Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial.
Many patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy show primary resistance. High-dose radiotherapy can lead to increased tumor antigen release, improved antigen presentation, and T-cell infiltration. This radiotherapy may enhance the effects of checkpoint inhibition. To assess whether stereotactic body radiotherapy on a single tumor site preceding pembrolizumab treatment enhances tumor response in patients with metastatic NSCLC. Multicenter, randomized phase 2 study (PEMBRO-RT) of 92 patients with advanced NSCLC enrolled between July 1, 2015, and March 31, 2018, regardless of programmed death-ligand 1 (PD-L1) status. Data analysis was of the intention-to-treat population. Pembrolizumab (200 mg/kg every 3 weeks) either alone (control arm) or after radiotherapy (3 doses of 8 Gy) (experimental arm) to a single tumor site until confirmed radiographic progression, unacceptable toxic effects, investigator decision, patient withdrawal of consent, or a maximum of 24 months. Improvement in overall response rate (ORR) at 12 weeks from 20% in the control arm to 50% in the experimental arm with P < .10. Of the 92 patients enrolled, 76 were randomized to the control arm (n = 40) or the experimental arm (n = 36). Of those, the median age was 62 years (range, 35-78 years), and 44 (58%) were men. The ORR at 12 weeks was 18% in the control arm vs 36% in the experimental arm (P = .07). Median progression-free survival was 1.9 months (95% CI, 1.7-6.9 months) vs 6.6 months (95% CI, 4.0-14.6 months) (hazard ratio, 0.71; 95% CI, 0.42-1.18; P = .19), and median overall survival was 7.6 months (95% CI, 6.0-13.9 months) vs 15.9 months (95% CI, 7.1 months to not reached) (hazard ratio, 0.66; 95% CI, 0.37-1.18; P = .16). Subgroup analyses showed the largest benefit from the addition of radiotherapy in patients with PD-L1-negative tumors. No increase in treatment-related toxic effects was observed in the experimental arm. Stereotactic body radiotherapy prior to pembrolizumab was well tolerated. Although a doubling of ORR was observed, the results did not meet the study's prespecified end point criteria for meaningful clinical benefit. Positive results were largely influenced by the PD-L1-negative subgroup, which had significantly improved progression-free survival and overall survival. These results suggest that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC toward a more inflamed tumor microenvironment. ClinicalTrials.gov identifier: NCT02492568.


Stochastic blockmodeling of the modules and core of the Caenorhabditis elegans connectome.
Recently, there has been much interest in the community structure or mesoscale organization of complex networks. This structure is characterised either as a set of sparsely inter-connected modules or as a highly connected core with a sparsely connected periphery. However, it is often difficult to disambiguate these two types of mesoscale structure or, indeed, to summarise the full network in terms of the relationships between its mesoscale constituents. Here, we estimate a community structure with a stochastic blockmodel approach, the Erdős-Rényi Mixture Model, and compare it to the much more widely used deterministic methods, such as the Louvain and Spectral algorithms. We used the Caenorhabditis elegans (C. elegans) nervous system (connectome) as a model system in which biological knowledge about each node or neuron can be used to validate the functional relevance of the communities obtained. The deterministic algorithms derived communities with 4-5 modules, defined by sparse inter-connectivity between all modules. In contrast, the stochastic Erdős-Rényi Mixture Model estimated a community with 9 blocks or groups which comprised a similar set of modules but also included a clearly defined core, made of 2 small groups. We show that the "core-in-modules" decomposition of the worm brain network, estimated by the Erdős-Rényi Mixture Model, is more compatible with prior biological knowledge about the C. elegans nervous system than the purely modular decomposition defined deterministically. We also show that the blockmodel can be used both to generate stochastic realisations (simulations) of the biological connectome, and to compress network into a small number of super-nodes and their connectivity. We expect that the Erdős-Rényi Mixture Model may be useful for investigating the complex community structures in other (nervous) systems.


Local crystallographic shear structures in a[201] extended mixed dislocations of SrTiO3 unraveled by atomic-scale imaging using transmission electron microscopy and spectroscopy.
Recently, extended mixed dislocations were observed at a [001]/(100) low-angle tilt grain boundary of a SrTiO3 bicrystal because of a slight twist between the two crystal parts. The b = a[201]/(100) mixed dislocations at the grain boundary dissociate into three dislocations with Burgers vector b of a/2[101], a[100], and a/2[101], respectively. A structure model has been proposed in particular for the dislocation cores of the two partials with b = a/2[101] based on the high-angle annular dark-field (HAADF) images acquired by scanning transmission electron microscopy (STEM). However, the details of the atomic structure and the chemical composition of the dislocation cores remain unexplored, especially for the b = a[100] dislocation that is evidently disassociated into two b = a/2[101] partial dislocations. In this work, we study the further atomic details of the extended mixed dislocations, in particular the local chemistry, in a SrTiO3 bicrystal using STEM, electron energy loss spectroscopy (EELS), and energy dispersive X-ray (EDX) spectroscopy techniques. By these atomic-scale imaging techniques, we reveal a unique feature for the atomic structure of the b = a[201]/(100) extended mixed dislocation, which we named as local crystallographic shear (LCS) structures. In addition, we identify a rock salt FCC-type TiOx (x = 0.66-1.24) phase at the locations of the extended mixed dislocations. In contrast to the insulating TiO2 phases, the TiOx phase is known to exhibit very low electrical resistivity of only several μΩ cm. In this regard, the extended mixed dislocations of SrTiO3 comprising the FCC TiOx phase may function as the conducting filament in resistive switching processes by completion and disruption of the TiOx phase along the dislocation cores through electrically stimulated redox reactions.


Microbial cell disruption methods for efficient release of enzyme L-asparaginase.
The efficacy of a simple laboratory method for cell disruption based on the glass bead stirring, sonication, osmotic shock, freezing and grinding, or use of solvents and detergents was assessed in this study, via measurements of the release of total protein and L-asparaginase activity. Three different microbial sources of L-asparaginase were used: Escherichia coli BL21 (DE3), Leucosporidium muscorum, and Aspergillus terreus (CCT 7693). This study adjusted and identified the best procedure for each kind of microorganism. Sonication and glass bead stirring led to obtaining filamentous fungus cell-free extracts containing high concentrations of soluble proteins and specific activity; however, sonication was the best since it obtained 4.61 ± 0.12 IU mg-1 after 3 min of operation time. Mechanical methods were also the most effective for yeast cell disruption, but sonication was the technique which yielded a higher efficiency releasing 7.3 IUtotal compared to glass bead stirring releasing 2.7 IUtotal at the same operation time. For bacterium, sonication proved to be the best procedure due to getting the highest specific activity (9.01 IU mg-1) and total enzyme activity (61.7 IU). The data presented lead to conclude that the mechanical methods appeared to be the most effective for the disintegration of the all microbial cells studies. This is the first report related to the experimental comparison of L-ASNase extraction procedures from different microorganisms, which can also be used for extracting periplasm located enzymes from other organisms.


Analysis of copy number variation using quantitative interspecies competitive PCR.
Over recent years small submicroscopic DNA copy-number variants (CNVs) have been highlighted as an important source of variation in the human genome, human phenotypic diversity and disease susceptibility. Consequently, there is a pressing need for the development of methods that allow the efficient, accurate and cheap measurement of genomic copy number polymorphisms in clinical cohorts. We have developed a simple competitive PCR based method to determine DNA copy number which uses the entire genome of a single chimpanzee as a competitor thus eliminating the requirement for competitive sequences to be synthesized for each assay. This results in the requirement for only a single reference sample for all assays and dramatically increases the potential for large numbers of loci to be analysed in multiplex. In this study we establish proof of concept by accurately detecting previously characterized mutations at the PARK2 locus and then demonstrating the potential of quantitative interspecies competitive PCR (qicPCR) to accurately genotype CNVs in association studies by analysing chromosome 22q11 deletions in a sample of previously characterized patients and normal controls.


Fasting as a Therapy in Neurological Disease.
Fasting is deeply entrenched in evolution, yet its potential applications to today's most common, disabling neurological diseases remain relatively unexplored. Fasting induces an altered metabolic state that optimizes neuron bioenergetics, plasticity, and resilience in a way that may counteract a broad array of neurological disorders. In both animals and humans, fasting prevents and treats the metabolic syndrome, a major risk factor for many neurological diseases. In animals, fasting probably prevents the formation of tumors, possibly treats established tumors, and improves tumor responses to chemotherapy. In human cancers, including cancers that involve the brain, fasting ameliorates chemotherapy-related adverse effects and may protect normal cells from chemotherapy. Fasting improves cognition, stalls age-related cognitive decline, usually slows neurodegeneration, reduces brain damage and enhances functional recovery after stroke, and mitigates the pathological and clinical features of epilepsy and multiple sclerosis in animal models. Primarily due to a lack of research, the evidence supporting fasting as a treatment in human neurological disorders, including neurodegeneration, stroke, epilepsy, and multiple sclerosis, is indirect or non-existent. Given the strength of the animal evidence, many exciting discoveries may lie ahead, awaiting future investigations into the viability of fasting as a therapy in neurological disease.


Bringing ecosystem services into economic decision-making: land use in the United Kingdom.
Landscapes generate a wide range of valuable ecosystem services, yet land-use decisions often ignore the value of these services. Using the example of the United Kingdom, we show the significance of land-use change not only for agricultural production but also for emissions and sequestration of greenhouse gases, open-access recreational visits, urban green space, and wild-species diversity. We use spatially explicit models in conjunction with valuation methods to estimate comparable economic values for these services, taking account of climate change impacts. We show that, although decisions that focus solely on agriculture reduce overall ecosystem service values, highly significant value increases can be obtained from targeted planning by incorporating all potential services and their values and that this approach also conserves wild-species diversity.


