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Setting Tuberculosis (TB) stigma is thought to delay or prevent the decision to seek health care, but the strength of this association and the prevalence of anticipated TB stigma in the general population in most countries is unknown. Objective To examine epidemiological, cultural and sociodemographic factors associated with TB courtesy stigma in 15 surveys across 13 countries, and its link to health seeking for cough in children under five. Design A multilevel survey weighted logistic regression model was used to analyse how individual characteristics and social contexts affect the occurrence of TB courtesy stigma. The same modelling approach was used to analyse associations between TB courtesy stigma and individual-level predictors of health-seeking behaviour of mothers for children with cough. Results TB courtesy stigma varies greatly among countries. TB courtesy stigma was negatively correlated with knowledge of TB's curability (adjusted OR [aOR] 0.82; 95%CI 0.78-0.86) and human immunodeficiency virus (HIV) accepting attitudes (proxy for HIV stigma) (aOR 0.15, 95%CI 0.15-0.16). Mothers' health-seeking behaviour for children under five with cough was found to be positively correlated with HIV accepting attitudes (OR 1.16, 95%CI 1.08-1.25), but was marginally affected by TB courtesy stigma (OR 0.99, 95%CI 0.98-1.00). Conclusion Improving the general awareness of the effectiveness of anti-tuberculosis treatment will help to diminish TB courtesy stigma, and should be prioritised over expanding knowledge of mode of transmission. Efforts to reduce HIV and TB stigma may increase care seeking for childhood TB symptoms.

BACKGROUND In the treatment of pediatric traumatic brain injury (TBI), timely treatment of patients can affect the outcome. Our objectives were to examine the treatment process of acute pediatric TBI and the impact of non-value-added time (NVAT) on patient outcomes. METHODS Data for 136 pediatric trauma patients (age < 18 years) with severe TBI from 2 trauma centers in the United States were collected. A process flow and value stream map identified NVATs and their sources in the treatment process. Cluster and regression analysis were used to examine the relationship between NVAT, as a percentage of the patient's length of stay (LOS), and the patient outcome, measured by their corresponding Glasgow outcome scale. RESULTS There were 14 distinct sources of NVAT identified. A regression analysis showed that increased NVAT was associated with less favorable outcomes (relative ratio = 1.015, confidence interval = [1.002-1.029]). Specifically, 1% increase in the NVAT-to-LOS ratio was associated with a 1.5% increase in the chance of a less favorable outcome (i.e., death or vegetative state). CONCLUSION The NVAT has a significant impact on the outcome of pediatric TBI, and every minute spent on performing non-value-added processes can lead to an increase in the likelihood of less favorable outcomes.

SETTING: While substantial progress is being made in tuberculosis (TB) control, the success of public health efforts is hampered by pervasive stigma. OBJECTIVE: To perform a systematic literature review to assess the effectiveness of interventions aimed at reducing TB stigma in patients, health care workers, care givers and the general community. DESIGN: Studies were eligible for inclusion if they evaluated interventions aimed at reducing TB stigma and were published between 1950 and 2015. We searched eight databases (PubMed, Cochrane Library, Ovid, Embase, PsycInfo, Sociological Abstracts, Cumulative Index to Nursing and Allied Health Literature, World Health Organization Latin American and Caribbean Health Sciences Literature), and complemented the searches by using the snowball strategy and by reviewing relevant grey literature. RESULTS: Only seven studies were identified as providing quantitative (n = 4) or qualitative (n = 3) evidence of effectiveness in reducing TB stigma. Quality assessment of the studies was poor. Knowledge-shaping and attitude-changing interventions aimed at the public, patients and their families were effective in reducing anticipated stigma. Home visits and support groups were effective in reducing both anticipated and internalised stigma. CONCLUSION: There is a dearth of reliable information on the effectiveness of TB stigma-reduction interventions. Knowledge-shaping, attitude-changing and patient-support interventions can be effective in reducing TB stigma, but more rigorous evaluations are needed.

Older adults are more susceptible to adverse events when administered certain medications at doses appropriate for younger adults. The aim of this study was to investigate the effect of default geriatric dosing on computerized physician order entry (CPOE) templates on the subsequent administration of recommended starting doses of opioids, benzodiazepines (BZDs) and non-steroidal anti-inflammatory drugs (NSAIDs) to older adults in the emergency department (ED). This was a before–after comparison of the frequency of the recommended starting doses of high-risk medications to adults aged 65 years and older. Computerized records were queried for the administration of the above medication classes in two academic EDs over two similar 4-month periods in 2015 and 2016. Between study periods, the doses of high-risk medications on ED CPOE templates were adjusted for older adults based on established pharmacy guidelines and expert consensus. There was a significant improvement in the rate of recommended dose administration of all medications of interest (27.3 vs. 32.5%, p

To examine the frequency of and factors associated with emergency department (ED) intracranial pressure (ICP) monitor placement in severe paediatric traumatic brain injury (TBI).Retrospective, multicentre cohort study of children18 years admitted to the ED with severe TBI and intubated for48 hours from 2007 to 2011.Two hundred and twenty-four children had severe TBI and 75% underwent either ED, operating room (OR) or paediatric intensive care unit (PICU) ICP monitor placement. Four out of five centres placed ICP monitors in the ED, mostly (83%) fibreoptic. Nearly 40% of the patients who received ICP monitors get it placed in the ED (29% overall). Factors associated with ED ICP monitor placement were as follows: age 13 to18 year olds compared to infants (aRR 2.02; 95% CI 1.37, 2.98), longer ED length of stay (LOS) (aRR 1.15; 95% CI 1.08, 1.21), trauma centre designation paediatric only I/II compared to adult/paediatric I/II (aRR 1.71; 95% CI 1.48, 1.98) and higher mean paediatric TBI patient volume (aRR 1.88;95% CI 1.68, 2.11). Adjusted for centre, higher bedside ED staff was associated with longer ED LOS (aRR 2.10; 95% CI 1.06, 4.14).ICP monitors are frequently placed in the ED at paediatric trauma centres caring for children with severe TBI. Both patient and organizational level factors are associated with ED ICP monitor placement.

