Search

A elaboração deste documento pelo grupo de trabalho da European Respiratory Society tem como objectivo apresentar as recomendações sobre o uso clínico dos testes de exercício em doentes com patologia cardiorrespiratória, dando particular ênfase à avaliação funcional, à avaliação do prognóstico e à avaliação das intervenções terapêuticas. A intolerância ao esforço físico é um dos sintomas mais frequentes, condicionando a perda de qualidade de vida do doente com patologia cardiorrespiratória crónica. Pode definir-se "intolerância ao exercício" numa perspectiva clínica à incapacidade que o doente apresenta para realizar tarefas que os indivíduos saudáveis considerariam toleráveis. A intolerância ao exercício, considerada em termos do pico de consumo de oxigénio atingido no esforço máximo (V’O2pico) não pode ser prevista por parâmetros avaliados em repouso, como o volume expiratório máximo no primeiro segundo (FEV1), a transferência alvéolo-capilar do monóxido de carbono (DLCO), a fracção de ejecção do ventrículo esquerdo ou o índice de massa corporal (IMC). A avaliação em exercício impõe alguns desafios técnicos: a aplicação de protocolos específicos de incremento de carga de forma precisa e reprodutível, com o recurso habitual a ergómetros, tais como a bicicleta ergométrica e o tapete rolante. A prova de exercício cardiorrespiratória (CPET) é considerada o gold standard na avaliação das causas de intolerância ao exercício em doentes com doença cardíaca e pulmonar e é baseado no princípio de que a falência do sistema ocorre tipicamente quando o sistema (seja ele músculo-energético, cardiovascular ou pulmonar) se encontra sob stress. A CPET compreende a imposição de um exercício com cargas crescentes (ou seja, incremental) limitado por sintomas, enquanto se monitorizam as variáveis cardiopulmonares (exemplo: consumo de oxigénio (V’O2), produção de dióxido de carbono (V’CO2), ventilação minuto (V’E), frequência cardíaca (fC)), a percepção de sintomas (exemplo: a dispneia e o desconforto nos membros inferiores) e, quando necessárias, as avaliações da dessaturação arterial do oxigénio relacionada com o esforço, da hiperinsuflação dinâmica e da força muscular dos membros. Os sistemas são forçados até ao seu limite tolerável, de forma controlada, o que permite detectar respostas que identificam padrões de alteração e que podem ser relacionadas com padrões de referência previamente estudados e publicados pelas sociedades respiratórias europeia e americanas1-3. Neste documento, é descrito o papel da CPET como auxiliar no diagnóstico e na avaliação funcional e prognóstica. A CPET pode: - Fornecer uma medição objectiva da capacidade para o exercício; - Identificar os mecanismos que limitam a tolerância ao exercício; - Estabelecer índices de prognóstico; - Monitorizar a progressão da doença e a resposta às intervenções terapêuticas. - Auxiliar no diagnóstico, em situações de broncoconstrição induzida pelo exercício e de dessaturação arterial do oxigénio. Na identificação das causas de intolerância ao exercício, a CPET pode detectar: - Alterações na entrega de oxigénio (desde a sua entrada nas vias aéreas, passando pelo sistema de transporte cardiocirculatório, até à entrega às mitocôndrias das fibras musculares); - Limitação ventilatória no exercício; - Alteração do controlo ventilatório; - Alteração das trocas gasosas pulmonares; - Percepção excessiva de sintomas (exemplos: dispneia, precordialgia, fadiga muscular periférica); - Disfunção metabólica muscular; - Descondicionamento; - Fraco esforço dispendido. Com um bom esforço realizado, se o valor do pico do consumo de oxigénio atingido foi normal e o motivo para parar a prova foi dispneia ou fadiga muscular, então pode considerar-se que o indivíduo estudado tem uma normal tolerância ao exercício. Este cenário irá excluir doença pulmonar (DPOC, doença intersticial pulmonar, doença vascular pulmonar) ou cardíaca (insuficiência cardíaca congestiva) significativas como causa de intolerância. A prova de exercício cardiopulmonar pode auxiliar no diagnóstico diferencial entre limitação no esforço de origem pulmonar ou cardiocirculatória. Pode fornecer um perfil de respostas que caracterizam determinadas doenças; exemplo: na DPOC são frequentes a limitação ventilatória, a hiperinsuflação dinâmica, a dessaturação arterial com o exercício, a dispneia, a disfunção dos músculos periféricos; na doença intersticial pulmonar são frequentes a dispneia, a restrição ventilatória mecânica e as alterações graves das trocas gasosas. Outros padrões de respostas podem ser encontrados na broncoconstrição induzida pelo exercício, na doença vascular pulmonar, na insuficiência cardíaca e em cardiopatias congénitas. A avaliação cardiorrespiratória no exercício fornece ainda indicadores prognósticos em várias doenças. Descrevem-se neste documento vários trabalhos que estudaram os parâmetros indicadores de prognóstico em doenças como a DPOC, a doença intersticial pulmonar, a hipertensão pulmonar primária, a fibrose quística e a insuficiência cardíaca. Este documento demonstra ainda a utilidade dos testes de exercício na definição das respostas às intervenções terapêuticas, em avaliações seriadas. O grupo de trabalho envolvido neste documento considerou importante apresentar as indicações baseadas na evidência para a realização dos testes de exercício na prática clínica. A evidência actual é clara quanto à utilidade da prova de exercício cardiopulmonar, das provas de marcha e das provas de carga constante na avaliação do grau de intolerância ao exercício, do prognóstico e dos efeitos das intervenções terapêuticas em doentes adultos com doença pulmonar crónica (DPOC, doença intersticial pulmonar, hipertensão pulmonar primária), em crianças e adultos com fibrose quística, em crianças e adultos com broncospasmo induzido pelo exercício, em adultos com insuficiência cardíaca congestiva e em crianças e adolescentes com cardiopatias congénitas. Na elaboração deste documento, os autores pretenderam fornecer as respostas às perguntas que se colocam com frequência na prática clínica: - Quando se deve pedir uma avaliação da intolerância ao esforço? - Qual o teste mais adequado? - Quais as variáveis a seleccionar na avaliação do prognóstico de determinada doença ou na avaliação do efeito de uma intervenção terapêutica particular? O documento contém ainda um suplemento que pode ser obtido on-line e que descreve as bases fisiológicas subjacentes aos parâmetros avaliados nas provas de exercício cardiopulmonar.