A horizontal bias in human visual processing of orientation and its correspondence to the structural components of natural scenes.
Many encoding mechanisms and processing strategies in the visual system appear to have evolved to better process the prevalent content in the visual world. Here we examine the relationship between the prevalence of natural scene content at different orientations and visual ability for detecting oriented natural scene content. Whereas testing with isolated gratings shows best performance at horizontal and vertical (the oblique effect), we report that when tested with natural scene content, performance is best at obliques and worst at horizontal (the horizontal effect). The present analysis of typical natural scenes shows that the prevalence of natural scene content matches the inverse of this horizontal effect pattern with most scene content at horizontal, next most at vertical, and least at obliques. We suggest that encoding of orientation may have evolved to accommodate the anisotropy in natural scene content by perceptually discounting the most prevalent oriented content in a scene, thereby increasing the relative salience of objects and other content in a scene when viewed against a typical natural background.


Potentially antioxidant compounds indicated from Mallotus and Phyllanthus species fingerprints.
The genera of Mallotus and Phyllanthus contain several species that are commonly used as traditional medicines in oriental countries. Some species show interesting pharmaceutical activities, such as an antioxidant activity. To produce clinically useful medicines or food supplements (nutraceuticals) from these herbs, the species should be identified and a thorough quality control should be implemented. Nowadays, the integration of chromatographic and chemometric approaches allows a high-throughput identification and activity prediction of medicinal plants. In this study, Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) were applied and compared to distinguish Mallotus and Phyllanthus species. Moreover, peaks from their chromatographic fingerprints, which were responsible for their antioxidant activity were assigned. For the latter purpose, the relevant information was extracted from the chromatographic fingerprints using linear multivariate calibration techniques, i.e., Partial Least Squares (PLS) and Orthogonal Projections to Latent Structures (O-PLS). Results reveal that exploratory analysis using PCA shows somewhat diverging clustering tendencies between Mallotus and Phyllanthus samples than HCA. However, both approaches mainly confirm each other. Concerning the multivariate calibration techniques, both PLS and O-PLS models demonstrate good predictive abilities. By comparing the regression coefficients of the models with the chromatographic fingerprints, the peaks that are potentially responsible for the antioxidant activity of the extracts could be confirmed.


Wolbachia Endosymbionts Modify Drosophila Ovary Protein Levels in a Context-Dependent Manner.
Endosymbiosis is a unique form of interaction between organisms, with one organism dwelling inside the other. One of the most widespread endosymbionts is Wolbachia pipientis, a maternally transmitted bacterium carried by insects, crustaceans, mites, and filarial nematodes. Although candidate proteins that contribute to maternal transmission have been identified, the molecular basis for maternal Wolbachia transmission remains largely unknown. To investigate transmission-related processes in response to Wolbachia infection, ovarian proteomes were analyzed from Wolbachia-infected Drosophila melanogaster and D. simulans. Endogenous and variant host-strain combinations were investigated. Significant and differentially abundant ovarian proteins were detected, indicating substantial regulatory changes in response to Wolbachia Variant Wolbachia strains were associated with a broader impact on the ovary proteome than endogenous Wolbachia strains. The D. melanogaster ovarian environment also exhibited a higher level of diversity of proteomic responses to Wolbachia than D. simulans. Overall, many Wolbachia-responsive ovarian proteins detected in this study were consistent with expectations from the experimental literature. This suggests that context-specific changes in protein abundance contribute to Wolbachia manipulation of transmission-related mechanisms in oogenesis. Millions of insect species naturally carry bacterial endosymbionts called Wolbachia. Wolbachia bacteria are transmitted by females to their offspring through a robust egg-loading mechanism. The molecular basis for Wolbachia transmission remains poorly understood at this time, however. This proteomic study identified specific fruit fly ovarian proteins as being upregulated or downregulated in response to Wolbachia infection. The majority of these protein responses correlated specifically with the type of host and Wolbachia strain involved. This work corroborates previously identified factors and mechanisms while also framing the broader context of ovarian manipulation by Wolbachia.


The effects of variations in the anti-G straining maneuver on blood pressure at +Gz acceleration.
The increase in blood pressure provided by the standard AGSM is caused by both the contraction of the muscles of the lower body and by an increased intrathoracic pressure due to a respiratory straining (Valsalva) maneuver. This study examined the relative effectiveness and fatigability of the two components at +1 Gz and during +Gz acceleration in a human centrifuge. Brachial arterial pressure was recorded from a pressure-tip transducer in six subjects performing isometric leg presses only and on a separate occasion while performing respiratory straining only. Measurements were made over a range of intensities for the leg press contractions and Valsalva maneuvers and were conducted at +1 Gz and during slow and rapid onset runs up to +5 Gz in a human centrifuge. Blood pressure was also recorded during pulsing or intermittent contractions of the legs. We found it difficult to completely separate the blood pressure response to the leg press component from that of the respiratory straining alone component, since a moderate respiratory straining maneuver usually accompanied forceful contractions of the legs. We conclude, however, that a major portion of the elevation in blood pressure caused by the AGSM can be attributed to contraction of the muscles of the lower body and that this component is less fatiguing than the respiratory straining component. At +1 Gz a pulsing isometric contraction of the legs was no more effective in elevating blood pressure than a constant isometric contraction over the same duration.


Acute mesenteric ischemia after cardiac surgery: an analysis of 52 patients.
Acute mesenteric ischemia (AMI) is a rare but serious complication after cardiac surgery. The aim of this retrospective study was to evaluate the incidence, outcome, and perioperative risk factors of AMI in the patients undergoing elective cardiac surgery. From January 2005 to May 2013, all patients who underwent cardiac surgery were screened for participation, and patients with registered gastrointestinal complications were retrospectively reviewed. Univariate analyses were performed. The study included 6013 patients, of which 52 (0.86%) patients suffered from AMI, 35 (67%) of whom died. The control group (150 patients) was randomly chosen from among cases undergoing cardiopulmonary bypass (CPB). Preoperative parameters including age (P = 0.03), renal insufficiency (P = 0.004), peripheral vascular disease (P = 0.04), preoperative inotropic support (P < 0.001), poor left ventricular ejection fraction (P = 0.002), cardiogenic shock (P = 0.003), and preoperative intra-aortic balloon pump (IABP) support (P = 0.05) revealed significantly higher levels in the AMI group. Among intra- and postoperative parameters, CPB time (P < 0.001), dialysis (P = 0.04), inotropic support (P = 0.007), prolonged ventilator time (P < 0.001), and IABP support (P = 0.007) appeared significantly higher in the AMI group than the control group. Prompt diagnosis and early treatment should be initiated as early as possible in any patient suspected of AMI, leading to dramatic reduction in the mortality rate.


Risk factors for uterine rupture among women who attempt a vaginal birth after a previous cesarean: a case-control study.
To identify risk factors associated with uterine rupture among term pregnancies attempting a vaginal birth after a previous cesarean. A case-control study was done of 348 uterine ruptures in Massachusetts between 1991 and 1998, initially screened by ICD-9 code and confirmed by medical record review, with 424 control women with a trial of labor randomly selected proportional to cases on year of delivery. Multivariable regression was used to estimate odds ratios and 95% confidence intervals. Successful previous vaginal birth decreased risk for uterine rupture, and gestation > 40 weeks and macrosomia increased risk. Oxytocin for induction increased risk, with a slightly lower effect when used for augmentation. Prostaglandin use in conjunction with oxytocin did not have an additive uterine rupture risk. Women using epidural analgesia have an increased uterine rupture risk. Certain labor management practices increase the risk for uterine rupture 2-3 times, although the absolute increase is small from a baseline uterine rupture rate of 0.5% to 1.0-1.5%. The association between epidural analgesia and uterine rupture deserves further study.


DNA base excision repair: a mechanism of trinucleotide repeat expansion.
The expansion of trinucleotide repeat (TNR) sequences in human DNA is considered to be a key factor in the pathogenesis of more than 40 neurodegenerative diseases. TNR expansion occurs during DNA replication and also, as suggested by recent studies, during the repair of DNA lesions produced by oxidative stress. In particular, the oxidized guanine base 8-oxoguanine within sequences containing CAG repeats may induce formation of pro-expansion intermediates through strand slippage during DNA base excision repair (BER). In this article, we describe how oxidized DNA lesions are repaired by BER and discuss the importance of the coordinated activities of the key repair enzymes, such as DNA polymerase β, flap endonuclease 1 (FEN1) and DNA ligase, in preventing strand slippage and TNR expansion.


Uncommon Presentation of Atypical Hemolytic Uremic Syndrome: A Case Report.
Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal damage. Its presentation as nephrotic syndrome (NS) during first year of life is uncommon; we describe a child with clinical and laboratory findings of NS whose renal biopsy revealed thrombotic microangiopathy (TMA). A previously healthy 4-month-old male was admitted with severe dehydration, diarrhea and anuria. Laboratory results showed electrolyte disturbances, increased serum creatinine, anemia without schistocytes, thrombocytosis, normal lactic dehydrogenase (LDH) levels, hypoalbuminemia hypercholesterolemia and decreased C3 levels. After rehydration hematuria and massive proteinuria were also documented and an initial diagnosis of NS of the first year was established. Studies seeking for infectious agents were negative. During hospitalization he continued to be oligo-anuric needing dialysis and a renal biopsy was performed, which showed TMA findings. We here considered the diagnosis of aHUS and started plasma infusions as a bridge until starting eculizumab. After two infusions urine output improved leading to discontinuation dialysis. The diagnoses of STEC infection and thrombocytopenic thrombotic purpura were ruled out. Factor B, H, I and properdin levels were normal. Antibodies against CFH negative were negative. Screening for genes causative of aHUS detected a heterozygous variant in CFHR3 of uncertain significance. On day 20, treatment was switched to eculizumab, which induced a progressive remission of the NS. This case outlines the need for a heightened diagnosis suspicion of this already rare disease since early initiation of eculizumab therapy improves its prognosis.