Apatites from the Verity, Fir, Gum, Howard Creek and Felix carbonatites of the Blue River (British Columbia, Canada) area have been investigated with respect to their paragenesis, cathodoluminescence, trace element and Sr–Nd isotopic composition. Although all of the Blue River carbonatites were emplaced as sills prior to amphibolite grade metamorphism and have undergone deformation, in many instances magmatic textures and mineralogy are retained. Attempts to constrain the U–Pb age of the carbonatites by SIMS, TIMS and LA–ICP-MS studies of zircon and titanite were inconclusive as all samples investigated have experienced significant Pb loss during metamorphism. The carbonatites are associated with undersaturated calcite–titanite amphibole nepheline syenite only at Howard Creek although most contain clasts of disaggregated phoscorite-like rocks. Apatite from each intrusion is characterized by distinct, but wide ranges, in trace element composition. The Sr and Nd isotopic compositions define an array on a 87Sr/86Sr vs²Nd diagram at 350 Ma indicating derivation from depleted sub-lithospheric mantle. This array could reflect mixing of Sr and Nd derived from HIMU and EM1 mantle sources, and implies that depleted mantle underlies the Canadian Cordillera. Although individual occurrences of carbonatites in the Blue River region are mineralogically and geochemically similar they are not identical and thus cannot be considered as rocks formed from a single batch of parental magma at the same stage of magmatic evolution. However, a common origin is highly probable. The variations in the trace element content and isotopic composition of apatite from each occurrence suggest that each carbonatite represents a combination of derivation of the parental magma(s) from mineralogically and isotopically heterogeneous depleted mantle sources coupled with different stages of limited differentiation and mixing of these magmas. We do not consider these carbonatites as primary direct partial melts of the sub-lithospheric mantle which have ascended from the asthenosphere without modification of their composition.

Longitudinal growth of bones occurs at the growth plates, where chondrocytes align into columns that allow directional growth. Mechanical load and force on chondrocytes regulate the organization of the postnatal growth plate and limb length., Longitudinal growth of bones occurs at the growth plates where chondrocytes align into columns that allow directional growth. Little is known about the mechanisms controlling the ability of chondrocytes to form columns. We hypothesize that mechanical load and the resulting force on chondrocytes are necessary during active growth for proper growth plate development and limb length. To test this hypothesis, we created a mouse model in which a portion of the sciatic nerve from one hind limb was transected at postnatal day 8 to cause paralysis to that limb. At 6 and 12 wk postsurgery, the hind limb had significantly less bone mineral density than contralateral controls, confirming reduced load. At 8 and 14 wk postsurgery, tibiae were significantly shorter than controls. The paralyzed growth plate showed disruptions to column organization, with fewer and shorter columns. Polarized light microscopy indicated alterations in collagen fiber organization in the growth plate. Furthermore, organization of the actin cytoskeleton in growth plate chondrocytes was disrupted. We conclude that mechanical load and force on chondrocytes within the growth plate regulate postnatal development of the long bones.

Objectives:Delayed initiation of appropriate antimicrobials is linked to higher sepsis mortality. We investigated interphysician variation in septic patients’ door-to-antimicrobial time.Design:Retrospective cohort study.Setting:Emergency department of an academic medical center.Subjects:Adult patien

The Ashram Zone, which is host to the Ashram Rare Earth Element (REE) Deposit, occurs within the Eldor Carbonatite Complex, Quebec, Canada. The complex is located within the Paleoproterozoic New Quebec Orogen (Labrador Trough), and has been subjected to greenschist metamorphism and folding during the Hudsonian Orogeny at 1.75 Ga. To date, consanguineous undersaturated alkaline rocks have not been recognized within or adjacent to the complex. It is evident that the bulk compositions of the rocks, essentially magnesiocarbonatites and ferrocarbonatites, do not represent those of liquid compositions, as many are complex breccias which have been subjected to later hydrothermal activity. The Ashram Zone is dominated by diverse textural varieties of carbonatite which include: fluorite-rich schlieren carbonatites; coarse-to-medium grained granular carbonatites; fine grained, commonly mosaic-textured, quartz-bearing carbonatites; and colloform carbonatites. Compositional and textural data are provided for the minerals present in the carbonatites. The major rock-forming minerals are diverse Ca-Mg-Fe carbonates, fluorite, and quartz. The carbonates range in their compositional evolution from rare dolomite through ferrodolomite and magnesian siderite to siderite. The principal REE-bearing minerals of the Ashram Deposit are monazite-(Ce) and monazite-(Nd), with lesser amounts of bastnaesite-(Ce) and bastnaesite-(Nd). The minor and accessory mineral suite is characterized by the presence of apatite, phlogopite, xenotime, diverse Sc- and sn-bearing Nb-Ti-minerals (niobian rutile, nioboaeschynite, samarskite), barite, sphalerite, several uncommon, but here relatively abundant, Ba- and Ba-Be minerals (bafertisite, magbasite, barylite, betrandite, sanbornite, cebaite), yangzhumingite, cassiterite, galena, pyrite, and rare magnetite and potassium feldspar. Pyrochlore is absent and the Nb-Ti oxide assemblage is similar to that found in NYF-pegmatites associated with F-rich, A-type granitoids. The mineralogy of the Ashram Deposit, compared to that of other carbonatites associated with undersaturated silicate rocks is unique, especially with respect to the abundance of fluorite and monazite (commonly with Nd-enrichment), Ba-Be-enrichment, the NYF-type Nb-Ti oxide assemblage (especially xenotime, Y-Nb-aeschynite, samarskite), phlogopite-potassium feldspar quartz-rich residua with granitoid characteristics, paucity of magnetite, pyrochlore, and Sr-bearing carbonates. The Ashram Deposit is considered to be a late-magmatic-to-hydrothermal F-REE magnesio-to-ferrocarbonatite derived from as yet unknown consanguineous antecedents.

