Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.
Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.


Atomic structures and functional implications of the archaeal RecQ-like helicase Hjm.
Pyrococcus furiosus Hjm (PfuHjm) is a structure-specific DNA helicase that was originally identified by in vitro screening for Holliday junction migration activity. It belongs to helicase superfamily 2, and shares homology with the human DNA polymerase Theta (PolTheta), HEL308, and Drosophila Mus308 proteins, which are involved in DNA repair. Previous biochemical and genetic analyses revealed that PfuHjm preferentially binds to fork-related Y-structured DNAs and unwinds their double-stranded regions, suggesting that this helicase is a functional counterpart of the bacterial RecQ helicase, which is essential for genome maintenance. Elucidation of the DNA unwinding and translocation mechanisms by PfuHjm will require its three-dimensional structure at atomic resolution. We determined the crystal structures of PfuHjm, in two apo-states and two nucleotide bound forms, at resolutions of 2.0-2.7 A. The overall structures and the local conformations around the nucleotide binding sites are almost the same, including the side-chain conformations, irrespective of the nucleotide-binding states. The architecture of Hjm was similar to that of Archaeoglobus fulgidus Hel308 complexed with DNA. An Hjm-DNA complex model, constructed by fitting the five domains of Hjm onto the corresponding Hel308 domains, indicated that the interaction of Hjm with DNA is similar to that of Hel308. Notably, sulphate ions bound to Hjm lie on the putative DNA binding surfaces. Electron microscopic analysis of an Hjm-DNA complex revealed substantial flexibility of the double stranded region of DNA, presumably due to particularly weak protein-DNA interactions. Our present structures allowed reasonable homology model building of the helicase region of human PolTheta, indicating the strong conformational conservation between archaea and eukarya. The detailed comparison between our DNA-free PfuHjm structure and the structure of Hel308 complexed with DNA suggests similar DNA unwinding and translocation mechanisms, which could be generalized to all of the members in the same family. Structural comparison also implied a minor rearrangement of the five domains during DNA unwinding reaction. The unexpected small contact between the DNA duplex region and the enzyme appears to be advantageous for processive helicase activity.


Childhood leukemia near nuclear plants in the United Kingdom: the evolution of a systematic approach to studying rare disease in small geographic areas.
A cluster of childhood leukemia in a village near a nuclear plant in northern England prompted further studies of cancer in the vicinity of other nuclear plants in the United Kingdom. These studies demonstrated that the risk of childhood leukemia was increased near certain other nuclear plants. Although the reasons for the increase are still unclear, the scientific debate stimulated by these findings has clarified some of the special methodological problems encountered when studying rare diseases in small areas. Firstly, unless a specific hypothesis is defined in advance, the relevance of a single geographic cluster of disease can rarely be interpreted. Even when a prior hypothesis exists, the small number of cases which generally occur in a small area make the findings highly sensitive to reporting, diagnostic, or classification errors. The statistical power of such investigations is also usually low and only marked increases in risk can be detected. Furthermore, conventional statistical tests may be inappropriate if the underlying spatial distribution of the disease is not random; and little is known about the background distribution of disease in small areas. Investigations of specific hypotheses about defined sources of environmental contamination, especially if they can be replicated, are more likely to result in conclusive findings that are in-depth studies of individual clusters.


The hyaluronate synthase from a eukaryotic cell line.
The hyaluronate synthase complex was identified in plasma membranes from B6 cells. It contained two subunits of molecular masses 52 kDa and 60 kDa which bound the precursor UDP-GlcA in digitonin solution and partitioned into the aqueous phase, together with nascent hyaluronate upon Triton X-114 phase separation. The 52 kDa protein cross-reacted with poly- and monoclonal antibodies raised against the streptococcal hyaluronate synthase and the 60 kDa protein was recognized by monoclonal antibodies raised against a hyaluronate receptor. The 52 kDa protein was purified to homogeneity by affinity chromatography with monoclonal anti-hyaluronate synthase.


Aquatic therapy: scientific foundations and clinical rehabilitation applications.
The aquatic environment has broad rehabilitative potential, extending from the treatment of acute injuries through health maintenance in the face of chronic diseases, yet it remains an underused modality. There is an extensive research base supporting aquatic therapy, both within the basic science literature and clinical literature. This article describes the many physiologic changes that occur during immersion as applied to a range of common rehabilitative issues and problems. Because of its wide margin of therapeutic safety and clinical adaptability, aquatic therapy is a very useful tool in the rehabilitative toolbox. Through a better understanding of the applied physiology, the practitioner may structure appropriate therapeutic programs for a diverse patient population.


Dynamics of conflict during the Ebola outbreak in the Democratic Republic of the Congo 2018-2019.
The 2018-2019 Ebola virus disease (EVD) outbreak in North Kivu and Ituri provinces in the Democratic Republic of the Congo (DRC) is the largest ever recorded in the DRC. It has been declared a Public Health Emergency of International Concern. The outbreak emerged in a region of chronic conflict and insecurity, and directed attacks against health care workers may have interfered with disease response activities. Our study characterizes and quantifies the broader conflict dynamics over the course of the outbreak by pairing epidemiological and all available spatial conflict data. We build a set of conflict variables by mapping the spatial locations of all conflict events and their associated deaths in each of the affected health zones in North Kivu and Ituri, eastern DRC, before and during the outbreak. Using these data, we compare patterns of conflict before and during the outbreak in affected health zones and those not affected. We then test whether conflict is correlated with increased EVD transmission at the health zone level. The incidence of conflict events per capita is ~ 600 times more likely in Ituri and North Kivu than for the rest of the DRC. We identified 15 time periods of substantial uninterrupted transmission across 11 health zones and a total of 120 bi-weeks. We do not find significant short-term associations between the bi-week reproduction numbers and the number of conflicts. However, we do find that the incidence of conflict per capita was correlated with the incidence of EVD per capita at the health zone level for the entire outbreak (Pearson's r = 0.33, 95% CI 0.05-0.57). In the two provinces, the monthly number of conflict events also increased by a factor of 2.7 in Ebola-affected health zones (p value < 0.05) compared to 2.0 where no transmission was reported and 1.3 in the rest of the DRC, in the period between February 2019 and July 2019. We characterized the association between variables documenting broad conflict levels and EVD transmission. Such assessment is important to understand if and how such conflict variables could be used to inform the outbreak response. We found that while these variables can help characterize long-term challenges and susceptibilities of the different regions they provide little insight on the short-term dynamics of EVD transmission.


SVOC exposure indoors: fresh look at dermal pathways.
This paper critically examines indoor exposure to semivolatile organic compounds (SVOCs) via dermal pathways. First, it demonstrates that--in central tendency--an SVOC's abundance on indoor surfaces and in handwipes can be predicted reasonably well from gas-phase concentrations, assuming that thermodynamic equilibrium prevails. Then, equations are developed, based upon idealized mass-transport considerations, to estimate transdermal penetration of an SVOC either from its concentration in skin-surface lipids or its concentration in air. Kinetic constraints limit air-to-skin transport in the case of SVOCs that strongly sorb to skin-surface lipids. Air-to-skin transdermal uptake is estimated to be comparable to or larger than inhalation intake for many SVOCs of current or potential interest indoors, including butylated hydroxytoluene, chlordane, chlorpyrifos, diethyl phthalate, Galaxolide, geranyl acetone, nicotine (in free-base form), PCB28, PCB52, Phantolide, Texanol and Tonalide. Although air-to-skin transdermal uptake is anticipated to be slow for bisphenol A, we find that transdermal permeation may nevertheless be substantial following its transfer to skin via contact with contaminated surfaces. The paper concludes with explorations of the influence of particles and dust on dermal exposure, the role of clothing and bedding as transport vectors, and the potential significance of hair follicles as transport shunts through the epidermis. Human exposure to indoor pollutants can occur through dietary and nondietary ingestion, inhalation, and dermal absorption. Many factors influence the relative importance of these pathways, including physical and chemical properties of the pollutants. This paper argues that exposure to indoor semivolatile organic compounds (SVOCs) through the dermal pathway has often been underestimated. Transdermal permeation of SVOCs can be substantially greater than is commonly assumed. Transport of SVOCs from the air to and through the skin is typically not taken into account in exposure assessments. Yet, for certain SVOCs, intake through skin is estimated to be substantially larger than intake through inhalation. Exposure scientists, risk assessors, and public health officials should be mindful of the dermal pathway when estimating exposures to indoor SVOCs. Also, they should recognize that health consequences vary with exposure pathway. For example, an SVOC that enters the blood through the skin does not encounter the same detoxifying enzymes that an ingested SVOC would experience in the stomach, intestines, and liver before it enters the blood.


