Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone.
To evaluate the outcome of children with cryptogenic infantile spasms treated with high-dose synthetic adrenocorticotropic hormone (ACTH) and the relation between early treatment, within 1 month of onset, and outcome. We assessed the long-term cognitive and seizure outcomes of 37 patients with cryptogenic infantile spasms (onset, age 3 to 9 months) receiving standardized treatment regimen of high-dose tetracosactide depot, 1 mg IM every 48 h for 2 weeks, with a subsequent 8- to 10-week slow taper and followed by oral prednisone, 10 mg/day for a month, with a subsequent slow taper for 5 months or until the infant reached the age of 1 year, whichever came later. Development was assessed before treatment. Seizure outcomes were followed up prospectively. Cognitive outcomes were determined after 6 to 21 years and analyzed in relation to treatment lag and pretreatment regression. Twenty-two infants were treated within 1 month of onset of infantile spasms, and 15 after 1 to 6.5 months. Normal cognitive outcome was found in all 22 (100%) patients of the early-treatment group, and in 40% of the late-treatment group. Normal cognitive outcome was found in all 25 (100%) patients who had no or only mild mental deterioration at presentation, including four in the late-treatment group but in only three of the 12 patients who had had marked or severe deterioration before treatment. Early treatment of cryptogenic infantile spasms with a high-dose ACTH protocol is associated with favorable long-term cognitive outcomes. Once major developmental regression lasts for a month or more, the prognosis for normal cognitive outcome is poor. Further studies are needed on the optimal treatment regimen for this disorder.


Postural function of the diaphragm in persons with and without chronic low back pain.
A case-control study. To examine the function of the diaphragm during postural limb activities in patients with chronic low back pain and healthy controls. Abnormal stabilizing function of the diaphragm may be an etiological factor in spinal disorders. However, a study designed specifically to test the dynamics of the diaphragm in chronic spinal disorders is lacking. Eighteen patients with chronic low back pain due to chronic overloading, as ascertained via clinical assessment and magnetic resonance imaging, and 29 healthy subjects were examined. Both groups presented with normal pulmonary function test results. A dynamic magnetic resonance imaging system and specialized spirometric readings were used with subjects in the supine position. Measurements during tidal breathing (TB) and isometric flexion of the upper and lower extremities against external resistance with TB were performed. Standard pulmonary function tests, including respiratory muscle drive (PI(max) and PE(max)), were also assessed. Using multivariate analysis of covariance, smaller diaphragm excursions and higher diaphragm position were found in the patient group (P<.05) during the upper extremity TB and lower extremity TB conditions. Maximum changes were found in costal and middle points of the diaphragm. A 1-way analysis of covariance showed a steeper slope in the middle-posterior diaphragm in the patient group both in the upper extremity TB and lower extremity TB conditions (P<.05). Patients with chronic low back pain appear to have both abnormal position and a steeper slope of the diaphragm, which may contribute to the etiology of the disorder.


Saturation of fluorescence in flames with a Gaussian laser beam.
The method of saturated fluorescence for measuring species concentrations in flames is usually performed with laser beams that do not provide a constant intensity distribution across the focal volume. Because of the intensity distribution across the beam, the fluorescence signal does not depend on laser power or intensity in the same manner as for uniform illumination. This leads to anomolous apparent saturation intensities. In the following, the effect is considered for atomic fluorescence. Relations for the fluorescence signal under two common excitation geometries are derived and uncertainty relations used to consider the benefits of high laser intenstiy.


Observation of the validity of the upper lip bite test in predicting difficult intubation.
The upper lip bite test (ULBT) is considered an effective method for predicting difficult airways, but data on the ULBT for predicting difficult tracheal intubation are lacking. This study aimed to examine the clinical utility of the ULBT in predicting difficult endotracheal intubation. We conducted an observational case-cohort study of adult patients undergoing elective surgery and requiring endotracheal intubation for general anesthesia. Difficult airway assessment was performed on the recruited patients before the operation, including the ULBT, mouth opening, thyromental distance, modified Mallampati test, and body mass index. The primary outcome was the incidence of difficult tracheal intubation. The receiver operating characteristic curve analysis was used to compare the performance of variables in predicting difficult tracheal intubation. We successfully recruited 2522 patients for analysis and observed 64 patients with difficult tracheal intubation. When predicting difficult tracheal intubation, grade 2 ULBT had a sensitivity of 0.75 and a specificity of 0.54, and grade 3 had a sensitivity of 0.28 and a specificity of 0.75. Compared with mouth opening, the area under the receiver operating characteristic curve of the ULBT was lower in predicting difficult tracheal intubation (0.69 [95% confidence interval: 0.67-0.71] vs. 0.84 [95% confidence interval: 0.82-0.87], P < 0.05).Clinical Trials Registry: ChiCTR-ROC-16009050, principal investigator: Weidong Yao.


Gene expression data classification with Kernel principal component analysis.
One important feature of the gene expression data is that the number of genes M far exceeds the number of samples N. Standard statistical methods do not work well when N < M. Development of new methodologies or modification of existing methodologies is needed for the analysis of the microarray data. In this paper, we propose a novel analysis procedure for classifying the gene expression data. This procedure involves dimension reduction using kernel principal component analysis (KPCA) and classification with logistic regression (discrimination). KPCA is a generalization and nonlinear version of principal component analysis. The proposed algorithm was applied to five different gene expression datasets involving human tumor samples. Comparison with other popular classification methods such as support vector machines and neural networks shows that our algorithm is very promising in classifying gene expression data.


Characterization and regulation of expression of an antifungal peptide from hemolymph of an insect, Manduca sexta.
Insects secrete antimicrobial peptides as part of the innate immune response. Most antimicrobial peptides from insects have antibacterial but not antifungal activity. We have characterized an antifungal peptide, diapausin-1 from hemolymph of a lepidopteran insect, Manduca sexta (tobacco hornworm). Diapausin-1 was isolated by size exclusion chromatography from hemolymph plasma of larvae that were previously injected with a yeast, Saccharomyces cerevisiae. Fractions containing activity against S. cerevisiae were analyzed by SDS-PAGE and MALDI-TOF MS/MS and found to contain a 45-residue peptide that was encoded by sequences identified in M. sexta transcriptome and genome databases. A cDNA for diapausin-1 was cloned from cDNA prepared from fat body RNA. Diapausin-1 is a member of the diapausin family of peptides, which includes members known to have antifungal activity. The M. sexta genome contains 14 genes with high similarity to diapausin-1, each with 6 conserved Cys residues. Diapausin-1 was produced as a recombinant protein in Escherichia coli. Purified recombinant diapausin-1 was active against S. cerevisiae, with IC50 of 12 μM, but had no detectable activity against bacteria. Spores of some plant fungal pathogens treated with diapausin-1 had curled germination tubes or reduced and branched hyphal growth. Diapausin-1 mRNA level in fat body strongly increased after larvae were injected with yeast or with Micrococcus luteus. In addition, diapausin-1 mRNA levels increased in midgut and fat body at the wandering larval stage prior to pupation, suggesting developmental regulation of the gene. Our results indicate that synthesis of diapausin-1 is part of an antifungal innate immune response to infection in M. sexta.


