transit time may contribute to malabsorption. To determine whether the whole gastrointestinal transit time (WGTT) correlates with disease stages or degrees of malnutrition in HIV-infected children. Forty HIV-seropositive children, at various stages of disease, and thirty seronegative age-matched controls, aged between 1 mo and 3 yr, were enrolled in the present study. The body weight, length, or height and the WGTT were assessed Then the WGTT of children in different stages of HIV disease and in different degrees of malnutrition were compared with those of the control group. The mean ages were 15.5 and 14.3 mo in HIV-infected and control groups respectively. A greater degree of malnutrition was found in HIV-infected children with more advances HIV clinical symptoms. Compared to controls, WGTT was most rapid in severely symptomatic acquired immunodeficiency syndrome (AIDS) patients (Category C) (14.32 +/- 3.88 versus 7.22 +/- 3.17 h; p < 0.01) but not in asymptomatic, mildly and moderately symptomatic children. Accelerated WGTT in HIV-infected children was also significantly associated with a higher degree of malnutrition. Malnutrition is clearly related to the progression ofHIV disease. Accelerated WGTT is associated with HIV seropositivity, severe clinical symptoms, and higher degrees of malnutrition.


Cooking Matters for Adults Improves Food Resource Management Skills and Self-confidence Among Low-Income Participants.
Determine the impact of Cooking Matters for Adults (CM) on food resource management (FRM) skills and self-confidence 6 months after course completion. Quasi-experimental design with nonequivalent comparison group and 6-month follow-up. Cooking Matters for Adults programs in CA, CO, ME, MA, MI, and OR. Participants in CM attending classes in April to July, 2016 (n = 332); comparison group (n = 336). Cooking Matters for Adults educated low-income adults to shop for and prepare healthy meals economically using hands-on meal preparation, facilitated discussion, and an interactive grocery store tour. Classes met for 2 hours, once a week for 6 weeks. Food resource management practices; FRM self-confidence (ie, in shopping for and preparing healthy foods on a budget); worrying that food might run out. Pearson's chi-square test and t tests identified measures associated with outcomes of interest and between-group differences. Repeated-measures linear mixed models with fixed and random effects were used to examine differences in outcomes between participants in CM and nonequivalent comparison group and to estimate the treatment effect of the program at 3 and 6 months after course completion. Six months after course completion, CM participants demonstrated improvements in all outcome measures of interest: Use of FRM practices improved (P = .002) as did FRM confidence (P < .001). Participants also worried less that food would run out before they had money to buy more (P = .03). This study demonstrated a positive impact of including FRM skills and confidence building in a nutrition education program, the effects of which could be seen for 6 months after participation in the program. Equipping low-income families with FRM skills allowed them to access healthier foods even during times of hardship.


Understanding the role of cleaning in the control of Salmonella Typhimurium in grower-finisher pigs: a modelling approach.
Salmonella Typhimurium (STM) infection in pigs represents a considerable food safety concern. This study used mathematical modelling to evaluate the effectiveness of cleaning (faeces removal) as a measure to control STM spread among grower-finisher pigs. A modified Susceptible-Infected-Recovered-Susceptible (SIRS) model of STM transmission through a contaminated environment was developed. Infected pigs were divided into three states according to the pathogen level being shed in their faeces. Infection transmission was evaluated using the basic reproduction number (R 0) and the prevalence of infectious pigs at slaughter age. Although increased frequency and efficiency of cleaning did reduce the prevalence of STM shedding at the time of slaughter, these efforts alone were not capable of eliminating the infection from the population. The level of STM faecal shedding by infectious pigs strongly influenced the infection spread and prevalence at slaughter. To control STM in pigs, cleaning should be combined with vaccination and/or isolation of high-level shedders.


CourseQ: the impact of visual and interactive course recommendation in university environments.
The abundance of courses available in a university often overwhelms students as they must select courses that are relevant to their academic interests and satisfy their requirements. A large number of existing studies in course recommendation systems focus on the accuracy of prediction to show students the most relevant courses with little consideration on interactivity and user perception. However, recent work has highlighted the importance of user-perceived aspects of recommendation systems, such as transparency, controllability, and user satisfaction. This paper introduces CourseQ, an interactive course recommendation system that allows students to explore courses by using a novel visual interface so as to improve transparency and user satisfaction of course recommendations. We describe the design concepts, interactions, and algorithm of the proposed system. A within-subject user study (N=32) was conducted to evaluate our system compared to a baseline interface without the proposed interactive visualization. The evaluation results show that our system improves many user-centric metrics including user acceptance and understanding of the recommendation results. Furthermore, our analysis of user interaction behaviors in the system indicates that CourseQ could help different users with their course-seeking tasks. Our results and discussions highlight the impact of visual and interactive features in course recommendation systems and inform the design of future recommendation systems for higher education.