Background: Distal scaphoid excision is one treatment option for osteoarthritis of the scaphotrapeziotrapezoid (STT) joint following failure of conservative measures. Potential complications of this procedure include injury to the carpal ligaments, cartilage, and radial artery. Methods: A single case was identified by the senior author, and the medical record was reviewed for surgical notes, progress notes, and radiographs. Results: A 68-year-old male sustained ruptures of the flexor digitorum superficialis (FDS) and flexor digitorum profundus to the index finger 3 years following a distal scaphoid excision for symptomatic STT osteoarthritis. He required a flexor tendon reconstruction using the remaining FDS tendon for graft incorporated with a Pulvertaft weave. His midcarpal pain continued after recovery of his index finger function, eventually requiring a 4-corner fusion of the wrist. Conclusions: Flexor tendon rupture is a previously unreported complication of distal scaphoid excision for STT arthritis.

Background Mechanical strain in neural tissues can lead to the upregulation and release of multiple cytokines including IL-6. In the retina, the mechanosensitive release of ATP can autostimulate P2X7 receptors on both retinal ganglion cell neurons and optic nerve head astrocytes. Here we asked whether the purinergic signaling contributed to the IL-6 response to increased intraocular pressure (IOP) in vivo, and stretch or swelling in vitro. Methods Rat and mouse eyes were exposed to non-ischemic elevations in IOP to 50-60 mmHg for 4 hrs. A PCR array was used to screen cytokine changes, with quantitative (q)PCR used to confirm mRNA elevations and immunoblots used for protein levels. P2X7 antagonist Brilliant Blue G (BBG) and agonist BzATP were injected intravitreally. ELISA was used to quantify IL-6 release from optic nerve head astrocytes or retinal ganglion cells. Receptor identity was confirmed pharmacologically and in P2X7-/- mice. Results Acute elevation of IOP altered retinal expression of multiple cytokine genes. Elevation of IL-6 was greatest, with expression of IL1m, IL24, Tnf, Csf1 and Lif also increased more than two-fold, while Tnfsf11, Gdf9 and Tnfsf4 were reduced. qPCR confirmed the rise in IL-6 and extracellular ATP marker ENTPD1, but not pro-apoptotic genes. Intravitreal injection of P2X7 receptor antagonist BBG prevented the pressure-dependent rise in IL-6 mRNA and protein in the rat retina, while injection of P2X7 receptor agonist BzATP was sufficient to elevate IL-6 expression. IOP elevation increased IL-6 in wild type but not P2X7R knockout mice. Application of mechanical strain to isolated optic nerve head astrocytes increased IL-6 levels. This response was mimicked by agonist BzATP, but blocked by antagonists BBG and A839977. Stretch or BzATP led to IL-6 release from both astrocytes and isolated retinal ganglion cells. Conclusions The mechanosensitive upregulation and release of cytokine IL-6 from the retina involves the P2X7 receptor, with both astrocytes and neurons contributing to the response. This article is protected by copyright. All rights reserved.

The biomechanical environment within the optic nerve head (ONH) is complex and is likely directly involved in the loss of retinal ganglion cells (RGCs) in glaucoma. Unfortunately, our understanding of this process is poor. Here we describe factors that influence ONH biomechanics, including ONH connective tissue microarchitecture and anatomy; intraocular pressure (IOP); and cerebrospinal fluid pressure (CSFp). We note that connective tissue factors can vary significantly from one individual to the next, as well as regionally within an eye, and that the understanding of ONH biomechanics is hindered by anatomical differences between small-animal models of glaucoma (rats and mice) and humans. Other challenges of using animal models of glaucoma to study the role of biomechanics include the complexity of assessing the degree of glaucomatous progression; and inadequate tools for monitoring and consistently elevating IOP in animal models. We conclude with a consideration of important open research questions/challenges in this area, including: (i) Creating a systems biology description of the ONH; (ii) addressing the role of astrocyte connective tissue remodeling and reactivity in glaucoma; (iii) providing a better characterization of ONH astrocytes and non-astrocytic constituent cells; (iv) better understanding the role of ONH astrocyte phagocytosis, proliferation and death; (v) collecting gene expression and phenotype data on a larger, more coordinated scale; and (vi) developing an implantable IOP sensor.

We have investigated the effects of porosity on the crystallization kinetics of amorphous solid water (ASW). Porosity in ASW films, condensed from the vapor phase at varying incidences at 10 K, was characterized using ultraviolet-visible interferometry and quartz crystal microgravimetry. The films were heated to crystallization temperatures between 130 and 141 K, resulting in partial pore compaction. The isothermal phase transformation was characterized using transmission infrared spectroscopy to monitor the time evolution of the 3.1-µm O H stretch absorption band. We find that ASW crystallization unfolds in two distinct stages. The first stage, responsible for ∼10% transformation, is initiated from nucleation at the external surface. The dominant second stage begins with nucleation at the internal pore surfaces and completes the transformation of the film at a faster rate compared to the first stage. A key finding is that porosity has major influence on crystallization kinetics; a film with five-times-higher porosity was observed to crystallize ∼15 times faster, compared to the less porous counterpart. We extrapolate our results to predict crystallization times for amorphous ices condensed on Europa's surface from plume sources, as recently observed by the Hubble Space Telescope.