[Production and evaluation of a purified protein derivative from an Argentine strain of Mycobacterium avium subsp. paratuberculosis].
Purified Protein Derivatives (PPDs) are non-defined antigens prepared from mycobacteria cultures. They are usually employed to evaluate the specific cellular immune response both in animals and humans. Bovine and avian PPDs are usually employed as antigens in mycobacterial infections such as tuberculosis and paratuberculosis. Nevertheless, PPD from Mycobacterium avium subsp. paratuberculosis, (PPDj) is neither commonly used nor frequently available. However, PPD from Mycobacterium avium subsp. avium is in fact used. We aimed to obtain and evaluate the performance of a PPDj from a local isolate of MAP using the ãInterferon-release assay. The stimulation of ãInterferon-release was significantly different between infected and control cattle when this antigen, named PPDj-IB, was used. Stimulation in the infected animals was similar with both antigens (PPDa and PPDj-IB). However, some animals were positively stimulated with PPDj-IB and not with PPDa. We demonstrated by Western blot that two antigenic molecules, lipoarabinoman and APA/ModD antigen were differentially represented in both PPDs. This could explain the difference in stimulation induction of yIFN observed at individual level. Although PPDj-IB could not improve PPDa performance, we could easily produce an effective purified protein derivative for in vitro assays.


Family and cultural processes linking family instability to Mexican American adolescent adjustment.
Despite the rapidly growing Mexican American population, no studies to date have attempted to explain the underlying relations between family instability and Mexican American children's development. Using a diverse sample of 740 Mexican American adolescents (49% female; 5th grade, M age = 10.4 years; 7th grade, M age = 12.8 years) and their mothers, we prospectively examined the relations between family instability and adolescent academic outcomes and mental health in the 7th grade. The model fit the data well and results indicated that family instability between 5th and 7th grade was related to increased 7th-grade mother-adolescent conflict, and, in turn, mother-adolescent conflict was related to decreased school attachment and to increased externalizing and internalizing symptoms in the 7th grade. Results also indicated that 7th-grade mother-adolescent conflict mediated the relations between family instability and 7th-grade academic outcomes and mental health. Further, we explored adolescent familism values as a moderator and found that adolescent familism values served as a protective factor in the relation between mother-adolescent conflict and grades. Implications for future research and intervention strategies are discussed.


Imaging ocular immune responses by intravital microscopy.
The eye offers excellent opportunities to observe cellular interactions in vivo. This applies especially to the immune response in which discrete events can be studied, including cell trafficking, transendothelial migration, adhesion, antigen presentation, and T cell activation. Intravital microscopy has allowed study of immune cell interactions in tissues such as the conjunctiva, the inflamed cornea, and the iris. Thus the realtime observation of presentation of antigen injected into the anterior chamber of the eye can be imaged using fluorescently labelled antigen and cells. Application of the scanning laser ophthalmoscope to the rat and mouse eye allows analysis of leukocyte-endothelial interactions in the retinal and choroidal circulations. These studies have provided important information on rolling and adhesion of leukocytes in real time in different microvascular beds that have not been manipulated in any way and has, for instance, provided quantitation to the effects of shear stress on leukocyte-endothelial adhesion. In addition, the model permits an accurate analysis of the timing of trafficking of T cells into the eye and the possibility of determining which cells, if any, may be responsible for antigen presentation in the tissues as opposed to the secondary lymphoid organs. Finally, these experimental methods are now being applied to the human eye and should prove valuable in determining the nature of tissue damage events in the eye as well as evaluating the response to treatments.


Twin studies in autoimmune disease: genetics, gender and environment.
Twin studies are powerful tools to discriminate whether a complex disease is due to genetic or environmental factors. High concordance rates among monozygotic (MZ) twins support genetic factors being predominantly involved, whilst low rates are suggestive of environmental factors. Twin studies have often been utilised in the study of systemic and organ specific autoimmune diseases. As an example, type I diabetes mellitus has been investigated to establish that that disease is largely affected by genetic factors, compared to rheumatoid arthritis or scleroderma, which have a weaker genetic association. However, large twin studies are scarce or virtually non-existent in other autoimmune diseases which have been limited to few sets of twins and individual case reports. In addition to the study of the genetic and environmental contributions to disease, it is likely that twin studies will also provide data in regards to the clinical course of disease, as well as risk for development in related individuals. More importantly, genome-wide association studies have thus far reported genomic variants that only account for a minority of autoimmunity cases, and cannot explain disease discordance in MZ twins. Future research is therefore encouraged not only in the analysis of twins with autoimmune disease, but also in regards to epigenetic factors or rare variants that may be discovered with next-generation sequencing. This review will examine the literature surrounding twin studies in autoimmune disease including discussions of genetics and gender.


Adoption of pediatric-inspired acute lymphoblastic leukemia regimens by adult oncologists treating adolescents and young adults: A population-based study.
Studies have demonstrated superior outcomes for adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) who are treated using pediatric versus adult therapeutic regimens. To the best of our knowledge, whether adult oncologists in the United States have adopted this approach to ALL in AYA patients is currently unknown. The objective of the current study was to provide a population-based description of ALL treatment patterns in AYA individuals over the past decade. Data regarding AYA patients aged 15 to 39 years and diagnosed with ALL between 2004 and 2014 while living in the Greater Bay Area were obtained from the Greater Bay Area Cancer Registry (GBACR). Treating facilities were designated as pediatric or adult centers; induction treatment regimens were abstracted from registry text data fields. Of 304 patients diagnosed in the GBACR catchment region, complete treatment data were available for 229 (75%). The location of care was identified for 296 patients (97%) treated at 31 unique centers. Approximately 70% of AYA patients received induction therapy at an adult treatment center. All AYA patients who were treated at pediatric centers received pediatric ALL regimens. Among AYA patients treated by adult oncologists with complete treatment data, none received a pediatric regimen before 2008. Between 2008 and 2012, while the US Adult Intergroup C10403 pediatric-inspired ALL protocol was open to accrual, 31% of AYA patients treated by adult oncologists received pediatric regimens. This rate fell to 21% from 2013 through 2014. Adult facilities treating ≥ 2 AYA patients with ALL per year captured in the GBACR were more likely to administer pediatric regimens than lower volume centers (P = .03). As of 2014, only a minority of AYA patients with ALL received pediatric ALL regimens at adult cancer centers. Cancer 2017;122-130. © 2016 American Cancer Society.