Transcriptional profiling of Gram-positive Arthrobacter in the phyllosphere: induction of pollutant degradation genes by natural plant phenolic compounds.
Arthrobacter chlorophenolicus A6 is a Gram-positive, 4-chlorophenol-degrading soil bacterium that was recently shown to be an effective colonizer of plant leaf surfaces. The genetic basis for this phyllosphere competency is unknown. In this paper, we describe the genome-wide expression profile of A.chlorophenolicus on leaves of common bean (Phaseolus vulgaris) compared with growth on agar surfaces. In phyllosphere-grown cells, we found elevated expression of several genes known to contribute to epiphytic fitness, for example those involved in nutrient acquisition, attachment, stress response and horizontal gene transfer. A surprising result was the leaf-induced expression of a subset of the so-called cph genes for the degradation of 4-chlorophenol. This subset encodes the conversion of the phenolic compound hydroquinone to 3-oxoadipate, and was shown to be induced not only by 4-chlorophenol but also hydroquinone, its glycosylated derivative arbutin, and phenol. Small amounts of hydroquinone, but not arbutin or phenol, were detected in leaf surface washes of P.vulgaris by gas chromatography-mass spectrometry. Our findings illustrate the utility of genomics approaches for exploration and improved understanding of a microbial habitat. Also, they highlight the potential for phyllosphere-based priming of bacteria to stimulate pollutant degradation, which holds promise for the application of phylloremediation.


Financial incentives to improve adherence to anti-psychotic maintenance medication in non-adherent patients - a cluster randomised controlled trial (FIAT).
Various interventions have been tested to achieve adherence to anti-psychotic maintenance medication in non-adherent patients with psychotic disorders, and there is no consistent evidence for the effectiveness of any established intervention. The effectiveness of financial incentives in improving adherence to a range of treatments has been demonstrated; no randomised controlled trial however has tested the use of financial incentives to achieve medication adherence for patients with psychotic disorders living in the community. In a cluster randomised controlled trial, 34 mental health teams caring for difficult to engage patients in the community will be randomly allocated to either the intervention group, where patients will be offered a financial incentive for each anti-psychotic depot medication they receive over a 12 month period, or the control group, where all patients will receive treatment as usual. We will recruit 136 patients with psychotic disorders who use these services and who have problems adhering to antipsychotic depot medication, although all conventional methods to achieve adherence have been tried. The primary outcome will be adherence levels, and secondary outcomes are global clinical improvement, number of voluntary and involuntary hospital admissions, number of attempted and completed suicides, incidents of physical violence, number of police arrests, number of days spent in work/training/education, subjective quality of life and satisfaction with medication. We will also establish the cost effectiveness of offering financial incentives. The study aims to provide new evidence on the effectiveness and cost effectiveness of offering financial incentives to patients with psychotic disorders to adhere to antipsychotic maintenance medication. If financial incentives improve adherence and lead to better health and social outcomes, they may be recommended as one option to improve the treatment of non-adherent patients with psychotic disorders. Current controlled trials ISRCTN77769281.


Development of the Korean version of Short-Form 36-Item Health Survey: health related QOL of healthy elderly people and elderly patients in Korea.
The health-related QOL (HRQOL) has been used extensively in clinical and epidemiological research and health service studies. Especially, the Medical Outcome Study Short-form 36-Item Health Survey (SF-36) is a widely used health status measure. However, a Korean version has not been developed and tested yet. The purpose of this study was to develop a Korean version of the Short-form Health Survey (SF-36) for use in health related quality of life measurements for Korean elderly people. SF-36 data from 90 healthy elderly people using Social Education Service and 120 elderly patients using a day care service in Seoul, Korea, were examined. We translated SF-36 version 2.0 into Korean and assessed its reliability and validity. In the results, the content validity and discriminant validity were found to be satisfactory. Cronbach's alpha coefficients ranged from 0.9298 to 0.9383. The test-retest reliability coefficients ranged from 0.710 to 0.895. In addition, the utility was examined by testing the correlation between the health-related QOL and related factors (sex, age, motor function, ability of daily life) among the elderly people. The present findings suggested that the Korean version of SF-36 would be useful as a measure of the health related QOL in Korean elderly people.