Comparative bioaccumulation of trace elements between Nautilus pompilius and Nautilus macromphalus (Cephalopoda: Nautiloidea) from Vanuatu and New Caledonia.
The concentrations of 16 trace elements were investigated and compared for the first time in the digestive and excreting tissues of two Nautilus species (Cephalopoda: Nautiloidea) from two geologically contrasted areas: (1) N. macromphalus from New Caledonia, a region characterized by its richness in nickel ores and its lack of tectonic activities and (2) N. pompilius from the Vanuatu archipelago showing high volcanic and tectonic activities. In both Nautilus species, results clearly highlighted that the digestive gland played a key role in the bioaccumulation and storage of Ag, Cd, Ce, Co, Cu, Fe, La, Nd, V, and Zn whereas As, Cr, Mn, Ni, Pb, and Se were accumulated in a greater extent in the excreting tissues (i.e. pericardial and renal appendages). Despite contrasting environments, no significant difference (p<0.05) was found between the two Nautilus species in the concentrations of most of the essential and non-essential elements, including Ni and associated metals in Ni ores (i.e. Co and Mn). As nautilus lives on the outer shelf of barrier reefs, these results strongly support the hypothesis that the New Caledonian lagoon traps the major amount of the trace elements derived from natural erosion and the intense mining activities conducted on land. In contrast, the concentrations of the rare earth elements (Ce, La, and Nd) were significantly higher in N. pompilius than in N. macromphalus, probably as a result of the local enrichment of Vanuatu waters by specific environmental processes, such as volcanism or upwelling.


Altered circadian blood pressure rhythm in patients with Cushing's syndrome.
The circadian blood pressure rhythm was compared in patients with Cushing's syndrome, essential hypertension, and primary aldosteronism. In patients with essential hypertension or primary aldosteronism, a clear nocturnal fall in systolic and diastolic blood pressure and heart rate was observed. This fall was seen in untreated subjects as well as in patients receiving combined treatment with a calcium antagonist, diuretic, converting enzyme inhibitor, alpha-blocker and beta-blocker, or sympatholytic drug. In these groups, there was a positive correlation between heart rate and systolic or diastolic blood pressure. On the other hand, in patients with Cushing's syndrome, there was no nocturnal fall in blood pressure but in some patients a rise was observed. In all patients there was a nocturnal fall in heart rate. Thus, there was no significant correlation between heart rate and blood pressure in these patients. Exogenous glucocorticoid eliminated the normal nocturnal fall of blood pressure in patients with chronic glomerulonephritis or systemic lupus erythematosus. These results suggest that the changed circadian blood pressure pattern in patients with Cushing's syndrome is not due to antihypertensive treatment or to the mineralocorticoid excess accompanying this disease, but it is attributable to excess glucocorticoid or the associated disturbance in the adrenocorticotropic hormone-glucocorticoid system (or both). This conclusion also implies that the normal circadian rhythm of blood pressure may be regulated at least in part by the adrenocorticotropic hormone-glucocorticoid system.


Global Economic Impact of Dental Diseases.
Reporting the economic burden of oral diseases is important to evaluate the societal relevance of preventing and addressing oral diseases. In addition to treatment costs, there are indirect costs to consider, mainly in terms of productivity losses due to absenteeism from work. The purpose of the present study was to estimate the direct and indirect costs of dental diseases worldwide to approximate the global economic impact. Estimation of direct treatment costs was based on a systematic approach. For estimation of indirect costs, an approach suggested by the World Health Organization's Commission on Macroeconomics and Health was employed, which factored in 2010 values of gross domestic product per capita as provided by the International Monetary Fund and oral burden of disease estimates from the 2010 Global Burden of Disease Study. Direct treatment costs due to dental diseases worldwide were estimated at US$298 billion yearly, corresponding to an average of 4.6% of global health expenditure. Indirect costs due to dental diseases worldwide amounted to US$144 billion yearly, corresponding to economic losses within the range of the 10 most frequent global causes of death. Within the limitations of currently available data sources and methodologies, these findings suggest that the global economic impact of dental diseases amounted to US$442 billion in 2010. Improvements in population oral health may imply substantial economic benefits not only in terms of reduced treatment costs but also because of fewer productivity losses in the labor market.


Structure of severe acute respiratory syndrome coronavirus receptor-binding domain complexed with neutralizing antibody.
The severe acute respiratory syndrome coronavirus (SARS-CoV, or SCV), which caused a world-wide epidemic in 2002 and 2003, binds to a receptor, angiotensin-converting enzyme 2 (ACE2), through the receptor-binding domain (RBD) of its envelope (spike, S) glycoprotein. The RBD is very immunogenic; it is a major SCV neutralization determinant and can elicit potent neutralizing antibodies capable of out-competing ACE2. However, the structural basis of RBD immunogenicity, RBD-mediated neutralization, and the role of RBD in entry steps following its binding to ACE2 have not been elucidated. By mimicking immune responses with the use of RBD as an antigen to screen a large human antibody library derived from healthy volunteers, we identified a novel potent cross-reactive SCV-neutralizing monoclonal antibody, m396, which competes with ACE2 for binding to RBD, and determined the crystal structure of the RBD-antibody complex at 2.3-A resolution. The antibody-bound RBD structure is completely defined, revealing two previously unresolved segments (residues 376-381 and 503-512) and a new disulfide bond (between residues 378 and 511). Interestingly, the overall structure of the m396-bound RBD is not significantly different from that of the ACE2-bound RBD. The antibody epitope is dominated by a 10-residue-long protruding beta6-beta7 loop with two putative ACE2-binding hotspot residues (Ile-489 and Tyr-491). These results provide a structural rationale for the function of a major determinant of SCV immunogenicity and neutralization, the development of SCV therapeutics based on the antibody paratope and epitope, and a retrovaccinology approach for the design of anti-SCV vaccines. The available structural information indicates that the SCV entry may not be mediated by ACE2-induced conformational changes in the RBD but may involve other conformational changes or/and yet to be identified coreceptors.


[Evaluation of the effects of a school breakfast program on attention and memory].
The purpose of the study was to evaluate the impact of a school breakfast program in Sonora, Mexico. The study was conducted in four counties classified as extremely poor. Three hundred children from twelve schools pertaining to three counties under research received a school breakfast; one hundred and fifty children from four schools pertaining to a fourth county did not received school breakfast. Children were four to six years old. Attention, memory and cognition tests were applied before and after the program. Results showed an improvement for those groups receiving the breakfast program, specially on response speed and behavior executions. Group without breakfast showed better results on the pre-test, nevertheless, on the post-test, performances in both groups appear the same. At the beginning of school courses any county was different, but speed in selection and running show significatives differences for the schools. The program shows similar results on response speed, no matter social condition, nevertheless, program differentially affects the number of correct behavior executions on stimulus selection and reproduction. The breakfast program benefit children, but its effects are differentially distributed improving behavioral, repertories depending of children's group vulnerability.


Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation.
Immune cells, e.g. microglial cells of the retina, appear to be involved in pathological processes in neovascular age-related macular degeneration. Therefore, the purpose of this study was to immunohistochemically check the expression of various factors and cytokines by CD11b-positive (CD11b+) immune cells in an animal model of choroidal neovascularisation (CNV). We used the animal model of laser-induced CNV in mice. Eyes were isolated at 1, 4, 7, and 14 days after laser treatment. Cryosections were prepared and checked immunohistochemically for the presence of different growth factors and cytokines on microglial cells and other immune cells identified by CD11b immunoreactivity. We found that the number of CD11b+ cells at the laser spots increased dramatically 4 days after laser treatment, the majority of them entering the laser spot most probably by migration. CD11b+ cells in the laser spot were positive for a variety of pro-angiogenic factors, such as PDGF-β, FGF-1, FGF-2, and TGF-β1. They were also positive for some inflammatory cytokines, in particular TNF-α, IL-6, and CXCL1. In non-treated retinas, CD11b+ cells showed almost no immunoreactivity for these proteins. Microglial cells, macrophages, and other CD11b+ cells may promote the neovascularisation in the laser spot and show a moderate inflammatory behaviour. Immunoreactivity for most of these molecules was found to decrease during the time of observation. Modulation of immune cell activity may thus be a tool to reduce the extent of CNV.


Understanding heart failure; explaining telehealth - a hermeneutic systematic review.
Enthusiasts for telehealth extol its potential for supporting heart failure management. But randomised trials have been slow to recruit and produced conflicting findings; real-world roll-out has been slow. We sought to inform policy by making sense of a complex literature on heart failure and its remote management. Through database searching and citation tracking, we identified 7 systematic reviews of systematic reviews, 32 systematic reviews (including 17 meta-analyses and 8 qualitative reviews); six mega-trials and over 60 additional relevant empirical studies and commentaries. We synthesised these using Boell's hermeneutic methodology for systematic review, which emphasises the quest for understanding. Heart failure is a complex and serious condition with frequent co-morbidity and diverse manifestations including severe tiredness. Patients are often frightened, bewildered, socially isolated and variably able to self-manage. Remote monitoring technologies are many and varied; they create new forms of knowledge and new possibilities for care but require fundamental changes to clinical roles and service models and place substantial burdens on patients, carers and staff. The policy innovation of remote biomarker monitoring enabling timely adjustment of medication, mediated by "activated" patients, is based on a modernist vision of efficient, rational, technology-mediated and guideline-driven ("cold") care. It contrasts with relationship-based ("warm") care valued by some clinicians and by patients who are older, sicker and less technically savvy. Limited uptake of telehealth can be analysed in terms of key tensions: between tidy, "textbook" heart failure and the reality of multiple comorbidities; between basic and intensive telehealth; between activated, well-supported patients and vulnerable, unsupported ones; between "cold" and "warm" telehealth; and between fixed and agile care programmes. The limited adoption of telehealth for heart failure has complex clinical, professional and institutional causes, which are unlikely to be elucidated by adding more randomised trials of technology-on versus technology-off to an already-crowded literature. An alternative approach is proposed, based on naturalistic study designs, application of social and organisational theory, and co-design of new service models based on socio-technical principles. Conventional systematic reviews (whose goal is synthesising data) can be usefully supplemented by hermeneutic reviews (whose goal is deepening understanding).


