Calculation of single detector efficiencies and extension of the normalization sinogram in PET.
A fast iterative method is presented for calculating single detector efficiencies for positron emission tomographs. These efficiencies can be used to extend the normalization scan to areas outside that covered by the normalization source. The root mean square (rms) error of the calculated single detector efficiencies decreases exponentially with the number of iterations. Thirty iterations per normalization image are sufficient and take about 1 s on a SUN Classic. The geometry factors are composed of factors which only depend on the distance from the centre of the field-of-view (FOV) and of factors which show a more complex pattern over the normalization sinogram. The geometry factors are specific to each scanner. On the ECAT 931 scanner the complex part of the geometry factors showed a diamond shaped pattern (caused by the varying sensitivity of single detectors in a detector block with varying angle of incidence) and S-shaped curves (representing attenuation caused by supporting rods for the ring source). The coefficient of variation of the diamond-shaped pattern was 4% for detectors farthest from the centre of the FOV. Extensions of the normalization scan may, therefore, contain a relative rms error of about 4% if the applied geometry factors only take the distance from the centre of the FOV into account.


A Dynamic Picture of the Early Events in Nociceptin Binding to the NOP Receptor by Metadynamics.
Nociceptin (NCC, also known as FQ (N/OFQ)) is the 17-amino acid neuropeptide, endogenous ligand for the G-protein-coupled receptor (NOP, also known as ORL-1). In this study, starting from the recently reported x-ray structure at pH 7 of NOP in complex with an antagonist, new insights, to our knowledge, on the binding geometry of NCC to NOP have been provided in silico. After a rigid docking of NCC in an α-helix conformation, molecular dynamics (MD) and metadynamics (METAD), a method for the analysis of free-energy surfaces (FES), were performed on the protein-peptide complex. Free-energy profiles were obtained as a function of the α-helix content of different segments of the 17-mer ligand, and a structural ensemble of conformations of NCC, corresponding to the minimum of the FES, was extracted, thus representing the NCC bound to the inactive form of NOP. The structural features were compared with many known experimental data. The pose of the "message" domain (residues 1-4) of NCC differs from that of the known NOP antagonists, as being slightly slipped deeper inside the protein core. A residual α-helix content in the central part of the peptide (residues 4-9) is maintained, whereas the C-terminal segment (residues 13-17) is unstructured and highly flexible. An important stabilization due to interactions with residues D130 and D110 of the receptor has been found, in agreement with the large decrease in agonist potency reported for the D130A and D110A mutants. The importance of the extracellular domain 2 (ECL2) in the selectivity toward the endogenous ligand has been confirmed. A pivotal role for the conserved residue N133 is suggested and further supported by a study of the N133A in silico mutant. Accordingly, N133 can work as a molecular microswitch driving the change between the inactive and active NOP conformations, in the framework of an extended H-bond and water network rearrangement in the deep binding site.


Antibodies to sperm-whale myoglobin evoked by free synthetic peptides of an antigenic site.
Previous studies from this laboratory have resulted in the determination of the entire antigenic structure of myoglobin (Mb). The present work was carried out to investigate the antigenicity of the synthetic antigenic sites of Mb in their free form (i.e. without coupling to a carrier) and the effect of peptide size on antigenicity. Site 5 (peptide 145-151) and the longer peptides 145-153, 143-153 and 132-153, each of which carries within it the region of site 5, were synthesized. Immunization of three different mouse strains with each of these peptides, in their free form, resulted in the formation of antibodies that bound specifically to intact Mb. The advantages and significance of these findings are discussed.


Kinesin-dependent transport of keratin filaments: a unified mechanism for intermediate filament transport.
Keratin intermediate filaments (IFs) are the major cytoskeletal component in epithelial cells. The dynamics of keratin IFs have been described to depend mostly on the actin cytoskeleton, but the rapid transport of fully polymerized keratin filaments has not been reported. In this work, we used a combination of photoconversion experiments and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 genome editing to study the role of microtubules and microtubule motors in keratin filament transport. We found that long keratin filaments, like other types of IFs, are transported along microtubules by kinesin-1. Our data revealed that keratin and vimentin are nonconventional kinesin-1 cargoes because their transport did not require kinesin light chains, which are a typical adapter for kinesin-dependent cargo transport. Furthermore, we found that the same domain of the kinesin heavy chain tail is involved in keratin and vimentin IF transport, strongly suggesting that multiple types of IFs move along microtubules using an identical mechanism.-Robert, A., Tian, P., Adam, S. A., Kittisopikul, M., Jaqaman, K., Goldman, R. D., Gelfand, V. I. Kinesin-dependent transport of keratin filaments: a unified mechanism for intermediate filament transport.


Cellular and molecular biology of glycosphingolipid glycosylation.
Brain tissue is characterized by its high glycosphingolipid content, particularly those containing sialic acid (gangliosides). As a result of this observation, brain tissue was a focus for studies leading to the characterization of the enzymes participating in ganglioside biosynthesis, and their participation in driving the compositional changes that occur in glycolipid expression during brain development. Later on, this focus shifted to the study of cellular aspects of the synthesis, which lead to the identification of the site of synthesis in the neuronal soma and their axonal transport toward the periphery. In this review article, we will focus in subcellular aspects of the biosynthesis of glycosphingolipid oligosaccharides, particularly the mechanisms underlying the trafficking of glycosphingolipid glycosyltransferases from the endoplasmic reticulum to the Golgi, those that promote their retention in the Golgi and those that participate in their topological organization as part of the complex membrane bound machinery for the synthesis of glycosphingolipids.


COVID-19 mortality may be reduced among fully vaccinated solid organ transplant recipients.
Solid organ transplant (SOT) recipients are at increased risk for morbidity and mortality from COVID-19 due to their immunosuppressed state and reduced immunogenicity from COVID-19 mRNA vaccines. This investigation examined the association between COVID-19 mRNA vaccination status and mortality among SOT recipients diagnosed with COVID-19. A retrospective, registry-based chart review was conducted investigating COVID-19 mortality among immunosuppressed solid organ transplant (SOT) recipients in a large metropolitan healthcare system in Houston, Texas, USA. Electronic health record data was collected from consecutive SOT recipients who received a diagnostic SARS-CoV-2 test between March 1, 2020, and October 1, 2021. The primary exposure was COVID-19 vaccination status at time of COVID-19 diagnosis. Patients were considered 'fully vaccinated' at fourteen days after completing their vaccine course. COVID-19 mortality within 60 days and intensive care unit admission within 30 days were primary and secondary endpoints, respectively. Among 646 SOT recipients who were diagnosed with COVID-19 at Houston Methodist Hospital between March 2020, and October 2021, 70 (10.8%) expired from COVID-19 within 60 days. Transplanted organs included 63 (9.8%) heart, 355 (55.0%) kidney, 108 (16.7%) liver, 70 (10.8%) lung, and 50 (7.7%) multi-organ. Increasing age was a risk factor for COVID-19 mortality, while vaccination within 180 days of COVID-19 diagnosis was protective in Cox proportional hazard models with hazard ratio 1.04 (95% CI: 1.01-1.06) and 0.31 (0.11-0.90), respectively). These findings were confirmed in the propensity score matched cohort between vaccinated and unvaccinated patients. This investigation found COVID-19 mortality may be significantly reduced among immunosuppressed SOT recipients within 6 months following vaccination. These findings can inform vaccination policies targeting immunosuppressed populations worldwide.


New advances in acute graft-versus-host disease prophylaxis.
Immunocompetent donor T cells in Allogeneic Haematopoietic Stem Cell grafts mediate acute Graft versus Host Disease (GvHD), still a major cause of recipient morbidity and mortality post transplant. Despite the advent of high resolution HLA-typing and matching at HLA loci, acute GvHD remains a significant problem, even in HLA matched siblings, due primarily to minor histocompatability antigen mismatches. Treatment of GvHD remains ineffective and highly immunosuppressive and the challenge to find effective methods of prevention continues. Non selective removal of donor T cells from the graft has been proven to be effective in preventing GvHD but the beneficial effects of donor T cells, namely effective immune reconstitution and anti tumour activity, are lost. This review considers mechanisms by which acute GvHD may be prevented in the context of the current model of GvHD immunopathogenesis, with a special emphasis on the recent techniques of selective removal or destruction of donor allogeneic T cells that have been described.


Cell cycle length, cell size, and proliferation rate in hydra stem cells.
We have analyzed the cell cycle parameters of interstitial cells in Hydra oligactis. Three subpopulations of cells with short, medium, and long cell cycles were identified. Short-cycle cells are stem cells; medium-cycle cells are precursors to nematocyte differentiation; long-cycle cells are precursors to gamete differentiation. We have also determined the effect of different cell densities on the population doubling time, cell cycle length, and cell size of interstitial cells. Our results indicate that decreasing the interstitial cell density from 0.35 to 0.1 interstitial cells/epithelial cell (1) shortens the population doubling time from 4 to 1.8 days, (2) increases the [3H]thymidine labeling index from 0.5 to 0.75 and shifts the nuclear DNA distribution from G2 to S phase cells, and (3) decreases the length of G2 in stem cells from 6 to 3 hr. The shortened cell cycle is correlated with a significant decrease in the size of interstitial stem cells. Coincident with the shortened cell cycle and increased growth rate there is an increase in stem cell self-renewal and a decrease in stem cell differentiation.


Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia.
Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with tau-containing lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.


Why is Southern African canine babesiosis so virulent? An evolutionary perspective.
Canine babesiosis is a common, highly virulent disease in Southern Africa with even pups and juveniles being severely affected. This contrasts with bovine babesiosis, for example, where host, parasite and vector co-evolved and young animals develop immunity after infection without showing clinical signs. Babesia rossi, the main causative organism of canine babesiosis in sub-Saharan Africa, was first described from a side-striped jackal (Canis adustus) in Kenya. Although data are meagre, there is evidence that indigenous African canids, such as jackals and wild dogs (Lycaon pictus), can harbour the parasite without showing untoward effects. Dogs are not indigenous to Africa. The vast majority of dogs presented at veterinary facilities in South Africa represent recently introduced European, Asian or American breeds. The contention is that B. rossi is a new challenge to which these dogs have not adapted. With intensive treatment of clinical cases, natural selection is effectively negated and the status quo will probably be maintained indefinitely. It is postulated that Babesia vogeli, which frequently results in unapparent infections or mild manifestations in dogs, represents or is closely related to the ancestral form of the canine parasite, possibly originating from wolves (Canis lupus).