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

This article reports on a survey done among nurses registered with the South African Nursing Council. The survey was carried out in the last quarter of 2003. The purpose of the survey was to investigate aspects of the working life of women in the nursing profession in South Africa and to make recommendations on how their working environment could be improved. The important findings were that pay-related issues dominate as the main problem at work. Improving pay scales and being paid according to extra experience, responsibilities and qualifications could improve the nurses’ working environment. Furthermore, training opportunities, medical insurance and equal opportunities should be addressed as a matter of urgency. In general, respondents had a positive attitude towards their job, which leaves the impression that nurses still regard their jobs as something they do for the sake of a service to the community and not only for the money they earn.

Although the vision and mission are important to the strategic planning of a business and much time and effort are spent on their formulation, they aren’t used as planning instruments. The purpose of this paper was to determine whether management understands the vision and mission as complementary concepts and whether they use them effectively in the planning process. This study was conducted by sending questionnaires to businesses in the Gauteng Province where most SMEs in South Africa are situated. Findings confirmed that the majority of businesses, especially small businesses, can distinguish between and have visions and missions, but do not apply them optimally in strategy implementation. Recommendations include that businesses should have a written vision and mission statement, which should be communicated effectively and applied in planning and strategy implementation.

Neonicotinoids (NNs) are commonly found throughout the environment on surfaces such as seeds, soil, vegetation, and blowing dust particles. However, there is a paucity of data on the kinetics and oxidation products formed on contact with the atmosphere which limits understanding of their potentially far-reaching impacts. In this study, in situ attenuated total reflectance (ATR) FTIR spectroscopy was used to investigate the OH oxidation of thin films of three solid NNs, imidacloprid (IMD), dinotefuran (DNF) and clothianidin (CLD) at 295 ± 3 K. The experimentally measured reaction probabilities based on initial rates of NN loss are (1.6 ± 0.8) × 10-2 for IMD, (1.5 ± 0.6) × 10-2 for DNF and (0.9 ± 0.2) × 10-2 for CLD (±1s), suggesting initial NN lifetimes with respect to OH of 10-17 days. The kinetics were interpreted using a multiphase kinetics model, KM-SUB, which showed that the OH uptake and reaction occurred primarily in the surface layer. Products identified by mass spectrometry included carbonyl-, alcohol- and olefin-containing species formed via hydrogen abstraction from aliphatic C-H groups. Additionally, carbonyl-containing desnitro and urea derivative products were observed from secondary reactions of the initially formed photodegradation products. Reaction with OH will contribute to NN loss both during the day as well as at night when there are non-photolytic sources of this radical. Thus, OH reactions with both the parent neonicotinoid and its photodegradation products should be considered in assessing their environmental impacts.