Protein lysine methyltransferases (PKMTs) regulate diverse physiological processes including transcription and the maintenance of genomic integrity. Genetic studies suggest that the PKMTs SUV420H1 and SUV420H2 facilitate proficient nonhomologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation (me2 and me3, respectively) of lysine 20 on histone 4 (H4K20). Here we report the identification of A-196, a potent and selective inhibitor of SUV420H1 and SUV420H2. Biochemical and co-crystallization analyses demonstrate that A-196 is a substrate-competitive inhibitor of both SUV4-20 enzymes. In cells, A-196 induced a global decrease in H4K20me2 and H4K20me3 and a concomitant increase in H4K20me1. A-196 inhibited 53BP1 foci formation upon ionizing radiation and reduced NHEJ-mediated DNA-break repair but did not affect homology-directed repair. These results demonstrate the role of SUV4-20 enzymatic activity in H4K20 methylation and DNA repair. A-196 represents a first-in-class chemical probe of SUV4-20 to investigate the role of histone methyltransferases in genomic integrity.

We define an abstract Apollonian supergasket using the solution set of a certain Diophantine equation, showing that the solutions are in bijective correspondence with the circles of any concrete supergasket. Properties of the solution set translate directly to geometric and algebraic properties of Apollonian gaskets, facilitating their study. In particular, curvatures of individual circles are explored and geometric relationships among multiple circles are given simple algebraic expressions. All results can be applied to a concrete gasket using the curvaturecenter coordinates of its four defining circles. These techniques can also be applied to other types of circle packings and higher-dimensional analogs. An Apollonian gasket is a type of circle packing in the plane generated recursively starting from a set of four mutually tangent circles. The curvatures of any four such circles are related by an equation discovered by Descartes, and every circle in a gasket generated by four circles with integer curvatures will have integer curvature. While these gaskets have been fascinating to mathematicians for some time — the use of group theory in their study was initiated by Keith Hirst [1967] and they even inspired a poem 1 — it was only relatively recently that Jeffrey Lagarias, Colin Mallows, and Allan Wilks [Lagarias et al. 2002] gave an algebraic characterization of Descartes configurations. One question in particular has inspired much work but resisted a complete answer: given the four original integer curvatures, which other curvatures can or will occur, and how frequently? Peter Sarnak [2011], Elena Fuchs [2013], and Hee Oh [2014] have recent surveys on this topic, which has seen significant progress in the past five years [Bourgain 2012; Bourgain and Kontorovich 2014; Bourgain and Fuchs 2011; Fuchs and Sanden 2011]. In this paper, inspired by recent work of Sam Northshield [2015], we provide a four-dimensional label to each circle that does not depend on the location of the circle but refers instead to its geometric relationship to the original four circles. Since we consider only the process of generating the gasket, the labels provide an

The Proterozoic Sushina Hill Complex is the only agpaitic complex, reported from India and is characterized by a eudialyte-rinkite-bearing nepheline syenite. The complex is considered a ‘metamorphosed agpaitic complex'. This study describes the mineral assemblages formed during successive stages of evolution from magmatic to hydrothermal stages and low-temperature subsolidus re-equilibration assemblage. The primary-late magmatic assemblage is characterized by albite, orthoclase, unaltered nepheline, zoned diopside-hedenbergite, rinkite, late magmatic eudialyte and magnesio-arfvedsonite formed at ∼700°C with maximum aSiO2 of 0.60. In contrast, a deuteric assemblage (400-348°C) is represented by aegirine-jadeite-rich clinopyroxene, post-magmatic eudialyte, sodalite, analcime and the decomposition assemblages formed after eudialyte with decreasing aSiO2 (0.52-0.48). A further low-temperature subsolidus assemblage (≤250°C) represented by late-forming natrolite could be either related to regressive stages of metamorphism or a continuum of the subsolidus processes. Considering the P/T range of the greenschist - lower-amphibolite facies of metamorphism it is evident that the incorporation of a jadeite component within pyroxene is related to a subsolidus process between ∼400°C and 348°C in a silica deficient environment. We emphasize that the deuteric fluid itself acted as an agent of metamorphism and the decomposition assemblage formed after eudialyte is retained even after metamorphism due to the convergence of subsolidus and metamorphic domains. The formation of jadeite-rich aegirine is not considered to result from metamorphism. Overall it is near-impossible to discern any bona fide metamorphic textures or mineral assemblages in these syenites which appear to preserve a relict mineralogy regardless of their occurrence in country rocks which have experienced greenschist - amphibolite facies metamorphism. The Sushina complex is very similar in this respect to the Norra Kärr complex (Sweden).

ObjectiveTo develop a robust prognostic model, the more diverse the settings in which the system is tested and found to be accurate, the more likely it will be generalisable to untested settings. This study aimed to externally validate the International Mission for Prognosis and Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomization after Significant Head Injury (CRASH) models for low-income and middle-income countries using a dataset of patients with severe traumatic brain injury (TBI) from the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure study and a simultaneously conducted observational study.MethodA total of 550 patients with severe TBI were enrolled in the study, and 466 of those were included in the analysis. Patient admission characteristics were extracted to predict unfavourable outcome (Glasgow Outcome Scale: GOS<3) and mortality (GOS 1) at 14 days or 6 months.ResultsThere were 48% of the participants who had unfavourable outcome at 6 months and these included 38% who had died. The area under the receiver operating characteristic curve (AUC) values were 0.683–0.775 and 0.640–0.731 for the IMPACT and CRASH models respectively. The IMPACT CT model had the highest AUC for predicting unfavourable outcomes, and the IMPACT Lab model had the best discrimination for predicting 6-month mortality. The discrimination for both the IMPACT and CRASH models improved with increasing complexity of the models. Calibration revealed that there were disagreement between observed and predicted outcomes in the IMPACT and CRASH models.ConclusionThe overall performance of all IMPACT and CRASH models was adequate when used to predict outcomes in the dataset. However, some disagreement in calibration suggests the necessity for updating prognostic models to maintain currency and generalisability.