Oligotrophic Growth of Nitrate-Dependent Fe2+-Oxidising Microorganisms Under Simulated Early Martian Conditions.
Nitrate-dependent Fe2+ oxidation (NDFO) is a microbially mediated process observed in many anaerobic, low-nutrient (oligotrophic) neutral-alkaline environments on Earth, which describes oxidation of Fe2+ to Fe3+ in tandem with microbial nitrate reduction. Evidence suggests that similar environments existed on Mars during the Noachian epoch (4.1-3.7 Ga) and in periodic, localised environments more recently, indicating that NDFO metabolism could have played a role in a potential early martian biosphere. In this paper, three NDFO microorganisms, Acidovorax sp. strain BoFeN1, Pseudogulbenkiania sp. strain 2002 and Paracoccus sp. strain KS1, were assessed for their ability to grow oligotrophically in simulated martian brines and in a minimal medium with olivine as a solid Fe2+ source. These simulant-derived media were developed from modelled fluids based on the geochemistry of Mars sample locations at Rocknest (contemporary Mars soil), Paso Robles (sulphur-rich soil), Haematite Slope (haematite-rich soil) and a Shergottite meteorite (common basalt). The Shergottite medium was able to support growth of all three organisms, while the contemporary Mars medium supported growth of Acidovorax sp. strain BoFeN1 and Pseudogulbenkiania sp. strain 2002; however, growth was not accompanied by significant Fe2+ oxidation. Each of the strains was also able to grow in oligotrophic minimal media with olivine as the sole Fe2+ source. Biomineralised cells of Pseudogulbenkiania sp. strain 2002 were identified on the surface of the olivine, representing a potential biosignature for NDFO microorganisms in martian samples. The results suggest that NDFO microorganisms could have thrived in early martian groundwaters under oligotrophic conditions, depending on the local lithology. This can guide missions in identifying palaeoenvironments of interest for biosignature detection. Indeed, biomineralised cells identified on the olivine surface provide a previously unexplored mechanism for the preservation of morphological biosignatures in the martian geological record.


Comparison and interpretation of characteristics of Rhizosphere microbiomes of three blueberry varieties.
Studies on the rhizosphere microbiome of various plants proved that rhizosphere microbiota carries out various vital functions and can regulate the growth and improve the yield of plants. However, the rhizosphere microbiome of commercial blueberry was only reported by a few studies and remains elusive. Comparison and interpretation of the characteristics of the rhizosphere microbiome of blueberry are critical important to maintain its health. In this study, a total of 20 rhizosphere soil samples, including 15 rhizosphere soil samples from three different blueberry varieties and five bulk soil samples, were sequenced with a high-throughput sequencing strategy. Based on these sequencing datasets, we profiled the taxonomical, functional, and phenotypic compositions of rhizosphere microbial communities for three different blueberry varieties and compared our results with a previous study focused on the rhizosphere microbiome of blueberry varieties. Our results demonstrated significant differences in alpha diversity and beta diversity of rhizosphere microbial communities of different blueberry varieties and bulk soil. The distribution patterns of taxonomical, functional, and phenotypic compositions of rhizosphere microbiome differ across the blueberry varieties. The rhizosphere microbial communities of three different blueberry varieties could be distinctly separated, and 28 discriminative biomarkers were selected to distinguish these three blueberry varieties. Core rhizosphere microbiota for blueberry was identified, and it contained 201 OTUs, which were mainly affiliated with Proteobacteria, Actinobacteria, and Acidobacteria. Moreover, the interactions between OTUs of blueberry rhizosphere microbial communities were explored by a co-occurrence network of OTUs from an ecological perspective. This pilot study explored the characteristics of blueberry's rhizosphere microbial community, such as the beneficial microorganisms and core microbiome, and provided an integrative perspective on blueberry's rhizosphere microbiome, which beneficial to blueberry health and production.


The impact on quality of life for people with brain tumours of entering a research trial involving new anti-cancer agents.
The intention of this study was to offer an alternative perspective to the quantitative findings of larger randomised controlled trials by using a phenomenological approach to explore the impact on Quality of Life (QoL) for people with brain tumours of entering a research trial involving new anti-cancer agents. Given the subjective nature of the proposed topic, a phenomenological approach was adopted. Sample size was limited to five participants. A semi-structured interview technique was used. Interviews were digitally audio recorded with permission from those involved. In order to guide data analysis for this study, Colaizzi's framework was utilised. As a result of data analysis, two major themes were identified. These were 'Hope and optimism' and 'The therapeutic relationship'. Three minor themes were also found. These were 'A complex symptom profile', 'The importance of non-medical coping strategies' and 'Impressions of the QoL tools used'. This phenomenological study has highlighted key themes relating to QoL which are not addressed in some of the widely used assessment tools such as the EORTC QLQ C30 and BN20. They generally focus on health status, and do not capture issues identified in this study as being of significant importance to the QoL of participants such as hope and optimism, and the importance of the therapeutic relationship. They also omit reference to coping and management strategies.


Effect of an evidence-based answering service on GPs and their patients: a pilot study.
For general practitioners (GPs), an important obstacle to practising evidence-based medicine is lack of time. An evidence-based answering service was developed that took over searching and appraisal of medical evidence from the GPs. GPs sent in questions, and the informationist formulated the answers. Our objectives were to find out if such an evidence-based answering service was feasible, including assessing the effect of the answers on GPs and their patients, as reported by the GPs. After attending a workshop on building well-formulated questions from daily practice, the GPs sent in questions to the informationist. The literature was searched, the relevant information was appraised, and the answers to the questions were formulated. With a questionnaire, the effect of the answers on the GP and the patient was assessed, as well as the perceived barriers to implementing the answers. From 26 GPs, 61 questions were received. For 12% of questions, information was found with the highest evidence level, while for 36%, no information was found. However, for 89% of the questions for which no information could be found, the answer 'no information found' did have an effect on the GP concerned. In total, 81% of all the answers had an effect on the GP, and, according to the GP, 52% had an effect on the patient. Few barriers to implementing the evidence were perceived. Most of the answers were found in Pubmed/Medline, the Cochrane Library and Embase. This study indicates that an evidence-based answering service can have an impact on GPs and their patients. Librarians can provide an evidence-based answering service for GPs and their patients. The evidence-based answering service for GPs in this study had an impact on 81% of the GPs and on 52% of their patients. Although for one-third of the questions no evidence-based answer was found, this message in itself had an impact on 89% of the GPs. An informationist as mediator between medical information and doctors can save doctors' time.


Power, politics and rehabilitation in sub-Saharan Africa: from the personal to the political.
This article discusses the complexities of facilitating community-based rehabilitation in resource-poor contexts in Sub-Saharan Africa. It does so through a reflection on the book Able-Bodied: Scenes from a Curious Life, written by Leslie Swartz, a South African expert on disability in the context of international development. Swartz uses his own personal experiences as son of a disabled father as a springboard for reflections on his long involvement in the often-fraught areas of disability research and activism. He pays particular attention to the way in which emotions shape the struggles around expertise and power that bedevil disability identity politics. In particular, his work highlights how the complex dynamics of race, class and disability undermine the effectiveness of the movement.


Adherence characteristics of coagulase-negative staphylococci isolated from patients with infective endocarditis.
Coagulase-negative staphylococci isolated from patients with endocarditis were divided according to whether the infection was of native or of prosthetic valves and was acquired either in the community or in hospital. Comparisons were made with strains from intravenous line-associated bacteraemias. All strains were examined by direct and indirect adherence tests. Line-associated bacteraemia strains were more likely to produce slime and were more hydrophilic but were less likely to attach HEp2 tissue culture cells than were endocarditis strains, and almost equally likely to adhere to plastic and extracellular matrix proteins. Amongst the endocarditis strains, there was little difference in slime production but hospital-acquired or prosthetic-valve strains were more hydrophobic and more likely to adhere to silicone than were the native-valve or community-acquired strains. Exposure of extracellular matrix proteins on native valves due to a pre-existing non-infective heart condition may account for the selection of strains able to adhere to fibronectin or laminin.


MRI of pediatric cardiac masses.
The purpose of this article is to describe the characteristic cardiac MRI features of primary and secondary cardiac tumors, including differentiation from masslike lesions, such as thrombus or focal myocardial hypertrophy. The frequency and type of cardiac tumors in children differ from those in adults. Although transthoracic echocardiography is the initial imaging technique of choice for evaluation of cardiac tumors, cardiac MRI is an important complementary modality for characterization of the mass and effect on cardiac function.


[Treatment of refractory primary depression].
Refractory depressions are depressions that respond insufficiently to treatment with the standard antidepressants, given long enough and in adequate dosage. If tricyclic antidepressants or selective serotonin reuptake inhibitors are insufficiently efficacious, an augmentation strategy may be applied. Drugs with a reinforcing effect on antidepressant medication are lithium and possibly liothyronine (triiodothyronine). If the results are nil or insufficient, administration of MAO inhibitors may be resorted to. Finally, electroconvulsive treatment may be administered to patients with a vital depression. If in depression there are indications of personality disorders and/or stressful life situations, treatment should comprise not only antidepressants but also psychological intervention and psychosocial measures.