For polymer solar cells (PSCs), the mixture of polymer donors and small-molecule acceptors (SMAs) is fine-tuned to realize a favorable kinetically trapped morphology and thus a commercially viable device efficiency. However, the thermodynamic relaxation of the mixed domains within the blend raises concerns related to the long-term operational stability of the devices, especially in the record-holding Y-series SMAs. Here, a new class of dimeric Y6-based SMAs tethered with differential flexible spacers is reported to regulate their aggregation and relaxation behavior. In their polymer blends with PM6, it is found that they favor an improved structural order relative to that of Y6 counterpart. Most importantly, the tethered SMAs show large glass transition temperatures to suppress the thermodynamic relaxation in mixed domains. For the high-performing dimeric blend, an unprecedented open circuit voltage of 0.87 V is realized with a conversion efficiency of 17.85%, while those of regular Y6-base devices only reach 0.84 V and 16.93%, respectively. Most importantly, the dimer-based device possesses substantially reduced burn-in efficiency loss, retaining more than 80% of the initial efficiency after operating at the maximum power point under continuous illumination for 700 h. The tethering approach provides a new direction to develop PSCs with high efficiency and excellent operating stability.

The ability to formulate maps of minimum detectable activities (MDAs) that describe the sensitivity of an ad hoc measurement that used one or more freely moving radiation detector systems would be significantly beneficial for the conduct and understanding of many radiological search activities. In a real-time scenario with a free-moving detector system, an MDA map can provide useful feedback to the operator about which areas have not been searched as thoroughly as others, thereby allowing the operator to prioritize future actions. Similarly, such a calculation could be used to inform subsequent navigation decisions of autonomous platforms. Here we describe a near real-time MDA mapping approach that can be applied when searching for point sources using detected events in a spectral region of interest (ROI) while assuming a constant, unknown background rate. We show the application of this MDA mapping method to a real scenario, a survey of the interior of a small building using a handheld detector system. Repeated measurements with no sources and with 137Cs sources of different strengths yield results consistent with the estimated thresholds and MDA values; namely, that for background-only measurements no sources are seen above threshold anywhere in the scene, while when sources are present they are detected above the thresholds calculated for their locations.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Systems of correlated particles appear in many fields of modern science and represent some of the most intractable computational problems in nature. The computational challenge in these systems arises when interactions become comparable to other energy scales, which makes the state of each particle depend on all other particles1. The lack of general solutions for the three-body problem and acceptable theory for strongly correlated electrons shows that our understanding of correlated systems fades when the particle number or the interaction strength increases. One of the hallmarks of interacting systems is the formation of multiparticle bound states2-9. Here we develop a high-fidelity parameterizable fSim gate and implement the periodic quantum circuit of the spin-½ XXZ model in a ring of 24 superconducting qubits. We study the propagation of these excitations and observe their bound nature for up to five photons. We devise a phase-sensitive method for constructing the few-body spectrum of the bound states and extract their pseudo-charge by introducing a synthetic flux. By introducing interactions between the ring and additional qubits, we observe an unexpected resilience of the bound states to integrability breaking. This finding goes against the idea that bound states in non-integrable systems are unstable when their energies overlap with the continuum spectrum. Our work provides experimental evidence for bound states of interacting photons and discovers their stability beyond the integrability limit.

Abstract: We present the Spectroscopic Classification of Astronomical Transients (SCAT) survey, which is dedicated to spectrophotometric observations of transient objects such as supernovae and tidal disruption events. SCAT uses the SuperNova Integral-Field Spectrograph (SNIFS) on the University of Hawai’i 2.2 m (UH2.2m) telescope. SNIFS was designed specifically for accurate transient spectrophotometry, including absolute flux calibration and host-galaxy removal. We describe the data reduction and calibration pipeline including spectral extraction, telluric correction, atmospheric characterization, nightly photometricity, and spectrophotometric precision. We achieve ≲5% spectrophotometry across the full optical wavelength range (3500–9000 Å) under photometric conditions. The inclusion of photometry from the SNIFS multi-filter mosaic imager allows for decent spectrophotometric calibration (10%–20%) even under unfavorable weather/atmospheric conditions. SCAT obtained ≈640 spectra of transients over the first 3 yr of operations, including supernovae of all types, active galactic nuclei, cataclysmic variables, and rare transients such as superluminous supernovae and tidal disruption events. These observations will provide the community with benchmark spectrophotometry to constrain the next generation of hydrodynamic and radiative transfer models.