Regional anaesthesia is a fundamental aspect of anaesthesia practice. Structured Fellowships in regional anaesthesia facilitate the development of expert clinicians, scholars and future leaders. The Australian and New Zealand College of Anaesthetists accredits training sites for the final year of Fellowship training but does not outline specific guidance for subspecialty training. Based on evidence from a systematic literature review and best-practice medical education principles, the ideal structure for a regional anaesthesia Fellowship programme in Australia and New Zealand is outlined in four categories: (a) structure and duration of training; (b) educational aspects; (c) institutional organization; (d) evaluation and improvement. Departments may use this resource to help design, implement and improve their Fellowship programmes while trainees may employ it as a reference to achieve their learning goals at any training stage. Continuing professional education plays a central role in achieving and maintaining mastery of regional anaesthesia competencies.

Diamond-bearing kimberlites were born from similar melts in the deep Earth and variably modified during ascent., Quantifying the compositional evolution of mantle-derived melts from source to surface is fundamental for constraining the nature of primary melts and deep Earth composition. Despite abundant evidence for interaction between carbonate-rich melts, including diamondiferous kimberlites, and mantle wall rocks en route to surface, the effects of this interaction on melt compositions are poorly constrained. Here, we demonstrate a robust linear correlation between the Mg/Si ratios of kimberlites and their entrained mantle components and between Mg/Fe ratios of mantle-derived olivine cores and magmatic olivine rims in kimberlites worldwide. Combined with numerical modeling, these findings indicate that kimberlite melts with highly variable composition were broadly similar before lithosphere assimilation. This implies that kimberlites worldwide originated by partial melting of compositionally similar convective mantle sources under comparable physical conditions. We conclude that mantle assimilation markedly alters the major element composition of carbonate-rich melts and is a major process in the evolution of mantle-derived magmas.

Research supports the idea that "delay discounting," also known as temporal discounting, intertemporal choice, or impulsive choice, is a transdisease process with a strong connection to substance use disorders (SUDs) and other psychopathologies, like attention deficit hyperactivity disorder and depression. This article briefly reviews the evidence used to conclude that delay discounting is heritable and should be considered to be an endophenotype, as well as evidence of its behavioral and genetic associations with SUDs. It also discusses the limitations that should be considered when evaluating the strength of these associations. Finally, this article briefly describes research examining relationships among delay discounting and SUD-associated intermediate phenotypes to better understand the conceptual relationships underlying the links between SUDs and delay discounting, and identifies research gaps that should be addressed.

Background and purpose Little is known about the real-life factors that clinicians use in selection of patients that would receive endovascular treatment (EVT) in the real world. We sought to determine patient, practitioner, and health system factors associated with therapeutic decisions around endovascular treatment. Methods We conducted a multinational cross-sectional web-based study comprising of 607 clinicians and interventionalists from 38 countries who are directly involved acute stroke care. Participants were randomly allocated to 10 from a pool of 22 acute stroke case scenarios and stated how they would treat the patient A) under current local resources, and B) under assumed ideal conditions (i.e. without monetary or infrastructural constraints). Descriptive statistics and logistic regression was performed to determine multilevel factors associated with EVT, adherence to current EVT guidelines, and practice gaps between current local resources and assumed ideal conditions. Results Of the 1330 invited participants, 607 (45.6%) participants completed the study (53.7% neurologists, 28.5% neuro-interventional radiologists, 17.8% other clinicians). NIHSS (34.9%), level of evidence (30.2%), ASPECTS or ischemic core volume (22.4%), patient’s age (21.6%), and clinicians’ experience in EVT use (19.3%) are the most important factors for EVT decision. Of all responses that met Class IA evidence for EVT, 86.8% were in favor of EVT. In case scenarios Class IIB evidence, 66.3% of responses favored EVT. Comparison between current and ideal practice settings revealed an overall practice gap of 4% (Class 1A evidence scenarios) and 3% (Class 2B evidence scenarios).EVT decision rates differed significantly between regions and specialties under current local resources (p Conclusions In this large multinational survey, stroke severity, guideline-based level of evidence, baseline brain imaging, patients’ age and physicians’ experience were the most relevant factors for EVT decision-making. The high agreement between responses and Class I guideline recommendations and high EVT use even when guidelines were not available reflect the real-world acceptance of EVT as standard of care in patients with disabling acute ischemic stroke. The overall practice gap and the significant differences in EVT decision rates under current local resources suggest that physicians of different specialties and practicing in different geographic regions succumb to variable external restraints. Disclosures M. Goyal: 1; C; This study was funded through an unrestricted Research Grant to the University of Calgary by Stryker Inc. 2; C; Medtronic, Stryker, Microvention, GE Healthcare, Mentice. B. Menon: None. N. Kashani: None. A. Wilson: None. S. Yoshimura: None. B. Campbell: None. B. Baxter: 2; C; Penumbra, Medtronic, Stryker, 880 Medical, Metactive. 4; C; Penumbra, viz.ai. 5; C; ownership interests on Route 92 and Marblehead. A. Rabinstein: None. F. Turjman: 2; C; consultant for Balt and Stryker. U. Fischer: 2; C; Medtronic, Stryker, CSL Behring. 6; C; Co-PI Swift direct trial (Medtronic). J. Ospel: None. W. Kunz: None. P. Mitchell: None. P. Sylaia: None. M. Cherian: None. B. Kim: None. J. Heo: None. A. Podlasek: None. M. Almekhlafi: None. M. Foss: None. A. Demchuk: None. M. Hill: None. G. Saposnik: 6; C; Gustavo Saposnik is supported by the Heart and Stroke Foundation of Canada Career Award.