Glycerol monolaurate does not alter rhesus macaque (Macaca mulatta) vaginal lactobacilli and is safe for chronic use.
Glycerol monolaurate (GML) is a fatty acid monoester that inhibits growth and exotoxin production of vaginal pathogens and cytokine production by vaginal epithelial cells. Because of these activities, and because of the importance of cytokine-mediated immune activation in human immunodeficiency virus type 1 (HIV-1) transmission to women, our laboratories are performing studies on the potential efficacy of GML as a topical microbicide to interfere with HIV-1 transmission in the simian immunodeficiency virus-rhesus macaque model. While GML is generally recognized as safe by the FDA for topical use, its safety for chronic use and effects on normal vaginal microflora in this animal model have not been evaluated. GML was therefore tested both in vitro for its effects on vaginal flora lactobacilli and in vivo as a 5% gel administered vaginally to monkeys. In vitro studies demonstrated that lactobacilli are not killed by GML; GML blocks the loss of their viability in stationary phase and does not interfere with lactic acid production. GML (5% gel) does not quantitatively alter monkey aerobic vaginal microflora compared to vehicle control gel. Lactobacilli and coagulase-negative staphylococci are the dominant vaginal aerobic microflora, with beta-hemolytic streptococci, Staphylococcus aureus, and yeasts sporadically present; gram-negative rods are not part of their vaginal flora. Colposcopy and biopsy studies indicate that GML does not alter normal mucosal integrity and does not induce inflammation; instead, GML reduces epithelial cell production of interleukin 8. The studies suggest that GML is safe for chronic use in monkeys when applied vaginally; it does not alter either mucosal microflora or integrity.


Wound healing in the media of the normolipemic rabbit carotid artery injured by air drying or by balloon catheter de-endothelialization.
The response to air-dry injury to the carotid artery of the normolipemic rabbit was compared with the response to de-endothelialization with a balloon catheter. Air drying induced an inflammatory response that resembled arteritis rather than atherosclerosis. There was medial damage, neutrophil but not macrophage infiltration, and fibrin formation, limited smooth muscle proliferation, which regressed after 3 months, and no lipid deposition. Within 1 week the smooth muscle cells were mainly of the secretory phenotype, and a neointima had formed. At 4 weeks the neointimal proliferation continued, but most cells showed a contractile phenotype. By 3 months, the lesion consisted of fibromuscular thickening with few small smooth muscle cells. Balloon injury induced minimal medial damage and continuing intimal proliferation with no evidence of regression by 3 months. It is concluded that air drying the carotid artery induces smooth muscle damage as well as endothelial cell loss, and this stimulates a wound-healing mechanism that is different from the response to selective intimal injury.


Prevalence of small-scale jets from the networks of the solar transition region and chromosphere.
As the interface between the Sun's photosphere and corona, the chromosphere and transition region play a key role in the formation and acceleration of the solar wind. Observations from the Interface Region Imaging Spectrograph reveal the prevalence of intermittent small-scale jets with speeds of 80 to 250 kilometers per second from the narrow bright network lanes of this interface region. These jets have lifetimes of 20 to 80 seconds and widths of ≤300 kilometers. They originate from small-scale bright regions, often preceded by footpoint brightenings and accompanied by transverse waves with amplitudes of ~20 kilometers per second. Many jets reach temperatures of at least ~10(5) kelvin and constitute an important element of the transition region structures. They are likely an intermittent but persistent source of mass and energy for the solar wind.


Mechanical Evaluation of Two Grades of Titanium Used in Implant Dentistry.
To investigate the effect of core dental implant materials supporting single crowns on the probability of survival and failure modes. Thirty-six standard external-hex titanium implants (4.0 mm in diameter) were selected to restore single crowns and divided into two groups according to core material: commercially pure grade 2 titanium (G2) and grade 5 titanium-aluminum-vanadium alloy (Ti-6Al-4V) (G5). Abutments were screwed to the implants, and standardized maxillary central incisor metal crowns were cemented and subjected to step-stress accelerated life testing in water. Use-level probability Weibull curves and reliability for missions of 100,000 cycles at 150 N and 200 N (with 90% two-sided confidence intervals [CIs]) were calculated. Polarized light and scanning electron microscopes were used to determine the failure modes. Use-level probability Weibull calculations showed beta values of 0.59 (CI, 0.31 to 1.11) and 1.22 (CI 0.81 to 1.84) for G2 and G5, respectively, and significantly higher characteristic strength and Weibull modulus for G5. The calculated reliability (90% CIs) for a mission of 100,000 cycles at 150 N showed that cumulative damage would lead to survival of 45% of implant-supported crowns of G2 and 98% of G5. At 200 N the probability of survival decreased to 0.03% for G2 and 21% for G5. Abutment screw fracture was the failure mode for all groups. Reliability, characteristic strength, and Weibull modulus were significantly higher for Ti-6Al-4V dental implants than for commercially pure (grade 2) titanium implants. Failure modes were similar for both groups.


Optimization of a preclinical therapy of cannabinoids in combination with temozolomide against glioma.
Glioblastoma multiforme (GBM) is the most frequent and aggressive form of brain cancer. These features are explained at least in part by the high resistance exhibited by these tumors to current anticancer therapies. Thus, the development of novel therapeutic approaches is urgently needed to improve the survival of the patients suffering this devastating disease. Δ9-Tetrahydrocannabinol (THC, the major active ingredient of marijuana), and other cannabinoids have been shown to exert antitumoral actions in animal models of cancer, including glioma. The mechanism of these anticancer actions relies, at least in part, on the ability of these compounds to stimulate autophagy-mediated apoptosis in tumor cells. Previous observations from our group demonstrated that local administration of THC (or of THC + CBD at a 1:1 ratio, a mixture that resembles the composition of the cannabinoid-based medicine Sativex®) in combination with Temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts. With the aim of optimizing the possible clinical utilization of cannabinoids in anti-GBM therapies, in this work we explored the anticancer efficacy of the systemic administration of cannabinoids in combination with TMZ in preclinical models of glioma. Our results show that oral administration of Sativex-like extracts (containing THC and CBD at a 1:1 ratio) in combination with TMZ produces a strong antitumoral effect in both subcutaneous and intracranial glioma cell-derived tumor xenografts. In contrast, combined administration of Sativex-like and BCNU (another alkylating agent used for the treatment of GBM which share structural similarities with the TMZ) did not show a stronger effect than individual treatments. Altogether, our findings support the notion that the combined administration of TMZ and oral cannabinoids could be therapeutically exploited for the management of GBM.


Human delta opioid receptor: functional studies on stably transfected Chinese hamster ovary cells after acute and chronic treatment with the selective nonpeptidic agonist SNC-80.
The SNC-80 series of nonpeptidic agonists for the delta-opioid receptor are being developed as potential analgesic drugs. It is important to understand their acute and chronic effects at human delta-opioid receptors. Thus, we measured the ability of SNC-80 and [D-Pen2,4'-Cl-Phe4,D-Pen5]enkephalin to inhibit forskolin-stimulated adenylyl cyclase activity in recombinant Chinese hamster ovary cells stably expressing the cloned human delta-opioid receptor. The calculated EC50 values for [D-Pen2,4'-Cl-Phe4,D-Pen5]enkephalin and SNC-80 were 0.6 +/- 0.1 nM and 6.3 +/- 0.1 nM, respectively. Pretreatment of these cells with SNC-80 (100 nM) for 24 hr produced 1) a time-dependent reduction of delta receptor density, as measured by radioligand binding studies with [3H]naltrindole; 2) a shift in the EC50 value of SNC-80 from 7.7 +/- 4.2 nM to 44.1 +/- 12 nM, as measured by the cyclic AMP assay; 3) a reduction in the maximum inhibition of adenylyl cyclase activity from 86% to 48%; 4) a marked increase in the forskolin stimulation of basal cyclic AMP accumulation by nearly 100% (from 442 pmol/mg of protein to 824 pmol/mg of protein); and 5) a 5-fold increase in forskolin-stimulated cyclic AMP accumulation after addition of naltrindole. These studies showed that SNC-80 produced desensitization and down-regulation of human delta-opioid receptors in recombinant Chinese hamster ovary cells after chronic treatment and that this effect was associated with an increase in adenylyl cyclase activity.


Positive, limited and negative responders: The variability in physical fitness adaptation to basic military training.
To investigate the heterogeneity of physical adaptation in Australian Army recruits completing a 12-week basic military training regimen. A prospective research design. Volunteer recruits (n=195) completed 12-weeks of basic military training. Recruit physical fitness was assessed at week 1, weeks 6-8 and week 12. Recruits in the upper (75th) and lower (25th) quartiles for each assessment were then analysed using a repeated measures two-way ANOVA. The relative magnitude of recruit adaptions were classified as positive response (Rpositive, ≥5%), limited response (Rlimited, >-5% to <5%) and negative response (Rnegative, ≤-5%); Chi-square analysis determined the proportional differences in the distribution of each quartile. An interaction (p<0.001) was observed in the lower and upper recruit quartiles for all assessments of physical fitness at each time point. After 12 weeks of military training the mean difference of the highest quartile was; 20-m multi-stage fitness test 7.4mL·kg-1·min-1, (CI:5.8:9.1), 2-min push-ups 20.1 reps, (CI:16.2:23.9), 1RM box lift 5.6kg, (CI:2.6:5.8) and load carriage 222.1s, (CI:174.7:269.4) compared to the lowest recruit quartile. The highest quartile demonstrated no improvement in 1RM box lift (-4%, -1%) and push-ups (2%, 0%) performance at weeks 6-8 and week 12 respectively. In contrast, adaptations in the lowest quartile for 1RM box lift (16%, 21%) and push-ups (46%, 46%) over the same time periods were observed. A significant proportion of recruits may complete basic military training with a decline in physical performance. Higher relative-intensity cardiorespiratory and resistance exercise should be considered to facilitate physical adaptation in all recruits.


Propagation of shear horizontal surface waves in a layered piezoelectric half-space with an imperfect interface.
We investigate the dispersive behavior of shear horizontal (SH) surface waves propagating in a layered structure consisting of a piezoelectric layer and an elastic half-space, in which the top and bottom of the layer are electrically shorted. The interface between the layer and the half-space is assumed to be imperfect bonding. The degree of imperfection of the interface is described by the so-called shear-lag model. The dispersion equations are expressed in an explicit closed form. The phase velocities are calculated to show the influences of the interfacial imperfection and the material properties of piezoelectric layers on the dispersive characteristics.