The Loaded Disc Culture System (LDCS) is an Intervertebral Disc (IVD)-oriented bioreactor developed by the VU Medical Center (VUmc, Amsterdam, The Netherlands), which has the capacity of maintaining up to 12 IVDs in culture, for approximately 3 weeks after extraction. Using this system, 8 goat IVDs were provided with the essential nutrients and submitted to compression tests without losing their biomechanical and physiological properties, for 22 days. Based on previous reports (Detiger et al., 2013; Paul et al., 2013, 2012), 4 of these IVDs were kept in physiological condition (control) and the other 4 were previously injected with chondroitinase ABC (CABC), in order to promote Degenerative Disc Disease (DDD). The loading profile intercalated 16h of activity loading with 8h of loading recovery to express the standard circadian variations.The displacement behavior of these 8 IVDs along the first 2 days of the experiment was numerically reproduced, using an IVD osmo-poro-hyper-viscoelastic and fiber-reinforced Finite Element (FE) model. The simulations were run on a custom FE solver (Castro et al., 2014).The analysis of the experimental results allowed concluding that the effect of the CABC injection was only significant in 2 of the 4 IVDs. The 4 control IVDs showed no signs of degeneration, as expected. In what concerns to the numerical simulations, the IVD FE model was able to reproduce the generic behavior of the two groups of goat IVDs (control and injected). However, some discrepancies were still noticed on the comparison between the injected IVDs and the numerical simulations, namely on the recovery periods. This may be justified by the complexity of the pathways for DDD, associated with the multiplicity of physiological responses to each direct or indirect stimulus. Nevertheless, one could conclude that ligaments, muscles and IVD covering membranes could be added to the FE model, in order to improve its accuracy and properly describe the recovery periods.

Gene therapy strategies for congenital myopathies may require repeat administration of adeno-associated viral (AAV) vectors due to aspects of the clinical application, such as: (i) administration of doses below therapeutic efficacy in patients enrolled in early phase clinical trials; (ii) progressive reduction of the therapeutic gene expression over time as a result of increasing muscle mass in patients treated at a young age; and (iii) a possibly faster depletion of pathogenic myofibers in this patient population. Immune response triggered by the first vector administration, and to subsequent doses, represents a major obstacle for successful gene transfer in young patients. Anti-capsid and anti-transgene product related humoral and cell-mediated responses have been previously observed in all preclinical models and human subjects who received gene therapy or enzyme replacement therapy (ERT) for congenital myopathies. Immune responses may result in reduced efficacy of the gene transfer over time and/or may preclude for the possibility of re-administration of the same vector. In this study, we evaluated the immune response of a Pompe patient dosed with an AAV1-GAA vector after receiving Rituximab and Sirolimus to modulate reactions against ERT. A key finding of this single subject case report is the observation that B-cell ablation with rituximab prior to AAV vector exposure results in non-responsiveness to both capsid and transgene, therefore allowing the possibility of repeat administration in the future. This observation is significant for future gene therapy studies and establishes a clinically relevant approach to blocking immune responses to AAV vectors.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

The exchange coupling between a hard magnetic layer MnBi and a soft magnetic layer Co-Fe has been found to significantly improve the maximum energy product. In this work, the spin structure of exchange-coupled MnBi:Co-Fe bilayers is experimentally investigated by X-ray magnetic circular dichroism (XMCD) and polarized neutron reflectometry (PNR). We find that the out-of-plane magnetization reversal process of the MnBi:Co-Fe bilayer structure involves formation of a curling-type twisting of the magnetization in the film plane at low or intermediate reversal fields. Micromagnetic simulations are further performed to provide a detailed view of the spins at the curling center. Reminiscent of chiral spin structures known as spin bobbers, this curling in the exchange-coupled hard-soft magnetic bilayers is a new type of skyrmionic spin structure and worth further investigation.

The effects of concentrating particles using the Versatile Aerosol Concentration Enrichment System (VACES) were investigated with a focus on the organic particle composition. The VACES uses water condensation to grow particles and allow enrichment in particle concentrations by virtual impaction, followed by diffusion drying to remove excess liquid water. Aerosol mass spectrometry was used to compare the submicron organic composition before and after the VACES for laboratory-generated secondary organic aerosol (SOA) from ozonolysis of α-pinene as well as ambient particles. Size distributions were retained after the VACES for both types of samples. SOA particles showed evidence of high molecular weight compounds forming after enrichment, suggesting that some oligomerization occurs during the water condensation and/or evaporation stages, but with only slight changes in the elemental composition. Oligomerization was also observed for ambient particles, especially those with higher O/C in the accumulation mode. Ambient ultrafine particles with low O/C were not as efficiently enriched. Such composition changes in the organic fraction may be relevant to other methodologies where particles are grown through water uptake and then dried, as well as to atmospheric processes involving water uptake and evaporation. In the context of particle mass, the extent of oligomerization is small. However, given the widespread use of particle concentrators in health effects and particle composition studies, whether this impacts interpretation of health effects and particle composition data when using particle concentrators needs further exploration. Copyright © 2022 American Association for Aerosol Research.