Elevated replication stress is evident at telomeres of about 10-15% of cancer cells, which maintain their telomeres via a homologous recombination (HR)-based mechanism, referred to as alternative lengthening of telomeres (ALT). How ALT cells resolve replication stress to support their growth remains incompletely characterized. Here, we report that CSB (also known as ERCC6) promotes recruitment of HR repair proteins (MRN, BRCA1, BLM and RPA32) and POLD3 to ALT telomeres, a process that requires the ATPase activity of CSB and is controlled by ATM- and CDK2-dependent phosphorylation. Loss of CSB stimulates telomeric recruitment of MUS81 and SLX4, components of the structure-specific MUS81-EME1-SLX1-SLX4 (MUS-SLX) endonuclease complex, suggesting that CSB restricts MUS-SLX-mediated processing of stalled forks at ALT telomeres. Loss of CSB coupled with depletion of SMARCAL1, a chromatin remodeler implicated in catalyzing regression of stalled forks, synergistically promotes not only telomeric recruitment of MUS81 but also the formation of fragile telomeres, the latter of which is reported to arise from fork stalling. These results altogether suggest that CSB-mediated HR repair and SMARCAL1-mediated fork regression cooperate to prevent stalled forks from being processed into fragile telomeres in ALT cells.

Background Adolescents are a prime target group for tuberculosis (TB) vaccine trials that include prevention of infection (POI). The BCG vaccine is given at birth and does not prevent TB infection. TB infection, a critical endpoint for POI vaccine trials would need to be documented to estimate sample sizes in target populations. Methods Adolescents aged 12–18 years of age were enrolled in an area under continuous demographic surveillance. A tuberculin skin test (TST) survey was conducted as part of a study on TB prevalence and incidence. All adolescents got TSTs at enrolment and returned after 72 h for reading. A TST of ≥10 mm if HIV negative or ≥ 5 mm if HIV positive, was considered positive. Results Of 4808 adolescents returning for TST readings (96% of those enrolled), mean age was 14.4 (SD 1.9), 4518(94%) were enrolled in school and 21(0.4%) gave a previous history of tuberculosis. Among adolescents with TST reactivity, the mean TST induration was 13.2 mm (SD 5.4). The overall prevalence of latent TB infection was 1544/4808 (32.1, 95% CI 29.2–35.1) with a corresponding annual risk of TB infection (ARTI) of 2.6% (95% CI 2.2–3.1). Risk factors for a positive TST included being male (OR 1.3, 95% CI 1.2,1.5), history of having a household TB contact (OR 1.5, 95% CI 1.2,1.8), having a BCG scar (OR 1.5,95% CI 1.2,1.8), living in a rural area (OR 1.4, 95% CI 1.1,1.9), and being out of school (OR 1.8, 95% CI 1.4,2.3). Conclusion We conclude that the high TB transmission rates we found in this study, suggest that adolescents in this region may be an appropriate target group for TB vaccine trials including TB vaccine trials aiming to prevent infection. Electronic supplementary material The online version of this article (10.1186/s12879-019-4314-7) contains supplementary material, which is available to authorized users.

Community-led tuberculosis (TB) active case finding is widely promoted, heavily funded, but many efforts fail to meet expectations. The underlying reasons why TB symptom screening programs underperform are poorly understood. This study examines Nigerian stakeholders' insights to characterize the mechanisms, enabling structures and influences that lead programs to succeed or fail. Eight focus group discussions were held with Community Health Workers (CWs) from four models of community-based TB screening and referral. In-depth interviews were conducted with 2 State TB program managers, 8 Community based organizations (CBOs), and 6 state TB and Leprosy Local Government supervisors. Transcripts were coded using Framework Analysis to assess how divergent understandings of CWs' roles, expectations, as well as design, political and structural factors contributed to the observed underperformance. Altruism, religious faith, passion, and commitment to the health and well-being of their communities were reasons CWs gave for starting TB symptom screening and referral. Yet politicized or donor-driven CWs' selection processes at times yielded implementers without a firm grounding in TB or the social, cultural, and physical terrain. CWs encountered suspicion, stigma, and hostility in both health facilities and communities. As the interface between the TB program and communities, CWs often bore the brunt of frustrations with inadequate TB services and CBO/iNGO collaboration. Some CWs expended their own social and financial capital to cover gaps in the active case finding (ACF) programs and public health services or curtailed their screening activities. Effective community-led TB active case finding is challenging to design, implement and sustain. Contrary to conventional wisdom, CWs did not experience it as inherently empowering. Sustainable, supportive models that combine meaningful engagement for communities with effective program stewardship and governance are needed. Crucially effective and successful implementation of community-based TB screening and referral requires a functional public health system to which to refer.

Microglial cells are involved in a complex series of physiologic and pathophysiologic interactions in the nervous system, and the receptors responsible for mediating these responses are central to ...

RATIONALE: Alcohol-use disorder (AUD) is associated with the propensity to choose smaller sooner options on the delay discounting task. It is unclear, however, how inherent risk underlies delay discounting behavior. As impulsive choice is a hallmark feature in AUD, it is important to understand the neural response to reward and delay, while accounting for risk in impulsive decision-making. OBJECTIVE: This study examined activation associated with delay and reward magnitude, while controlling for risk in a probabilistic delay discounting task in AUD and examined if differences in activation were associated with treatment outcomes. METHODS: Thirty-nine recently abstinent alcohol dependent volunteers and 46 controls completed a probabilistic delay discounting task paired with functional magnetic resonance imaging. Alcohol use was collected using a self-report journal for three months following baseline scan. RESULTS: During delay stimulus presentations, Controls exhibited greater activation compared to the Alcohol group notably in the anterior insula, middle/dorsal anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (PFC), and inferior parietal lobule. For magnitude, the Alcohol group exhibited greater activation than Controls primarily in medial PFC, rostral ACC, left posterior parietal cortex and right precuneus. Within the Alcohol group, alcohol craving severity negatively correlated with right lateral PFC activation during reward magnitude in individuals who completed the three month study without relapse, while non-completers showed the opposite relationship. CONCLUSIONS: The results of this study extend previous findings that alcohol use disorder is associated with differences in activation during an immediate or delayed choice by delineating activation associated with the parameters of impulsive choice.