Matrix metalloproteinases: fold and function of their catalytic domains.
Matrix metalloproteinases (MMPs) are zinc-dependent protein and peptide hydrolases. They have been almost exclusively studied in vertebrates and 23 paralogs are present in humans. They are widely involved in metabolism regulation through both extensive protein degradation and selective peptide-bond hydrolysis. If MMPs are not subjected to exquisite spatial and temporal control, they become destructive, which can lead to pathologies such as arthritis, inflammation, and cancer. The main therapeutic strategy to combat the dysregulation of MMPs is the design of drugs to target their catalytic domains, for which purpose detailed structural knowledge is essential. The catalytic domains of 13 MMPs have been structurally analyzed so far and they belong to the "metzincin" clan of metalloendopeptidases. These compact, spherical, approximately 165-residue molecules are divided by a shallow substrate-binding crevice into an upper and a lower sub-domain. The molecules have an extended zinc-binding motif, HEXXHXXGXXH, which contains three zinc-binding histidines and a glutamate that acts as a general base/acid during catalysis. In addition, a conserved methionine lying within a "Met-turn" provides a hydrophobic base for the zinc-binding site. Further earmarks of MMPs are three alpha-helices and a five-stranded beta-sheet, as well as at least two calcium sites and a second zinc site with structural functions. Most MMPs are secreted as inactive zymogens with an N-terminal approximately 80-residue pro-domain, which folds into a three-helix globular domain and inhibits the catalytic zinc through a cysteine imbedded in a conserved motif, PRCGXPD. Removal of the pro-domain enables access of a catalytic solvent molecule and substrate molecules to the active-site cleft, which harbors a hydrophobic S(1')-pocket as main determinant of specificity. Together with the catalytic zinc ion, this pocket has been targeted since the onset of drug development against MMPs. However, the inability of first- and second-generation inhibitors to distinguish between different MMPs led to failures in clinical trials. More recent approaches have produced highly specific inhibitors to tackle selected MMPs, thus anticipating the development of more successful drugs in the near future. Further strategies should include the detailed structural characterization of the remaining ten MMPs to assist in achieving higher drug selectivity. In this review, we discuss the general architecture of MMP catalytic domains and its implication in function, zymogenic activation, and drug design.


Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis.
Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring.


Effects of hypoxic-ischemic encephalopathy and whole-body hypothermia on neonatal auditory function: a pilot study.
We assessed the effects of hypoxic-ischemic encephalopathy (HIE) and whole-body hypothermia therapy on auditory brain stem evoked responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We performed serial assessments of ABRs and DPOAEs in newborns with moderate or severe HIE, randomized to hypothermia ( N = 4) or usual care ( N = 5). Participants were five boys and four girls with mean gestational age (standard deviation) of 38.9 (1.8) weeks. During the first week of life, peripheral auditory function, as measured by the DPOAEs, was disrupted in all nine subjects. ABRs were delayed but central transmission was intact, suggesting a peripheral rather than a central neural insult. By 3 weeks of age, peripheral auditory function normalized. Hypothermia temporarily prolonged the ABR, more so for waves generated higher in the brain stem but the effects reversed quickly on rewarming. Neonatal audiometric testing is feasible, noninvasive, and capable of enhancing our understanding of the effects of HIE and hypothermia on auditory function.


'You give us rangoli, we give you talk': using an art-based activity to elicit data from a seldom heard group.
The exclusion from health research of groups most affected by poor health is an issue not only of poor science, but also of ethics and social justice. Even if exclusion is inadvertent and unplanned, policy makers will be uninformed by the data and experiences of these groups. The effect on the allocation of resources is likely to be an exacerbation of health inequalities. We subject to critical analysis the notion that certain groups, by virtue of sharing a particular identity, are inaccessible to researchers - a phenomenon often problematically referred to as 'hard to reach'. We use the term 'seldom heard' to move the emphasis from a perceived innate characteristic of these groups to a consideration of the methods we choose as researchers. Drawing on a study exploring the intersections of faith, culture, health and food, we describe a process of recruitment, data collection and analysis in which we sought to overcome barriers to participation. As we were interested in the voices of South Asian women, many of whom are largely invisible in public life, we adopted an approach to data collection which was culturally in tune with the women's lives and values. A collaborative activity mirroring food preparation provided a focus for talk and created an environment conducive to data collection. We discuss the importance of what we term 'shoe leather research' which involves visiting the local area, meeting potential gatekeepers, and attending public events in order to develop our profile as researchers in the community. We examine issues of ethics, data quality, management and analysis which were raised by our choice of method. In order to work towards a more theoretical understanding of how material, social and cultural factors are connected and influence each other in ways that have effects on health, researchers must attend to the quality of the data they collect to generate finely grained and contextually relevant findings. This in turn will inform the design of culturally sensitive health care services. To achieve this, researchers need to consider methods of recruitment; the makeup of the research team; issues of gender, faith and culture; and data quality, management and analysis.


A randomized controlled trial of the reciprocating procedure device for intraarticular injection of corticosteroid.
Injection of intraarticular corticosteroid remains an important therapy for inflammatory arthritis. In a randomized controlled trial we compared the new reciprocating procedure device (RPD) to the traditional syringe for injection of intraarticular corticosteroid. One hundred fifty-four intraarticular corticosteroid injection procedures were randomized to the conventional syringe or the RPD. Using the syringe or RPD, the needle was introduced into the joint, any effusion that was present was aspirated, and the corticosteroid (methylprednisolone acetate) was injected. Outcome measures included patient pain measured by visual analog scale (VAS pain), procedure duration, operator satisfaction, complications, and immediate and delayed response to the injected medication. The RPD reduced pain scores by 49% (RPD VAS pain score: 2.40 +/- 2.17; conventional syringe VAS pain score: 4.73 +/- 3.39; p < 0.001), reduced procedure time by 31% (RPD: 1.28 +/- 1.08 min, conventional syringe: 1.86 +/- 1.26; p < 0.01), and improved physician satisfaction with the joint procedure device by 63% (RPD visual analog satisfaction scale score: 9.12 +/- 0.80, conventional syringe 5.59 +/- 1.28; p < 0.001). Fifty-five percent (43/78) of patients experienced moderate to severe pain (VAS pain > or = 5) with the conventional syringe, while 17% (13/76) experienced moderate to severe pain with the RPD. The same beneficial response was present when intermediate or large joints were analyzed separately. Longterm outcomes were equivalent. When a conventional syringe is used for corticosteroid injection, many patients experience significant procedural pain. The RPD significantly reduces patient pain, reduces procedure time, and improves operator satisfaction. The RPD is superior to the traditional syringe for injection of intraarticular corticosteroid.


Regime shifts in coastal lagoons: Evidence from free-living marine nematodes.
We test the validity of using the regime shift theory to account for differences in environmental state of coastal lagoons as a response to variation in connectivity with the sea, using free-living nematodes as a surrogate. The study is based on sediment samples from the inner and outer portions of 15 coastal lagoons (5 open to the sea, 5 intermittently open/closed, and 5 permanently closed lakes) along the southern coast of Brazil. Environmental data suggested that there are two contrasting environmental conditions, with coastal lakes being significantly different from open and intermittent lagoons. Marine nematode assemblages corroborate these two mutually exclusive alternative stable states (open vs. closed systems), but assemblages from the intermittently open/closed lagoons showed a gradual change in species composition between both systems independently of the environmental conditions. The gradient in the structural connectivity among lagoons and the sea, due to their regime shifts, changes the movement of resources and consumers and the internal physico-chemical gradients, directly affecting regional species diversity. Whereas openness to the sea increased similarity in nematode assemblage composition among connected lagoons, isolation increased dissimilarity among closed lagoons. Our results from a large-scale sampling program indicated that as lagoons lose connectivity with the sea, shifting the environmental state, local processes within individual intermittently open/closed lagoons and particularly within coastal lakes become increasingly more important in structuring these communities. The main implication of these findings is that depending on the local stable state we may end up with alternative regional patterns of biodiversity.


Survey of safety and health care in British medical laboratories.
A retrospective postal survey of 24 000 medical laboratory workers in England, Wales, and Scotland showed highly variable standards of safety and health care. Pre-employment health screening was offered to two-thirds of employees, the physicians being the least likely to be examined (15%). Scottish laboratories provided better safety control than English and Welsh laboratories, while Public Health Service Laboratories had a better record than National Health Service establishments. Mouth pipetting is still practised in 65% of English and Welsh laboratories, and the use of protective clothing is rarely compulsory. The servicing of safety cabinets is often inadequate. Known and suspected carcinogens are still apparently used in a few laboratories (2-10%). In view of the wide variation in standards among laboratories, urgent consideration should be given to establishing regulations for codes of safe practice rather than relying merely on recommendations as at present.


Stepwise development of MAIT cells in mouse and human.
Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)alpha (iTCRalpha) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanValpha7.2 antibody and MAIT cell-specific iTCRalpha and TCRbeta transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRalpha and TCRbeta transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%-4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and gammadelta T cells.