We model the strong lensing effect in the galaxy cluster PSZ1 G311.65-18.48 (z=0.443) with an improved version of the hybrid method WSLAP+. We extend the number of constraints by including the position of critical points, which are combined with the classic positional constraints of the lensed galaxies. We pay special attention to a transient candidate source (Tr) previously discovered in the giant Sunburst arc (z=2.37). Our lens model predicts Tr to be within a fraction of an arcsecond from the critical curve, which has a larger magnification factor than previously found, but still not large enough to explain the observed flux and lack of counterimages. Possible candidate counterimages are discussed that would lower the magnification required to explain Tr, but extreme magnification factors (> 600) are still required, even in that case. The presence of a small mass perturber with a mass comparable to a dwarf galaxy (M108M) near the position of Tr is needed in order to explain the required magnification and morphology of the lensed galaxy. We discuss how the existence of this perturber could potentially be used to constrain models of dark matter. The large apparent brightness and unresolved nature of the magnified object implies a combination of extreme magnification and a very luminous and compact source (ralt;0.4 pc). Possible candidates are discussed, including an hyperluminous star, a small group of stars, or an accretion disk around a relatively small supermassive black hole (SMBH). Based on spectral information and flux requirements, we argue that a luminous blue variable (LBV) star caught during an outburst is the most likely candidate. Owing to the extreme magnification and luminosity of this source, we dub it Godzilla.

Three experiments were performed to assess the effect backgrounds have on object discrimination. Experiment 1 investigated the discrimination of foveally presented Gaborised objects and non-objects with and without a surrounding background. Thresholds were obtained by modulating the Gabor patches in 7 different directions, either isolating the L-M, S-(L+M) and L+M geniculate mechanisms, or stimulating these mechanisms in combination. The spacing between background Gabor elements and the object contour was chosen so as to not cause crowding, on the basis of previously published work with luminance stimuli. No differences were found between the Michelson contrasts required for threshold with or without a background, except when signals in the S-(L+M) and L+M were combined. The signals were combined at an elevation of 30° in DKL colour space, which resulted in a mixture with a proportionally strong chromatic signal. Experiment 2 investigated this finding further using three background conditions: no background, a sparse background and a densely populated background. Object vs. non-object discrimination thresholds were obtained for the L+M and S-(L+M) isolating directions, along with two conditions that combined them at DKL luminance elevations of 30° and 60°. In the 60° combination, the proportion of the chromatic signal was lower than in the 30° combination. Thresholds were found to be largely stable across chromatic and luminance conditions and background class, again with the exception of the combination at 30° elevation. The final experiment examined Gabor orientation discrimination over the same conditions as experiment 2 using a classical crowding paradigm, with a peripheral target and a set of three target-flanker separations. Crowding was most pronounced in the 30° combination. We conclude that when S-(L+M) signals above a certain level are combined with luminance signals, an increase in crowding results. This is likely to underlie the adverse effect of such signals on the discrimination of objects with backgrounds. [Research supported by BBSRC New Investigator grant to JM].

BACKGROUND AND DESIGN: Methotrexate (MTX) hepatotoxicity in psoriatic patients is well recognized, but there are discrepancies in the reported incidence and associated risk factors. This retrospective study describes 104 Nova Scotian patients with psoriasis seen between 1979 and 1990. Patients received MTX over one to 11 years (mean 3.38), with baseline and annual follow-up liver biopsies. Clinical data were obtained by chart review. Statistical analysis evaluated the risks associated with obesity, diabetes, alcohol consumption and duration of therapy, with the histological grade of liver biopsies.

The discovery of the G protein-coupled estrogen receptor GPER (also GPR30) and the resulting development of selective chemical probes have revealed new aspects of estrogen receptor biology. The potential clinical relevance of this receptor has been suggested from numerous studies that have identified GPER expression in breast, endometrial, ovarian and other cancers. Thus GPER can be considered a candidate biomarker and target for non-invasive imaging and therapy. We have designed and synthesized a series of organometallic tricarbonyl-rhenium complexes conjugated to a GPER-selective small molecule derived from tetrahydro-3H-cyclopenta[c]quinoline. The activity and selectivity of these chelates in GPER-mediated signaling pathways were evaluated. These results demonstrate that GPER targeting characteristics depend strongly on the structure of the chelate and linkage. Ethanone conjugates functioned as agonists, a 1,2,3-triazole spacer yielded an antagonist, and derivatives with increased steric volume exhibited decreased activities. Promising GPER selectivity was observed, as none of the complexes interacted with the nuclear estrogen receptors. Radiolabeling with technetium-99m in aqueous media was efficient and gave radioligands with high radiochemical yields and purity. These chelates have favorable physicochemical properties, show excellent stability in biologically relevant media, exhibit receptor specificity and are promising candidates for continuing development as diagnostic imaging agents targeting GPER expression in cancer.