Extended Lifetime of Respiratory Droplets in a Turbulent Vapor Puff and Its Implications on Airborne Disease Transmission.
To quantify the fate of respiratory droplets under different ambient relative humidities, direct numerical simulations of a typical respiratory event are performed. We found that, because small droplets (with initial diameter of 10 μm) are swept by turbulent eddies in the expelled humid puff, their lifetime gets extended by a factor of more than 30 times as compared to what is suggested by the classical picture by Wells, for 50% relative humidity. With increasing ambient relative humidity the extension of the lifetimes of the small droplets further increases and goes up to around 150 times for 90% relative humidity, implying more than 2 m advection range of the respiratory droplets within 1 sec. Employing Lagrangian statistics, we demonstrate that the turbulent humid respiratory puff engulfs the small droplets, leading to many orders of magnitude increase in their lifetimes, implying that they can be transported much further during the respiratory events than the large ones. Our findings provide the starting points for larger parameter studies and may be instructive for developing strategies on optimizing ventilation and indoor humidity control. Such strategies are key in mitigating the COVID-19 pandemic in the present autumn and upcoming winter.


Mitochondrial DNA deletions in mitochondrial cytopathies: observations in 19 patients.
Among 56 patients with mitochondrial myopathies or cytopathies, 19 had large-scale deletions of mitochondrial DNA (mtDNA). Consistent with previous observations, all 19 had progressive external ophthalmoplegia and 12 had complete or partial Kearns-Sayre syndrome. One of two patients in whom mitochondrial rather than whole muscle DNA was analyzed had multiple populations of deleted mtDNA (dmtDNA). In all patients, the length of dmtDNA was inversely related to age of onset, but was not related to multiplicity of organ involvement. Patients with greater than 50% dmtDNA tended to have an earlier onset of symptoms and a higher proportion of ragged-red fibers and cytochrome c oxidase (CCO)-negative fibers than patients with less than 50% dmtDNA, but these differences did not reach statistical significance. In some patients, CCO-negative fibers were more abundant than ragged-red fibers, indicating that the distribution of abnormal mitochondria can be more widespread than suggested by the frequency of ragged-red fibers. In biochemical assays, citrate synthase activity was a better reference for detecting defects in the respiratory complexes than the wet weight of muscle. Using this reference, 10 of 14 patients had one or more respiratory complex defects, and 74% of the observed defects could be correlated with an appropriate mtDNA deletion.


Daily cannabis and reduced risk of steatosis in human immunodeficiency virus and hepatitis C virus-co-infected patients (ANRS CO13-HEPAVIH).
Liver steatosis is common in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-co-infected patients. Some recent studies have found that cannabis use is negatively associated with insulin resistance in the general population and in HIV-HCV-co-infected patients. Given the causal link between insulin resistance and steatosis, we hypothesized that cannabis use has a positive impact on steatosis. Therefore, we aimed to study whether cannabis use in this population was associated with a reduced risk of steatosis, measured by ultrasound examination. ANRS CO13-HEPAVIH is a French nationwide multicentre cohort of HIV-HCV-co-infected patients. Medical and socio-behavioural data from clinical follow-up visits and annual self-administered questionnaires were prospectively collected. A cross-sectional analysis was conducted using data from the first visit where both ultrasound examination data for steatosis (positive or negative diagnosis) and data on cannabis use were available. A logistic regression model was used to evaluate the association between cannabis use and steatosis. Among study sample patients (n = 838), 40.1% had steatosis. Fourteen per cent reported daily cannabis use, 11.7% regular use and 74.7% no use or occasional use ("never or sometimes"). Daily cannabis use was independently associated with a reduced prevalence of steatosis (adjusted odds ratio [95% CI] = 0.64 [0.42;0.99]; P = .046), after adjusting for body mass index, hazardous alcohol consumption and current or lifetime use of lamivudine/zidovudine. Daily cannabis use may be a protective factor against steatosis in HIV-HCV-co-infected patients. These findings confirm the need for a clinical evaluation of cannabis-based pharmacotherapies in this population. Eudract.ema.europa.eu number, DGS050367.


The importance of pyruvate availability to PDC activation and anaplerosis in human skeletal muscle.
No studies have singularly investigated the relationship between pyruvate availability, pyruvate dehydrogenase complex (PDC) activation, and anaplerosis in skeletal muscle. This is surprising given the functional importance attributed to these processes in normal and disease states. We investigated the effects of changing pyruvate availability with dichloroacetate (DCA), epinephrine, and pyruvate infusions on PDC activation and accumulation of acetyl groups and tricarboxylic acid (TCA) cycle intermediates (TCAI) in human muscle. DCA increased resting PDC activity sixfold (P < 0.05) but decreased the muscle TCAI pool (mmol/kg dry muscle) from 1.174 +/- 0.042 to 0.747 +/- 0.055 (P < 0.05). This was probably a result of pyruvate being diverted to acetyl-CoA and acetylcarnitine after near-maximal activation of PDC by DCA. Conversely, neither epinephrine nor pyruvate activated PDC. However, both increased the TCAI pool (1.128 +/- 0.076 to 1.614 +/- 0.188, P < 0.05 and 1.098 +/- 0.059 to 1.385 +/- 0.114, P < 0.05, respectively) by providing a readily available pool of pyruvate for anaplerosis. These data support the hypothesis that TCAI pool expansion is principally a reflection of increased muscle pyruvate availability and, together with our previous work (J. A. Timmons, S. M. Poucher, D. Constantin-Teodosiu, V. Worrall, I. A. Macdonald, and P. L. Greenhaff. J. Clin. Invest. 97: 879-883, 1996), indicate that TCA cycle expansion may be of little functional significance to TCA cycle flux. It would appear therefore that the primary effect of DCA on oxidative ATP provision is to provide a readily available pool of acetyl groups to the TCA cycle at the onset of exercise rather than increasing TCA cycle flux by expanding the TCAI pool.


Unglycosylated Trk protein does not co-localize nor associate with ganglioside GM1 in stable clone of PC12 cells overexpressing Trk (PCtrk cells).
Our previous studies have shown that acidic glycosphingolipid, ganglioside GM1 (GM1), is an endogenous regulator of high affinity nerve growth factor receptor, Trk, which is an essential factor for the normal development and differentiation of neuronal cells by forming a complex with Trk. GM1 is also known to be a major constituent of caveola or glycosphingolipid-enriched microdomain (GEM) of the plasma membrane. In order to study the effect of the glycosylation of Trk on the formation of GM1-Trk complex and subcellular distribution of this protein, we generated PC12 cells stably overexpressing Trk (PCtrk). Pretreatment of this stable clones with tunicamycin, a potent inhibitor of N-glycosylation, caused the appearance of unglycosylated Trk core protein. These unglycosylated Trk can hardly respond to its ligand, NGF. Sucrose density gradient analysis revealed that unglycosylated Trk core protein was recovered in high density fractions, whereas most of GM1 is present in low density fractions corresponding to caveola or GEM fractions. Moreover, these unglycosylated Trk proteins lose their ability to form a complex with GM1, although GM1 is present in the same high density fractions. These data strongly suggest that spatial segregation of GM1 from the Trk protein by the inhibition of the glycosylation of Trk might be an important molecular mechanism for the unresponsiveness to NGF. Moreover, the binding site of GM1 in the Trk protein might act as an important determinant for the normal trafficking of the Trk protein within the cells.


The Development and Psychometric Investigation of the Cyberbullying Scale.
Accurate assessment of cyberbullying is essential for intervention planning and evaluation. Limitations to many currently available self-report measures of cyberbullying victimization include a lack of psychometric information and a limited scope (i.e., not assessing multiple electronic mediums of cybervictimization). To address these limitations, we developed and investigated the psychometric properties of a broad self-report measure of cyberbullying, the Cyberbullying Scale (CBS). We examined the factor structure and reliability of the CBS across 736 students in Grades 6 to 12 in six Northern Mississippi schools. Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) results indicated that the structure of the CBS was best represented by a one-factor model. The finding of a single-factor structure suggests that cyberbullying is a unidimensional construct, which is consistent with previous research. In the current sample, the CBS demonstrated strong psychometric properties, including excellent internal consistency (Cronbach's α = .94) and significant positive correlations with related constructs of anxiety, depression, and loneliness. Results from the present study provide initial support for the CBS as a measure of cybervictimization among adolescents.


Laser Direct Writing of a High-Performance All-Graphene Humidity Sensor Working in a Novel Sensing Mode for Portable Electronics.
This paper reports a fast and highly sensitive all-graphene humidity sensor working in a novel alternating current (ac) detection mode for the first time, which is capable of sensing humidity on a smartphone for portable electronics. The humidity sensor is based on an interdigitated reduced graphene oxide/graphene oxide/rGO (rGO/GO/rGO) structure patterned by a facile laser direct writing method. It works in an ac sensing mode with a rectangular input voltage wave and measures the output voltage wave instead of conventional resistance, impedance, or capacitance, exhibiting a dramatically enhanced sensitivity by about 45 times compared to the low and unstable response in dc mode. The humidity sensor shows an obvious response to the relative humidity (RH) ranging from RH 6.3% to RH 100%. The response and recovery toward humidity change are almost instantaneous, and the corresponding costed times including humidity rise and decay times are less than 1.9 and 3.9 s, respectively, which are among the best results in the literature. The sensor also exhibits outstanding cycling stability, flexibility, and long-term stability (>1 year), as well as good reproducibility of device preparation. Besides, it can be easily connected to an iPhone and the humidity sensing can be conducted with an oscilloscope application on iOS. What's more, an electronic circuit simulation method was employed to fit the output waves, which can not only explain the sensing mechanism, but also determine the resistance and capacitance of the rGO/GO/rGO structure, agreeing well with the results obtained from the electrochemical measurements. It can be reasonably expected that the approach combining humidity sensing and electronic circuit simulation can be applied in real-time monitoring on a smartphone based on the Internet of things and big data technologies.