Molecular evolution of peptide tyrosine--tyrosine: primary structure of PYY from the lampreys Geotria australis and Lampetra fluviatilis, bichir, python and desert tortoise.
Peptide tyrosine-tyrosine (PYY) has been isolated from the intestines of two species of reptile, the desert tortoise Gopherus agassizii (Testudines) and the Burmese python Python molurus (Squamata), from the primitive Actinopterygian fish, the bichir Polypterus senegalis (Polypteriformes) and from two agnathans, the Southern-hemisphere lamprey Geotria australis (Geotriidae) and the holarctic lamprey Lampetra fluviatilis (Petromyzontidae). The primary structure of bichir PYY is identical to the proposed ancestral sequence of gnathostome PYY (YPPKPENPGE10/DAPPEELAKY20/YSALR HYINL30/ITRQRY). Tortoise and python PYY differ by six and seven residues, respectively, from the ancestral sequence consistent with the traditional view that the Testudines represent an earlier divergence from the primitive reptilian stock than the Squamates. The current views of agnathan phylogeny favor the hypothesis that the Southern-hemisphere lampreys and the holarctic lampreys arose from a common ancestral stock but their divergence is of a relatively ancient (pre-Tertiary) origin. The Geotria PYY-related peptide shows only two amino acid substitutions (Pro10-->Gln and Leu22-->Ser) compared with PYY from the holarctic lamprey Petromyzon marinus. This result was unexpected as Petromyzon PYY differs from Lampetra PYY deduced from the nucleotide sequence of a cDNA (Söderberg et al. J. Neurosci. Res. 1994;37:633-640) by 10 residues. However, a re-examination of an extract of Lampetra intestine revealed the presence of a PYY that differed in primary structure from Petromyzon PYY by only one amino acid residue (Pro10-->Ser). This result suggests that the structure of PYY has been strongly conserved during the evolution of Agnatha and that at least two genes encoding PYY-related peptides are expressed in Lampetra tissues.


Clinical nurse specialists and nurse practitioners: title confusion and lack of role clarity.
Title confusion and lack of role clarity pose barriers to the integration of advanced practice nursing roles (i.e., clinical nurse specialist [CNS] and nurse practitioner [NP]). Lack of awareness and understanding about NP and CNS roles among the healthcare team and the public contributes to ambiguous role expectations, confusion about NP and CNS scopes of practice and turf protection. This paper draws on the results of a scoping review of the literature and qualitative key informant interviews conducted for a decision support synthesis commissioned by the Canadian Health Services Research Foundation and the Office of Nursing Policy in Health Canada. The goal of this synthesis was to develop a better understanding of advanced practice nursing roles and the factors that influence their effective development and integration in the Canadian healthcare system. Specific recommendations from interview participants and the literature to enhance title and role clarity included the use of consistent titles for NP and CNS roles; the creation of a vision statement to articulate the role of CNSs and NPs across settings; the use of a systematic planning process to guide role development and implementation; the development of a communication strategy to educate healthcare professionals, the public and employers about the roles; attention to inter-professional team dynamics when introducing these new roles; and addressing inter-professionalism in all health professional education program curricula.


The Pif1 family helicase Pfh1 facilitates telomere replication and has an RPA-dependent role during telomere lengthening.
Pif1 family helicases are evolutionary conserved 5'-3' DNA helicases. Pfh1, the sole Schizosaccharomyces pombe Pif1 family DNA helicase, is essential for maintenance of both nuclear and mitochondrial DNAs. Here we show that its nuclear functions include roles in telomere replication and telomerase action. Pfh1 promoted semi-conservative replication through telomeric DNA, as replication forks moved more slowly through telomeres when Pfh1 levels were reduced. Unlike other organisms, S. pombe cells overexpressing Pfh1 displayed markedly longer telomeres. Because this lengthening occurred in the absence of homologous recombination but not in a replication protein A mutant (rad11-D223Y) that has defects in telomerase function, it is probably telomerase-mediated. The effects of Pfh1 on telomere replication and telomere length are likely direct as Pfh1 exhibited high telomere binding in cells expressing endogenous levels of Pfh1. These findings argue that Pfh1 is a positive regulator of telomere length and telomere replication.


Divergent reactivity of a new dinuclear xanthene-bridged bis(iminopyridine) di-nickel complex with alkynes.
The reaction of a dinucleating bis(iminopyridine) ligand L bearing a xanthene linker (L = N,N'-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis(1-(pyridin-2-yl)methanimine)) with Ni2(COD)2(DPA) (COD = cyclooctadiene, DPA = diphenylacetylene) leads to the formation of a new dinuclear complex Ni2(L)(DPA). Ni2(L)(DPA) can also be obtained in a one-pot reaction involving Ni(COD)2, DPA and L. The X-ray structure of Ni2(L)(DPA) reveals two square-planar Ni centers bridged by a DPA ligand. DFT calculations suggest that this species features NiI centers antiferromagnetically coupled to each other and their iminopyridine ligand radicals. Treatment of Ni2(L)(DPA) with one equivalent of ethyl propiolate (HCCCO2Et) forms the Ni2(L)(HCCCO2Et) complex. Addition of the second equivalent of ethyl propiolate leads to the observation of cyclotrimerised products by 1H NMR spectroscopy. Carrying out the reaction under catalytic conditions (1 mol% of Ni2(L)(DPA), 24 h, room temperature) transforms 89% of the substrate, forming primarily benzene products (triethyl benzene-1,2,4-tricarboxylate and triethyl benzene-1,3,5-tricarboxylate) in 68% yield, in a ca. 5 : 1 relative ratio. Increasing catalyst loading to 5 mol% leads to the full conversion of ethyl propiolate to benzene products; no cyclotetramerisation products were observed. In contrast, the reaction is significantly more sluggish with methyl propargyl ether. Using 1 mol% of the catalyst, only 25% conversion of methyl propargyl ether was observed within 24 h at room temperature. Furthermore, methyl propargyl ether demonstrates the formation of cyclooctatetraenes in significant amounts at a low catalyst concentration, whereas a higher catalyst concentration (5 mol%) leads to benzene products exclusively. Density functional theory was used to provide insight into the reaction mechanism, including structures of putative dinuclear metallocyclopentadiene and metallocycloheptatriene intermediates.


Structure/function analysis of Xenopus cryptochromes 1 and 2 reveals differential nuclear localization mechanisms and functional domains important for interaction with and repression of CLOCK-BMAL1.
Circadian rhythms control the temporal arrangement of molecular, physiological, and behavioral processes within an organism and also synchronize these processes with the external environment. A cell autonomous molecular oscillator, consisting of interlocking transcriptional/translational feedback loops, drives the approximately 24-hour duration of these rhythms. The cryptochrome protein (CRY) plays a central part in the negative feedback loop of the molecular clock by translocating to the nucleus and repressing CLOCK and BMAL1, two transcription factors that comprise the positive elements in this cycle. In order to gain insight into the inner workings of this feedback loop, we investigated the structure/function relationships of Xenopus laevis CRY1 (xCRY1) and xCRY2 in cultured cells. The C-terminal tails of both xCRY1 and xCRY2 are sufficient for their nuclear localization but achieve it by different mechanisms. Through the generation and characterization of xCRY/photolyase chimeras, we found that the second half of the photolyase homology region (PHR) of CRY is important for repression through facilitating interaction with BMAL1. Characterization of these functional domains in CRYs will help us to better understand the mechanism of the known roles of CRYs and to elucidate new intricacies of the molecular clock.


Trends in Physical Activity and Sedentary Behaviors of United States Youth.
Increases in childhood and adolescent obesity are a growing concern in the United States (U.S.), and in most countries throughout the world. Declines in physical activity are often postulated to have contributed to the rise in obesity rates during the past 40 years. We searched for studies of trends in physical activity and sedentary behaviors of U.S. youth, using nontraditional data sources. Literature searches were conducted for active commuting, physical education, high-school sports, and outdoor play. In addition, trends in sedentary behaviors were examined. Data from the Youth Risk Behavior Surveillance System (YRBSS) and other national surveys, as well as longitudinal studies in the transportation, education, electronic media, and recreation sectors showed evidence of changes in several indicators. Active commuting, high school physical education, and outdoor play (in 3- to 12-year-olds) declined over time, while sports participation in high school girls increased from 1971 to 2012. In addition, electronic entertainment and computer use increased during the first decade of the 21st century. Technological and societal changes have impacted the types of physical activities performed by U.S. youth. These data are helpful in understanding the factors associated with the rise in obesity, and in proposing potential solutions.


Escherichia coli has two homologous glutamate decarboxylase genes that map to distinct loci.
Degenerate oligonucleotides based on the published Escherichia coli glutamate decarboxylase (GAD) protein sequence were used in a polymerase chain reaction to generate a DNA probe for the E. coli GAD structural gene. Southern blots showed that there were two cross-hybridizing GAD genes, and both of these were cloned and sequenced. The two GAD structural genes, designated gadA and gadB, were found to be 98% similar at the nucleotide level. Each gene encoded a 466-residue polypeptide, named, respectively, GAD alpha and GAD beta, and these differed by only five amino acids. Both GAD alpha and GAD beta contain amino acid residues which are highly conserved among pyridoxal-dependent decarboxylases, but otherwise the protein sequences were not homologous to any other known proteins. By restriction mapping and hybridization to the Kohara miniset library, the two GAD genes were located on the E. coli chromosome. gadA maps at 4046 kb and gadB at 1588 kb. Neither of these positions is in agreement with the current map position for gadS as determined by genetic means. Analysis of Southern blots indicated that two GAD genes were present in all E. coli strains examined, including representatives from the ECOR collection. However, no significant cross-hybridizing gene was found in Salmonella species. Information about the DNA sequences and map positions of gadA and gadB should facilitate a genetic approach to elucidate the role of GAD in E. coli metabolism.