Many mass spectrometry methods using various ionization sources provide bulk composition of airborne particles, but little is known about the surface species that play a major role in determining their physicochemical properties that impact air quality, climate, and health. The present work shows that the composition of surface layers of atmospherically relevant submicron organic particles can be probed without the use of an external ionization source. Solid dicarboxylic acid particles are used as models, with glutaric acid being the most efficient at generating ions. Coating with small diacids or products from α-pinene ozonolysis demonstrates that ions are ejected from the surface, providing surface molecular characterization of organic particles on the fly. This unique approach provides a path forward for elucidating the role of the surface in determining chemical and physical properties of particles, including heterogeneous reactions, particle growth, water uptake, and interactions with biological systems.

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

The age- and time-dependent effects of binge drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume (GMV) development was examined using 5 waves of longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study. Binge drinkers (n = 166) were compared with non-binge drinkers (n = 82 after matching on potential confounders). Number of binge drinking episodes in the past year was linked to decreased GMVs in bilateral Desikan-Killiany cortical parcellations (26 of 34 with P

This paper reports results from a search for single and multinucleon disappearance from the O16 nucleus in water within the SNO+ detector using all of the available data. These so-called "invisible"decays do not directly deposit energy within the detector but are instead detected through their subsequent nuclear deexcitation and gamma-ray emission. New limits are given for the partial lifetimes: τ(n→inv)>9.0×1029 years, τ(p→inv)>9.6×1029 years, τ(nn→inv)>1.5×1028 years, τ(np→inv)>6.0×1028 years, and τ(pp→inv)>1.1×1029 years at 90% Bayesian credibility level (with a prior uniform in rate). All but the (nn→inv) results improve on existing limits by a factor of about 3.

Sr2IrO4 has often been described via a simple, one-band pseudospin-12 model subject to electron-electron interactions on a square lattice, fostering analogies with cuprate superconductors believed to be well described by a similar model. In this work we argue - based on a detailed study of the low-energy electronic structure by circularly polarized spin and angle-resolved photoemission spectroscopy combined with dynamical mean-field theory calculations - that a pseudospin-12 model fails to capture the full complexity of the system. We show instead that a realistic multiband Hubbard Hamiltonian, accounting for the full correlated t2g manifold, provides a detailed description of the interplay between spin-orbital entanglement and electron-electron interactions and yields quantitative agreement with experiments. Our analysis establishes that the j3/2 states make up a substantial percentage of the low-energy spectral weight, i.e., approximately 74% as determined from the integration of the j-resolved spectral function in the 0 to -1.64eV energy range. The results in our work are of relevance not only to Ir-based materials but also more generally to multiorbital materials with closely spaced energy scales.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

The ability to measure the total concentration of low density lipoprotein (LDL) receptors in hepatic tissues is of crucial importance to understanding changes in hepatic cholesterol metabolism. Such measurements can be made in conjunction with estimates of LDL receptor transcriptional activity, cell surface LDL receptor number, and rates of hepatic LDL uptake to evaluate the mechanisms controlling cellular LDL receptor expression. Current methods for assessing hepatic LDL receptor levels use microsomes as a source of LDL receptor, and thus rely on consistent contamination of the microsomal preparation with LDL receptor-containing plasma membranes, endocytic vesicles, and/or secretory vesicles. Because this contamination is variable, and may vary with alterations in either the distribution of LDL receptors among the various cellular membrane fractions or in the composition of the intracellular membranes, measurement of LDL receptor concentration in microsomal fractions may not accurately reflect the total compliment of LDL receptors within the cell. We have developed the methodology for isolating the full complement of hepatic LDL receptor containing membranes by discontinuous sucrose density gradient centrifugation, and for quantitating LDL receptor concentration using a Western immunoblotting procedure that uses an anti-C-terminal LDL receptor peptide polyclonal antiserum and assesses the intensity of color formation by reflectance densitometry. Using this methodology, we observed a 126 kDa immunoreactive band for the bovine adrenal cortex LDL receptor that also exhibited LDL binding activity as visualized by biotinylated LDL-ligand blotting, and a doublet of 140 kDa for the hamster liver LDL receptor. These bands were not observed when ligand blotting was conducted in the presence of either 10 mM EDTA or a 5-fold excess of unlabeled LDL, or when immunoblotting was conducted using either preimmune serum or antiserum that had been preabsorbed with LDL receptor peptide. The intensity of color formation was a linear function of the amount of membrane extract separated by electrophoresis. Intra-assay variation averaged 7%, and inter-animal variation averaged 20%. Cholestyramine, tiqueside, CP-88488, 17 alpha-ethinyl estradiol, mevinolin, and the combination of cholestyramine plus mevinolin, pharmacological interventions known to increase LDL receptor activity in experimental animals, produced the predicted increases in hamster total hepatic LDL receptor concentration that were highly correlated with concomitant increases in HMG-CoA reductase activity and reductions in serum cholesterol.(ABSTRACT TRUNCATED AT 400 WORDS)