Assessing the personal impact of epilepsy in a population-based cohort of Veterans.
Epilepsy impacts patient lives in multidimensional ways. Although previous work has investigated epilepsy impact on health status, little is known about the overall quantified impact of epilepsy in Veterans. Our goal was to describe the impact of epilepsy on Veterans' lives using the Personal Impact of Epilepsy Scale (PIES) and determine the patient and clinical characteristics most strongly correlated with epilepsy impact. We described cohort characteristics and developed regression models to determine which characteristics were most strongly associated with PIES subscale (seizure, medication, comorbidity) scores and quality of life (QOL). Approximately 36% of those who were invited responded to the survey. Of the 438 respondents included in the analyses, roughly 50% were aged 45-64 years (35% >65; 14% 18-44); 19% were women. Almost 90% had previously received care by an epilepsy specialist, 37% of which was in Veterans Health Administration (VHA) and 38% in both VHA and community. The PIES scores were moderately low (mean: 88.68, [standard deviation (SD) = 63.24]; 300 total). The PIES overall and subscale scores were significantly lower for older Veterans with epilepsy (VWE) (>65) compared with younger (18-44 years) and middle-aged (45-64 years) VWE [p < 0.001], indicating that older Veterans had a lower epilepsy impact overall, and for seizures, medication, and comorbidity. The younger and middle-aged VWE had a significantly higher proportion with psychiatric diagnosis compared with older VWE [p < 0.001]. There was a trend for significance for the overall PIES scores by gender, with women having total higher (worse) scores (mean = 93.10, SD = 69.68) than men (mean = 74.39, SD = 59.97), which was driven by a statistically higher score on the seizure subscale for women (mean = 27.66, SD = 27.97) compared with men (mean = 19.29, SD 25.35; p = 0.04). Regression models revealed that frequent seizures (>1/month, >2/month) and diagnoses of dementia significantly predicted higher (more negative) Seizure Severity PIES score [all p < 0.05]. Frequent seizures (>1/month), number of antiepileptic drugs (AEDs), and diagnosis of dementia predicted negative impact, and older age predicted positive impact for medication subscale. Frequent seizures (>1/month) and diagnoses of depression and dementia predicted negative mood and social impact [all p < 0.05]. Seizure frequency (>2/month) was the only variable that significantly predicted lack of excellent QOL [p < 0.05]. Effects for gender were not significant after controlling for other variables. Findings were similar to a prior study of generic health outcomes in younger and older VWE using the 36-Item Short Form Survey (SF-36). Seizure frequency was consistently associated with negative impact of epilepsy in all age groups. While dementia and other diagnosed health conditions also contributed to epilepsy impact, older VWE had significantly lower PIES scores even after controlling for physical conditions and dementia. Lower (better) scores for comorbidity and medication scales in older VWE may be due to fewer diagnosed psychiatric comorbidities and psychiatric medication that have similar cognitive impact as AEDs, and which may also interact with AEDs. Implementation of patient self-management programs to improve seizure control may reduce epilepsy impact for Veterans and reduce Veterans Affairs (VA) healthcare utilization. The PIES may also be useful to measure outcomes of self-management interventions.


Vertical Transmission of Coronavirus Disease 19 (COVID-19) from Infected Pregnant Mothers to Neonates: A Review.
Background: Since early December 2019, the Coronavirus Disease 19 (COVID-19) infection has been prevalent in China and eventually spread to other countries. There are a few published cases of COVID-19 occurring during pregnancy and due the possibility of mother-fetal vertical transmission, there is a concern that the fetuses may be at risk of congenital COVID-19. Methods: We reviewed the risk of vertical transmission of COVID-19 to the fetus of infected mothers by using data of published articles or official websites up to March 4, 2020. Results: A total of 31 infected pregnant mothers with COVID-19 were reported. No COVID-19 infection was detected in their neonates or placentas. Two mothers died from COVID-19-related respiratory complications after delivery. Conclusions: Currently, based on limited data, there is no evidence for intrauterine transmission of COVID-19 from infected pregnant women to their fetuses. Mothers may be at increased risk for more severe respiratory complications.


Subtype-selective GABAA receptor mimetics--novel antihyperalgesic agents?
Agonists at the benzodiazepine-binding site of ionotropic gamma-aminobutyric acid (GABA(A)) receptors are in clinical use as hypnotics, anxiolytics, and anticonvulsants since the early 1960. Analgesic effects of classical benzodiazepines have occasionally been reported in certain subgroups of patients suffering from chronic pain or after spinal delivery through intrathecal catheters. However, these drugs are generally not considered as analgesics but should in fact be avoided in patients with chronic pain. Recent evidence from genetically modified mice now indicates that agents targeting only a subset of benzodiazepine (GABA(A)) receptors should provide pronounced antihyperalgesic activity against inflammatory and neuropathic pain. Several such compounds have been developed recently, which exhibit significant antihyperalgesia in mice and rats and appear to be devoid of the typical side-effects of classical benzodiazepines.


Models of parasite virulence.
Several evolutionary processes influence virulence, the amount of damage a parasite causes to its host. For example, parasites are favored to exploit their hosts prudently to prolong infection and avoid killing the host. Parasites also need to use some host resources to reproduce and transmit infections to new hosts. Thus parasites face a tradeoff between prudent exploitation and rapid reproduction-a life history tradeoff between longevity and fecundity. Other tradeoffs among components of parasite fitness also influence virulence. For example, competition among parasite genotypes favors rapid growth to achieve greater relative success within the host. Rapid growth may, however, lower the total productivity of the local group by overexploiting the host, which is a potentially renewable food supply. This is a problem of kin selection and group selection. I summarize models of parasite virulence with the theoretical tools of life history analysis, kin selection, and epidemiology. I then apply the theory to recent empirical studies and models of virulence. These applications, to nematodes, to the extreme virulence of hospital epidemics, and to bacterial meningitis, show the power of simple life history theory to highlight interesting questions and to provide a rich array of hypotheses. These examples also show the kinds of conceptual mistakes that commonly arise when only a few components of parasite fitness are analysed in isolation. The last part of the article connects standard models of parasite virulence to diverse topics, such as the virulence of bacterial plasmids, the evolution of genomes, and the processes that influenced conflict and cooperation among the earliest replicators near the origin of life.


Back to the roots: Reducing evolutionary rate heterogeneity among sequences gives support for the early morphological hypothesis of the root of Siluriformes (Teleostei: Ostariophysi).
Catfishes (Teleostei: Siluriformes) are a highly diverse order within Ostariophysi that is distributed worldwide. At the base of this clade emerge three lineages with well-defined monophylies: Diplomystidae, Loricarioidei, and Siluroidei. Morphological phylogeny studies place the Diplomystidae as the earliest branching of these three lineages, but studies based on molecular phylogenetics consistently find the fast-evolving Loricarioidei instead. The high lineage evolutionary rate heterogeneity in this order and the fact that the lineage placed closest to the root in the molecular phylogenies is fast evolving, including many long branches, raises the possibility that the discrepancy between morphological and molecular phylogenies may be the result of a long branch attraction inference artifact. We test this hypothesis by using a 10-gene dataset to evaluate the arrangement of the three main siluriform lineages, and apply the LS3 and LS4 taxon sequence subsampling methods to reduce evolutionary rate heterogeneity among lineages. The initial and complete dataset supports the basal branching of Loricarioidei as in all previous molecular phylogenies, but once lineage rate heterogeneity is reduced with LS3 or LS4 through the removal of sequences disrupting homogeneity, the phylogeny shows Diplomystidae as the earliest branching group, with high supports, as proposed by morphological phylogeny. The result obtained with LS3, however, introduces the misplacement of one of the species with the highest amount of missing data, Scoloplax sp. Because the sequence sub-selection criterion of LS4 has been optimized to reduce data removal, the phylogeny resulting from the LS4-processed data is in agreement with the known intra-lineage relationships in addition to supporting the morphologically-based rooting hypothesis. Our results are the first instance in which a consensus between molecular and morphological phylogeny is reached concerning the root of this order.


Quantitative image cytometry for analyzing intracellular trafficking of G protein-coupled receptors on a chemical-trapping single cell array.
G protein-coupled receptors (GPCRs) are important targets in medical and pharmaceutical research fields, because they play key roles in a variety of biological processes. Recently, intracellular trafficking of GPCRs involving endosomal internalization and recycling to the plasma membrane has been studied as a regulation mechanism for GPCR activities. However, the absence of a quantitative single-cell analysis method has hampered conditional GPCR trafficking studies and the possibility of gaining significant insights into the mechanism of regulation of GPCR signaling. Here, we report a facile image cytometry method to analyze the trafficking of GPCRs. In this method, GPCR-expressing cells were arrayed with a photo-responsive cell-immobilizing reagent in a single-cell manner, and the tagged GPCR was visualized by pulse-labeling with a fluorescent dye through sortase-mediated peptide-tag ligation. We quantified the intracellular distribution changes of a pH-dependent GPCR, G2A, by time-course observation under mildly acidic and slightly basic pH conditions. The difference in pH-dependent G2A trafficking between individual cells was automatically detected by an image analysis custom software program, and simultaneously, the average distribution ratios were also determined for understanding the properties of G2A. The present method should be applicable for investigating the dynamic intracellular trafficking of a wide variety of GPCRs under various conditions in a high-throughput manner.


Prevalence of peptic ulcer in Helicobacter pylori positive blood donors.
This study aimed to determine the importance of raised antibodies to Helicobacter pylori in an asymptomatic population. A total of 128 asymptomatic blood donors who were seropositive for H pylori and consented to endoscopy were investigated. These subjects were from a population of 1010 blood donors screened for antibodies to H pylori. A questionnaire was completed to determine if any subjects had complained of symptoms, and they subsequently had endoscopy. Altogether 121 of 128 were positive for H pylori by histology and urease test and/or culture and all 121 had chronic active gastritis on histology. Twenty five of these subjects had peptic ulcer (20 duodenal, five gastric), a further 21 had erosive duodenitis, and two were found to have gastric cancer. H pylori associated peptic ulcer disease and duodenitis occur more frequently than previously recognised and this suggests that H pylori infection, even if asymptomatic, is of far greater clinical relevance than originally thought.