Culturally Appropriate Outreach Specialist Respiratory Medical Care Improves the Lung Function of Children in Regional and Remote Queensland.
Indigenous Respiratory Outreach Care (IROC) is a culturally appropriate specialist respiratory service established to deliver multidisciplinary respiratory care to regional and remote Queensland communities. Our objective was to evaluate the impact of an outreach specialist respiratory service on the spirometry of children attending IROC clinics, particularly Indigenous children with asthma and bronchiectasis. Retrospective single-arm cohort study of 189 children who performed spirometry at twelve sites across regional and remote Queensland between October 2010 and December 2017. Each child's baseline spirometry was compared to their best spirometry at follow-up visit occurring within (1) 12 months of their most recent visit with at least 12 months of specialist care and; (2) each year of their first 3 years of care. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) z-scores improved significantly across the whole group from baseline to follow-up (change in z-scores (Δz) of FEV1 = 0.38, 95% CI 0.22, 0.53; ΔzFVC = 0.36, 95% CI 0.21, 0.51). In subgroup analyses, lung function significantly improved in Indigenous children (n = 141, ΔzFEV1 = 0.37, 95% CI 0.17, 0.57; ΔzFVC = 0.36, 95% CI 0.17, 0.55) including those with asthma (n = 117, ΔzFEV1 = 0.41, 95% CI 0.19, 0.64; ΔzFVC = 0.46, 95% CI 0.24, 0.68) and bronchiectasis (n = 38, ΔzFEV1 = 0.33, 95% CI 0.07, 0.59; ΔzFVC = 0.26, 95% CI - 0.03, 0.53). Significant improvements in FEV1 and FVC were observed within the first and second year of follow-up for Indigenous children, but not for non-Indigenous children. The IROC model of care in regional and remote settings leads to significant lung function improvement in Indigenous children with asthma and bronchiectasis.


Nephroprotective Effects of Anthocyanin from the Fruits of Panax ginseng (GFA) on Cisplatin-Induced Acute Kidney Injury in Mice.
Cisplatin is an effective anticancer chemotherapeutic agent, but the use of cisplatin in the clinic is severely limited by side effects. Nephrotoxicity is a major factor that contributes to the side effects of cisplatin chemotherapy. The aim of this research was to survey the nephroprotective effects of anthocyanin from the fruits of Panax ginseng (GFA) in a murine model of cisplatin-induced acute kidney injury. We observed that pretreatment with GFA attenuated cisplatin-induced elevations in blood urea nitrogen and creatinine levels and histopathological injury induced by cisplatin. The formation of kidney malondialdehyde, heme oxygenase-1, cytochrome P450 E1 and 4-hydroxynonenal with a concomitant reduction in reduced glutathione was also inhibited by GFA, while the activities of kidney superoxide dismutase and catalase were all increased. GFA also inhibited the increase in serum tumour necrosis factor-α and interleukin-1β induced by cisplatin. In addition, the levels of induced nitric oxide synthase and cyclooxygenase-2 were suppressed by GFA. Furthermore, GFA supplementation inhibited the activation of apoptotic pathways by increasing B cell lymphoma 2 and decreasing Bcl2-associated X protein expression. In conclusion, the findings from the present investigation demonstrate that GFA pre-administration can significantly prevent cisplatin-induced nephrotoxicity, which may be related to its antioxidant, anti-apoptotic and antiinflammatory effects. Copyright © 2017 John Wiley & Sons, Ltd.


Thoughts in flight: automation use and pilots' task-related and task-unrelated thought.
The objective was to examine the relationship between cockpit automation use and task-related and task-unrelated thought among airline pilots. Studies find that cockpit automation can sometimes relieve pilots of tedious control tasks and afford them more time to think ahead. Paradoxically, automation has also been shown to lead to lesser awareness. These results prompt the question of what pilots think about while using automation. A total of 18 airline pilots flew a Boeing 747-400 simulator while we recorded which of two levels of automation they used. As they worked, pilots were verbally probed about what they were thinking. Pilots were asked to categorize their thoughts as pertaining to (a) a specific task at hand, (b) higher-level flight-related thoughts (e.g.,planning ahead), or (c) thoughts unrelated to the flight. Pilots' performance was also measured. Pilots reported a smaller percentage of task-at-hand thoughts (27% vs. 50%) and a greater percentage of higher-level flight-related thoughts (56% vs. 29%) when using the higher level of automation. However, when all was going according to plan, using either level of automation, pilots also reported a higher percentage of task-unrelated thoughts (21%) than they did when in the midst of an unsuccessful performance (7%). Task-unrelated thoughts peaked at 25% when pilots were not interacting with the automation. Although cockpit automation may provide pilots with more time to think, it may encourage pilots to reinvest only some of this mental free time in thinking flight-related thoughts. This research informs the design of human-automation systems that more meaningfully engage the human operator.


Coexistence and independence between a mental disorder and female stalking.
There are few studies of female stalkers in literature addressing different study populations. There appears to be a high incidence of mental disease among female stalkers, having an important role in inducing the harassment. We present a woman affected by a bipolar disorder who had a long affair with her victim, broken off in 2007. Stalking began in January 2009 and continued for 6 months, during which time she was not taking drugs and was in a decompensated clinical phase. In July 2009, she was denounced for harassment; the authorities demanded a psychiatric examination. The woman then resumed taking the medication regularly. In December 2009, although she was in complete remission, she began stalking once more. This case shows that even when there seems to be an evident relation between psychopathology and crime, it is always necessary to evaluate to what extent the mental disorder is responsible for the criminal behavior.


Barriers to the management of alcohol use disorder and alcohol-associated liver disease: strategies to implement integrated care models.
Despite its increased recognition as a major public health issue, alcohol use disorder is mostly underdiagnosed and undertreated. The undertreatment and underdiagnosis of alcohol use disorder is most concerning in the management of patients with alcohol-associated liver disease, which is one of the main medical consequences of chronic and excessive alcohol use. Dual pathology (alcohol use disorder and alcohol-associated liver disease) requires multidisciplinary care involving hepatologists and addiction specialists. Such integrated care models are widely accepted as optimal care for treating comorbid medical and mental health conditions. However, the implementation of such models in clinical practice is challenging and often represents the exception, rather than the rule, in managing patients with alcohol use disorder and alcohol-associated liver disease. Barriers at the patient, clinician, and system levels are encountered in treating patients with alcohol use disorder and alcohol-associated liver disease. In this Viewpoint, we synthesise the emerging literature on the potential barriers encountered in caring for patients with alcohol-associated liver disease and alcohol use disorder and focus on how integrated models of care could overcome these barriers. We provide our perspective on why these barriers exist and propose strategies to overcome them.


Physiological disposition of i.v. morphine in sheep.
In a crossover design study we have measured the total body and regional clearances of morphine. Thirteen experiments were performed in four conscious sheep that had been prepared previously with appropriate intravascular cannulae. Morphine (as sulphate pentahydrate) was infused i.v. at 2.5, 5, 10 and 20 mg h-1 to produce constant blood concentrations. Morphine (base) concentrations were measured in blood, urine and tissues with a specific HPLC method. The mean (SEM) total body clearance of morphine was 1.63 (0.21) litre min-1; this comprised 1.01 (0.10) litre min-1 clearance by the liver and 0.55 (0.06) litre min-1 by the kidneys. There was no evidence of dose-dependent clearance or significant extraction of morphine by the lungs, brain, heart, gut or hindquarters at any dose. The kidney clearance of morphine was greater than the 0.21 (0.06) litre min-1 renal clearance determined from the product of the mean total body clearance and the 12.3 (2.4%) of the administered dose recovered as unmetabolized morphine from 48 h urine collection (P less than 0.05). It was concluded that the liver and kidneys account for the majority of morphine clearance, and that the kidneys both excrete and metabolize morphine.


Successive mechanochemical activation and small molecule release in an elastomeric material.
We have developed a mechanochemically responsive material capable of successively releasing small organic molecules from a cross-linked network upon repeated compressions. The use of a flex activated mechanophore that does not lead to main chain scission and an elastomeric polyurethane enabled consecutive compressions with incremental increases in the % mechanophore activation. Additionally, we examined the effect of multiple applications of compressive stress on both mechanophore activity and the mechanical behavior of the elastomeric matrix in which the mechanophore is embedded.


Exosomal ANGPTL1 attenuates colorectal cancer liver metastasis by regulating Kupffer cell secretion pattern and impeding MMP9 induced vascular leakiness.
Angiopoietin-like protein 1 (ANGPTL1) has been proved to suppress tumor metastasis in several cancers. However, its extracellular effects on the pre-metastatic niches (PMNs) are still unclear. ANGPTL1 has been identified in exosomes, while its function remains unknown. This study was designed to explore the role of exosomal ANGPTL1 on liver metastasis in colorectal cancer (CRC). Exosomes were isolated by ultracentrifugation. The ANGPTL1 level was detected in exosomes derived from human CRC tissues. The effects of exosomal ANGPTL1 on CRC liver metastasis were explored by the intrasplenic injection mouse model. The liver PMN was examined by vascular permeability assays. Exosomal ANGPTL1 localization was validated by exosome labeling. The regulatory mechanisms of exosomal ANGPTL1 on Kupffer cells were determined by RNA sequencing. qRT-PCR, Western Blot, and ELISA analysis were conducted to examine gene expressions at mRNA and protein levels. ANGPTL1 protein level was significantly downregulated in the exosomes derived from CRC tumors compared with paired normal tissues. Besides, exosomal ANGPTL1 attenuated liver metastasis and impeded vascular leakiness in the liver PMN. Moreover, exosomal ANGPTL1 was mainly taken up by KCs and regulated the KCs secretion pattern, enormously decreasing the MMP9 expression, which finally prevented the liver vascular leakiness. In mechanism, exosomal ANGPTL1 downregulated MMP9 level in KCs by inhibiting the JAK2-STAT3 signaling pathway. Taken together, exosomal ANGPTL1 attenuated CRC liver metastasis and impeded vascular leakiness in the liver PMN by reprogramming the Kupffer cell and decreasing the MMP9 expression. This study suggests a suppression role of exosomal ANGPTL1 on CRC liver metastasis and expands the approach of ANGPTL1 functioning.