Objective: Although some research has identified correlates of high-dose opioid prescriptions, relatively little is known about factors that lead to higher doses. Delay discounting (DD), defined as the subjective value of a reward declining as a function of the delay to that reward, is an objective measure of impulsivity. DD is commonly studied in the context of addictive behaviors, and findings consistently demonstrate greater DD among individuals with opioid use disorders. The authors conducted a preliminary investigation to examine the extent to which DD is associated with prescription opioid dose among patients with musculoskeletal pain. Design: Cross-sectional study. Setting: A single veterans affairs medical center located in the Pacific Northwest. Subjects: Participants with chronic musculoskeletal pain. The authors identified patients prescribed with high doses of opioids (100 mg morphine equivalent per day [MED] or more; n = 17), traditional doses of opioids (5-99 mg MED; n = 34), and patients with pain who were not prescribed opioids (n = 24). Methods: All participants completed a battery of self-report measures assessing demographic characteristics, pain-related variables, and psychiatric symptoms. Participants also completed a computerized DD task. Results: DD was negatively correlated with average daily opioid dose (p = 0.003) and positively correlated with anxiety (p = 0.013). In a multivariable regression analysis, after controlling for the effects of demographic and clinical factors, DD was significantly associated with prescription opioid dose. Conclusions: Contrary to study expectations, higher opioid dose was associated with less DD. These findings call for prospective research to further elucidate the relationships between DD and other measures of impulsivity and prescription opioid doses.

Objectives Quality improvement in geriatric trauma depends on timely identification of frailty, yet little is known about providers' knowledge and beliefs about frailty assessment. This study sought to understand trauma providers' understanding, beliefs, and practices for frailty assessment. Methods We developed a 20-question survey using the Health Belief Model of health behavior and surveyed physicians, advanced practice providers, and trainees on the trauma services at a single institution that does not use formal frailty screening of all injured seniors. Results were analyzed via mixed methods. Results One hundred fifty-one providers completed the survey (response rate 92%). Respondents commonly included calendar age as an integral factor in their determinations of frailty but also included a variety of other factors, highlighting limited definitional consensus. Respondents perceived frailty as important to older adult patient outcomes, but assessment techniques were varied because only 24/151 respondents (16%) were familiar with current formal frailty assessment tools. Perceived barriers to performing a formal frailty screening on all injured older adults included the burdensome nature of assessment tools, insufficient training, and lack of time. When prompted for solutions, 20% of respondents recommended automation of the screening process by trained, dedicated team members. Conclusions Providers seem to recognize the impact that a diagnosis of frailty has on outcomes, but most lack a working knowledge of how to assess for frailty syndrome. Some providers recommended screening by designated, formally trained personnel who could notify decision makers of a positive screen result.

Background Increased blood pressure ( BP ) variability and nondipping status seen on 24‐hour ambulatory BP monitoring are often observed in autonomic failure ( ATF ). Methods and Results We assessed BP variability and nocturnal BP dipping in 273 patients undergoing ambulatory BP monitoring at Southwestern Medical Center between 2010 and 2017. SD , average real variability, and variation independent of mean were calculated from ambulatory BP monitoring. Patients were divided into a discovery cohort (n=201) and a validation cohort (n=72). ATF was confirmed by formal autonomic function test. In the discovery cohort, 24‐hour and nighttime average real variability, SD , and variation independent of mean did not differ significantly between ATF (n=25) and controls (n=176, all P >0.05). However, daytime SD, daytime coefficient of variation, and daytime variation independent of mean of systolic BP ( SBP ) were all significantly higher in patients with ATF than in controls in both discovery and validation cohorts. Nocturnal BP dipping was more blunted in ATF patients than controls in both cohorts (both P SBP yielded a sensitivity of 77% and specificity of 82% in detecting ATF in the validation cohort, whereas nondipping status had a sensitivity of 80% and specificity of 44%. The area under the receiver operator characteristic of daytime SD SBP was greater than the area under the receiver operator characteristic of nocturnal SBP dipping (0.79 [0.66‐0.91] versus 0.73 [0.58‐0.87], respectively). Conclusions Daytime SD of SBP is a better screening tool than nondipping status in detecting autonomic dysfunction.

Background Stigma is associated with health conditions that drive disease burden in low- and middle-income countries (LMICs), including HIV, tuberculosis, mental health problems, epilepsy, and substance use disorders. However, the literature discussing the relationship between stigma and health outcomes is largely fragmented within disease-specific siloes, thus limiting the identification of common moderators or mechanisms through which stigma potentiates adverse health outcomes as well as the development of broadly relevant stigma mitigation interventions. Methods We conducted a scoping review to provide a critical overview of the breadth of research on stigma for each of the five aforementioned conditions in LMICs, including their methodological strengths and limitations. Results Across the range of diseases and disorders studied, stigma is associated with poor health outcomes, including help- and treatment-seeking behaviors. Common methodological limitations include a lack of prospective studies, non-representative samples resulting in limited generalizability, and a dearth of data on mediators and moderators of the relationship between stigma and health outcomes. Conclusions Implementing effective stigma mitigation interventions at scale necessitates transdisciplinary longitudinal studies that examine how stigma potentiates the risk for adverse outcomes for high-burden health conditions in community-based samples in LMICs. Electronic supplementary material The online version of this article (10.1186/s12916-019-1250-8) contains supplementary material, which is available to authorized users.