Trends in incidence and outcome of out-of-hospital cardiac arrest among people with validated myocardial infarction.
To describe trends in incidence, outcome, and background characteristics among people who suffered an out-of-hospital cardiac arrest with validated myocardial infarction aetiology (OHCA-V). People from the northern Sweden MONICA myocardial registry (1989-2007) with OHCA-V (n = 2977) were divided in two age groups (25-64 and 65-74 years). Both those who were resuscitated outside hospital and those who died before resuscitation was started were included in the study. The younger age group was studied during 1989-2007 and the older group during 2000-2007. The incidence of OHCA-V decreased in both the younger group (men p < 0.0001, women p = 0.04) and the older group (men p < 0.0001, women p < 0.0007, respectively). The proportion with a history of ischaemic heart disease prior to the event decreased (p < 0.0001). The proportion of previous myocardial infarction decreased (p < 0.0001), diabetes mellitus increased (p = 0.001), coronary interventions increased (p < 0.0001), and survival after OHCA-V increased (p < 0.0001) in the younger group but not in the older group. Long-term survival after OHCA-V was better in the younger than in the older group (p = 0.026). The incidence of OHCA-V decreased in both sexes. The proportion surviving after OHCA-V was small but increased, and long-term survival (≥ 28 days) was better in the younger age group. Primary preventive measures may explain most of the improvements. However, the effects of secondary preventive measures cannot be excluded.


The gene for enhancer binding proteins E12/E47 lies at the t(1;19) breakpoint in acute leukemias.
The gene (E2A) that codes for proteins with the properties of immunoglobulin enhancer binding factors E12/E47 was mapped to chromosome region 19p13.2-p13.3, a site associated with nonrandom translocations in acute lymphoblastic leukemias. The majority of t(1;19)(q23;p13)-carrying leukemias and cell lines studied contained rearrangements of E2A as determined by DNA blot analyses. The rearrangements altered the E2A transcriptional unit, resulting in the synthesis of a transcript larger than the normal-sized E2A mRNAs in one of the cell lines with this translocation. These observations indicate that the gene for a transcription factor is located at the breakpoint of a consistently recurring chromosomal translocation in many acute leukemias and suggest a direct role for alteration of such factors in the pathogenesis of some malignancies.


Lactobacillus reuteri increases mucus thickness and ameliorates dextran sulphate sodium-induced colitis in mice.
The aim of this study was to investigate whether two Lactobacillus reuteri strains (rat-derived R2LC and human-derived ATCC PTA 4659 (4659)) could protect mice against colitis, as well as delineate the mechanisms behind this protection. Mice were given L. reuteri R2LC or 4659 by gavage once daily for 14 days, and colitis was induced by addition of 3% DSS (dextran sulphate sodium) to drinking water for the last 7 days of this period. The severity of disease was assessed through clinical observations, histological evaluation and ELISA measurements of myeloperoxidase (MPO) and pro-inflammatory cytokines from colonic samples. Mucus thickness was measured in vivo with micropipettes, and tight junction protein expression was assessed using immunohistochemistry. Colitis severity was significantly reduced by L. reuteri R2LC or 4659 when evaluated both clinically and histologically. The inflammation markers MPO, IL-1β, IL-6 and mKC (mouse keratinocyte chemoattractant) were increased by DSS and significantly reduced by the L. reuteri strains. The firmly adherent mucus thickness was reduced by DSS, but significantly increased by L. reuteri in both control and DSS-treated mice. Expression of the tight junction proteins occludin and ZO-1 was significantly increased in the bottom of the colonic crypts by L. reuteri R2LC. These results demonstrate that each of the two different L. reuteri strains, one human-derived and one-rat-derived, protects against colitis in mice. Mechanisms behind this protection could at least partly be explained by the increased mucus thickness as well as a tightened epithelium in the stem cell area of the crypts.


Scholarly publishing and journal targeting in the time of the Coronavirus Disease 2019 (COVID-19) pandemic: a cross-sectional survey of rheumatologists and other specialists.
The evolving research landscape in the time of the Coronavirus disease 2019 (COVID-19) pandemic calls for greater understanding of the perceptions of scholars regarding the current state and future of publishing. An anonymised and validated e-survey featuring 30 questions was circulated among rheumatologists and other specialists over social media to understand preferences while choosing target journals, publishing standards, commercial editing services, preprint archiving, social media and alternative publication activities. Of 108 respondents, a significant proportion were clinicians (68%), researchers (60%) and educators (47%), with median 23 publications and 15 peer-review accomplishments. The respondents were mainly rheumatologists from India, Ukraine and Turkey. While choosing target journals, relevance to their field (69%), PubMed Central archiving (61%) and free publishing (59%) were the major factors. Thirty-nine surveyees (36%) claimed that they often targeted local journals for publishing their research. However, only 18 (17%) perceived their local society journals as trustworthy. Occasional publication in the so-called predatory journals (5, 5%) was reported and obtaining support from commercial editing agencies to improve English and data presentation was not uncommon (23, 21%). The opinion on preprint archiving was disputed; only one-third believed preprints were useful. High-quality peer review (56%), full and immediate open access (46%) and post-publication social media promotion (32%) were identified as key anticipated features of scholarly publishing in the foreseeable future. These perceptions of surveyed scholars call for greater access to free publishing, attention to proper usage of English and editing skills, and a larger role for engagement over social media.


Revision Surgery in the Management of Anorectal Malformations: Experience from a Tertiary Center of India.
Despite the significant advancements in the management of anorectal malformations (ARMs), there are various surgical and functional complications reported. Complications are closely related with the surgical techniques adopted and the types of malformations. In this article, we present our experiences with ARM patients who required reoperation after unsuccessful previous surgeries or who had developed complications related to the previous surgical techniques. We retrospectively reviewed clinical and electronic records of all the patients with ARM who were operated for ARMs in our institute from June 2010 to May 2016. All ARM patients who needed reoperation were included in the study. These patients were previously operated outside our institute and referred to us with ongoing problems of constipation, stool impaction with overflow incontinence, perineal soiling, and difficult urination. There were 31 patients (M:F = 2.1:1) of ARM, reoperated for 38 indications during the above-mentioned period. Five patients had more than one problem. Presentation included neoanal stenosis (11), complete obliteration of neoanus (2), malpositioned neoanus (2), persistent/recurrent rectourethral fistula (3), iatrogenic rectovaginal fistula (4), rectal prolapse (5), large widened neoanus with soiling (2), and urethral stricture (2), which required revision interventions. Six patients had megarectum. All patients showed improvement in their symptoms after revision surgery, but 10 (41.7%) patients required further regular bowel management program (BMP) to avoid the soiling and constipation. Fourteen (58.3%) patients stayed clean without regular BMP. All these complications had clear explanations and are well described in the literature. Revision surgery in such patients had fair outcome, but some sort of BMP was required. Both posterior sagittal anorectoplasty and anterior sagittal anorectoplasty are excellent techniques for revision surgery with few simple modifications.


C-terminal interactions between the XerC and XerD site-specific recombinases.
Studies of the site-specific recombinase Cre suggest a key role for interactions between the C-terminus of the protein and a region located about 30 residues from the C-terminus in linking in a cyclical manner the four recombinase monomers present in a recombination complex, and in controlling the catalytic activity of each monomer. By extrapolating the Cre DNA recombinase structure to the related site-specific recombinases XerC and XerD, it is predicted that the extreme C-termini of XerC and XerD interact with alpha-helix M in XerD and the equivalent region of XerC respectively. Consequently, XerC and XerD recombinases deleted for C-terminal residues, and mutated XerD proteins containing single amino acid substitutions in alphaM or in the C-terminal residues were analysed. Deletion of C-terminal residues of XerD has no measurable effect on co-operative interactions with XerC in DNA-binding assays to the recombination site dif, whereas deletion of 5 or 10 residues of XerC reduces co-operativity with XerD some 20-fold. Co-operative interactions between pairs of truncated proteins during dif DNA binding are reduced 20- to 30-fold. All of the XerD mutants, except one, were catalytically proficient in vitro; nevertheless, many failed to mediate a recombination reaction on supercoiled plasmid in vivo or in vitro, implying that the ability to form a productive recombination complex and/or mediate a controlled recombination reaction is impaired.


Canadian administrative health data can identify patients with myasthenia gravis.
Incidence and prevalence estimates for myasthenia gravis (MG) have varied widely, and the ability of administrative health data (AHD) records to accurately identify cases of MG is yet to be ascertained. The goal of the current study was to validate an algorithm to identify patients with MG in Ontario, Canada using AHD - thereby enabling future disease surveillance. A reference standard population was established using automated key word searching within EMRALD (Electronic Medical Record Administrative data Linked Database) and chart review of potential cases. AHD algorithms were generated and tested against the reference standard. The data was used to calculate MG prevalence rates. There were 123,997 eligible adult patients, and 49 patients had definite MG (forming the reference standard). An algorithm requiring: (1 hospital discharge abstract with MG listed as a reason for hospitalization or a comorbid condition), or (5 outpatient MG visits and 1 relevant diagnostic test, within 1 year), or (3 pyridostigmine prescriptions, within 1 year) identified MG with sensitivity = 81.6%, specificity = 100%, positive predictive value = 80.0% and negative predictive value = 100%. The population prevalence within our cohort was 0.04%. This novel validation method demonstrates the feasibility of using administrative health data to identify patients with myasthenia gravis among the Ontario population.


Frequency specific activity in subthalamic nucleus correlates with hand bradykinesia in Parkinson's disease.
Local field potential recordings made from the basal ganglia of patients undergoing deep brain stimulation have suggested that frequency specific activity is involved in determining the rate of force development and the peak force at the outset of a movement. However, the extent to which the basal ganglia might be involved in motor performance later on in a sustained contraction is less clear. We therefore recorded from the subthalamic nucleus region (STNr) in patients with Parkinson's disease (PD) as they made maximal voluntary grips. Relative to age-matched controls they had more rapid force decrement when contraction was meant to be sustained and prolonged release reaction time and slower rate of force offset when they were supposed to release the grip. These impairments were independent from medication status. Increased STNr power over 5-12 Hz (in the theta/alpha band) independently predicted better performance-reduced force decrement, shortened release reaction time and faster rate of force offset. In contrast, lower mean levels and progressive reduction of STNr power over 55-375 Hz (high gamma/high frequency) over the period when contraction was meant to be sustained were both strongly associated with greater force decrement over time. Higher power over 13-23 Hz (low beta) was associated with more rapid force decrement during the period when grip should have been sustained, and with a paradoxical shortening of the release reaction time. These observations suggest that STNr activities at 5-12 Hz and 55-375 Hz are necessary for optimal grip performance and that deficiencies of such activities lead to motor impairments. In contrast, increased levels of 13-25 Hz activity both promote force decrement and shorten the release reaction time, consistent with a role in antagonising (and terminating) voluntary movement. Frequency specific oscillatory activities in the STNr impact on motor performance from the beginning to the end of a voluntary grip.