Investigation of the capacity of low glass transition temperature excipients to minimize amorphization of sulfadimidine on comilling.
The coprocessing of active pharmaceutical ingredient (API) with an excipient which has a high glass transition temperature (T(g)) is a recognized strategy to stabilize the amorphous form of a drug. This work investigates whether coprocessing a model API, sulfadimidine (SDM) with a series of low T(g) excipients, prevents or reduces amorphization of the crystalline drug. It was hypothesized that these excipients could exert a T(g) lowering effect, resulting in composite T(g) values lower than that of the API alone and promote crystallization of the drug. Milled SDM and comilled SDM with glutaric acid (GA), adipic acid (AA), succinic acid (SA), and malic acid (MA) were characterized with respect to their thermal, X-ray diffraction, spectroscopic, and vapor sorption properties. SDM was predominantly amorphous when milled alone, with an amorphous content of 82%. No amorphous content was detected by dynamic vapor sorption (DVS) on comilling SDM with 50% w/w GA, and amorphous content of the API was reduced by almost 30%, relative to the API milled alone, on comilling with 50% w/w AA. In contrast, amorphization of SDM was promoted on comilling with 50% w/w SA and MA, as indicated by near-infrared (NIR) spectroscopy. Results indicated that the API was completely amorphized in the SDM:MA comilled composite. The saturated solubility of GA and AA in the amorphous API was estimated by thermal methods. It was observed that the T(g) of the comelt quenched composites reached a minimum and leveled out at this solubility concentration. Maximum crystallinity of API on comilling was reached at excipient concentrations comparable to the saturated concentration solubility of excipient in the API. Moreover, the closer the Hildebrand solubility parameter of the excipient to the API, the greater the inhibition of API amorphization on comilling. The results reported here indicate that an excipient with a low T(g) coupled with high solubility in the API can prevent or reduce the generation of an amorphous phase on comilling.


Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.
Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.


Hepatitis B Reverse Seroconversion and Transmission in a Hemodialysis Center: A Public Health Investigation and Case Report.
In March 2013, public health authorities were notified of a new hepatitis B virus (HBV) infection in a patient receiving hemodialysis. We investigated to identify the source and prevent additional infections. We reviewed medical records, interviewed the index patient regarding hepatitis B risk factors, performed HBV molecular analysis, and observed infection control practices at the outpatient hemodialysis facility where she received care. The index patient's only identified hepatitis B risk factor was hemodialysis treatment. The facility had no other patients with known active HBV infection. One patient had evidence of a resolved HBV infection. Investigation of this individual, who was identified as the source patient, indicated that HBV reverse seroconversion and reactivation had occurred in the setting of HIV (human immunodeficiency virus) infection and a failed kidney transplant. HBV whole genome sequences analysis from the index and source patients indicated 99.9% genetic homology. Facility observations revealed multiple infection control breaches. Inadequate dilution of the source patient's sample during HBV testing might have led to a false-negative result, delaying initiation of hemodialysis in isolation. In conclusion, HBV transmission occurred after an HIV-positive hemodialysis patient with transplant-related immunosuppression experienced HBV reverse seroconversion and reactivation. Providers should be aware of this possibility, especially among severely immunosuppressed patients, and maintain stringent infection control.


Achieving quality health outcomes through the implementation of a spontaneous awakening and spontaneous breathing trial protocol.
Continuous sedation infusions can lead to prolonged treatment with mechanical ventilation (MV), resulting in serious complications. Spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs) are strategies that limit the amount of sedative agents a patient receives and promote extubation. The objective of this performance improvement project was to evaluate the outcomes of an evidence-based practice protocol that included SATs and SBTs on the duration of treatment with MV, ventilator utilization ratio (VUR), intensive care unit (ICU) length of stay (LOS), and incidence of self-extubations and reintubations. A convenience sample of 112 discharged patients' medical records was used for this descriptive, comparative secondary data analysis. An evidence-based SAT/SBT practice protocol was designed by a multidisciplinary team and implemented. Three months after the implementation, a retrospective medical record review was conducted to evaluate patient outcomes. The median duration of treatment with MV was significantly lower in the postprotocol group (3.8 days vs 2.7 days, U = 1222, Z = -2.013, P = .04, r = 0.19). A significant decrease was found in the VUR (0.68 vs 0.52, U = 2.5, Z = -2.293, P = .02, r = 0.69). No difference was found in the ICU LOS and frequency of self-extubation or reintubation after a self-extubation between the preprotocol and postprotocol groups. Ten of 45 SAT opportunities (22%) and 67 of 130 SBT opportunities (52%) were missed by the nurse or the respiratory therapist. The duration of treatment with MV and the VUR were reduced in patients who received the SAT/SBT protocol. The incidence of self-extubation was not different when an SAT was implemented. The ICU LOS was not reduced in patients who received SATs and SBTs.


Allosteric inhibition of [(125I)] ET-1 binding to ET(A) receptors by aldoxime and hydroxamic acid derivatives.
Endothelin-1 (ET-1), a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ET(A) and ET(B). An unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid (SA) are allosteric inhibitors of ET-1 binding to ET(A) receptors. Dihalogenated derivatives of SA have been identified as more potent allosteric inhibitors than aspirin. In this study, disubstituted benzohydroxamic acid, benzaldoximes and dihalosalicylic acid dimers were synthesized and tested as inhibitors of [(125)I]ET-1 binding to ET(A) receptors in rat embryonic cardiomyocyte (H9c2 cell) membranes. Some dihalosalicylic acid dimers 2h showed good inhibitory activity, the most active compounds are the hydroxamic acids derived from anthranilic acid. Among these compounds, the 3, 5-diiodo-2-aminobenzohydroxamic acid e compound 2a is three-folds more potent as inhibitor of [(125I)] ET-1 binding to ET(A) receptors than the 3; 5-diiodosalicylic acid reported in literature. Most aryl aldoximes in this study were biologically inactive as inhibitors of [(125I)] ET-1 binding to ET(A) receptors.


Increased use of safety-seeking behaviors in chronic back pain patients with high health anxiety.
Many patients with chronic pain also exhibit elevated levels of health anxiety. This study examined the effect of health anxiety on the use of safety-seeking behaviors (SSBs) in pain-provoking situations. Participants were 20 chronic back pain patients with high health anxiety (Group H), 20 with low health anxiety (Group L) and 20 pain-free controls (Group C). Two physical tasks were video recorded, and compared both for overt pain behavior (identified by blind observers following a standardized procedure) and for the occurrence of SSB (identified by showing the participants video playback and asking them to specify motivation for all actions/behaviors displayed during the tasks). While there were no differences in the display of overt pain behaviors, Group H deployed a greater number of SSBs than Groups L and C. This finding held true for both tasks and remained significant when concurrent pain and mood ratings were statistically controlled for. SSB was correlated with catastrophizing thoughts but not pain intensity; pain intensity was correlated with overt pain behavior but not catastrophizing. Taken together, these findings suggest that SSB is distinct from overt pain behavior and may be a defining characteristic of chronic pain patients reporting high levels of health anxiety.


Temporal Dynamics of Gene Expression During Endothelial Cell Differentiation From Human iPS Cells: A Comparison Study of Signalling Factors and Small Molecules.
Endothelial cell (EC) therapy may promote vascular growth or reendothelization in a variety of disease conditions. However, the production of a cell therapy preparation containing differentiated, dividing cells presenting typical EC phenotype, functional properties and chemokine profile is challenging. We focused on comparative analysis of seven small molecule-mediated differentiation protocols of ECs from human induced pluripotent stem cells. Differentiated cells showed a typical surface antigen pattern of ECs as characterized with flow cytometry analysis, functional properties, such as tube formation and ability to uptake acetylated LDL. Gene expression analysis by RNA sequencing revealed an efficient silencing of pluripotency genes and upregulation of genes related to cellular adhesion during differentiation. In addition, distinct patterns of transcription factor expression were identified during cellular reprogramming providing targets for more effective differentiation protocols in the future. Altogether, our results suggest that the most optimal EC differentiation protocol includes early inhibition of Rho-associated coiled-coil kinase and activation of cyclic AMP signaling, and inhibition of transforming growth factor beta signaling after mesodermal stage. These findings provide the first systematic characterization of the most potent signalling factors and small molecules used to generate ECs from human induced pluripotent stem cells and, consequently, this work improves the existing EC differentiation protocols and opens up new avenues for controlling cell fate for regenerative EC therapy.


Reverse audience effects on helping in cooperatively breeding marmoset monkeys.
Cooperatively breeding common marmosets show substantial variation in the amount of help they provide. Pay-to-stay and social prestige models of helping attribute this variation to audience effects, i.e. that individuals help more if group members can witness their interactions with immatures, whereas models of kin selection, group augmentation or those stressing the need to gain parenting experience do not predict any audience effects. We quantified the readiness of adult marmosets to share food in the presence or absence of other group members. Contrary to both predictions, we found a reverse audience effect on food-sharing behaviour: marmosets would systematically share more food with immatures when no audience was present. Thus, helping in common marmosets, at least in related family groups, does not support the pay-to-stay or the social prestige model, and helpers do not take advantage of the opportunity to engage in reputation management. Rather, the results appear to reflect a genuine concern for the immatures' well-being, which seems particularly strong when solely responsible for the immatures.