Time to death and health expenditure: an improved model for the impact of demographic change on health care costs.
Obtaining well-founded estimates of the effect of demographic change on future health expenditures is a pressing issue in all developed countries. Thus far, expenditure projections have examined the effect of age on health care costs, but fail to account for the influence of remaining life expectancy on costs. This paper seeks to create a more accurate projection model that considers the concentration of costs towards the end of life, and to compare this model with the more traditional approach that holds age- and sex-specific per capita expenditures constant. We used a longitudinal hospital dataset which followed 90 929 patients aged 65 and older from 1970 to death, to create an economic model of hospital costs based on patient age and time remaining to death. We then applied the model to England population projections to predict the effect of demographic changes on hospital expenditures from 2002 to 2026. The decline in age-specific mortality rates over time postpones death to later ages, pushing back death-related costs. Accounting for this in expenditure projections gave a predicted annual growth rate of 0.40%-half of the rate predicted with a traditional method. Using richer data and more refined methods than have hitherto been employed, this study strongly confirms that the pressure of population increases and ageing demographic structure on hospital expenditures will be partially countered by the postponement of death-related hospital costs to later in life-a finding consistent with emerging epidemiological evidence, and heartening for policy makers and physicians alike.


Molecular heterogeneity in medulloblastoma with implications for differing tumor biology.
Medulloblastomas and related primitive neuroectodermal tumors are the second most common malignant tumors of childhood. In spite of improvements in cancer therapy, these tumors are still associated with significant morbidity and mortality. Although these tumors share similar histologic features, recent molecular studies suggest that they could represent a genetically mixed group of tumors. The genetic events that might play a role in the biology of these tumors also could allow a molecular subtyping of medulloblastomas. Such molecular subtyping of medulloblastomas could allow for the use of newer therapeutic techniques, such as gene therapy, for selective targeting of critical genetic events in subsets of medulloblastomas. It is becoming increasingly clear that in medulloblastomas, the morphologic similarity of "small blue" cells does not imply similar or shared molecular characteristics, with implications for differing tumor biology.


Multilevel-Regulated Metal-Organic Framework Platform Integrating Pore Space Partition and Open-Metal Sites for Enhanced CO2 Photoreduction to CO with Nearly 100% Selectivity.
Rational design and regulation of atomically precise photocatalysts are essential for constructing efficient photocatalytic systems tunable at both the atomic and molecular levels. Herein, we propose a platform-based strategy capable of integrating both pore space partition (PSP) and open-metal sites (OMSs) as foundational features for constructing high-performance photocatalysts. We demonstrate the first structural prototype obtained from this strategy: pore-partitioned NiTCPE-pstp (TCPE = 1,1,2,2-tetra(4-carboxylphenyl)ethylene, pstp = partitioned stp topology). Nonpartitioned NiTCPE-stp is constructed from six-connected [Ni3(μ3-OH)(COO)6] trimer and TCPE linker to form 1D hexagonal channels with six coplanar OMSs directed at channel centers. After introducing triangular pore-partitioning ligands, half of the OMSs were retained, while the other half were used for PSP, leading to unprecedented microenvironment regulation of the pore structure. The resulting material integrates multiple advanced properties, including robustness, wider absorption range, enhanced electronic conductivity, and high CO2 adsorption, all of which are highly desirable for photocatalytic applications. Remarkably, NiTCPE-pstp exhibits excellent CO2 photoreduction activity with a high CO generation rate of 3353.6 μmol g-1 h-1 and nearly 100% selectivity. Theoretical and experimental studies show that the introduction of partitioning ligands not only optimizes the electronic structure to promote the separation and transfer of photogenerated carriers but also reduces the energy barrier for the formation of *COOH intermediates while promoting CO2 activation and CO desorption. This work is believed to be the first example to integrate PSP strategies and OMSs within metal-organic framework (MOF) photocatalysts, which provides new insight as well as new structural prototype for the design and performance optimization of MOF-based photocatalysts.


Characterization of the binding site on thioglycolate-stimulated mouse peritoneal macrophages that mediates the uptake of very low density lipoproteins.
Isolated mouse peritoneal macrophages that had been stimulated with thioglycolate were shown to take up and degrade normal human 125I-very low density lipoproteins (VLDL). Uptake occurred via a specific cell surface receptor which was shown to be 1) temperature-dependent, 2) calcium-dependent, and 3) susceptible to proteolytic digestion. The receptor-mediated uptake and degradation of VLDL markedly stimulated the synthesis and accumulation of triglyceride and cholesteryl ester within macrophages. The degradation of the protein and lipid portions of VLDL occurred within lysosomes. Competition studies showed that the binding site for VLDL was different from the receptor for normal low density lipoproteins or for acetylated low density lipoproteins but that there was cross competition with beta-VLDL. In addition, positive charges appeared to play an important role in the recognition of VLDL by their receptors since polyamines were able to markedly inhibit VLDL binding, degradation, and lipid accumulation while negatively charged compounds were without effects. These studies indicate that 1) stimulated mouse peritoneal macrophages possess specific receptors which recognize normal human VLDL and 2) the receptor-mediated uptake of VLDL results in the accumulation of triglyceride and cholesteryl ester within macrophages.


Comparison of intravenous versus intracarotid therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea in a rat brain tumor model.
Currently numerous clinical trials are in progress utilizing intracarotid (i.c.) 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of malignant gliomas based upon the proposed focal nature of these tumors and the assumption that the i.c. route delivers higher levels of drug to the tumor. To date, however, increased efficacy in an animal model has not been clearly demonstrated for the i.c. delivery of BCNU. We have evaluated the dose-response curve for the i.v. and i.c. administration of BCNU in a commonly utilized experimental brain tumor model, the 9L rat gliosarcoma. An initial toxicity trial utilizing the i.p. 10% lethal dose (LD10) of BCNU by the i.v. and i.c. routes failed to demonstrate any significance in toxicity between the two routes. Tumor-bearing animals were then treated on Day 15-16 after tumor inoculations with 1, 10, 25, 50, 75, and 100% of the LD10 dose by either the i.v. or the i.c. route. Both i.v. and i.c. BCNU gave maximum survival increases at 75-100% LD10 doses, and there was no therapeutic advantage seen from i.c. delivery. However, at 50% of the LD10 dose (6.65 mg/kg), triplicate experiments demonstrated that the i.c. but not the i.v. dose maintained maximum efficacy equivalent to 100% of the LD10 given either i.v. or i.c. When the dose was reduced to 25% of the LD10 dose (3.33 mg/kg), two of three experiments showed efficacy of the i.c. delivery of this lower drug dosage to be equivalent to 100% of the LD10 given i.v. or i.c. The i.v. dosage resulted in a significant reduction in survival in all three trials. At 10% of the LD10 dose (1.30 mg/kg), neither the i.v. nor the i.c. administration retained equivalent efficacy to 100% of the LD10. However, in one of two trials, the i.c. groups had statistically better survival than controls, while in neither experiment was any advantage over controls seen in the i.v. treated groups. At 1% of the LD10 dose, neither the i.v. nor the i.c. route demonstrated any therapeutic efficacy. From our data, the advantage of the i.c. delivery of BCNU in the intracranial 9L rat gliosarcoma appears to be in the fact that significantly lower dosages than those given i.v. may be utilized to achieve equivalent survival with potentially less systemic toxicity.


Intraocular pressure, blood pressure, and retinal blood flow autoregulation: a mathematical model to clarify their relationship and clinical relevance.
This study investigates the relationship between intraocular pressure (IOP) and retinal hemodynamics and predicts how arterial blood pressure (BP) and blood flow autoregulation (AR) influence this relationship. A mathematical model is developed to simulate blood flow in the central retinal vessels and retinal microvasculature as current flowing through a network of resistances and capacitances. Variable resistances describe active and passive diameter changes due to AR and IOP. The model is validated by using clinically measured values of retinal blood flow and velocity. The model simulations for six theoretical patients with high, normal, and low BP (HBP-, NBP-, LBP-) and functional or absent AR (-wAR, -woAR) are compared with clinical data. The model predicts that NBPwAR and HBPwAR patients can regulate retinal blood flow (RBF) as IOP varies between 15 and 23 mm Hg and between 23 and 29 mm Hg, respectively, whereas LBPwAR patients do not adequately regulate blood flow if IOP is 15 mm Hg or higher. Hemodynamic alterations would be noticeable only if IOP changes occur outside of the regulating range, which, most importantly, depend on BP. The model predictions are consistent with clinical data for IOP reduction via surgery and medications and for cases of induced IOP elevation. The theoretical model results suggest that the ability of IOP to induce noticeable changes in retinal hemodynamics depends on the levels of BP and AR of the individual. These predictions might help to explain the inconsistencies found in the clinical literature concerning the relationship between IOP and retinal hemodynamics.


An epistatic interaction between the PAX8 and STK17B genes in papillary thyroid cancer susceptibility.
Papillary Thyroid Cancer (PTC) is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date. Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date. In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8. The interaction was detected by MD-MBR (p = 0.00010) and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017). Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas. Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies.


[The actualization of nursing care for the child living with AIDS: being, knowing and shared doing].
This article is the result of considerations resulting from the dissertation Meeting of care, lived and dialogued, of the nursing team with the child-being who lives with AIDS, which aimed at understanding the meaning of such care under the look of the Humanistic Nursing Theory of Paterson and Zderad. It is a phenomenological-existential and qualitative study with hermeneutic analysis proposed by Motta and Crossetti in the light of Ricouer. The expressiveness of caring was unveiled as: act of life; authentic; the lived and dialogued meeting; need for taking care of oneself as an opening for the meeting; maternity handling; the need of approaching the hospital world to the child's world and compassion attitude.


Measurements of right ventricular volumes during fluid challenge.
The effects of fluid loading on RV function were studied in 41 acutely ill patients monitored with a modified pulmonary artery catheter equipped for measuring RVef. Hemodynamic evaluation was performed before and after infusion of 300 ml of 4.5 percent albumin solution in 30 min. Changes in SI did not correlate with Pra or Ppao but did with RVEDVI. For the entire group, RVef was unchanged (27 +/- 9 vs 27 +/- 9 percent). In the eight patients with an initial RVEDVI greater than 140 ml/m2, the fluid challenge increased Pra and Ppao and reduced LVSWI without any other significant effect. There was no significant correlation between RVEDVI and Pra and only a weak correlation between RVESVI and Ppa. However, there was a highly linear correlation between both RVEDVI and RVESVI and changes in RVEDVI and in RVESVI, suggesting that in the absence of severe pulmonary hypertension RV output is primarily dependent on RV preload.


JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity.
We have previously shown that nitric oxide (NO) inhibits growth and induces differentiation and apoptosis in acute myeloid leukemia cells, with the HL-60 human myeloid leukemia line being particularly sensitive to NO-mediated cytolysis. With the goal of identifying a prodrug that can target NO to the leukemia cells without inducing NO-mediated systemic hypotension, we have screened a series of O(2)-aryl diazeniumdiolates designed to be stable at physiological pH but to release NO upon reaction with glutathione. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) proved to be the most active antiproliferative agent among those tested in HL-60 cells, with an IC(50) of 0.2-0.5 microM. After 5 days of exposure to 0.5 micro M JS-K, HL-60 cells had differentiated and acquired some of the phenotypic features of normal monocytes. One- to 2-day treatment with JS-K at concentrations of 0.5-1 microM resulted in apoptosis induction in a concentration- and caspase-dependent manner. JS-K also inhibited the growth of solid tumor cell lines but to a lesser extent than HL-60 cells. JS-K was administered i.v. to nonobese diabetic-severe combined immune deficient mice at doses of up to 4 micromol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by approximately 50% when the mice received i.v. injections three times/week with 4 micromol/kg boluses of JS-K. Histological examination of tumor explants from JS-K-treated animals revealed extensive necrosis. Similar results were seen with s.c. human prostate cancer (PPC-1) xenografts. Our data indicate that JS-K is a promising lead compound for the possible development of a novel class of antineoplastic agents.


[Identification of health priorities: a technical alternative for support in decision-making].
The scope of this study is to propose and discuss the application of an Index of Prioritization in Health (PIHealth). PIHealth is an objective criterion that reveals the magnitude of health problems and determinants in planning situations. PIHealth was used in identifying health priorities in different administrative health regions of the state of Rio Grande do Sul (RS) during the development of the 2009-2011 State Health Plan. The calculation of PIHealth made it possible to express the indicators analyzed within a given range (0 to 1) used to identify regional priorities (insufficient: 0 to 0.4; average: 0.41 to 0.69; and adequate: 0.7 to 1). The application of the index helped to identify the relationship in terms of magnitude of health problems based on an internal reference of the territories analyzed. Use of the index was a technical option in identifying priorities, which provided a simplification in the language used to express health problems and determinants. Its discretionary power and the intuitive simplicity of its interpretation showed that PIHealth is a promising tool, providing objective answers to key questions frequently addressed in health planning contexts.


Nonoperative management of splenic injury in combat: 2002-2012.
Selective nonoperative management of combat-related blunt splenic injury (BSI) is controversial. We evaluated the impact of the November 2008 blunt abdominal trauma clinical practice guideline that permitted selective nonoperative management of some patients with radiological suggestion of hemoperitoneum on implementation of nonoperative management (NOM) of splenic injury in austere environments. Retrospective evaluation of patients with splenic injuries from November 2002 through January 2012 in Iraq and Afghanistan was performed. International Classification of Diseases, 9th Revision, Clinical Modification procedure codes identified patients as laparotomy with splenectomy, or NOM. Delayed operative management had no operative intervention at earlier North American Treaty Organization (NATO) medical treatment facilities (MTFs), and had a definitive intervention at a latter NATO MTFs. Intra-abdominal complications and overall mortality were juxtaposed. A total of 433 patients had splenic injuries from 2002 to 2012. Initial NOM of BSI from 2002 to 2008 compared to 2009-2012 was 44.1% and 47.2%, respectively (p=0.75). Delayed operative management and NOM completion had intra-abdominal complication and mortality rates of 38.1% and 9.1% (p<0.01), and 6.3% and 8.1% (p=0.77). Despite high-energy explosive injuries, NATO Role II MTFs radiological constraints and limited medical resources, hemodynamically normal patients with BSI and low abdominal abbreviated injury scores underwent NOM in austere environments.


Pair creation in QED-strong pulsed laser fields interacting with electron beams.
QED effects are known to occur in a strong laser pulse interaction with a counterpropagating electron beam, among these effects being electron-positron pair creation. We discuss the range of laser pulse intensities of J≥5×10(22) W/cm2 combined with electron beam energies of tens of GeV. In this regime multiple pairs may be generated from a single beam electron, some of the newborn particles being capable of further pair production. Radiation backreaction prevents avalanche development and limits pair creation. The system of integro-differential kinetic equations for electrons, positrons and γ photons is derived and solved numerically.


The fair transaction model of informed consent: an alternative to autonomous authorization.
The doctrine of informed consent in bioethics has relied on the view that consent is valid when it represents a patient or research subject's autonomous authorization. In this article we challenge this reigning conception of the validity of informed consent in clinical research, focusing in particular on the problem of the therapeutic misconception. We argue that the autonomous authorization model of informed consent suffers from four defects: (1) it fails to do justice to the relevance of risk-benefit considerations in shaping the criteria for the validity of consent, (2) it compromises the interests of subjects by preventing them from consenting to research participation with less than substantial understanding when doing so would likely be consistent with their preferences and beneficial to them or at least be unlikely to cause them harm, (3) it jeopardizes the interests of investigators by denying them fair notice regarding when the consent of research subjects can be considered valid and thus make it permissible for them to be enrolled in research, and (4) it threatens the reasonable limits on the responsibility of investigators to assure the adequacy of subjects' understanding of what research participation involves. In place of the autonomous authorization model, we present and defend a fair transaction model of informed consent, which better reflects the values served by consent.


Edema-induced increase in tumour cell survival for 125I and 103Pd prostate permanent seed implants--a bio-mathematical model.
Edema caused by the surgical procedure of prostate seed implantation expands the source-to-point distances within the prostate and hence decreases the dose coverage. The decrease of dose coverage results in an increase in tumour cell survival. To investigate the effects of edema on tumour cell survival, a bio-mathematical model of edema and the corresponding cell killing by continuous low dose rate irradiation (CLDRI) was developed so that tumour cell surviving fractions can be estimated in an edematous prostate for both 125I and 103Pd seed implants. The dynamic nature of edema and its resolution were modelled with an exponential function V(T) = V(p)(1 + M exp(-0.693T/ T(e))) where V(p) is the prostate volume before implantation, M is the edema magnitude and T(e) is edema half-life (EHL). The dose rate of a radioactive seed was calculated according to AAPM TG43, i.e. D = SkAg(r)phi(an)/r2, where r is the distance between a seed and a given point. The distance r is now a function of time because of edema. The g(r) was approximated as 1/r(0,4) and 1/r(0.8) for 125I and 103Pd, respectively. By expanding the mathematical expression of the resultant dose rate in a Taylor series of exponential functions of time, the dose rate was made equivalent to that produced from multiple fictitious radionuclides of different decay constants and strengths. The biologically effective dose (BED) for an edematous prostate implant was then calculated using a generalized Dale equation. The cell surviving fraction was computed as exp(-alphaBED), where alpha is the linear coefficient of the survival curve. The tumour cell survival was calculated for both 125I and 103Pd seed implants and for different tumour potential doubling time (TPDT) (from 5 days to 30 days) and for edemas of different magnitudes (from 0% to 95%) and edema half-lives (from 4 days to 30 days). Tumour cell survival increased with the increase of edema magnitude and EHL. For a typical edema of a half-life of 10 days and a magnitude of 50%. the edema increased tumour cell survival by about 1 and 2 orders of magnitude for 125I and 103Pd seed implants respectively. At the extreme (95% edema magnitude and an edema half-life of 30 days), the increase was more than 3 and 5 orders of magnitude for 125I and I03Pd seed implants respectively. The absolute increases were almost independent of TPDT and the prostate edema did not significantly change the effective treatment time. Tumour cell survival for prostate undergoing CLDRI using 125I or 103Pd seeds may be increased substantially due to the presence of edema caused by surgical trauma. This effect appears to be more pronounced for 103Pd than 125I because of the shorter half-life of 103Pd. If significant edema is observed post implantation, then a boost to the prostate using external beam radiotherapy may be considered as a part of the treatment strategy.


[Castleman disease arising from cardiophrenic angle; report of a case].
We report the first case of Castleman disease arising from cardiophrenic angle. The patient was referred to our hospital to treat his mediastinal tumor. Computed tomography (CT) showed a well-enhanced mass arising from the right cardiophrenic angle. We speculated the tumor to be a Castleman disease or hemangioma. Right thoracotomy was performed, and the tumor was removed after the ligation of the feeding artery and drainage vein. The histological findings of the tumor led to a diagnosis of Castleman disease hyaline vascular type.


[Morphofunctional changes in the endocrine system of male rats during microgravity and suspension].
Morphofunctional changes in somatotrophs and gonadotrophs of the adenohypophysis and Leydig's cells in the testicles were investigated histologically and hystomorphometrically in male rats following microgravity or tail-suspension. Deficient loading of the musculoskeletal system in microgravity was shown to suppress the functional activity of somatotrophs, gonadotrophs and, seemingly, Leydig's cells. As a consequence, blood levels of the growth hormone and testosterone reduced in the space-flown rats. Reduction of the production of the main anabolic hormones is one of the causes for growth inhibition, prevalence of catabolism and consequent muscular atrophy and osteopenia. Simulation of the lack of weight loading inherent to the zero-g environment by suspension also leads to suppression of the somatotrophs activity, whereas the concentration and functional activity of gonadotrophs make a sharp rise. Proliferation of Leydig's cells in the testicles was noted to be very high despite desolation of the seminal canals and disintegration of the testicle epithelium. These findings drive to the conclusion that suspension affects deeply the spermiogenous and androgenous functions of the testicle which is not observed in animals exposed to microgravity. These differences evidence that genesis of the musculoskeletal atrophy in the suspended and space-flown rats was dissimilar.