Coating of adenovirus type 5 with polymers containing quaternary amines prevents binding to blood components.
Adenovirus type 5 (Ad5) gene therapy vectors require protection against antibodies, complement proteins and blood cells if they are to be delivered intravenously to treat metastatic disease. Such protection can be achieved by chemically modifying Ad5 with polymers based on hydrophilic HPMA. Here, such polymers were designed to include side chains bearing reactive carbonyl thiazolidine-2-thione groups (TTs) to covalently modify available amino groups of the lysine residues in the Ad5 capsid. Furthermore, the inclusion of side chains bearing positively charged quaternary ammonium groups (QAs) was designed to improve electrostatic interaction of the polymers with negatively charged Ad5 hexon protein. Finally, to enable triggered uncoating and reactivation of the Ad5, either the TTs or both the TTs and the QAs were linked to polymer backbone via reductively degradable disulfide bonds. SDS-PAGE demonstrated that these polymers covalently modified Ad5 capsid proteins in a reduction reversible manner. In infection studies, polymers containing QAs prevented binding of coagulation factor X to Ad5. Furthermore, the antibody and complement mediated binding of Ad5 to erythrocytes was reduced by such polymers (>95% without polymer, 25% following coating). These data indicate that coating Ad5 therapeutics with such polymers will improve blood circulation half-life and deposition at disease sites.


Development and implementation of a residency project advisory board.
The development and implementation of a residency project advisory board (RPAB) to manage multiple pharmacy residents' yearlong projects across several residency programs are described. Preceptor and resident feedback during our annual residency program review and strategic planning sessions suggested the implementation of a more-coordinated approach to the identification, selection, and oversight of all components of the residency project process. A panel of 7 department leaders actively engaged in residency training and performance improvement was formed to evaluate the residency project process and provide recommendations for change. These 7 individuals would eventually constitute the RPAB. The primary objective of the RPAB at Aurora Health Care is to provide oversight and a structured framework for the selection and execution of multiple residents' yearlong projects across all residency programs within our organization. Key roles of the RPAB include developing expectations, coordinating residency project ideas, and providing oversight and feedback. The development and implementation of the RPAB resulted in a significant overhaul of our entire yearlong resident project process. Trends toward success were realized after the first year of implementation, including consistent expectations, increased clarity and engagement in resident project ideas, and more projects meeting anticipated endpoints. The development and implementation of an RPAB have provided a framework to optimize the organization, progression, and outcomes of multiple pharmacy resident yearlong projects in all residency programs across our pharmacy enterprise.


Patient-centered care requires a patient-oriented workflow model.
Effective design of health information technology (HIT) for patient-centered care requires consideration of workflow from the patient's perspective, termed 'patient-oriented workflow.' This approach organizes the building blocks of work around the patients who are moving through the care system. Patient-oriented workflow complements the more familiar clinician-oriented workflow approaches, and offers several advantages, including the ability to capture simultaneous, cooperative work, which is essential in care delivery. Patient-oriented workflow models can also provide an understanding of healthcare work taking place in various formal and informal health settings in an integrated manner. We present two cases demonstrating the potential value of patient-oriented workflow models. Significant theoretical, methodological, and practical challenges must be met to ensure adoption of patient-oriented workflow models. Patient-oriented workflow models define meaningful system boundaries and can lead to HIT implementations that are more consistent with cooperative work and its emergent features.


Estimating the size of the homeless adolescent population across seven cities in Cambodia.
The Government of Cambodia has committed to supporting family care for vulnerable children, including homeless populations. Collecting baseline data on the numbers and characteristics of homeless adolescents was prioritized to illuminate the scope of the issue, mobilize resources and direct the response. Administrative zones across seven cities were purposively selected to cover the main urban areas known to have homeless populations in Cambodia. A complete enumeration of homeless individuals between the ages of 13 and 17 was attempted in the selected areas. In addition, a second independent count was conducted to enable a statistical estimation of completeness based on overlap across counts. This technique is known as capture-recapture. Adolescents were also interviewed about their schooling, health and other circumstances. After adjustment by the capture-recapture corrective multipliers (range: 3.53 -27.08), the study yielded an estimate of 2,697 13-17 year old homeless adolescents across all seven cities. The total number of homeless boys counted was significantly greater than homeless girls, especially in older ages. To the authors' knowledge, this is the first time capture-recapture methods have been applied to a homeless estimation of this scale in a resource-limited setting. Findings suggest the number of homeless adolescents in Cambodia is much greater than one would expect if relying on single count data alone and that this population faces many hardships.