Ball and rackets: Inferring fiber fanning from diffusion-weighted MRI.
A number of methods have been proposed for resolving crossing fibers from diffusion-weighted (DW) MRI. However, other complex fiber geometries have drawn minimal attention. In this study, we focus on fiber orientation dispersion induced by within-voxel fanning. We use a multi-compartment, model-based approach to estimate fiber dispersion. Bingham distributions are employed to represent continuous distributions of fiber orientations, centered around a main orientation, and capturing anisotropic dispersion. We evaluate the accuracy of the model for different simulated fanning geometries, under different acquisition protocols and we illustrate the high SNR and angular resolution needs. We also perform a qualitative comparison between our parametric approach and five popular non-parametric techniques that are based on orientation distribution functions (ODFs). This comparison illustrates how the same underlying geometry can be depicted by different methods. We apply the proposed model on high-quality, post-mortem macaque data and present whole-brain maps of fiber dispersion, as well as exquisite details on the local anatomy of fiber distributions in various white matter regions.


Daytime Versus Nighttime Extubations: A Comparison of Reintubation, Length of Stay, and Mortality.
Despite studies regarding outcomes of day versus night medical care, consequences of nighttime extubations are unknown. It may be favorable to extubate patients off-hours, as soon as weaning parameters are met, since this could decrease complications and shorten length of stay (LOS). Conversely, nighttime extubation could be deleterious, as staffing varies during this time. We hypothesized that patients have similar reintubation rates, irrespective of extubation time. A retrospective cohort study performed at 2 hospitals within a tertiary academic medical center included all adult intensive care unit (ICU) patients extubated between July 01, 2009 and May 31, 2011. Those extubated due to withdrawal of support were excluded. The nighttime group included patients extubated between 7:00 pm and 6:59 am and the daytime group included patients extubated between 7:00 am and 6:59 pm. Of 2240 extubated patients, 1555 were extubated during the day and 685 were extubated at night. Of these, 119 (7.7%) and 26 (3.8%), respectively, were reintubated in 24 hours with likelihood of reintubation significantly lower for nighttime than daytime after multivariable adjustment (odds ratio [OR] = 0.5, 95% confidence interval [CI] 0.3-0.9, P = .01), with a similar trend for reintubation within 72 hours (OR = 0.7, 95% CI = 0.5-1.0, P = .07). There was a trend toward decreased mortality for patients extubated at night (OR = 0.6, 95% CI = 0.3-1.0, P = .06). There was also a significantly lower LOS for patients extubated at night (P = .002). In a confirmatory frequency-matched analysis, there was no significant difference in reintubation proportion or mortality, but LOS was significantly less in those extubated at night. Intensive care unit extubations at night did not have higher likelihood of reintubation, LOS, or mortality compared to those during the day. Since patients should be extubated as soon as they meet parameters in order to potentially decrease complications of mechanical ventilation, these data provide no support for delaying extubation until daytime.


The cyclical lower extremity exercise for Parkinson's trial (CYCLE): methodology for a randomized controlled trial.
Motor and non-motor impairments affect quality of life in individuals with Parkinson's disease. Our preliminary research indicates that forced exercise cycling, a mode of exercise in which a participant's voluntary rate of exercise is augmented on a stationary cycle, results in global improvements in the cardinal symptoms of Parkinson's disease. The objective of the Cyclical Lower Extremity Exercise (CYCLE) trial for Parkinson's disease is to determine the effects of forced exercise cycling on motor and non-motor performance when compared to voluntary rate cycling and a non-exercise control group. Additionally, we plan to identify any associated changes in neural activity determined by functional magnetic resonance imaging. A total of 100 individuals with mild to moderate idiopathic Parkinson's disease will participate in a single-center, parallel-group, rater-blind study. Participants will be randomized 2:2:1 into a forced exercise, voluntary exercise, or no-exercise control group, respectively. Both exercise groups will cycle 3 times per week for 8 weeks at identical aerobic intensities for 40 minutes, but participants in the forced exercise group will cycle 30% faster than their voluntary rate by means of an augmented motorized bicycle. Neuroimaging, clinical, and biomechanical assessments of motor and non-motor performance will be made at baseline both 'on' and 'off' medication, after four weeks of exercise (midpoint), end of treatment, 4 weeks after end of treatment, and 8 weeks after end of treatment. CYCLE trial will play a critical role in determining the effectiveness of two different types of aerobic exercise, forced and voluntary, on motor and non-motor performance in individuals with Parkinson's disease. Additionally, the coupling of clinical, biomechanical, and neuroimaging outcomes has the potential to provide insight into mechanisms underlying change in function as a result of exercise. Clinicaltrials.gov registration number NCT01636297.


Large scale clinical trials: lessons from the COVID-19 pandemic.
The COVID-19 pandemic has presented substantial new challenges to clinical and research teams. Our objective was to analyse the experience of investigators and research delivery staff regarding the research response to COVID-19 in order to identify these challenges as well as solutions for future pandemic planning. We conducted a survey of diverse research staff involved in delivery of COVID-19 clinical trials across the UK. This was delivered online across centres linked to the NIHR Respiratory Translational Research Collaboration. Responses were analysed using a formal thematic analysis approach to identify common themes and recommendations. 83 survey participants from ten teaching hospitals provided 922 individual question responses. Respondents were involved in a range of research delivery roles but the largest cohort (60%) was study investigators. A wide range of research experiences were captured, including early and late phase trials. Responses were coded into overarching themes. Among common observations, complex protocols without adaptation to a pandemic were noted to have hampered recruitment. Recommendations included the need to develop and test pandemic-specific protocols, and make use of innovations in information technology. Research competition needs to be avoided and drug selection processes should be explicitly transparent. Delivery of clinical trials, particularly earlier phase trials, in a pandemic clinical environment is highly challenging, and was reactive rather than anticipatory. Future pandemic studies should be designed and tested in advance, making use of pragmatic study designs as far as possible and planning for integration between early and later phase trials and regulatory frameworks.