Building a Clinical Research Network in Trauma Orthopaedics: The Major Extremity Trauma Research Consortium (METRC).
Lessons learned from battle have been fundamental to advancing the care of injuries that occur in civilian life. Equally important is the need to further refine these advances in civilian practice, so they are available during future conflicts. The Major Extremity Trauma Research Consortium (METRC) was established to address these needs. METRC is a network of 22 core level I civilian trauma centers and 4 core military treatment centers-with the ability to expand patient recruitment to more than 30 additional satellite trauma centers for the purpose of conducting multicenter research studies relevant to the treatment and outcomes of orthopaedic trauma sustained in the military. Early measures of success of the Consortium pertain to building of an infrastructure to support the network, managing the regulatory process, and enrolling and following patients in multiple studies. METRC has been successful in maintaining the engagement of several leading, high volume, level I trauma centers that form the core of METRC; together they operatively manage 15,432 major fractures annually. METRC is currently funded to conduct 18 prospective studies that address 6 priority areas. The design and implementation of these studies are managed through a single coordinating center. As of December 1, 2015, a total of 4560 participants have been enrolled. Success of METRC to date confirms the potential for civilian and military trauma centers to collaborate on critical research issues and leverage the strength that comes from engaging patients and providers from across multiple centers.


Generalized colloidal synthesis of high-quality, two-dimensional cesium lead halide perovskite nanosheets and their applications in photodetectors.
All-inorganic cesium lead halide perovskite (CsPbX3, X = Cl, Br, and I) nanocrystals (NCs) are emerging as an important class of semiconductor materials with superior photophysical properties and wide potential applications in optoelectronic devices. So far, only a few studies have been conducted to control the shape and geometry of CsPbX3 NCs. Here we report a general approach to directly synthesize two-dimensional (2D) CsPbX3 perovskite and mixed perovskite nanosheets with uniform and ultrathin thicknesses down to a few monolayers. The key to the high-yield synthesis of perovskite nanosheets is the development of a new Cs-oleate precursor. The as-synthesized CsPbX3 nanosheets exhibit bright photoluminescence with broad wavelength tunability by composition modulation. The excellent optoelectronic properties of CsPbX3 nanosheets combined with their unique 2D geometry and large lateral dimensions make them ideal building blocks for building functional devices. To demonstrate their potential applications in optoelectronics, photodetectors based on CsPbBr3 nanosheets are fabricated, which exhibit high on/off ratios with a fast response time.


Increased frontal sleep slow wave activity in adolescents with major depression.
Sleep slow wave activity (SWA), the major electrophysiological characteristic of deep sleep, mirrors both cortical restructuring and functioning. The incidence of Major Depressive Disorder (MDD) substantially rises during the vulnerable developmental phase of adolescence, where essential cortical restructuring is taking place. The goal of this study was to assess characteristics of SWA topography in adolescents with MDD, in order to assess abnormalities in both cortical restructuring and functioning on a local level. All night high-density EEG was recorded in 15 patients meeting DSM-5 criteria for MDD and 15 sex- and age-matched healthy controls. The actual symptom severity was assessed using the Children's Depression Rating Scale-Revised (CDRS-R). Topographical power maps were calculated based on the average SWA of the first non-rapid eye movement (NREM) sleep episode. Depressed adolescents exhibited significantly more SWA in a cluster of frontal electrodes compared to controls. SWA over frontal brain regions correlated positively with the CDRS-R subscore "morbid thoughts". Self-reported sleep latency was significantly higher in depressed adolescents compared to controls whereas sleep architecture did not differ between the groups. Higher frontal SWA in depressed adolescents may represent a promising biomarker tracing cortical regions of intense use and/or restructuring.


Rare variant mutations identified in pediatric patients with dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) in infants and children can be partially explained by genetic cause but the catalogue of known genes is limited. We reviewed our database of 41 cases diagnosed with DCM before 18 years of age who underwent detailed clinical and genetic evaluation, and summarize here the evidence for mutations causing DCM in these cases from 15 genes (PSEN1, PSEN2, CSRP3, LBD3, MYH7, SCN5A, TCAP, TNNT2, LMNA, MYBPC3, MYH6, TNNC1, TNNI3, TPM1, and RBM20). Thirty-five of the 41 pediatric cases had relatives with adult-onset DCM. More males (66%) were found among children diagnosed after 1 year of age with DCM. Nineteen mutations in 9 genes were identified among 15 out of 41 patients; 3 patients (diagnosed at ages 2 weeks, 9 and 13 years) had multiple mutations. Of the 19 mutations identified in 12 families, mutations in TPM1 (32%) and TNNT2 (21%) were the most commonly found. Of the 6 patients diagnosed before 1 year of age, 3 had mutations in TPM1 (including a set of identical twins), 1 in TNNT2, 1 in MYH7, and 1 with multiple mutations (MYH7 and TNNC1). Most DCM was accompanied by advanced heart failure and need for cardiac transplantation. We conclude that in some cases pediatric DCM has a genetic basis, which is complicated by allelic and locus heterogeneity as seen in adult-onset DCM. We suggest that future prospective comprehensive family-based genetic studies of pediatric DCM are indicated to further define mutation frequencies in known genes and to discover novel genetic cause.


Semaphorin 3F and neuropilin-2 control the migration of human T-cell precursors.
Neuropilins and semaphorins are known as modulators of axon guidance, angiogenesis, and organogenesis in the developing nervous system, but have been recently evidenced as also playing a role in the immune system. Here we describe the expression and role of semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) in human T cell precursors. NRP2 and SEMA3F are expressed in the human thymus, in both lymphoid and non-lymphoid compartments. SEMA3F have a repulsive effect on thymocyte migration and inhibited CXCL12- and sphingosine-1-phosphate (S1P)-induced thymocyte migration by inhibiting cytoskeleton reorganization prior to stimuli. Moreover, NRP2 and SEMA3F are expressed in human T-cell acute lymphoblastic leukemia/lymphoma primary cells. In these tumor cells, SEMA3F also blocks their migration induced by CXCL12 and S1P. Our data show that SEMA3F and NRP2 are further regulators of human thymocyte migration in physiological and pathological conditions.


Case report of asthma associated with 3D printing.
Three-dimensional (3D) printing is being increasingly used in manufacturing and by small business entrepreneurs and home hobbyists. Exposure to airborne emissions during 3D printing raises the issue of whether there may be adverse health effects associated with these emissions. We present a case of a worker who developed asthma while using 3D printers, which illustrates that respiratory problems may be associated with 3D printer emissions. The patient was a 28-year-old self-employed businessman with a past history of asthma in childhood, which had resolved completely by the age of eight. He started using 10 fused deposition modelling 3D printers with acrylonitrile-butadiene-styrene filaments in a small work area of approximately 3000 cubic feet. Ten days later, he began to experience recurrent chest tightness, shortness of breath and coughing at work. After 3 months, his work environment was modified by reducing the number of printers, changing to polylactic acid filaments and using an air purifier with an high-efficiency particulate air filter and organic cartridge. His symptoms improved gradually, although he still needed periodic treatment with a salbutamol inhaler. While still symptomatic, a methacholine challenge indicated a provocation concentration causing a 20% fall in FEV1 (PC20) of 4 mg/ml, consistent with mild asthma. Eventually, his symptoms resolved completely and a second methacholine challenge after symptom resolution was normal (PC20 > 16 mg/ml). This case indicates that workers may develop respiratory problems, including asthma when using 3D printers. Further investigation of the specific airborne emissions and health problems from 3D printing is warranted.


Saddle and leg forces during lateral movements in dressage.
In the equestrian world it is assumed that riders use changes in weight distribution and leg forces as important instruments to give horses directions about speed and direction of movement. However, the changes of these forces have never been quantified. To investigate the distribution of normal forces (perpendicular to surface) underneath the saddle and of normal forces exerted by the rider's legs during lateral movements. Eleven riders performed 3 different exercises: riding straight ahead, shoulder-in and travers at trot. Three saddle force systems were used simultaneously. The magnitudes of the forces were summed for the total area, the inside and the outside half of the saddle and inside and outside leg. Mean and maximum summed forces were analysed statistically. The saddle forces showed a rhythmic pattern but leg forces were more irregular. Mean total saddle force was lower (P = 0.006) when riding straight ahead (671 ± 143 N) than when riding shoulder-in (707 ± 150 N) or travers (726 ± 165 N). Mean inside saddle force was higher (P = 0.003) when riding travers (468 ± 151 N) than when riding straight on (425 ± 121 N) or shoulder-in (413 ± 136 N). Maximum outside leg force was higher (P = 0.013) when riding travers (47.2 ± 33.9 N) than when riding straight on (31.6 ± 24.1 N) or shoulder-in (34.2 ± 27.3 N). The study helps to give a biomechanical background to well established but intuitive horse riding techniques.