Tumor cell plasticity and angiogenesis in human melanomas.
Recent molecular studies provide evidence for a significant transcriptional plasticity of tumor cell subpopulations that facilitate an active contribution to tumor vasculature. This feature is accompanied by morphological changes both in vitro and in vivo. Herein, we investigated the morphological plasticity of tumor cells with special focus on vasculogenic mimicry and neovascularisation in human melanoma and mouse xenografts of human melanoma cell lines. In melanoma xenograft experiments, different vessel markers and green fluorescent protein expression were used to show how melanoma cells contribute to neovascularization. Additionally, we analyzed neovascularization in 49 primary melanomas and 175 melanoma metastases using immunostaining for blood (CD34) and lymphatic (D2-40) vessel-specific markers. We found significantly more lymphatic vessels in primary melanomas than in melanoma metastases (p<0.0001). In contrast to the near absence of lymphatic vessels within metastases, we found extensive blood micro-neovascularization. Blood micro-neovascularization was absent in micro metastases (less than 2 mm). A significant inverse correlation between Glut-1 expression (implying local hypoxia) and the presence of microvessels indicates their functional activity as blood vessels (p<0.0001). We suggest that the hypoxic microenvironment in metastases contributes to a phenotype switch allowing melanoma cells to physically contribute to blood vessel formation.


Plant mediated green synthesis: modified approaches.
Plant mediated green synthesis of different metallic nanoparticles has emerged as one of the options for implementation of green chemistry principles, and successfully made an important contribution towards green nanotechnology. However, beyond the synthesis and application aspects, the science of green synthesis has carried some wrong perceptions in an unforeseen fashion. In this review, some of the key issues related to the green synthesis of metallic nanoparticles employing plants as reducing/capping agents have been addressed. Random selection of plants and its overall impact on the different aspects of green synthesis have been discussed. Emphasis is given to the setting of some standard selection criteria to be adopted for selecting a plant for use in green synthesis. How selection of a plant can positively or negatively influence both procedure and products of a green synthesis process is the prime concern of this article. In addition to selection, the key issue of biocompatibility associated with green synthesized metallic nanoparticles has been considered. Both selection of plant and biocompatibility were reconsidered for their minute details in terms of synthesis, analysis and data interpretation in the green synthesis approach. The key factors capable of fine tuning the core meaning of "green" in the synthesis of any metallic nanoparticles were taken into consideration. This article is an effort towards keeping the core meaning of green synthesis.


Elements in scenario-based simulation associated with nursing students' self-confidence and satisfaction: A cross-sectional study.
To identify elements in scenario-based simulation associated with nursing students' satisfaction with the simulation activity and self-confidence in managing the simulated patient situation. The study will provide insight to improve the use of simulation as a learning strategy. A cross-sectional study. The Student Satisfaction and Self-Confidence in Learning scale was used as the outcome measure to identify associations with elements of the Simulation Design Scale and the Educational Practices Questionnaire scale after scenario-based simulation using patient simulators. First-year nursing students at a university college in Norway (N = 202) were invited to participate and (N = 187) responded to the questionnaires. The mean scores for self-confidence and satisfaction were 4.16 and 4.57, respectively. In the final multiple linear regression analysis, active learning was associated with satisfaction with the simulation activity, while clear objectives and active learning were associated with self-confidence in managing the simulated patient situation.


Crystal structure of the human two-pore domain potassium channel K2P1.
Two-pore domain potassium (K(+)) channels (K2P channels) control the negative resting potential of eukaryotic cells and regulate cell excitability by conducting K(+) ions across the plasma membrane. Here, we present the 3.4 angstrom resolution crystal structure of a human K2P channel, K2P1 (TWIK-1). Unlike other K(+) channel structures, K2P1 is dimeric. An extracellular cap domain located above the selectivity filter forms an ion pathway in which K(+) ions flow through side portals. Openings within the transmembrane region expose the pore to the lipid bilayer and are filled with electron density attributable to alkyl chains. An interfacial helix appears structurally poised to affect gating. The structure lays a foundation to further investigate how K2P channels are regulated by diverse stimuli.


What areas of everyday functioning are affected by theory of mind deficits in recent-onset schizophrenia spectrum disorders?
Functional recovery is now a recognized treatment goal for schizophrenia. It is therefore important to better understand the cognitive and psychological factors that influence functioning. Theory of mind (ToM) deficits are common in schizophrenia and have been linked to greater impairments in functioning. The current study aimed to identify which specific areas of functioning are linked to ToM in a group of 54 patients with a recent-onset of a schizophrenia spectrum disorder. ToM was assessed with the Combined Stories Test (COST). Several areas of functioning were rated based on an extensive semi-structured interviews. Among the different areas of functioning that were examined, ToM showed a significant, positive relationship with ratings for productive activities (e.g. work or school) as well as with collaboration to psychiatric care. These results suggest that ToM can impair functioning especially in situations in which patients need to collaborate with others, including the interactions with the clinical team.


Functionalized carbon nanotubes in the brain: cellular internalization and neuroinflammatory responses.
The potential use of functionalized carbon nanotubes (f-CNTs) for drug and gene delivery to the central nervous system (CNS) and as neural substrates makes the understanding of their in vivo interactions with the neural tissue essential. The aim of this study was to investigate the interactions between chemically functionalized multi-walled carbon nanotubes (f-MWNTs) and the neural tissue following cortical stereotactic administration. Two different f-MWNT constructs were used in these studies: shortened (by oxidation) amino-functionalized MWNT (oxMWNT-NH3(+)) and amino-functionalized MWNT (MWNT-NH3(+)). Parenchymal distribution of the stereotactically injected f-MWNTs was assessed by histological examination. Both f-MWNT were uptaken by different types of neural tissue cells (microglia, astrocytes and neurons), however different patterns of cellular internalization were observed between the nanotubes. Furthermore, immunohistochemical staining for specific markers of glial cell activation (GFAP and CD11b) was performed and secretion of inflammatory cytokines was investigated using real-time PCR (qRT-PCR). Injections of both f-MWNT constructs led to a local and transient induction of inflammatory cytokines at early time points. Oxidation of nanotubes seemed to induce significant levels of GFAP and CD11b over-expression in areas peripheral to the f-MWNT injection site. These results highlight the importance of nanotube functionalization on their interaction with brain tissue that is deemed critical for the development nanotube-based vector systems for CNS applications.


Early mobility and walking program for patients in intensive care units: creating a standard of care.
New technologies in critical care and mechanical ventilation have led to long-term survival of critically ill patients. An early mobility and walking program was developed to provide guidelines for early mobility that would assist clinicians working in intensive care units, especially clinicians working with patients who are receiving mechanical ventilation. Prolonged stays in the intensive care unit and mechanical ventilation are associated with functional decline and increased morbidity, mortality, cost of care, and length of hospital stay. Implementation of an early mobility and walking program could have a beneficial effect on all of these factors. The program encompasses progressive mobilization and walking, with the progression based on a patient's functional capability and ability to tolerate the prescribed activity. The program is divided into 4 phases. Each phase includes guidelines on positioning, therapeutic exercises, transfers, walking reeducation, and duration and frequency of mobility sessions. Additionally, the criteria for progressing to the next phase are provided. Use of this program demands a collaborative effort among members of the multidisciplinary team in order to coordinate care for and provide safe mobilization of patients in the intensive care unit.


Species-Specific Colocalization of Middle East Respiratory Syndrome Coronavirus Attachment and Entry Receptors.
Middle East respiratory syndrome coronavirus (MERS-CoV) uses the S1B domain of its spike protein to bind to dipeptidyl peptidase 4 (DPP4), its functional receptor, and its S1A domain to bind to sialic acids. The tissue localization of DPP4 in humans, bats, camelids, pigs, and rabbits generally correlates with MERS-CoV tropism, highlighting the role of DPP4 in virus pathogenesis and transmission. However, MERS-CoV S1A does not indiscriminately bind to all α2,3-sialic acids, and the species-specific binding and tissue distribution of these sialic acids in different MERS-CoV-susceptible species have not been investigated. We established a novel method to detect these sialic acids on tissue sections of various organs of different susceptible species by using nanoparticles displaying multivalent MERS-CoV S1A We found that the nanoparticles specifically bound to the nasal epithelial cells of dromedary camels, type II pneumocytes in human lungs, and the intestinal epithelial cells of common pipistrelle bats. Desialylation by neuraminidase abolished nanoparticle binding and significantly reduced MERS-CoV infection in primary susceptible cells. In contrast, S1A nanoparticles did not bind to the intestinal epithelium of serotine bats and frugivorous bat species, nor did they bind to the nasal epithelium of pigs and rabbits. Both pigs and rabbits have been shown to shed less infectious virus than dromedary camels and do not transmit the virus via either contact or airborne routes. Our results depict species-specific colocalization of MERS-CoV entry and attachment receptors, which may be relevant in the transmission and pathogenesis of MERS-CoV.IMPORTANCE MERS-CoV uses the S1B domain of its spike protein to attach to its host receptor, dipeptidyl peptidase 4 (DPP4). The tissue localization of DPP4 has been mapped in different susceptible species. On the other hand, the S1A domain, the N-terminal domain of this spike protein, preferentially binds to several glycotopes of α2,3-sialic acids, the attachment factor of MERS-CoV. Here we show, using a novel method, that the S1A domain specifically binds to the nasal epithelium of dromedary camels, alveolar epithelium of humans, and intestinal epithelium of common pipistrelle bats. In contrast, it does not bind to the nasal epithelium of pigs or rabbits, nor does it bind to the intestinal epithelium of serotine bats and frugivorous bat species. This finding supports the importance of the S1A domain in MERS-CoV infection and tropism, suggests its role in transmission, and highlights its potential use as a component of novel vaccine candidates.