Molecular Characterization and Cluster Analysis of Field Isolates of Avian Infectious Laryngotracheitis Virus from Argentina.
Avian infectious laryngotracheitis (ILT) is a worldwide infectious disease that causes important economic losses in the poultry industry. Although it is known that ILT virus (ILTV) is present in Argentina, there is no information about the circulating strains. With the aim to characterize them, seven different genomic regions (thymidine kinase, glycoproteins D, G, B, C, and J, and infected cell polypeptide 4) were partially sequenced and compared between field samples. The gJ sequence resulted to be the most informative segment, it allowed the differentiation among field sample strains, and also, between wild and vaccine viruses. Specific changes in selected nucleotidic positions led to the definition of five distinct haplotypes. Tests for detection of clustering were run to test the null hypothesis that ILTV haplotypes were randomly distributed in time in Argentina and in space in the most densely populated poultry region of this country, Entre Rios. From this study, it was possible to identify a 46 km radius cluster in which higher proportions of haplotypes 4 and 5 were observed, next to a provincial route in Entre Rios and a significant decline of haplotype 5 between 2009 and 2011. Results here provide an update on the molecular epidemiology of ILT in Argentina, including data on specific genome segments that may be used for rapid characterization of the virus in the field. Ultimately, results will contribute to the surveillance of ILT in the country.


Creatures of habit: accounting for the role of habit in implementation research on clinical behaviour change.
Social cognitive theories on behaviour change are increasingly being used to understand and predict healthcare professionals' intentions and clinical behaviours. Although these theories offer important insights into how new behaviours are initiated, they provide an incomplete account of how changes in clinical practice occur by failing to consider the role of cue-contingent habits. This article contributes to better understanding of the role of habits in clinical practice and how improved effectiveness of behavioural strategies in implementation research might be achieved. Habit is behaviour that has been repeated until it has become more or less automatic, enacted without purposeful thinking, largely without any sense of awareness. The process of forming habits occurs through a gradual shift in cognitive control from intentional to automatic processes. As behaviour is repeated in the same context, the control of behaviour gradually shifts from being internally guided (e.g., beliefs, attitudes, and intention) to being triggered by situational or contextual cues. Much clinical practice occurs in stable healthcare contexts and can be assumed to be habitual. Empirical findings in various fields suggest that behaviours that are repeated in constant contexts are difficult to change. Hence, interventions that focus on changing the context that maintains those habits have a greater probability of success. Some sort of contextual disturbance provides a window of opportunity in which a behaviour is more likely to be deliberately considered. Forming desired habits requires behaviour to be carried out repeatedly in the presence of the same contextual cues. Social cognitive theories provide insight into how humans analytically process information and carefully plan actions, but their utility is more limited when it comes to explaining repeated behaviours that do not require such an ongoing contemplative decisional process. However, despite a growing interest in applying behavioural theory in interventions to change clinical practice, the potential importance of habit has not been explored in implementation research.


Role of the acylated amino terminus of recoverin in Ca(2+)-dependent membrane interaction.
Recoverin, a calcium ion (Ca2+)-binding protein of vertebrate photoreceptors, binds to photoreceptor membranes when the Ca2+ concentration is greater than 1 micromolar. This interaction requires a fatty acyl residue covalently linked to the recoverin amino (NH2)-terminus. Removal of the acyl residue, either by proteolytic cleavage of the NH2-terminus or by production of nonacylated recoverin, prevented recoverin from binding to membranes. The acylated recoverin NH2-terminus could be cleaved by trypsin only when Ca2+ was bound to recoverin. These results suggest that the hydrophobic NH2-terminus is constrained in Ca(2+)-free recoverin and liberated by Ca2+ binding. The hydrophobic acyl moiety of recoverin may interact with the membrane only when recoverin binds Ca2+.


Stimulant Formulations for the Treatment of Attention-Deficit/Hyperactivity Disorder.
Clinicians have access to a variety of formulations of methylphenidate and amphetamine to treat attention-deficit/hyperactivity disorder (ADHD). However, due to new emerging formulations, clinicians may lack up-to-date knowledge about all available stimulant formulations. Presented here is a comprehensive guide to13 formulations of methylphenidate and 10 formulations of amphetamine that have US Food and Drug Administration approval to treat ADHD. PubMed was searched using the following MeSH terms: attention-deficit/hyperactivity disorder, ADHD, stimulant, amphetamine, and methylphenidate. Inclusion criteria were randomized controlled trials and systematic reviews published through 2017. Forty-eight articles were identified; however, these included analyses using product labels and anecdotal or uncontrolled reports of apparent clinical inequivalence. Thus, 34 articles were included in the final review to provide a thorough evidence-based guide. Each formulation has a unique pharmacokinetic profile. Clinically, one formulation may not be suitable for all patients. To select the most appropriate formulation, clinicians should consider the individual patient's preferences such as dosing schedule, time required to reach peak plasma concentration and duration of action, and tolerability. This review provides clinical guidance to help clinicians prescribe the most suitable treatment for an individual..


The role of flagella and chemotaxis genes in host pathogen interaction of the host adapted Salmonella enterica serovar Dublin compared to the broad host range serovar S. Typhimurium.
The importance of flagella and chemotaxis genes in host pathogen interaction in Salmonella enterica is mainly based on studies of the broad host range serovar, S. Typhimurium, while little is known on the importance in host specific and host adapted serovars, such as S. Dublin. In the current study we have used previously characterized insertion mutants in flagella and chemotaxis genes to investigate this and possible differences in the importance between the two serovars. fliC (encoding the structural protein of the flagella) was essential for adhesion and fliC and cheB (CheB restores the chemotaxis system to pre-stimulus conformation) were essential for invasion of S. Dublin into epithelial Int407 cells. In S. Typhimurium, both lack of flagella (fliC/fljB double mutant) and cheB influenced adhesion, and invasion was influenced by lack of both cheA (the histidine-kinase of the chemotaxis system), fliC/fljB and cheB mutation. Uptake in J774A.1 macrophage cells was significantly reduced in cheA, cheB and fliC mutants of S. Dublin, while cheA was dispensable in S. Typhimurium. Removal of flagella in both serotypes caused an increased ability to propagate intracellular in J774 macrophage cells and decreased cytotoxicity toward these cells. Flagella and chemotaxis genes were found not to influence the oxidative response. The induction of IL-6 from J774A-1 cells depended on the presence of flagella in S. Typhimurium, whilst this was not the case following challenge with S. Dublin. Addition of fliC from S. Typhimurium in trans to a fliC mutant of S. Dublin increased cytotoxicity but it did not increase the IL-6 production. Flagella were demonstrated to contribute to the outcome of infection following oral challenge of mice in S. Dublin, while an S. Typhimurium fliC/fljB mutant showed increased virulence following intra peritoneal challenge. The results showed that flagella and chemotaxis genes differed in their role in host pathogen interaction between S. Dublin and S. Typhimurium. Notably, lack of flagella conferred a more virulent phenotype in S. Typhimurium at systemic sites, while this was not the case in S. Dublin. In vitro assays suggested that this could be related to flagella-induced induction of the IL-6 pro-inflammatory response, but further in vivo studies are needed to confirm this.