Static and dynamic balance deficiencies in chronic low back pain.
According to previously conducted studies, people with Low Back Pain (LBP) present with static balance deficiencies. The aim of the present study was to compare static, as well as dynamic balance ability between Chronic Low Back Pain (CLBP) and healthy subjects. The CLBP group comprised 17 subjects and the control group of 16 subjects, matched for age, BMI and gender. The protocol applied compared the balance ability when performing the Star Excursion Balance Test (SEBT) and the static 1-leg stance position. The innovation introduced in the protocol was that the participants performed not only the static 1-leg stance, but also the dynamic SEBT on a force plate which recorded the target sway (TS), i.e. the Center of Pressure (CoP) excursion. The CLBP group had significantly reduced performance in SEBT, coupled with greater static and dynamic TS values. Age and especially BMI also bear a significant effect on SEBT execution. The inclusion of SEBT and TS derived scores in a stepwise logistic regression equation lead to the correct classification of 85% of the subjects. Dynamic and static balance ability provide supplementary information for the identification of the presence of CLBP, with dynamic balance being more instrumental.


Analysis of Whole Mitogenomes from Ancient Samples.
Ancient mitochondrial DNA has been used in a wide variety of paleontological and archeological studies, ranging from population dynamics of extinct species to patterns of domestication. Most of these studies have traditionally been based on the analysis of short fragments from the mitochondrial control region, analyzed using PCR coupled with Sanger sequencing. With the introduction of high-throughput sequencing, as well as new enrichment technologies, the recovery of full mitochondrial genomes (mitogenomes) from ancient specimens has become significantly less complicated. Here we present a protocol to build ancient extracts into Illumina high-throughput sequencing libraries, and subsequent Agilent array-based capture to enrich for the desired mitogenome. Both are based on previously published protocols, with the introduction of several improvements aimed to increase the recovery of short DNA fragments, while keeping the cost and effort requirements low. This protocol was designed for enrichment of mitochondrial DNA in ancient or other degraded samples. However, the protocols can be easily adapted for using for building libraries for shotgun-sequencing of whole genomes, or enrichment of other genomic regions.


Archaic human genomics.
For much of the 20th century, the predominant view of human evolutionary history was derived from the fossil record. Homo erectus was seen arising in Africa from an earlier member of the genus and then spreading throughout the Old World and into the Oceania. A regional continuity model of anagenetic change from H. erectus via various intermediate archaic species into the modern humans in each of the regions inhabited by H. erectus was labeled the multiregional model of human evolution (MRE). A contrasting model positing a single origin, in Africa, of anatomically modern H. sapiens with some populations later migrating out of Africa and replacing the local archaic populations throughout the world with complete replacement became known as the recent African origin (RAO) model. Proponents of both models used different interpretations of the fossil record to bolster their views for decades. In the 1980s, molecular genetic techniques began providing evidence from modern human variation that allowed not only the different models of modern human origins to be tested but also the exploration demographic history and the types of selection that different regions of the genome and even specific traits had undergone. The majority of researchers interpreted these data as strongly supporting the RAO model, especially analyses of mitochondrial DNA (mtDNA). Extrapolating backward from modern patterns of variation and using various calibration points and substitution rates, a consensus arose that saw modern humans evolving from an African population around 200,000 years ago. Much later, around 50,000 years ago, a subset of this population migrated out of Africa replacing Neanderthals in Europe and western Asia as well as archaics in eastern Asia and Oceania. mtDNA sequences from more than two-dozen Neanderthals and early modern humans re-enforced this consensus. In 2010, however, the complete draft genomes of Neanderthals and of heretofore unknown hominins from Siberia, called Denisovans, demonstrated gene flow between these archaic human species and modern Eurasians but not sub-Saharan Africans. Although the levels of gene flow may be very limited, this unexpected finding does not fit well with either the RAO model or MRE model. More thorough sampling of modern human diversity, additional fossil discoveries, and the sequencing of additional hominin fossils are necessary to throw light onto our origins and our history.