Central command (CC) and the exercise pressor reflex (EPR) regulate blood pressure during exercise. We previously demonstrated that experimental stimulation of the CC and EPR pathways independently contribute to the exaggerated pressor response to exercise in hypertension. It is known that CC and EPR modify one another functionally. Whether their interactive relationship is altered in hypertension, contributing to the generation of this potentiated blood pressure response, remains unknown. To address this issue, the pressor response to activation of the CC pathway with and without concurrent stimulation of the EPR pathway, and vice versa, was examined in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. In decerebrated, paralyzed animals, activation of the CC pathway was evoked by electrical stimulation of the mesencephalic locomotor region (MLR; 20–50 μA in 10-μA steps). Electrical stimulation of the sciatic nerve (SN, 3, 5, and 10 × motor threshold; MT) was used to activate hindlimb afferents known to carry EPR sensory information. In both WKY and SHR, the algebraic sum of the pressor responses to individual stimulation of the MLR and SN were greater than when both inputs were stimulated simultaneously. Although the blood pressure response to a constant level of SN stimulation was not significantly affected by concurrent MLR stimulation at variable intensities, the pressor response to a constant level of MLR simulation was significantly attenuated by concurrent SN stimulation in WKY but not in SHR. These findings suggest the interactive relationship between CC and the EPR is inhibitory in nature in both WKY and SHR. However, the neural occlusion between these central and peripheral pressor mechanisms is attenuated in hypertension.

Stigma in health facilities undermines diagnosis, treatment, and successful health outcomes. Addressing stigma is fundamental to delivering quality healthcare and achieving optimal health. This correspondence article seeks to assess how developments over the past 5 years have contributed to the state of programmatic knowledge - both approaches and methods - regarding interventions to reduce stigma in health facilities, and explores the potential to concurrently address multiple health condition stigmas. It is supported by findings from a systematic review of published articles indexed in PubMed, Psychinfo and Web of Science, and in the United States Agency for International Development's Development Experience Clearinghouse, which was conducted in February 2018 and restricted to the past 5 years. Forty-two studies met inclusion criteria and provided insight on interventions to reduce HIV, mental illness, or substance abuse stigma. Multiple common approaches to address stigma in health facilities emerged, which were implemented in a variety of ways. The literature search identified key gaps including a dearth of stigma reduction interventions in health facilities that focus on tuberculosis, diabetes, leprosy, or cancer; target multiple cadres of staff or multiple ecological levels; leverage interactive technology; or address stigma experienced by health workers. Preliminary results from ongoing innovative responses to these gaps are also described. The current evidence base of stigma reduction in health facilities provides a solid foundation to develop and implement interventions. However, gaps exist and merit further work. Future investment in health facility stigma reduction should prioritize the involvement of clients living with the stigmatized condition or behavior and health workers living with stigmatized conditions and should address both individual and structural level stigma.

Aim: The IMPACT (Improving the Management of Patients with Advanced Colorectal Tumours) initiative was established by the Association of Coloproctology of Great Britain and Ireland in 2017 as a consortium of surgeons (colorectal, hepatobiliary, thoracic), oncologists, radiologists, pathologists, palliative care physicians, patients, carers and charity stakeholders who will work together to improve outcomes in patients with advanced and metastatic colorectal cancer. To establish this initiative, better information is required to establish how further intervention is focused. This paper details the approaches used, and outcomes generated, from a priority setting exercise to inform the design of the IMPACT initiative. Methods: A mixed method approach was employed to set the priorities of patients, clinicians and other key stakeholders in the delivery of optimal care. This consisted of two patient centered consultation events and a questionnaire. Results: A total of 128 participants took part in the consultation exercise; 15 patients, 5 carers/family members, 5 charity representatives and 113 healthcare professionals. Nine key themes for focus were identified, these were: current service provision, specialist services, communication, education, access to care, definitions and standardisation, research and audit, outcome measures, and funding of specialist care. Conclusion: These future priorities will be developed with collaborative engagement in a systematic manner to produce an overall cohesive programme which will deliver a sustainable and efficient clinical and academic service to improving the management of patients with advanced colorectal tumours.

Impulsivity has been linked to academic performance in the context of Attention Deficit Hyperactivity Disorder, though its influence on a wider spectrum of students remains largely unexplored, particularly in the context of STEM learning (i.e. science, technology, engineering, and math). STEM learning was hypothesized to be more challenging for impulsive students, since it requires the practice and repetition of tasks as well as concerted attention to task performance. Impulsivity was assessed in a cross-sectional sample of 2,476 students in grades 6–12. Results show impulsivity affects a larger population of students, not limited to students with learning disabilities. Impulsivity was associated with lower sources of self-efficacy for science (SSSE), interest in most STEM domains (particularly math), and self-reported STEM skills. The large negative effect size observed for impulsivity was opposed by higher mindset, which describes a student’s belief in the importance of effort when learning is difficult. Mindset had a large positive effect size associated with greater SSSE, STEM interest, and STEM skills. When modeled together, results offer that mindset interventions may benefit impulsive students who struggle with STEM. Together, these data suggest important interconnected roles for impulsivity and mindset that can influence secondary students’ STEM trajectories.

Debates about the utility of p values and correct ways to analyze data have inspired new guidelines on statistical inference by the American Psychological Association (APA) and changes in the way results are reported in other scientific journals, but their impact on the Journal of the Experimental Analysis of Behavior (JEAB) has not previously been evaluated. A content analysis of empirical articles published in JEAB between 1992 and 2017 investigated whether statistical and graphing practices changed during that time period. The likelihood that a JEAB article reported a null hypothesis significance test, included a confidence interval, or depicted at least one figure with error bars has increased over time. Features of graphs in JEAB, including the proportion depicting single-subject data, have not changed systematically during the same period. Statistics and graphing trends in JEAB largely paralleled those in mainstream psychology journals, but there was no evidence that changes to APA style had any direct impact on JEAB. In the future, the onus will continue to be on authors, reviewers and editors to ensure that statistical and graphing practices in JEAB continue to evolve without interfering with characteristics that set the journal apart from other scientific journals.