Functionalisation of hollow gold nanospheres for use as stable, red-shifted SERS nanotags.
Hollow Gold Nanospheres (HGNs) exhibit a unique combination of properties which provide great scope for their use in many biomedical applications. However, they are highly unstable to changes in their surrounding environment and have a tendency to aggregate, particularly when exposed to high salt concentrations or changes in pH which is not ideal for applications such as cell imaging and drug delivery where stable solutions are required for efficient cellular uptake. Therefore there is a significant need to find a suitable stabilising agent for HGNs, however potential stabilising agents for these nanostructures have not previously been compared. Within this work we present an improved method for stabilising HGNs which simultaneously shifts the SPR from around 700 nm to 800 nm or greater. Herein, we compare three different materials which are commonly used as stabilising agents; polymers, sugars and silica in order to determine the optimum stabilising agent for HGNs. Analysis was performed using extinction spectroscopy and dynamic light scattering, supported with SEM imaging. Results showed PEG to be the most suitable stabilising agent for HGNs displaying both an increased stability to changes in salt concentration and pH as well as increased long term stability in solution. Furthermore, we demonstrate that in addition to increased stability, SERS detection can be achieved at both 1064 nm and 785 nm excitation. This combination of improved stability with a SPR in the NIR region along with SERS detection demonstrates the great potential for these nanostructures to be used in applications such as biological SERS imaging and drug delivery.


Retrospective survey of youth sports participation: Development and assessment of reliability using school records.
Many youths participate in sports, and it is of interest to understand the impact of youth sports participation on later-life outcomes. However, prospective studies take a long time to complete and retrospective studies may be more practical and time-efficient to address some questions. We pilot a retrospective survey of youth sports participation and examine agreement between respondent's self-reported participation with high school records in a sample of 84 adults who graduated from high school between 1948 and 2018. The percent agreement between our survey and the school resources for individual sports ranged between 91.5% and 100%. These findings provide preliminary evidence for the reliability of retrospective self-report of youth sports participation. This survey may serve as an efficient approach for evaluating relationships between involvement in youth sports and health outcomes later in adulthood.


Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies.
Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB). We analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts. In the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison's disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture's syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)). These two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies.


Age-related macular degeneration and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study.
To examine the association of age-related macular degeneration (AMD) with incident coronary heart disease (CHD) and all-cause mortality. Population-based prospective cohort study. From the Atherosclerosis Risk in Communities Study (n = 12 536; age range, 49-73 years). Participants had retinal photographs of one eye taken between 1993 and 1995. Photographs were evaluated for the presence of early and late AMD signs according to the Wisconsin grading system. Incident CHD events (acute myocardial infarction, silent myocardial infarction, fatal CHD, and cardiac revascularization procedures) and all-cause mortality were identified prospectively using standardized methods. Incident CHD events and all-cause mortality. Of 11,414 persons at risk of CHD, there were 555 (4.9%) with AMD at baseline, of whom 540 were early AMD and 15 were late AMD cases. Over a 10-year follow-up, 922 persons developed an incident CHD event. After controlling for age, gender, race, systolic and diastolic blood pressure, pack-years of cigarette smoking, and other variables, early AMD was not associated with incident CHD (relative risk, 1.08; 95% confidence interval, 0.82-1.42). However, individuals with late AMD were significantly more likely to have an incident CHD event, with 4 CHD events among the 15 participants with late AMD at baseline (10-year cumulative incidence, 30.9%) as compared with 918 CHD events among the 11 399 participants without late AMD (incidence of 10.0%; P = 0.049, Fisher exact test). In the full cohort (n = 12 536), early AMD was not significantly associated with all-cause mortality. However, individuals with late AMD were more likely to die (10-year cumulative mortality rate, 23.5%) than those without late AMD (mortality rate, 8.9%; P = 0.088, Fisher exact test). These data provide no evidence of an association between early AMD signs with incident CHD and all-cause mortality in middle-aged persons. Individuals with late AMD appear to have a higher rate of CHD events than those without late AMD, but due to a small number of late AMD cases, this finding should be interpreted cautiously.


Cluster randomized controlled trial testing the effectiveness of a self-management intervention using the teach-back method for people with heart failure.
In this study, we examined the effectiveness of a self-management intervention delivered to people with heart failure in Vietnam. It used teach-back, a cyclical method of teaching content, checking comprehension, and re-teaching to improve understanding. A single-site cluster randomized controlled trial was conducted, and six hospital wards were randomized into two study groups. On the basis of ward allocation, 140 participants received either usual care or the teach-back heart failure self-management intervention plus usual care. The intervention involved, prior to discharge, an individual educational session on heart failure self-care, with understanding reinforced using teach-back, a heart failure booklet, weighing scales, diary, and a follow-up phone call 2 weeks post-discharge. The control group received usual care and the booklet. Outcomes were heart failure knowledge, self-care (maintenance, management and confidence), and all-cause hospitalizations assessed at 1 and 3 months (end-point). Upon completion of the study, the intervention group had significantly greater knowledge and self-care maintenance than the control group. Other outcomes did not differ between the two groups. The teach-back self-management intervention demonstrated promising benefits in promoting self-care for heart failure patients.


Snapping knee caused by a popliteomeniscal fascicle tear of the lateral meniscus in a professional Taekwondo athlete.
A 19-year-old male professional Taekwondo athlete presented with a 2-year history of pain-free snapping of his right knee. He reported that his right knee joint gave way during games and training and that he could induce pain-free snapping between the proximal-to-fibular head and the lateral knee joint line. None of these physical findings suggested a meniscal pathology or ligamentous instability. Routine radiographs were normal. Magnetic resonance imaging of his right knee joint showed that the shape of the lateral meniscus was normal, and no lateral meniscus tears existed. On arthroscopic examination, popliteal hiatus view showed a posterosuperior popliteomeniscal fascicle tear between the posterior horn of the lateral meniscus and the posterior joint capsule just posteromedial to the popliteus tendon. With medial traction by probing, this popliteomeniscal tear made visible the significant subluxation of the posterior horn of the lateral meniscus to the center or anterior half of the tibial plateau. Based on the diagnosis of a posterosuperior popliteomeniscal tear of the right knee, Fast-Fix (Smith & Nephew, Andover, Massachusetts) was used for the direct repair of the peripheral portion of the lateral meniscus and joint capsule, targeting the popliteomeniscal junction. At 24 months postoperatively, the patient was performing athletic exercises relevant to his profession and was taking part in Taekwondo games, with no pain or recurrence of snapping. To the authors' knowledge, this is the first report of snapping of the lateral aspect of the knee due to a popliteomeniscal fascicle tear.


Inducible resistance to maize streak virus.
Maize streak virus (MSV), which causes maize streak disease (MSD), is the major viral pathogenic constraint on maize production in Africa. Type member of the Mastrevirus genus in the family Geminiviridae, MSV has a 2.7 kb, single-stranded circular DNA genome encoding a coat protein, movement protein, and the two replication-associated proteins Rep and RepA. While we have previously developed MSV-resistant transgenic maize lines constitutively expressing "dominant negative mutant" versions of the MSV Rep, the only transgenes we could use were those that caused no developmental defects during the regeneration of plants in tissue culture. A better transgene expression system would be an inducible one, where resistance-conferring transgenes are expressed only in MSV-infected cells. However, most known inducible transgene expression systems are hampered by background or "leaky" expression in the absence of the inducer. Here we describe an adaptation of the recently developed INPACT system to express MSV-derived resistance genes in cell culture. Split gene cassette constructs (SGCs) were developed containing three different transgenes in combination with three different promoter sequences. In each SGC, the transgene was split such that it would be translatable only in the presence of an infecting MSV's replication associated protein. We used a quantitative real-time PCR assay to show that one of these SGCs (pSPLITrepIII-Rb-Ubi) inducibly inhibits MSV replication as efficiently as does a constitutively expressed transgene that has previously proven effective in protecting transgenic maize from MSV. In addition, in our cell-culture based assay pSPLITrepIII-Rb-Ubi inhibited replication of diverse MSV strains, and even, albeit to a lesser extent, of a different mastrevirus species. The application of this new technology to MSV resistance in maize could allow a better, more acceptable product.