Chronic low-level mercury exposure, BDNF polymorphism, and associations with self-reported symptoms and mood.
Recent reports have described neurobehavioral impairments in human subjects carrying a V66M polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF). Inasmuch as ventral nervous system (CNS) deficits associated with this BDNF polymorphism are similar to those observed among subjects with chronic exposure to elemental mercury (Hg degrees ), we examined the potential effect of this BDNF polymorphism on symptoms and mood in an established cohort of dental practitioners with chronic low-level Hg degrees exposure. Self-reported symptoms and mood were obtained by computerized questionnaire from 193 male dentists (DTs) and 230 female dental assistants (DAs). Spot urine samples were analyzed for mercury concentrations to evaluate recent exposure. Detailed work histories were obtained to calculate chronic indices of Hg degrees exposure. Buccal cell samples were obtained to identify the V66M polymorphism of BDNF. Scores for 11 current and 12 recent and chronic symptom groups, along with six mood factors, were evaluated with respect to recent and chronic Hg degrees exposure and BDNF polymorphism. Multiple regression analysis controlled for age, race, socioeconomic status, tobacco and alcohol use, self-reported health problems, and medications. Separate evaluations were conducted for DTs and DAs. Twenty-three associations between recent or chronic Hg degrees exposure and BDNF status and self-reported symptoms were observed with p < 0.10. All but three were in the expected direction (symptom scores increasing with Hg degrees exposure or BDNF polymorphism), and all but six were among DAs. All eight correlations between chronic exposure indices and recent and chronic symptoms among DAs were in the expected direction. All seven associations between BDNF and symptoms were in the expected direction and split between DTs and DAs. All three associations with mood factors were among DAs and in the expected direction. These results indicate that among DAs very low levels of occupational Hg degrees exposure are associated with increased symptoms. The BDNF polymorphism is also associated with increased symptom and mood scores. Notably, Hg degrees and BDNF polymorphism were additive with respect to their associations with the same symptom group.


Associations between Major Health Behaviors and Sleep Problems: Results from the 2015, 2016, 2017 Canadian Community Health Survey.
Key health behaviors including cigarette smoking, alcohol consumption, fruit and vegetable (FV) consumption, and physical activity have been associated with sleep-related problems. This cross-sectional study describes sleep quality and duration by gender in a large adult population and examines whether health behavioral factors are associated with short/long sleep duration and sleep problems (difficulty initiating/maintaining sleep [DIMS], daytime sleepiness, and finding sleep refreshing). Using Canadian Community Health Survey data from cycles 2015, 2016, and 2017, binary and multinomial logistic regression models were computed. Of the 44,911 respondents included, only half of respondents met the recommended sleep duration. Fifty-five percent of females and forty-one percent of males reported DIMS. Binge drinking was associated with increased DIMS, with the strongest relationship being among females reporting weekly binge drinking (odds ratio (OR) 2.03 [1.59,2.60]). Binge drinking was also associated with decreased odds of finding sleep refreshing among females only (OR 0.73 [0.56,0.96] in weekly binge drinkers). Compared to respondents who had never smoked, daily smokers had higher odds of short sleep (OR 1.50 [1.30,1.74] and OR 1.39 [1.21,1.60]; females and males, respectively). Similarly, former smokers had higher odds of DIMS (OR 1.18 [1.06,1.31]) and not finding sleep refreshing (OR 0.85 [0.77,0.95]), among females; similar OR among males. Increased FV consumption was associated with increased odds of finding sleep refreshing (OR 1.05 [1.03,1.07] and OR 1.06 [1.04,1.08] in females and males, respectively). There is a high prevalence of sleep problems among Canadians. Potential gender differences in the relationships between health behaviors and sleep problems warrant further research.