Public smoking ban and socioeconomic inequalities in smoking prevalence and cessation: a cross-sectional population-based study in Geneva, Switzerland (1995-2014).
Smoking bans were suggested to reduce smoking prevalence and increase quit ratio but their equity impact remains unclear. We aimed to characterise the socioeconomic status (SES)-related inequalities in smoking prevalence and quit ratio before and after the implementation of a public smoking ban. We included data from 17 544 participants in the population-based cross-sectional Bus Santé study in Geneva, Switzerland, between 1995 and 2014. We considered educational attainment (primary, secondary and tertiary) as a SES indicator. Outcomes were smoking prevalence (proportion of current smokers) and quit ratio (ex-smokers to ever-smokers ratio). We used segmented linear regression to assess the overall impact of smoking ban on outcome trends. We calculated the relative (RII) and slope (SII, absolute difference) indexes of inequality, quantifying disparities between educational groups in outcomes overall (1995-2014), before and after ban implementation (November 2009). Least educated participants displayed higher smoking prevalence (RII=2.04, P<0.001; SII=0.15, P<0.001) and lower quit ratio (RII=0.73, P<0.001; SII=-0.18, P<0.001). As in other studies, smoking ban implementation coincided with a temporary reduction of smoking prevalence (P=0.003) and increase in quit ratio (P=0.02), with a progressive return to preban levels. Inequalities increased (P<0.05) in relative terms for smoking prevalence (RIIbefore=1.84, P<0.001 and RIIafter=3.01, P<0.001) and absolute terms for both outcomes (smoking prevalence: SIIbefore=0.14, P<0.001 and SIIafter=0.19, P<0.001; quit ratio: SIIbefore=-0.15, P<0.001 and SIIafter=-0.27, P<0.001). Implementation of a public smoking ban coincided with a short-lived decrease in smoking prevalence and increase in quit ratio but also with a widening in SES inequalities in smoking-related outcomes.


Efficacy of Rectal Tacrolimus for Induction Therapy in Patients With Resistant Ulcerative Proctitis.
Resistant ulcerative proctitis can be extremely difficult to manage. Topically administered tacrolimus, however, may be effective in difficult-to-treat proctitis. This was a randomized, double-blind, placebo-controlled induction trial of rectal tacrolimus in patients with active ulcerative colitis. Eleven patients received rectal tacrolimus (0.5 mg/mL), and 10 placebo, for 8 weeks. The primary endpoint was clinical response by using the Mayo Clinic score. A planned interim analysis after 20 patients had completed the study demonstrated highly significant differences between the groups and the study was closed because of ethical considerations with patients already recruited allowed to complete the study. The primary endpoint was met in 8 of 11 patients receiving rectal tacrolimus and 1 of 10 patients receiving placebo (73% vs 10%; P = .004). Of the secondary endpoints, 5 patients with rectal tacrolimus achieved clinical remission compared with none receiving placebo (45% vs 0%; P = .015). Mucosal healing at Week 8 was achieved in 8 patients receiving rectal tacrolimus compared with 1 (73% vs 10%) receiving placebo (P = .004). The Inflammatory Bowel Disease Questionnaire increased ≥16 points over baseline in 5 of the tacrolimus and 2 (45% vs 20%) of the placebo patients (P = .36). Finally, the average partial Mayo score was numerically lower in the tacrolimus-treated group compared with placebo at Week 2 (4.3 ± 0.74 vs 5.8 ± 0.64; P = .15) and Week 4 (3.7 ± 0.96 vs 5.8 ± 0.6; P = .08) but was significantly lower at Week 8 (3.3 ± 1.2 vs 6.7 ± 0.62; P = .01). There were no safety issues identified with rectal tacrolimus use. Rectal tacrolimus was more effective than placebo for induction of a clinical response, clinical remission, and mucosal healing in resistant ulcerative proctitis (Clinicaltrials.gov registration: NCT01418131).


A deeper look into transcription regulatory code by preferred pair distance templates for transcription factor binding sites.
Modern experimental methods provide substantial information on protein-DNA recognition. Studying arrangements of transcription factor binding sites (TFBSs) of interacting transcription factors (TFs) advances understanding of the transcription regulatory code. We constructed binding motifs for TFs forming a complex with HIF-1α at the erythropoietin 3(')-enhancer. Corresponding TFBSs were predicted in the segments around transcription start sites (TSSs) of all human genes. Using the genome-wide set of regulatory regions, we observed several strongly preferred distances between hypoxia-responsive element (HRE) and binding sites of a particular cofactor protein. The set of preferred distances was called as a preferred pair distance template (PPDT). PPDT dramatically depended on the TF and orientation of its binding sites relative to HRE. PPDT evaluated from the genome-wide set of regulatory sequences was used to detect significant PPDT-consistent binding site pairs in regulatory regions of hypoxia-responsive genes. We believe PPDT can help to reveal the layout of eukaryotic regulatory segments. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Public knowledge of cardiovascular disease and response to acute cardiac events in three cities in China and India.
To inform interventions targeted towards reducing mortality from acute myocardial infarction (AMI) and sudden cardiac arrest in three megacities in China and India, a baseline assessment of public knowledge, attitudes and practices was performed. A household survey, supplemented by focus group and individual interviews, was used to assess public understanding of cardiovascular disease (CVD) risk factors, AMI symptoms, cardiopulmonary resuscitation (CPR) and automated external defibrillators (AEDs). Additionally, information was collected on emergency service utilisation and associated barriers to care. 5456 household surveys were completed. Hypertension was most commonly recognised among CVD risk factors in Beijing and Shanghai (68% and 67%, respectively), while behavioural risk factors were most commonly identified in Bangalore (smoking 91%; excessive alcohol consumption 64%). Chest pain/discomfort was reported by at least 60% of respondents in all cities as a symptom of AMI, but 21% of individuals in Bangalore could not name a single symptom. In Beijing, Shanghai and Bangalore, 26%, 15% and 3% of respondents were trained in CPR, respectively. Less than one-quarter of participants in all cities recognised an AED. Finally, emergency service utilisation rates were low, and many individuals expressed concern about the quality of prehospital care. Overall, we found low to modest knowledge of CVD risk factors and AMI symptoms, infrequent CPR training and little understanding of AEDs. Interventions will need to focus on basic principles of CVD and its complications in order for patients to receive timely and appropriate care for acute cardiac events.