Assessing the Economic Impact of Vaccine Availability When Controlling Foot and Mouth Disease Outbreaks.
Predictive models have been used extensively to assess the likely effectiveness of vaccination policies as part of control measures in the event of a foot and mouth disease (FMD) outbreak. However, the availability of vaccine stocks and the impact of vaccine availability on disease control strategies represent a key uncertainty when assessing potential control strategies. Using an epidemiological, spatially explicit, simulation model in combination with a direct cost calculator, we assessed how vaccine availability constraints may affect the economic benefit of a "vaccination-to-live" strategy during a FMD outbreak in Scotland, when implemented alongside culling of infected premises and dangerous contacts. We investigated the impact of vaccine stock size and restocking delays on epidemiological and economic outcomes. We also assessed delays in the initial decision to vaccinate, maximum daily vaccination capacity, and vaccine efficacy. For scenarios with conditions conducive to large outbreaks, all vaccination strategies perform better than the strategy where only culling is implemented. A stock of 200,000 doses, enough to vaccinate 12% of the Scottish cattle population, would be sufficient to maximize the relative benefits of vaccination, both epidemiologically and economically. However, this generates a wider variation in economic cost than if vaccination is not implemented, making outcomes harder to predict. The probability of direct costs exceeding £500 million is reduced when vaccination is used and is steadily reduced further as the size of initial vaccine stock increases. If only a suboptimal quantity of vaccine doses is initially available (100,000 doses), restocking delays of more than 2 weeks rapidly increase the cost of controlling outbreaks. Impacts of low vaccine availability or restocking delays are particularly aggravated by delays in the initial decision to vaccinate, or low vaccine efficacy. Our findings confirm that implementing an emergency vaccination-to-live strategy in addition to the conventional stamping out strategy is economically beneficial in scenarios with conditions conducive to large FMD outbreaks in Scotland. However, the size of the initial vaccine stock available at the start of the outbreak and the interplay with other factors, such as vaccine efficacy and delays in restocking or implementing vaccination, should be considered in making decisions about optimal control strategies for FMD outbreaks.


Eliminating flanker effects and negative priming in the flankers task: evidence for early selection.
Reports of negative priming in the absence of flanker effects (Fox, 1995) provide support for the notion that unattended stimuli are identified. I evaluated the hypothesis that such results are the outcome of attentional leakage to the flanker location. In Experiment 1, I assessed flanker effects and negative priming as a function of target-flanker proximity (.9 degrees and 2.7 degrees for near and far flankers, respectively) and of attention cuing to the target location (precued vs. uncued) on the prime trials. I report larger flanker effects in uncued than in precued conditions, and larger effects for near than for far flankers. More critically, when attention was precued, both flanker effects and negative priming vanished for far flankers. In Experiment 2, I show that the latter result was not linked to prime-probe contextual similarity (Neill, 1997). These results demonstrate that selective target processing is possible when attention is optimally focused to the target location.


Sudden drop in ground support produces force-related unload response in human overground walking.
Humans maneuver easily over uneven terrain. To maintain smooth and efficient gait the motor system needs to adapt the locomotor output to the walking environment. In the present study we investigate the role of sensory feedback in adjusting the soleus muscle activity during overground walking in 19 healthy volunteers. Subjects walked unrestrained over a hydraulically actuated platform. On random trials the platform was accelerated downward at 0.8 g, unloading the plantar flexor muscles in midstance or late stance. The drop of the platform resulted in a significant depression of the soleus muscle activity of -17.9% (SD 2) and -21.4% (SD 2), with an onset latency of 49 ms (SD 1) and 45 ms (SD 1) in midstance and late stance, respectively. Input to the vestibular apparatus (i.e., the head acceleration) occurred at a latency 10.0 ms (SD 2.4) following the drop and ankle dorsiflexion velocity was decreased starting 22 ms (SD 15) after the drop. To investigate the role of length- and velocity-sensitive afferents on the depression in soleus muscle activity, the ankle rotation was arrested by using an ankle foot orthotic as the platform was dropped. Preventing the ankle movement did not significantly change the soleus depression in late stance [-18.2% (SD 15)], whereas the depression in midstance was removed [+4.9% (SD 13)]. It is concluded that force feedback from ankle extensors increases the locomotor output through positive feedback in late stance. In midstance the effect of force feedback was not observed, suggesting that spindle afferents may have a more significant effect on the output during this phase of the step cycle.


Ambient illumination toggles a neuronal circuit switch in the retina and visual perception at cone threshold.
Gradual changes in the sensory environment can lead to abrupt changes in brain computations and perception. However, mechanistic understanding of the mediating microcircuits is missing. By sliding through light levels from starlight to daylight, we identify retinal ganglion cell types in the mouse that abruptly and reversibly switch the weighting of center and surround interactions in their receptive field around cone threshold. Two-photon-targeted recordings and genetic and viral tracing experiments revealed that the circuit element responsible for the switch is a large inhibitory neuron that provides direct inhibition to ganglion cells. Our experiments suggest that weak excitatory input via electrical synapses together with the spiking threshold in inhibitory cells act as a switch. We also reveal a switch-like component in the spatial integration properties of human vision at cone threshold. This work demonstrates that circuits in the retina can quickly and reversibly switch between two distinct states, implementing distinct perceptual regimes at different light levels.


Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells.
Malignant peripheral nerve sheath tumor (MPNST) is a life-threatening complication of neurofibromatosis type 1 (NF1). NF1 is caused by mutation in the gene encoding neurofibromin, a negative regulator of Ras signaling. There are no effective pharmacologic therapies for MPNST. To identify new therapeutic approaches targeting this dangerous malignancy, we developed assays in NF1(+/+) and NF1(-/-) MPNST cell lines and in budding yeast lacking the NF1 homologue IRA2 (ira2Δ). Here, we describe UC1, a small molecule that targets NF1(-/-) cell lines and ira2Δ budding yeast. By using yeast genetics, we identified NAB3 as a high-copy suppressor of UC1 sensitivity. NAB3 encodes an RNA binding protein that associates with the C-terminal domain of RNA Pol II and plays a role in the termination of nonpolyadenylated RNA transcripts. Strains with deletion of IRA2 are sensitive to genetic inactivation of NAB3, suggesting an interaction between Ras signaling and Nab3-dependent transcript termination. This work identifies a lead compound and a possible target pathway for NF1-associated MPNST, and shows a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation.


Pain medication management processes used by oncology outpatients and family caregivers part II: home and lifestyle contexts.
Despite the increasing complexity of medication regimens for persistent cancer pain, little is known about how oncology outpatients and their family caregivers manage pain medications at home. To describe the day-to-day management of pain medications from the perspectives of oncology outpatients and their family caregivers who participated in a randomized clinical trial of a psychoeducational intervention called the Pro-Self(©) Plus Pain Control Program. In this article, we focus on pain medication management in the context of highly individualized home environments and lifestyles. This qualitative study was conducted as part of a randomized clinical trial, in which an embedded mixed methods research design was used. Audio-recorded dialogue among patients, family caregivers, and intervention nurses was analyzed using qualitative research methods. Home and lifestyle contexts for managing pain medications included highly individualized home environments, work and recreational activities, personal routines, and family characteristics. Pain medication management processes particularly relevant in these contexts included understanding, organizing, storing, scheduling, remembering, and taking the medications. With the exception of their interactions with the intervention nurses, most study participants had little involvement with clinicians as they worked through these processes. Pain medication management is an ongoing multidimensional process, each step of which has to be mastered by patients and their family caregivers when cancer treatment and supportive care are provided on an outpatient basis. Realistic patient- and family-centered skill-building interventions are needed to achieve effective and safe pain medication management in the contexts of individual home environments and lifestyles.


Clustering with Hypergraphs: The Case for Large Hyperedges.
The extension of conventional clustering to hypergraph clustering, which involves higher order similarities instead of pairwise similarities, is increasingly gaining attention in computer vision. This is due to the fact that many clustering problems require an affinity measure that must involve a subset of data of size more than two. In the context of hypergraph clustering, the calculation of such higher order similarities on data subsets gives rise to hyperedges. Almost all previous work on hypergraph clustering in computer vision, however, has considered the smallest possible hyperedge size, due to a lack of study into the potential benefits of large hyperedges and effective algorithms to generate them. In this paper, we show that large hyperedges are better from both a theoretical and an empirical standpoint. We then propose a novel guided sampling strategy for large hyperedges, based on the concept of random cluster models. Our method can generate large pure hyperedges that significantly improve grouping accuracy without exponential increases in sampling costs. We demonstrate the efficacy of our technique on various higher-order grouping problems. In particular, we show that our approach improves the accuracy and efficiency of motion segmentation from dense, long-term, trajectories.


Regulation of motoneuron excitability via motor endplate acetylcholine receptor activation.
Motoneuron populations possess a range of intrinsic excitability that plays an important role in establishing how motor units are recruited. The fact that this range collapses after axotomy and does not recover completely until after reinnervation occurs suggests that muscle innervation is needed to maintain or regulate adult motoneuron excitability, but the nature and identity of underlying mechanisms remain poorly understood. Here, we report the results of experiments in which we studied the effects on rat motoneuron excitability produced by manipulations of neuromuscular transmission and compared these with the effects of peripheral nerve axotomy. Inhibition of acetylcholine release from motor terminals for 5-6 d with botulinum toxin produced relatively minor changes in motoneuron excitability compared with the effect of axotomy. In contrast, the blockade of acetylcholine receptors with alpha-bungarotoxin over the same time interval produced changes in motoneuron excitability that were statistically equivalent to axotomy. Muscle fiber recordings showed that low levels of acetylcholine release persisted at motor terminals after botulinum toxin, but endplate currents were completely blocked for at least several hours after daily intramuscular injections of alpha-bungarotoxin. We conclude that the complete but transient blockade of endplate currents underlies the robust axotomy-like effects of alpha-bungarotoxin on motoneuron excitability, and the low level of acetylcholine release that remains after injections of botulinum toxin inhibits axotomy-like changes in motoneurons. The results suggest the existence of a retrograde signaling mechanism located at the motor endplate that enables expression of adult motoneuron excitability and depends on acetylcholine receptor activation for its normal operation.