Combining fructooligosaccharide and dried plum has the greatest effect on restoring bone mineral density among select functional foods and bioactive compounds.
Functional foods and/or their bioactive compounds playing a role in improving skeletal health have received considerable attention. The objective of the present study was to determine the extent to which certain functional foods as (1) whole, e.g., dried plum (DP), figs, dates, raisin, and blueberry, (2) fractionated, e.g., DP puree, DP juice, and DP pulp/skin, or (3) isolated, e.g., DP polyphenols, fructooligosaccharides (FOS), and beta-hydroxy-beta-methylbutyrate, forms reverse bone loss in an ovariectomized (Ovx) rat model of osteoporosis. Additionally, some of these components were tested in reversal of bone loss in combination. For this purpose, 180 3-month-old female Sprague-Dawley rats were divided into 15 groups (n = 12) and either Ovx (14 groups) or sham-operated (Sham, one group). Rats were maintained on a semipurified standard diet for 45 days after surgery to establish bone loss. Thereafter, rats were placed on one of the following dietary treatments for 60 days: casein-based diet (Sham and Ovx). The remaining 13 Ovx groups were placed on various treatment diets. Results showed that diets supplemented with 5% FOS + 7.5% DP was most effective in reversing both right femur and fourth lumbar bone mineral density and fourth lumbar calcium loss while significantly decreasing trabecular separation. There were no significant effects of treatment on serum or urine measures of bone turnover. Although other treatments were good at altering some bone parameters, none had the success in altering several bone health indicators as the diets supplemented with 5% FOS + 7.5% DP. The findings of this study suggest the combination of 5% FOS + 7.5% DP is capable of reversing Ovx-induced bone loss.


Maneuvering the surface plasmon resonance of silver nanostructures through shape-controlled synthesis.
Silver nanostructures are containers for surface plasmons - the collective oscillation of conduction electrons in phase with incident light. By controlling the shape of the container, one can control the ways in which electrons oscillate, and in turn how the nanostructure scatters light, absorbs light, and enhances local electric fields. With a series of discrete dipole approximation (DDA) calculations, each of a distinctive morphology, we illustrate how shape control can tune the optical properties of silver nanostructures. Calculated predictions are validated by experimental measurements performed on nanocubes with controllable corner truncation, right bipyramids, and pentagonal nanowires. Control of nanostructure shape allows optimization of plasmon resonance for molecular detection and spectroscopy.


Rural population mixing and childhood leukaemia: effects of the North Sea oil industry in Scotland, including the area near Dounreay nuclear site.
To determine if any excess of childhood leukaemia and non-Hodgkin's lymphoma was associated with certain striking examples of population mixing in rural Scotland produced by the North Sea oil industry. Details were traced for over 30,000 workers involved in the construction of the large oil terminals in the Shetland and Orkney islands in northern Scotland or employed offshore. Home addresses of the 17,160 Scottish residents were postcoded, integrated with census data, and then classified as urban or rural. Rural postcode sectors, ranked by proportion of oil workers, were grouped into three categories with similar numbers of children but contrasting densities of oil workers. The incidence of leukaemia and non-Hodgkin's lymphoma was examined in these rural (and also in urban) categories in the periods 1974-8, 1979-83 and 1984-8. Scotland. Young people below age 25. A significant excess of leukaemia and non-Hodgkin's lymphoma was found in 1979-83 in the group of rural home areas with the largest proportion of oil workers, following closely on large increases in the workforce. The area near the Dounreay nuclear installation, where an excess of leukaemia is already well known, was within the rural high oil category. The findings support the infection hypothesis that population mixing can increase the incidence of childhood leukaemia in rural areas. They also suggest that the recent excess in the Dounreay-Thurso area is due to population mixing linked to the oil industry, promoted by certain unusual local demographic factors.


Safety of spinal decompression using an ultrasonic bone curette compared with a high-speed drill: outcomes in 337 patients.
Unintended durotomies are a common complication of spine surgery and are often correlated with increased postoperative morbidity. Recently, ultrasonic bone curettes have been introduced in spine surgery as a possible alternative to the conventional high-speed drill, offering the potential for greater bone-cutting precision and less damage to surrounding soft tissues. To date, however, few studies have investigated the safety and efficacy of the ultrasonic bone curette in reducing the rates of incidental durotomy compared with the high-speed drill. The authors retrospectively reviewed the records of 337 consecutive patients who underwent posterior cervical or thoracic decompression at a single institution between January 2009 and September 2011. Preoperative pathologies, the location and extent of spinal decompression, and the use of an ultrasonic bone curette versus the high-speed drill were noted. The rates of incidental durotomy, as well as hospital length of stay (LOS) and perioperative outcomes, were compared between patients who were treated using the ultrasonic bone curette and those treated using a high-speed drill. Among 88 patients who were treated using an ultrasonic bone curette and 249 who were treated using a high-speed drill, 5 (5.7%) and 9 (3.6%) patients had an unintentional durotomy, respectively. This finding was not statistically significant (p = 0.40). No patients in either cohort experienced statistically higher rates of perioperative complications, although patients treated using an ultrasonic bone curette tended to have a longer hospital LOS. This difference may be attributed to the fact that this series contained a statistically higher number of metastatic tumor cases (p < 0.0001) in the ultrasonic bone curette cohort, likely increasing the LOS for that patient population. In 13 patients, the dural defect was repaired intraoperatively. No patients who experienced an incidental durotomy had new-onset or permanent neurological deficits postoperatively. The safety and efficacy of ultrasonic bone curettes in spine surgery has not been well established. This study shows that the ultrasonic bone curette has a similar safety profile compared with the high-speed drill, although both are capable of causing iatrogenic dural tears during spine surgery.


Use of implantable cardioverter defibrillators for primary prevention in the community: do women and men equally meet trial enrollment criteria?
Fewer women than men undergo implantable cardioverter defibrillator (ICD) implantation for the primary prevention of sudden cardiac death. The criteria used to select patients for ICD implantation may be more permissive among men than for women. We hypothesized that women who undergo primary prevention ICD implantation more often meet strict trial enrollment criteria for this therapy. We studied 59,812 patients in the National Cardiovascular Data Registry ICD registry undergoing initial primary prevention ICD placement between January 2005 and April 2007. Patients were classified as meeting or not meeting enrollment criteria of either the MADIT-II or SCD-HeFT trials. Multivariable analyses assessed the association between gender and concordance with trial criteria adjusting for demographic, clinical, and system characteristics. Among the cohort, 27% (n = 16,072) were women. Overall, 85.2% of women and 84.5% of men met enrollment criteria of either trial (P = .05). In multivariable analyses, women were equally likely to meet trial criteria (OR 1.04, 95% CI 0.99-1.10) than men. Significantly more women than men met the trial enrollment criteria among patients older than age 65 (86.6% of women vs 85.3% of men, OR 1.11, 95% CI 1.03-1.19), but this difference was not found among younger patients (82.5% of women vs 83.0% of men, OR 0.97, 95% CI 0.89-1.07). In a national cohort undergoing primary prevention ICD implantation, older women were only slightly more likely then men to meet the enrollment criteria for MADIT II or SCD-HeFT. Relative overutilization in men is not an important explanation for gender differences in ICD implantation.


Effect of continuous psoas compartment block and intravenous patient controlled analgesia on postoperative pain control after total knee arthroplasty.
Total knee arthroplasty (TKA) generates severe postoperative pain in 60% of patients and moderate pain in 30% of patients. Because inadequate postoperative pain control can hinder early physiotherapy and rehabilitation, it is the most influential factor dictating a good outcome. The purpose of this study was to evaluate the effectiveness of continuous psoas compartment block (PCB) in comparison to intravenous patient-controlled analgesia (IVPCA) in TKA patients. 40 TKA patients were randomly divided into 2 groups. Group IVPCA (n = 20) received intravenous patient controlled analgesia (IVPCA) for 48 hours. Group PCB (n = 20) received continuous PCB for 48 hours at the fourth intertransverse process of the lumbar using the C-arm. Pain scores, side effects, satisfaction, the length of hospital stay, rescue antiemetics, and analgesics were recorded. Pain scores (VNRS 0-100) were higher in Group IVPCA than in Group PCB. Nausea and sedation occurred more frequently in Group IVPCA than in Group PCB. There were no differences between the groups in the length of the hospital stay, satisfaction scores, and the use of rescue antiemetics and analgesics. Continuous PCB seemed to be an appropriate and reliable technique for TKA patients, because it provided better analgesia and fewer side effects such as nausea and sedation when compared to IVPCA.


Portable and power-free serodiagnosis of Chagas disease using magnetic levitating microbeads.
This work describes the detection of anti-T. cruzi antibodies in whole blood solutions using magnetic levitating microbeads (MLμBs). This simple diagnostic method can be easily performed by minimally trained personnel using an inexpensive and portable magnetic stage that requires no electricity. A multiphase test tube containing the MLμBs facilitates the sequential incubation, filtering, and reading of the immunoassays. The diagnostic method starts by adding a blood sample to the top phase of the test tube where the anti-T. cruzi antibodies present in the blood attach to the T. cruzi antigens on the surface of the MLμBs. Shaking the test tube after incubation mixes the top layer with a paramagnetic medium loaded with SiO2 microcrystals. The attachment of SiO2 microcrystals to those MLμBs bound to T. cruzi antibodies decreases their levitation height once the tube is placed between two antialigned permanent magnets. Measuring the levitation height of MLμBs enables the accurate detection and quantification of anti-T. cruzi antibodies in the blood across the clinically relevant range, with a detection limit of 5 μg mL-1. The small size of the test tubes facilitates the simultaneous analysis of over 50 different samples. MLμBs act as partial collimators for non-polarized light, facilitating their visual identification by the naked eye or by projecting incident light on a thin paper screen. A machine-vision algorithm was created to automatically interpret the results of the MLμB tests from a digital image, resulting in a rapid, accurate, and user-friendly assay for Chagas disease that can be used in resource-limited settings.