A positive complement dependent cytotoxicity immunoglobulin G crossmatch due to auto-antibodies with a negative luminex bead assays in a renal transplant recipient: A Diagnostic dilemma.
Transplant recipients are always at a risk of developing anti-human leukocyte antigen (HLA) antibodies due to prior sensitizing events such as blood transfusions, multiple pregnancies, or transplantation. Unexpected positive outcomes can be seen in complement dependent cytotoxicity (CDC) based assays due to underlying autoimmune disorders or pharmacological treatment (rituximab/intravenous immunoglobulin/anti-thymocyte globulin administration), therefore, limiting its value. CDC based assay results strongly depend on the vitality of the donor lymphocytes, highlighting another major limitation of this assay. Thus, as an alternative approach, solid phase based crossmatch assays were introduced which function independently of the cell quality and have higher sensitivity and specificity in detecting anti-HLA antibodies. We describe a case where the patient awaiting renal transplantation from living related donor was evaluated by pretransplant histocompatibility testing for the detection of anti-HLA antibodies. The histocompatibility testing revealed positive CDC anti-human globulin and flow crossmatch along with negative Luminex based assays (HLA antibody screen, luminex crossmatch, and luminex single bead assay). Detailed histocompatibility workup revealed immunoglobulin G autoantibodies which were complement activating and lympocytoxic in nature.


Availability and readability of emergency preparedness materials for deaf and hard-of-hearing and older adult populations: issues and assessments.
A major public health challenge is to communicate effectively with vulnerable populations about preparing for disasters and other health emergencies. People who are Deaf or Hard of Hearing (Deaf/HH) and older adults are particularly vulnerable during health emergencies and require communications that are accessible and understandable. Although health literacy studies indicate that the readability of health communication materials often exceeds people's literacy levels, we could find no research about the readability of emergency preparedness materials (EPM) intended for Deaf/HH and older adult populations. The objective of this study was to explore issues related to EPM for Deaf/HH and older adult populations, to assess the availability and readability of materials for these populations, and to recommend improvements. In two California counties, we interviewed staff at 14 community-based organizations (CBOs) serving Deaf/HH clients and 20 CBOs serving older adults selected from a stratified, random sample of 227 CBOs. We collected 40 EPM from 10 CBOs and 2 public health departments and 40 EPM from 14 local and national websites with EPM for the public. We used computerized assessments to test the U.S. grade reading levels of the 16 eligible CBO and health department EPM, and the 18 eligible website materials. Results showed that less than half of CBOs had EPM for their clients. All EPM intended for clients of Deaf/HH-serving CBOs tested above the recommended 4(th) grade reading level, and 91% of the materials intended for clients of older adult-serving CBOs scored above the recommended 6(th) grade level. EPM for these populations should be widely available through CBOs and public health departments, adhere to health literacy principles, and be accessible in alternative formats including American Sign Language. Developers should engage the intended users of EPM as co-designers and testers. This study adds to the limited literature about EPM for these populations.


Global change-type drought-induced tree mortality: vapor pressure deficit is more important than temperature per se in causing decline in tree health.
Drought-induced tree mortality is occurring across all forested continents and is expected to increase worldwide during the coming century. Regional-scale forest die-off influences terrestrial albedo, carbon and water budgets, and land-surface energy partitioning. Although increased temperatures during drought are widely identified as a critical contributor to exacerbated tree mortality associated with "global-change-type drought", corresponding changes in vapor pressure deficit (D) have rarely been considered explicitly and have not been disaggregated from that of temperature per se. Here, we apply a detailed mechanistic soil-plant-atmosphere model to examine the impacts of drought, increased air temperature (+2°C or +5°C), and increased vapor pressure deficit (D; +1 kPa or +2.5 kPa), singly and in combination, on net primary productivity (NPP) and transpiration and forest responses, especially soil moisture content, leaf water potential, and stomatal conductance. We show that increased D exerts a larger detrimental effect on transpiration and NPP, than increased temperature alone, with or without the imposition of a 3-month drought. Combined with drought, the effect of increased D on NPP was substantially larger than that of drought plus increased temperature. Thus, the number of days when NPP was zero across the 2-year simulation was 13 or 14 days in the control and increased temperature scenarios, but increased to approximately 200 days when D was increased. Drought alone increased the number of days of zero NPP to 88, but drought plus increased temperature did not increase the number of days. In contrast, drought and increased D resulted in the number of days when NPP = 0 increasing to 235 (+1 kPa) or 304 days (+2.5 kPa). We conclude that correct identification of the causes of global change-type mortality events requires explicit consideration of the influence of D as well as its interaction with drought and temperature. This study disaggregates the influence of temperature and vapour pressure deficit on net primary productivity of an Australian woodland and their interactions with drought as potential causal agents in recent widespread forest mortality.


Atypical monoclonal plasma cell hyperplasia of the central nervous system: precursor of plasmacytoma with evolutionary considerations.
Hematopoietic proliferations rich in plasma cells rarely occur within the central nervous system without the involvement of other organ systems. Depending on their histological pattern and cellular composition, several different terms, including plasmacytoma, plasma cell granuloma, hyalinizing plasmacytic granulomatosis, and inflammatory meningioma, are used for these lesions. We report a left temporal dural lesion composed of plasma cells, lymphocytes, histiocytes, and rare eosinophils with hyaline changes and a suggestion of follicle formation, which stained predominantly for IgG and kappa light chains. This lesion arose in an otherwise healthy 52-year-old woman. Free kappa light chains without a monoclonal peak were found in the urine. We are aware of only two other heterogeneous, predominantly plasmacytic, solitary dural lesions that were found to be monoclonal on immunohistochemical examination. The label atypical monoclonal plasma cell hyperplasia appears to suit the morphological characteristics of our lesion. We suggest that a spectrum of solitary plasmacytic lesions may occur within the central nervous system and that atypical plasma cell hyperplasias have the potential to evolve into plasmacytoma. The preneoplastic nature of this lesion and its potential for evolution to malignant myeloma should be considered when planning treatment and lifelong follow-up for patients.


Eye Movements in Macular Degeneration.
In healthy vision, the fovea provides high acuity and serves as the locus for fixation achieved through saccadic eye movements. Bilateral loss of the foveal regions in both eyes causes individuals to adopt an eccentric locus for fixation. This review deals with the eye movement consequences of the loss of the foveal oculomotor reference and the ability of individuals to use an eccentric fixation locus as the new oculomotor reference. Eye movements are an integral part of everyday activities, such as reading, searching for an item of interest, eye-hand coordination, navigation, or tracking an approaching car. We consider how these tasks are impacted by the need to use an eccentric locus for fixation and as a reference for eye movements, specifically saccadic and smooth pursuit eye movements.