Pharmaceutical residues in the drinking water supply: modeling residue concentrations in surface waters of drugs prescribed in the United States.
Pharmaceutical residues and other organic wastewater contaminants (OWC) have been shown to survive conventional water-treatment processes and persist in potable water supplies. To estimate the geographical distribution of the Predicted Environmental Concentration (PEC) of selected drugs prescribed by office based physicians in the United States (US), after non-metabolized residues have been excreted and processed in wastewater treatment plants. The geographical distribution of the PEC in surface waters of pharmaceutical residues was calculated, in four regions of the US. Prescription drug data was obtained from the National Ambulatory Medical Care Survey (NAMCS). The PEC of three drugs prescribed by office based physicians in the US between 1998 and 2000 was compared to the concentrations of these pharmaceuticals found in a surface water characterization project conducted by the United States Geological Survey between 1999 and 2000. There were 803,185,420 medications prescribed by office-based physicians in the US between 1998 and 2000. Relief of pain, hormonal, cardiovascular and antimicrobial medications followed very similar prescription patterns, both in terms of quantity and geographical distribution. Together these four types of medications account for more than half of the medications prescribed between 1998 and 2000. The concentration of pharmaceutical residues found in the drinking water supply was not significantly correlated to the PEC of pharmaceuticals prescribed by office-based physicians. The geographical distribution of medications prescribed by office based physicians in the US underlines the need to implement effective public health strategies.


Tuning of temporo-occipital activity by frontal oscillations during virtual mirror exposure causes erroneous self-recognition.
Self-face recognition, a hallmark of self-awareness, depends on 'off-line' stored information about one's face and 'on-line' multisensory-motor face-related cues. The brain mechanisms of how on-line sensory-motor processes affect off-line neural self-face representations are unknown. This study used 3D virtual reality to create a 'virtual mirror' in which participants saw an avatar's face moving synchronously with their own face movements. Electroencephalographic (EEG) analysis during virtual mirror exposure revealed mu oscillations in sensory-motor cortex signalling on-line congruency between the avatar's and participants' movements. After such exposure and compatible with a change in their off-line self-face representation, participants were more prone to recognize the avatar's face as their own, and this was also reflected in the activation of face-specific regions in the inferotemporal cortex. Further EEG analysis showed that the on-line sensory-motor effects during virtual mirror exposure caused these off-line visual effects, revealing the brain mechanisms that maintain a coherent self-representation, despite our continuously changing appearance.


Critical decision-making in neonatology and pediatrics: the I-P-O framework.
Critical decision-making in neonatology and other areas of pediatrics often carries with it a complex and difficult ethical component. For any treatment under consideration, the impermissible-permissible-obligatory (I-P-O) spectrum provides a useful framework for determining how to proceed. Any proposed treatment can be located along this spectrum, and identified as either ethically impermissible, permissible, or obligatory. Treatments determined to be ethically impermissible should not be made available by physicians. Those deemed ethically permissible should be explained to parents, commonly with a specific recommendation. Informed parents should then be free to choose from among permissible options. Potential treatments deemed ethically obligatory should be provided to the patient, even in the face of parental objection. The fundamental ethical work in neonatology and pediatrics is determining where on the I-P-O spectrum a treatment under consideration should be located. This should be determined by the prognosis for the patient with and without the treatment, the feasibility of providing the treatment, and consideration of all relevant rights and obligations. Location on the line is dynamic, and clinicians should be open to movement of a given treatment along the spectrum as new information, particularly regarding effectiveness, toxicity, and/or alternatives, becomes available. This framework provides a structure for ethical conversation and decision-making related to a specific patient, as well as in the formation of institutional and national guidelines.


A computationally fast measure of epistasis for 2 SNPs and a categorical phenotype.
Complex diseases may be caused by interactions or combined effects between multiple genetic and environmental factors. One of the main limitations of testing for interaction between genetic loci in large whole genome studies is the high computational cost of performing such analyses. In this study a new methodology for interaction testing (commonly referred to in genetics as the epistatic effect) between two single nucleotide polymorphisms (SNPs) and a categorical phenotype is presented. It is shown that it provides reasonable approximations with a significantly shorter run time. The proposed measure based on the Pearson's chi-square additive property is compared to fitting a logistic regression model on a randomly selected subset of 218 SNP loci from a study that included 550,000 SNPs). For each possible pair of SNPs a chi-square test for the epistatic effect on case-control status is estimated by fitting a logistic regression model, and compared to the results of the proposed method. Results indicate strong agreement (Pearson's correlation r>0.95) while the proposed method is found to be 20 times faster. This provides a significant pragmatic advantage for the proposed method since the number of tests for epistasis can now be increased by a factor of 20 while the computational cost remains the same.