The present article reports a case involving an immunocompetent, previously well child who, despite two previous doses of inactivated poliovirus vaccine, developed severe flaccid paralysis consistent with polio after receiving oral polio vaccine.

BackgroundThe Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12.MethodsThis study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort's early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD).Primary resultsAt baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine,

A large number of copies of the sequence (dTG-dAC)n, where n is between 10 and 60, exist in the human genome, and many are useful as polymorphic markers. One of these sequences occurs about 3 kilobases 5‘ of the human apolipoprotein (apo) B gene as seven distinguishable alleles containing from (TG)12 to (TG)18. This repeat is also present in the DNA of other primates. A second alternating purine-pyrimidine sequence with nine dinucleotide repeats and located in intron 4 is not polymorphic. Together with the apoB hypervariable repeat immediately 3‘ of the gene, the (TG)n sequence will provide a useful haplotype marker capable of distinguishing a large number of human apoB alleles, some of which may be associated with disease states.

A 443-base pair fragment (+622 to +1064) from the second intron of the human apolipoprotein B gene was shown to contain a tissue-specific enhancer when placed in front of an apolipoprotein B promoter-chloramphenicol acetyltransferase construct in transfection experiments. To identify potential regulatory mutations in this region of the gene, DNA from various subjects was examined for the presence of point mutations by means of chemical cleavage of mismatched heteroduplexes. An A—-G substitution within the second intron of the gene at position +722 was identified in three unrelated subjects and confirmed by DNA sequencing. Although the base substitution was contained within a nuclear protein-binding site, as determined by DNase I footprinting, it did not appear to affect the protein/DNA interaction in its vicinity, as shown by gel retardation experiments. The single base substitution at position +722 abolishes a StyI restriction site, thus creating a StyI polymorphism. Using allele-specific oligonucleotides, we screened the DNA of 172 subjects for the presence of this polymorphism: two other subjects carrying the polymorphism were found. In each of the five unrelated subjects, the polymorphism was associated with the same haplotype.

Adipose tissue cellularity and metabolism are traditionally expressed in terms of mean cell size and number. The need for a simple method allowing rapid determination of cell size and number of freshly isolated, unfixed adipocyte preparations led us to compare estimates of cell size determined by the established method of optical sizing to a proposed method of electronic cell sizing and counting. In collagenase-isolated, unfixed adipocytes whose mean diameters ranged from approximately 40 to 65 microns (obtained from healthy rats weighing 100-360 g) the electronic method provided estimates of the mean cell diameter and size distribution that did not differ from the optical sizing technique. Estimates of mean cell diameter and cell number by the electronic method were rapid and reproducible (coefficients of variation 0.5 and 3.8%, respectively) and a less than 20 sec delay until sample analysis, after mixing of the adipocyte suspension, did not alter these estimates. Electronic determination of cell size and number, using freshly isolated, unfixed rat adipocyte populations (mean cell diameter less than or equal to 60 microns), is rapid and reliable. It will be particularly useful for studies of hormone binding and transport processes where it may be necessary to tightly control cell density.

Familial defective apolipoprotein B-100 is a genetic disorder of apolipoprotein B-100 that causes moderate to severe hypercholesterolemia. A single amino acid mutation in apolipoprotein B diminishes the ability of low density lipoproteins to bind to the low density lipoprotein receptor. Low density lipoproteins accumulate in the plasma because their efficient receptor-mediated catabolism is disrupted. This mutation has been identified in the United States, Canada, and Europe and is estimated to occur at a frequency of approximately 1/500 in these populations. Thus, it appears that this newly described disorder may be a significant genetic cause of hypercholesterolemia in Western societies.