Time-resolved laser fluorescence spectroscopy of organic ligands by europium: Fluorescence quenching and lifetime properties.
Time-resolved Laser Fluorescence Spectroscopy (TRLFS) has proved its usefulness in the fields of biophysics, life science and geochemistry to characterize the fluorescence probe molecule with its chemical environment. The purpose of this study is to demonstrate the applicability of this powerful technique combined with Steady-State (S-S) measurements. A multi-mode factor analysis, in particular CP/PARAFAC, was used to analyze the interaction between Europium (Eu) and Humic substances (HSs) extracted from Saint Lawrence Estuary in Canada. The Saint Lawrence system is a semi-enclosed water stream with connections to the Atlantic Ocean and is an excellent natural laboratory. CP/PARAFAC applied to fluorescence S-S data allows introspecting ligands-metal interactions and the one-site 1:1 modeling gives information about the stability constants. From the spectral signatures and decay lifetimes data given by TRLFS, one can deduce the fluorescence quenching which modifies the fluorescence and discuss its mechanisms. Results indicated a relatively strong binding ability between europium and humic substances samples (LogK value varies from 3.38 to 5.08 at pH 7.00). Using the Stern-Volmer plot, it has been concluded that static and dynamic quenching takes places in the case of salicylic acid and europium interaction while for HSs interaction only a static quenching is observed.


Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma.
Autologous stem cell transplantation (ASCT) improves survival in patients with previously untreated multiple myeloma (MM) and relapsed, chemotherapy-sensitive, aggressive non-Hodgkin lymphoma (NHL). Lower relapse rates seen in allogeneic stem cell transplantation have been related to early absolute lymphocyte count (ALC) recovery as a manifestation of early graft-verus-tumor effect. In ASCT, the relation between ALC recovery and clinical outcomes in MM and NHL was not previously described. This is a retrospective study of patients with MM and NHL who underwent ASCT at the Mayo Clinic between 1987 and 1999. The ALC threshold was determined at 500 cells/microL on day 15 after ASCT. The study identified 126 patients with MM and 104 patients with NHL. The median overall survival (OS) and progression-free survival (PFS) times for patients with MM were significantly longer in patients with an ALC of 500 cells/microL or more than patients with an ALC of fewer than 500 cells/microL (33 vs 12 months, P <.0001; 16 vs 8 months, P <.0003, respectively). For patients with NHL, the median OS and PFS times were significantly longer in patients with an ALC of 500 cells/microL or more versus those with fewer than 500 cells/microL (not reached vs 6 months, P <.0001; not reached vs 4 months, P <.0001, respectively). Multivariate analysis demonstrated day 15 ALC to be an independent prognostic indicator for OS and PFS rates for both groups of patients. In conclusion, ALC is correlated with clinical outcome and requires further study. (Blood. 2001;98:579-585)


Herpes Zoster During Immunosuppressive Therapy For Autoimmune Diseases.
Patients on immunosuppressive therapy are at a greater risk for herpes zoster reactivation and are more likely to have adverse outcomes. Propylactic antivrials and vaccinations may potentially prevent these complications. Medical literature addressing the clinical course and therapy of herpes zoster in patients receiving immunosuppressive therapy for autoimmune disorders, and the roles of anti-viral prophylaxis and vaccination was reviewed. Research databases including PubMed, Ovid, Medline, Google Scholar and Cochrane were utilized. Acyclovir and its derivatives are most commonly used in this setting for treatment and reduction of post-zoster complications. Foscarnet may be used for acyclovir-resistant strains. At both conventional and ultralow doses, acyclovir has proven effective when used as prophylaxis, reducing the incidence of zoster and its complications in immunosuppressed patients. Additionally, ultra-low doses are associated with significantly reduced side effects. The zoster vaccine, Zostavax, a live-attenuated vaccine has shown promising results in several clinical trials. However, live-attenuated vaccines should be cautiously used in immunosuppressed patients. For patients who require immunosuppressive therapy, vaccination 2-3 months prior to therapy may be appropriate. Prophylactic antiviral therapy and vaccination help significantly reduce morbidity and mortality from zoster reactivation in patients receiving immunosuppressive therapy.


Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population.
There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.


Can respiratory physiology predict thermal niches?
Predicting species responses to global warming is the holy grail of climate change science. As temperature directly affects physiological rates, it is clear that a mechanistic understanding of species vulnerability should be grounded in organismal physiology. Here, we review what respiratory physiology can offer the field of thermal ecology, showcasing different perspectives on how respiratory physiology can help explain thermal niches. In water, maintaining adequate oxygen delivery to fuel the higher metabolic rates under warming conditions can become the weakest link, setting thermal tolerance limits. This has repercussions for growth and scaling of metabolic rate. On land, water loss is more likely to become problematic as long as O2 delivery and pH balance can be maintained, potentially constraining species in their normal activity. Therefore, high temperatures need not be lethal, but can still affect the energy intake of an animal, with concomitant consequences for long-term fitness. While respiratory challenges and adaptive responses are diverse, there are clear recurring elements such as oxygen uptake, CO2 excretion, and water homeostasis. We show that respiratory physiology has much to offer the field of thermal ecology and call for an integrative, multivariate view incorporating respiratory challenges, thermal responses, and energetic consequences. Fruitful areas for future research are highlighted.


Exercise intensity-dependent immunomodulatory effects on encephalomyelitis.
Exercise training (ET) has beneficial effects on multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the intensity-dependent effects of ET on the systemic immune system in EAE remain undefined. (1) To compare the systemic immune modulatory effects of moderate versus high-intensity ET protocols in protecting against development of EAE; (2) To investigate whether ET affects autoimmunity selectively, or causes general immunosuppression. Healthy mice performed moderate or high-intensity treadmill running programs. Proteolipid protein (PLP)-induced transfer EAE was utilized to examine ET effects specifically on the systemic immune system. Lymph node (LN)-T cells from trained versus sedentary donor mice were transferred to naïve recipients and EAE severity was assessed, by clinical assessment and histopathological analysis. LN-T cells derived from donor trained versus sedentary PLP-immunized mice were analyzed in vitro for proliferation assays by flow cytometry analysis and cytokine and chemokine receptor gene expression using real-time PCR. T cell-dependent immune responses of trained versus sedentary mice to the nonautoantigen ovalbumin and susceptibility to Escherichia coli-induced acute peritonitis were examined. High-intensity training in healthy donor mice induced significantly greater inhibition than moderate-intensity training on proliferation and generation of encephalitogenic T cells in response to PLP-immunization, and on EAE severity upon their transfer into recipient mice. High-intensity training also inhibited LN-T cell proliferation in response to ovalbumin immunization. E. coli bacterial counts and dissemination were not affected by training. High-intensity training induces superior effects in preventing autoimmunity in EAE, but does not alter immune responses to E. coli infection.