Trends in Prevalence of Cannabis Use Disorder Among U.S. Veterans With and Without Psychiatric Disorders Between 2005 and 2019.
Cannabis use disorder diagnoses are increasing among U.S. adults and are more prevalent among people with comorbid psychiatric disorders. Recent changes in cannabis laws, increasing cannabis availability, and higher-potency cannabis may have placed people with cannabis use and psychiatric disorders at disproportionately increasing risk for cannabis use disorder. The authors used Veterans Health Administration (VHA) data to examine whether trends in cannabis use disorder prevalence among VHA patients differ by whether they have psychiatric disorders. VHA electronic health records from 2005 to 2019 (N range, 4,332,165-5,657,277) were used to identify overall and age-group-specific (<35, 35-64, and ≥65 years) trends in prevalence of cannabis use disorder diagnoses among patients with depressive, anxiety, posttraumatic stress, bipolar, or psychotic spectrum disorders and to compare these to corresponding trends among patients without any of these disorders. Given transitions in ICD coding, differences in trends were tested within two periods: 2005-2014 (ICD-9-CM) and 2016-2019 (ICD-10-CM). Greater increases in prevalence of cannabis use disorder diagnoses were observed among patients with psychiatric disorders compared to those without (difference in prevalence change, 2005-2014: 1.91%, 95% CI=1.87-1.96; 2016-2019: 0.34%, 95% CI=0.29-0.38). Disproportionate increases in cannabis use disorder prevalence among patients with psychiatric disorders were greatest among those under age 35 between 2005 and 2014, and among those age 65 or older between 2016 and 2019. Among patients with psychiatric disorders, the greatest increases in cannabis use disorder prevalences were observed among those with bipolar and psychotic spectrum disorders. The findings highlight disproportionately increasing disparities in risk of cannabis use disorder among VHA patients with common psychiatric disorders. Greater public health and clinical efforts are needed to monitor, prevent, and treat cannabis use disorder in this population.


Trametes versicolor glutathione transferase Xi 3, a dual Cys-GST with catalytic specificities of both Xi and Omega classes.
Glutathione transferases (GSTs) from the Xi and Omega classes have a catalytic cysteine residue, which gives them reductase activities. Until now, they have been assigned distinct substrates. While Xi GSTs specifically reduce glutathionyl-(hydro)quinones, Omega GSTs are specialized in the reduction of glutathionyl-acetophenones. Here, we present the biochemical and structural analysis of TvGSTX1 and TvGSTX3 isoforms from the wood-degrading fungus Trametes versicolor. TvGSTX1 reduces GS-menadione as expected, while TvGSTX3 reduces both Xi and Omega substrates. An in-depth structural analysis indicates a broader active site for TvGSTX3 due to specific differences in the nature of the residues situated in the C-terminal helix α9. This feature could explain the catalytic duality of TvGSTX3. Based on phylogenetic analysis, we propose that this duality might exist in saprophytic fungi and ascomycetes.


ZEBRA: a hierarchically integrated gene expression atlas of the murine and human brain at single-cell resolution.
The molecular causes and mechanisms of neurodegenerative diseases remain poorly understood. A growing number of single-cell studies have implicated various neural, glial, and immune cell subtypes to affect the mammalian central nervous system in many age-related disorders. Integrating this body of transcriptomic evidence into a comprehensive and reproducible framework poses several computational challenges. Here, we introduce ZEBRA, a large single-cell and single-nucleus RNA-seq database. ZEBRA integrates and normalizes gene expression and metadata from 33 studies, encompassing 4.2 million human and mouse brain cells sampled from 39 brain regions. It incorporates samples from patients with neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and Multiple sclerosis, as well as samples from relevant mouse models. We employed scVI, a deep probabilistic auto-encoder model, to integrate the samples and curated both cell and sample metadata for downstream analysis. ZEBRA allows for cell-type and disease-specific markers to be explored and compared between sample conditions and brain regions, a cell composition analysis, and gene-wise feature mappings. Our comprehensive molecular database facilitates the generation of data-driven hypotheses, enhancing our understanding of mammalian brain function during aging and disease. The data sets, along with an interactive database are freely available at https://www.ccb.uni-saarland.de/zebra.


Biosynthesis of bicyclomycin. I. Appearance of aerial mycelia negative strains (am-).
The degeneration of bicyclomycin-producing strains of Streptomyces sapporonensis resulted in sharply depressed bicyclomycin formation in a large scale fermentation. Degenerated strains, whose productivities were only 1/30 to 1/100 of normal strains, could not form aerial mycelia on glucose-BENNETT's agar; they were aerial mycelia negative strains (am-). Repeated transfers of culture, treatment of mycelia with acriflavin, mechanical agitation shock on mycelia or higher growth conditions stimulated the degeneration of producing strains, suggesting the involvement of extrachromosomal elements or plasmids in biosynthesis of bicyclomycin. Shake flask fermentation inoculated with a mixture of a normal high-producing strain and a degenerated low-producing strain resulted in sharply depressed bicyclomycin formation in proportion to the increase of low-producing strain added. It appears that the low-producing strain outgrew the high-producing strain.


New approaches to supporting the failing liver.
With the continued, growing disparity between the numbers of organ donations and patients waiting for liver transplantation, various efforts have been made to optimize the allocation of organs, as well as to devise means to support the failing liver. Over the years, the development of bioartificial liver-assist devices has aimed at replacing the three main functions of hepatocytes, which are synthetic, metabolic, and excretory. The application of porcine hepatocytes in humans to carry out biotransformation, as well as other metabolic functions and refinement of the membrane separator, have yielded some promising results in supporting patients with acute liver failure. Further advances will need to be made before these bioartificial devices can be considered for routine application in clinical settings.


Conformationally Switchable Silylone: Electron Redistribution Accompanied by Ligand Reorientation around a Monatomic Silicon.
Complexes that could be switched between two electronic states by external stimuli have attracted much attention for their potential application in molecular devices. However, a realization of such a phenomenon with low-valent main-group element-centered complexes remains challenging. Herein, we report the synthesis of cyclic (alkyl)(amino)silylene (CAASi)-ligated monatomic silicon(0) complexes (silylones). The bis(CAASi)-ligated silylone adopts a π-localized ylidene structure (greenish-black color) in the solid state and a π-delocalized ylidene structure (dark-purple color) in solution that could be reversibly switched upon phase transfer (ylidene [L: → :Si = L ↔ L = Si: ← :L]). The observed remarkable difference in the physical properties of the two isomers is attributed to the balanced steric demand and redox noninnocent character of the CAASi ligand which are altered by the orientation of the two terminal ligands with respect to the Si-Si-Si plane: twisted structure (π-localized ylidene) and planar structure (π-delocalized ylidene). Conversely, the CAASi/CDASi-ligated heteroleptic silylone (CDASi = cyclic dialkylsilylene) only exhibited the twisted π-localized ylidene structure regardless of the phase. The synthesized silylones also proved themselves as monatomic silicon surrogates. Thermolysis of the silylones in the presence of an ethane-1,2-diimine afforded the corresponding diaminosilylenes. Analyses of the products suggested a stepwise mechanism that proceeds via a disilavinylidene intermediate.


Emergence of glutaraldehyde-resistant Pseudomonas aeruginosa.
In November 2009, routine sampling of endoscopes performed to monitor the effectiveness of the endoscope-cleaning procedure at our hospital detected Pseudomonas aeruginosa. Herein we report the results of the subsequent investigation. The investigation included environmental cultures for source investigation, molecular analysis by pulsed-field gel electrophoresis (PFGE) to reveal the identity of the strains, and determination of the bactericidal activity of the glutaraldehyde-based disinfectant used for automated endoscope reprocessing. In addition, patient outcome was analyzed by medical chart review, and incidence rates of clinical samples with P. aeruginosa were compared. The University Hospital of Basel is an 855-bed tertiary care center in Basel, Switzerland. Approximately 1,700 flexible bronchoscopic, 2,500 gastroscopic, 1,400 colonoscopic, 140 endoscopic retrograde cholangiopancreatographic, and 140 endosonographic procedures are performed annually. P. aeruginosa was detected in samples obtained from endoscopes in November 2009 for the first time since the initiation of surveillance in 2006. It was found in the rinsing water and in the drain of 1 of the 2 automated endoscope reprocessors. PFGE revealed 2 distinct P. aeruginosa strains, one in each reprocessor. The glutaraldehyde-based disinfectant showed no activity against the 2 pseudo-outbreak strains when used in the recommended concentration under standard conditions. After medical chart review, 6 patients with lower respiratory tract and bloodstream infections were identified as having a possible epidemiological link to the pseudo-outbreak strain. This is the first description of a pseudo-outbreak caused by P. aeruginosa with reduced susceptibility to an aldehyde-based disinfectant routinely used in the automated processing of endoscopes.


Diversity shrinkage: Cross-validating pareto-optimal weights to enhance diversity via hiring practices.
To reduce adverse impact potential and improve diversity outcomes from personnel selection, one promising technique is De Corte, Lievens, and Sackett's (2007) Pareto-optimal weighting strategy. De Corte et al.'s strategy has been demonstrated on (a) a composite of cognitive and noncognitive (e.g., personality) tests (De Corte, Lievens, & Sackett, 2008) and (b) a composite of specific cognitive ability subtests (Wee, Newman, & Joseph, 2014). Both studies illustrated how Pareto-weighting (in contrast to unit weighting) could lead to substantial improvement in diversity outcomes (i.e., diversity improvement), sometimes more than doubling the number of job offers for minority applicants. The current work addresses a key limitation of the technique-the possibility of shrinkage, especially diversity shrinkage, in the Pareto-optimal solutions. Using Monte Carlo simulations, sample size and predictor combinations were varied and cross-validated Pareto-optimal solutions were obtained. Although diversity shrinkage was sizable for a composite of cognitive and noncognitive predictors when sample size was at or below 500, diversity shrinkage was typically negligible for a composite of specific cognitive subtest predictors when sample size was at least 100. Diversity shrinkage was larger when the Pareto-optimal solution suggested substantial diversity improvement. When sample size was at least 100, cross-validated Pareto-optimal weights typically outperformed unit weights-suggesting that diversity improvement is often possible, despite diversity shrinkage. Implications for Pareto-optimal weighting, adverse impact, sample size of validation studies, and optimizing the diversity-job performance tradeoff are discussed. (PsycINFO Database Record


Global control of cell-cycle transcription by coupled CDK and network oscillators.
A significant fraction of the Saccharomyces cerevisiae genome is transcribed periodically during the cell division cycle, indicating that properly timed gene expression is important for regulating cell-cycle events. Genomic analyses of the localization and expression dynamics of transcription factors suggest that a network of sequentially expressed transcription factors could control the temporal programme of transcription during the cell cycle. However, directed studies interrogating small numbers of genes indicate that their periodic transcription is governed by the activity of cyclin-dependent kinases (CDKs). To determine the extent to which the global cell-cycle transcription programme is controlled by cyclin-CDK complexes, we examined genome-wide transcription dynamics in budding yeast mutant cells that do not express S-phase and mitotic cyclins. Here we show that a significant fraction of periodic genes are aberrantly expressed in the cyclin mutant. Although cells lacking cyclins are blocked at the G1/S border, nearly 70% of periodic genes continued to be expressed periodically and on schedule. Our findings reveal that although CDKs have a function in the regulation of cell-cycle transcription, they are not solely responsible for establishing the global periodic transcription programme. We propose that periodic transcription is an emergent property of a transcription factor network that can function as a cell-cycle oscillator independently of, and in tandem with, the CDK oscillator.