Prenatal Exposure to Phthalates and the Development of Eczema Phenotypes in Male Children: Results from the EDEN Mother-Child Cohort Study.
Contradictory results exist regarding the importance of early-life exposure to phthalates for development of childhood eczema. We evaluated the association between maternal urinary concentrations of phthalate metabolites between the 24th and 28th week of gestation and occurrence of eczema in their sons up to 5 y of age, according to allergic sensitization as assessed by total immunoglobulin E (IgE) in a subsample of individuals. Data on health outcomes and background factors were collected using five standardized annual questionnaires completed by parents at the children's ages of 1-5 y, and their associations with phthalate metabolite urinary concentrations were assessed in 604 mother-son pairs with adjusted multiple logistic regression and Cox's survival model. Several eczema phenotypes were considered. Atopic status was assessed at 5 y of age in 293 boys through total IgE assessment. At 5 y of age, the prevalence of ever eczema was 30.4%. Metabolites of di-isobutyl phthalate (DiBP) and di-isononyl phthalate (DiNP) were positively associated with early-onset (0-24 mo of age) eczema (15.7%) and late-onset (24-60 mo of age) eczema (14.7%). Applying the Cox's model showed a significant association of occurrence of eczema in the first 5 y of life with DiBP and DiNP metabolites. Among IgE-sensitized boys, metabolites of di-n-butyl phthalate (DBP) and DiBP were significantly associated with ever eczema {hazard ratio (HR)=1.67 [95% confidence interval (CI): 1.10, 2.54], p=0.01 and HR=1.87 (95% CI: 1.01, 3.48), p=0.04, respectively}. Occurrence of eczema in early childhood may be influenced by prenatal exposure to certain phthalates in boys. Further investigations are needed to confirm this observation. https://doi.org/10.1289/EHP1829.


Functional activity of the sensorimotor cortex and cerebellum relates to cervical dystonia symptoms.
Cervical dystonia (CD) is the most common type of focal dystonia, causing abnormal movements of the neck and head. In this study, we used noninvasive imaging to investigate the motor system of patients with CD and uncover the neural correlates of dystonic symptoms. Furthermore, we examined whether a commonly prescribed anticholinergic medication in CD has an effect on the dystonia-related brain abnormalities. Participants included 16 patients with CD and 16 healthy age-matched controls. We collected functional MRI scans during a force task previously shown to extensively engage the motor system, and diffusion and T1-weighted MRI scans from which we calculated free-water and brain tissue densities. The dystonia group was also scanned ca. 2 h after a 2-mg dose of trihexyphenidyl. Severity of dystonia was assessed pre- and post-drug using the Burke-Fahn-Marsden Dystonia Rating Scale. Motor-related activity in CD was altered relative to controls in the primary somatosensory cortex, cerebellum, dorsal premotor and posterior parietal cortices, and occipital cortex. Most importantly, a regression model showed that increased severity of symptoms was associated with decreased functional activity of the somatosensory cortex and increased activity of the cerebellum. Structural imaging measures did not differ between CD and controls. The single dose of trihexyphenidyl altered the fMRI signal in the somatosensory cortex but not in the cerebellum. Symptom severity was not significantly reduced post-treatment. Findings show widespread changes in functional brain activity in CD and most importantly that dystonic symptoms relate to disrupted activity in the somatosensory cortex and cerebellum. Hum Brain Mapp 38:4563-4573, 2017. © 2017 Wiley Periodicals, Inc.


Evaluation of the multispecies coalescent method to explore intra-Trypanosoma cruzi I relationships and genetic diversity.
Chagas Disease is a zoonosis caused by the parasite Trypanosoma cruzi. Several high-resolution markers have subdivided T. cruzi taxon into at least seven lineages or Discrete Typing Units (DTUs) (TcI-TcVI and TcBat). Trypanosoma cruzi I is the most diverse and geographically widespread DTU. Recently a TcI genotype related to domestic cycles was proposed and named as TcIDOM. Herein, we combined traditional markers and housekeeping genes and applied a Multispecies Coalescent method to explore intra-TcI relationships, lineage boundaries and genetic diversity in a random set of isolates and DNA sequences retrieved from Genbank from different countries in the Americas. We found further evidence supporting TcIDOM as an independent and emerging genotype of TcI at least in Colombia and Venezuela. We also found evidence of high phylogenetic incongruence between parasite's gene trees (including introgression) and embedded species trees, and a lack of genetic structure among geography and hosts, illustrating the complex dynamics and epidemiology of TcI across the Americas. These findings provide novel insights into T. cruzi systematics and epidemiology and support the need to assess parasite diversity and lineage boundaries through hypothesis testing using different approaches to those traditionally employed, including the Bayesian Multispecies coalescent method.


Self-directed speech affects visual search performance.
People often talk to themselves, yet very little is known about the functions of this self-directed speech. We explore effects of self-directed speech on visual processing by using a visual search task. According to the label feedback hypothesis (Lupyan, 2007a), verbal labels can change ongoing perceptual processing-for example, actually hearing "chair" compared to simply thinking about a chair can temporarily make the visual system a better "chair detector". Participants searched for common objects, while being sometimes asked to speak the target's name aloud. Speaking facilitated search, particularly when there was a strong association between the name and the visual target. As the discrepancy between the name and the target increased, speaking began to impair performance. Together, these results speak to the power of words to modulate ongoing visual processing.


Gender impacts mortality after traumatic brain injury in teenagers.
Gender may influence outcomes following traumatic brain injury (TBI) although the mechanism is unknown. Animal TBI studies suggest that gender differences in endogenous hormone production may be the source. Limited retrospective clinical studies on gender present varied conclusions. Pediatric patients represent a unique population as pubescent children experience up-regulation of endogenous hormones that varies dramatically by gender. Younger children do not have these hormonal differences. The aim of this study was to compare pubescent and prepubescent females with males after isolated TBI to identify independent predictors of mortality. We performed a retrospective review of the National Trauma Data Bank Research Data Sets from 2007 and 2008 looking at all blunt trauma patients 18 years or younger who required hospital admission after isolated, moderate-to-severe TBI, defined as head Abbreviated Injury Scale (AIS) score 3 or greater. We excluded all individuals with AIS score of 3 or greater for any other region to limit the confounding effect of comorbidities. Based on the median age of menarche, we defined two age groups as follows: prepubescent (0-12 years) and pubescent (>12 years). Analysis was performed to compare trauma profiles and outcomes between groups. Our primary outcome measure was in-hospital mortality. A total of 20,280 patients met inclusion criteria; 10,135 were prepubescent, and 10,145 were pubescent. Overall mortality was 6.9%, and lower mortality was noted among prepubescent patients compared with pubescent (5.2% vs. 8.6%, p < 0.0001). Although female gender did not predict reduced mortality in the prepubescent cohort (adjusted odds ratio, 1.05; 95% confidence interval, 0.85-1.30; p = 0.63), female gender was associated with reduced mortality in the pubescent (adjusted odds ratio, 0.78; 95% confidence interval, 0.65-0.93; p = 0.007). In contrast to prepubescent female gender, pubescent female gender predicts reduced mortality following isolated, moderate-to-severe TBI. Endogenous hormonal differences may be a contributing factor and require further investigation. Prognostic study, level III.


Gaps in Understanding of the Epidemiology of Mood and Anxiety Disorders among Migrant Groups in Canada: A Systematic Review.
Estimates of mood and anxiety disorders are highly variable among migrant groups, as they are influenced by the socio-political context. Our objective was to conduct a systematic review and meta-analysis to synthesize available Canadian evidence on the prevalence and incidence of mood and anxiety disorders among migrant groups. Studies were identified from MEDLINE, EMBASE, and PsycINFO. They were included if they used population-based samples, presented data on the incidence or prevalence of diagnosed or self-reported mood or anxiety disorders for first-generation migrant groups in Canada, and used a Canadian-born or long-term resident reference group. Nineteen studies met our inclusion criteria. Prevalence ratios ranged from 0.48 to 0.87, and nearly all estimates were obtained from population health surveys. Prevalence estimates among migrant groups were lower than the reference group, with the 90th percentile of estimates ranging from 1.5% to 8.2%. Risk factors for mood and anxiety disorders among migrants included being female, younger, unemployed, having lower income, and living in neighborhoods with a lower proportion of migrants. There remain many gaps in our current understanding of mood and anxiety disorders among migrant groups in Canada. Although evidence suggests the prevalence of mood and anxiety disorders are consistently lower among migrant groups, a lack of incidence estimates limits the strength of this conclusion. Future research should focus on comparisons of self-reported and diagnosed estimates, the use of a range of different primary or secondary data sources, and consideration of important risk factors. Jordan Edwards, Malini Hu, Amardeep Thind, Saverio Stranges, Maria Chiu, Kelly Anderson. The burden of mood and anxiety disorders among immigrant and refugee populations in Canada: a systematic review. PROSPERO 2018 CRD42018087869 Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018087869 .