Subcellular fractionation of human monocyte-macrophages (HMM) yielded a fraction rich in endosomes, lysosomes, and mitochondria. This pellet was further fractionated in a metrizamide gradient and the subcellular organelles were distributed among seven distinct bands. All of the bands contained lysosomal enzymes in similar amounts. However one band, poor in mitochondria, was markedly enriched in cathepsin D and cholesteryl ester hydrolase activities. A number of different ligands (low density lipoproteins (LDL), malondialdehyde-altered LDL, beta-migrating very low density lipoprotein, high density lipoprotein, reductively methylated LDL, mannose-bovine serum albumin, and transferrin) were presented to HMM at a concentration of 20 micrograms/ml at 4 degrees C. Three minutes after warming the cells at 37 degrees C all ligands except two were found predominantly in the cathepsin D- and cholesteryl ester hydrolase-rich fraction. Unlike the other ligands, LDL had distributed to other more dense fractions and reductively methylated LDL was found mainly in less dense fractions. At a lower concentration, 2 micrograms/ml, the distribution of LDL was identical to the other ligands. In vitro incubation of the fractions obtained from the gradient suggested that cathepsin D was largely responsible for the hydrolysis of the lipoproteins. We conclude that studies of LDL metabolism in HMM must take into account the different processing of this ligand at commonly used concentrations.

Several recent reports have examined whether there is a correlation between the presence of some minor alleles of the highly polymorphic apolipoprotein B gene and atherosclerosis and premature heart disease. The present study extends this investigation. A high-resolution method was used to study the allele frequencies of a hypervariable minisatellite region close to the apolipoprotein B gene in 110 patients with severe coronary disease and in 117 normal controls. Alleles containing 38, 44, 46, or 48 hypervariable elements showed an association with coronary heart disease. These alleles were also associated with elevated serum levels of total cholesterol and apolipoprotein B among patients and with elevated serum levels of total triglycerides among controls. The hypervariable region showed strong linkage disequilibrium with a polymorphic EcoRI site in exon 29 and was in linkage equilibrium with a polymorphic MspI site in exon 26. Two patients carried a base change at codon 3500 that results in an arginine-to-glutamine substitution; the base change was linked in both instances to the allele with 48 hypervariable elements.

A rapid and inexpensive micro-assay for determining cholesterol in plasma and isolated lipoprotein fractions has been established which utilizes a commercially available enzymatic reagent with semi-automated instruments and microtiter plates. The assay is sensitive, precise, and easy to perform. The color development is linear from 0.4 to 20 micrograms cholesterol/well, with sample volumes of 2 to 100 microliters. Inter- and intra-assay variability yielded coefficients of variation (CV) of 2.75% (n = 51) and 1.09% (n = 32), respectively. The concentrations of total plasma and lipoprotein cholesterol (d greater than 1.006 g/ml) obtained with this method were compared with those analyzed in a lipid laboratory standardized to the Centers for Disease Control. The correlation coefficients between the two methods were 0.976 and 0.964, respectively. For total high density lipoprotein (HDL) and the HDL3 subfraction, inter-assay variability was 4.12% and 6.33% (n = 27), respectively; the intra-assay variability was 2.79% and 4.19% (n = 12).

The role of upper gastrointestinal and hepatobiliary endoscopy and colonoscopy in the diagnosis and management of patients with inflammatory bowel disease (IBD) is reviewed. The differentiation of IBD from other forms of colitis, mass lesions in the colon, strictures and polyps, and the management of the patient with dysplasia including clinical strategies for early detection are discussed. The role and value of endoscopic surveillance programs have yet to be defined.

A procurement decision model for a video rental store is presented in this paper. The model is based on inventory management, but many classical inventory management principles are inappropriate since the commodities (movie titles) are removed from, and after a certain time period, returned to inventory. The commodities also have a decaying demand in general; hence the video rental store owner (the decision maker) is required to procure new titles periodically. The question addressed in this paper is how to determine which movie titles to acquire, and how many copies of each in order to best maximise profit. An approximated demand function is presented, and attributes of movie titles in inventory are used to classify candidate movie titles and predict their future demand. This allows the decision maker to select the most profitable candidate items from a list, whilst remaining within a predetermined budget. The procurement decision model is evaluated by means of predicting the expected turnover using the procurement decision model solution, and then comparing it to the turnover achieved using the procurement strategy followed by the store owner. The model is not prescriptive - the decision maker may still utilise his/her experience to acquire new movie titles. The procurement decision model, however, does assist the decision making process by presenting a point of departure from which procurement decisions may be made.