Expression strategy of Aedes albopictus densovirus.
The transcription map of the Aedes albopictus densovirus (AalDNV) brevidensovirus was identified by Northern blotting, rapid amplification of cDNA ends (RACE) analysis, and RNase protection assays. AalDNV produced mRNAs of 3,359 (NS1), 3,345 (NS2), and 1,246 (VP) nucleotides. The two overlapping P7/7.4 NS promoters employed closely located alternate transcription initiation sites, positioned at either side of the NS1 initiation codon. All NS mRNAs coterminated with VP mRNA. All promoters, explored using luciferase assays, were functional in insect and human cell lines.


Wafer-scale single-orientation 2D layers by atomic edge-guided epitaxial growth.
Two-dimensional (2D) layered materials hold tremendous promise for post-Si nanoelectronics due to their unique optical and electrical properties. Significant advances have been achieved in device fabrication and synthesis routes for 2D nanoelectronics over the past decade; however, one major bottleneck preventing their immediate applications has been the lack of a reproducible approach for growing wafer-scale single-crystal films despite tremendous progress in recent experimental demonstrations. In this tutorial review, we provide a systematic summary of the critical factors-including crystal/substrate symmetry and energy consideration-necessary for synthesizing single-orientation 2D layers. In particular, we focus on the discussions of the atomic edge-guided epitaxial growth, which assists in unidirectional nucleation for the wafer-scale growth of single-crystal 2D layers.


Twenty-year United States national, demographic and regional mortality trends from traumatic thoracic aortic injury, 1999 to 2019.
Traumatic Thoracic Aortic Injury (TTAI) is associated with high mortality rates and is the second leading cause of death in traumatic patients. There has been a considerable advancement in the management of TTAI with novel and improved surgical procedures and imaging modalities. The aim of this study was to determine the national demographic and regional trends in mortality associated with TTAI in the United States across twenty years, 1999 to 2019. The multiple cause of death data on Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC-WONDER) database was utilized to query death certificates for TTAI from 1999 to 2019, in the United States. The International Classification of the Diseases, Tenth Revision (ICD-10) code S25.0 was used to identify and abstract data for TTAI related deaths. The data was further abstracted based on age, race, gender and Census-Bureau defined regions. The age-adjusted mortality rate (AAMR) per 100,000 population-year and Average Annual Percentage Change (AAPC) with 95 % Confidence Interval were computed. The JoinPoint software was utilized to compute the temporal trends in mortality based on a segmented change and AAPC calculation. A total of 20,842 TTAI associated deaths occurred from 1999 to 2019 corresponding to an AAMR of 0.407(0.401-0.412) per 100,000 population-year. The overall AAMR reduced from 0.759 to 0.223 per 100,000 population-year from 1999 to 2019[average APC -6.5(-7.5; -5.5)]. The reduction was reported in both <45 age group [average APC -6.5(-7.9; -5.1)] and >45 age group [-6.2(-7.3; -5.0)]; among females [average APC -6.1(-7.8; -4.3)] and males [-6.1(-7.2; -5.0)]; among Whites [average APC -6.9(-7.8; -5.9)] and Blacks [-5.0(-7.4; -2.5)]. The reduction in mortality as per the census region was highest in the west followed by Mid-West, North-East and South [average APC -6.8(-8.6; -5.0); -6.2(-8.8; -3.6); -5.7(-7.0; -4.4); -5.5(-7.4; -3.6), respectively]. There was a significant decrease in the TTAI associated mortality trends in the United States across 1999-2019 with a consistent decline in all demographic and regional subgroups.


Primary amyloidosis-induced nail dystrophy.
Primary amyloidosis is caused by a monoclonal proliferation of plasma cells and is capable of producing cutaneous lesions. A 56-year-old male was admitted to the hospital for evaluation of chronic back pain and acute lower extremity weakness. On examination, he was noted to have subungual verrucous plaques with overlying nail dystrophy on his bilateral thumbs. A biopsy of one subungual lesion showed a deposition of amorphous material in the dermis that stained with Congo red and crystal violet. These cutaneous lesions ultimately led to the diagnosis of plasma cell dyscrasia and primary amyloidosis. Based on the literature search, primary amyloidosis presenting with this degree of subungual thickening and overlying nail dystrophy has not been previously reported.


Metallic lead nanospheres discovered in ancient zircons.
Zircon (ZrSiO4) is the most commonly used geochronometer, preserving age and geochemical information through a wide range of geological processes. However, zircon U-Pb geochronology can be affected by redistribution of radiogenic Pb, which is incompatible in the crystal structure. This phenomenon is particularly common in zircon that has experienced ultra-high temperature metamorphism, where ion imaging has revealed submicrometer domains that are sufficiently heterogeneously distributed to severely perturb ages, in some cases yielding apparent Hadean (>4 Ga) ages from younger zircons. Documenting the composition and mineralogy of these Pb-enriched domains is essential for understanding the processes of Pb redistribution in zircon and its effects on geochronology. Using high-resolution scanning transmission electron microscopy, we show that Pb-rich domains previously identified in zircons from East Antarctic granulites are 5-30 nm nanospheres of metallic Pb. They are randomly distributed with respect to zircon crystallinity, and their association with a Ti- and Al-rich silica melt suggests that they represent melt inclusions generated during ultra-high temperature metamorphism. Metallic Pb is exceedingly rare in nature and previously has not been reported in association with high-grade metamorphism. Formation of these metallic nanospheres within annealed zircon effectively halts the loss of radiogenic Pb from zircon. Both the redistribution and phase separation of radiogenic Pb in this manner can compromise the precision and accuracy of U-Pb ages obtained by high spatial resolution methods.


Three-dimensional airway changes after Le Fort III advancement in syndromic craniosynostosis patients.
To investigate the changes of upper airway volume in syndromic craniosynostosis patients following Le Fort III advancement, computed tomographic scans were analyzed and related to the amount of advancement. In this retrospective study, the preoperative and postoperative computed tomographic scans of 19 patients with syndromic craniosynostosis who underwent Le Fort III advancement were analyzed. In four cases, preoperative polysomnography demonstrated obstructive sleep apnea. The airway was segmented using a semiautomatic region growing method with a fixed Hounsfield threshold value. Airway volumes of hypopharynx and oropharynx (compartment A) and nasopharynx and nasal cavity (compartment B) were analyzed separately, as was the total airway volume. Advancement of the midface was recorded using lateral skull radiographs. Data were analyzed for all patients together and for patients with Crouzon/Pfeiffer and Apert syndromes separately. Airway volume increased significantly in compartment A (20 percent; p = 0.044) and compartment B (48 percent; p < 0.001), as did total airway volume in (37 percent; p < 0.001) in the total study group. No significant differences in volume changes were found comparing Apert with Crouzon/Pfeiffer patients. No distinct relation could be found between advancement of the midface and volume gain either in the total study group or in Apert and Crouzon/Pfeiffer patient groups separately. Postoperative polysomnography showed significant improvement of obstructive sleep apnea in all four patients. A significant improvement of the upper airway after Le Fort III advancement in syndromic craniosynostosis patients is demonstrated. No distinct relation could be observed between advancement and airway volume changes.


Self-efficacy mediates the relationship between depression and length of abstinence after treatment among youth but not among adults.
We present two studies testing whether self-efficacy mediates the relationship between depression symptoms and initial abstinence duration after substance use treatment in adolescents and adults. Study 1: Adolescents (N = 208) were recruited from substance use treatment in an urban/suburban area in the United States between 1999 and 2005 and were followed monthly after discharge. Measures used were affective state (depression symptoms), drug-taking coping self-efficacy, and length of abstinence after treatment. Self-efficacy fully mediated the relationship between depression and time to use. Study 2: In a similar study design, adult veterans (N = 160) in outpatient substance user treatment were interviewed during treatment and monthly following treatment. Depression was negatively associated with self-efficacy, and self-efficacy predicted time to first substance use, but there was no mediation. Study implications and limitations are noted.


Nutrition component in a comprehensive child development program. I. The home visitor's role in the prenatal intervention phase.
Nutritional services were integrated in a comprehensive child development program for sixty-eight disadvantaged urban families in an attempt to promote maximum cognitive and psychosocial functioning in their children. Child development trainers made weekly home visits beginning in pregnancy, which combined data gathering, direct nutritional counseling, and early sensory excercises for infants. This paper describes the prenatal home visit program, the training of the home visitors, how the 24-hr. food recall method was adapted for their use, the nature of the home visits, and the complex role of the home visitor. The group whose families participated in the prenatal home visits and were also followed for six months after the infants' birth scored higher on six-month Cattell Scales than did a control group who entered the program at six months of age. There were no stillbirths or neonatal deaths. The incidence of low-birth-weight infants was lower than the national averages. Participation in the program was high.