An aboriginal and Torres Strait Islander oral health curriculum framework: development experiences in Western Australia.
Indigenous oral health is widely acknowledged as paralleling the significant issues faced in general health. It is recognized that as part of the process of addressing these issues, practitioners need to be aware of the complex nature of working in an Indigenous social and cultural context, including issues beyond direct health care services. It is against this backdrop that collaborators from The University of Western Australia's (UWA) Centre for Rural and Remote Oral Health (CRROH) and Centre for Aboriginal Medical and Dental Health (CAMDH) developed a comprehensive, integrated Indigenous Oral Health Curriculum Framework for the Bachelor of Dental Science (BDSc) course. This development was based on the existing framework developed by the Committee of Deans of Australian Medical Schools (CDAMS) for medical education but was tailored to the specific issues and needs of oral health. Additional consultation with the Oral Health Centre of Western Australia (OHCWA), the School of Indigenous Studies (SIS) as well as Indigenous Australian groups occurred to ensure the development process was inclusive. The inclusion of an Indigenous Oral Health Curriculum Framework in the BDSc will enable UWA dental graduates to practise dentistry in a culturally appropriate manner. The framework provides the structure for students to develop and demonstrate an understanding of Indigenous histories, cultures and social experiences and how these impact on Indigenous peoples' health. It is anticipated that this will foster more positive and culturally secure patient-practitioner interactions between UWA dental graduates and Indigenous Australians, thereby making it more likely for Indigenous Australians to present for treatment. The increased awareness of Indigenous oral health issues will hopefully encourage more graduates to become involved in the treatment of Indigenous peoples. The combination of these factors could lead to an improvement in oral health outcomes for Australia's Indigenous peoples and a concomitant positive impact on the general health of Indigenous Australians.


[A case of hepatocellular carcinoma with respiratory failure caused by widespread tumor microemboli].
A 76-year-old man with hepatocellular carcinoma (HCC) was admitted to our hospital suffering from rapidly progressing dyspnea. Chest computed tomography on admission merely showed ground-glass patterns in both lung fields without thrombi in the pulmonary trunk. On the third day, pulmonary blood flow scintigraphy was performed because of progression of his dyspnea, and showed multiple defects indicating widespread thrombi in the peripheral pulmonary arteries. He died of respiratory failure on day 13. A needle necropsy revealed the presence of multiple foci of adenocarcinoma nests in the lungs, suggesting venous thrombi from the poorly differentiated HCC. Although HCC frequently metastasizes to the lung, patients with lung metastasis rarely result in respiratory failure. It is well known that some patients with adenocarcinoma including HCC can develop respiratory failure owing to pulmonary tumor thrombotic microangiopathy (PTTM). In our case, however, pathological examination showed widespread tumor microemboli in the lung, but no stenosis or fibrocellular intimal proliferation in the small arteries and arterioles, which are essential findings of PTTM. Although we concluded that the respiratory failure in this case was mainly caused by widespread tumor microemboli, it remains unclear why such dissemination rapidly developed.


Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations.
The Tibetan and Andean Plateaus and Ethiopian highlands are the largest regions to have long-term high-altitude residents. Such populations are exposed to lower barometric pressures and hence atmospheric partial pressures of oxygen. Such "hypobaric hypoxia" may limit physical functional capacity, reproductive health, and even survival. As such, selection of genetic variants advantageous to hypoxic adaptation is likely to have occurred. Identifying signatures of such selection is likely to help understanding of hypoxic adaptive processes. Here, we seek evidence of such positive selection using five Ethiopian populations, three of which are from high-altitude areas in Ethiopia. As these populations may have been recipients of Eurasian gene flow, we correct for this admixture. Using single-nucleotide polymorphism genotype data from multiple populations, we find the strongest signal of selection in BHLHE41 (also known as DEC2 or SHARP1). Remarkably, a major role of this gene is regulation of the same hypoxia response pathway on which selection has most strikingly been observed in both Tibetan and Andean populations. Because it is also an important player in the circadian rhythm pathway, BHLHE41 might also provide insights into the mechanisms underlying the recognized impacts of hypoxia on the circadian clock. These results support the view that Ethiopian, Andean, and Tibetan populations living at high altitude have adapted to hypoxia differently, with convergent evolution affecting different genes from the same pathway.


Abstract shapes of RNA.
The function of a non-protein-coding RNA is often determined by its structure. Since experimental determination of RNA structure is time-consuming and expensive, its computational prediction is of great interest, and efficient solutions based on thermodynamic parameters are known. Frequently, however, the predicted minimum free energy structures are not the native ones, leading to the necessity of generating suboptimal solutions. While this can be accomplished by a number of programs, the user is often confronted with large outputs of similar structures, although he or she is interested in structures with more fundamental differences, or, in other words, with different abstract shapes. Here, we formalize the concept of abstract shapes and introduce their efficient computation. Each shape of an RNA molecule comprises a class of similar structures and has a representative structure of minimal free energy within the class. Shape analysis is implemented in the program RNAshapes. We applied RNAshapes to the prediction of optimal and suboptimal abstract shapes of several RNAs. For a given energy range, the number of shapes is considerably smaller than the number of structures, and in all cases, the native structures were among the top shape representatives. This demonstrates that the researcher can quickly focus on the structures of interest, without processing up to thousands of near-optimal solutions. We complement this study with a large-scale analysis of the growth behaviour of structure and shape spaces. RNAshapes is available for download and as an online version on the Bielefeld Bioinformatics Server.


Assessing the degradation of ancient milk proteins through site-specific deamidation patterns.
The origins, prevalence and nature of dairying have been long debated by archaeologists. Within the last decade, new advances in high-resolution mass spectrometry have allowed for the direct detection of milk proteins from archaeological remains, including ceramic residues, dental calculus, and preserved dairy products. Proteins recovered from archaeological remains are susceptible to post-excavation and laboratory contamination, a particular concern for ancient dairying studies as milk proteins such as beta-lactoglobulin (BLG) and caseins are potential laboratory contaminants. Here, we examine how site-specific rates of deamidation (i.e., deamidation occurring in specific positions in the protein chain) can be used to elucidate patterns of peptide degradation, and authenticate ancient milk proteins. First, we characterize site-specific deamidation patterns in modern milk products and experimental samples, confirming that deamidation occurs primarily at low half-time sites. We then compare this to previously published palaeoproteomic data from six studies reporting ancient milk peptides. We confirm that site-specific deamidation rates, on average, are more advanced in BLG recovered from ancient dental calculus and pottery residues. Nevertheless, deamidation rates displayed a high degree of variability, making it challenging to authenticate samples with relatively few milk peptides. We demonstrate that site-specific deamidation is a useful tool for identifying modern contamination but highlight the need for multiple lines of evidence to authenticate ancient protein data.


Evidence for multiple-antibiotic resistance in Campylobacter jejuni not mediated by CmeB or CmeF.
An efflux system, CmeABC, in Campylobacter jejuni was previously described, and a second efflux system, CmeDEF, has now been identified. The substrates of CmeDEF include ampicillin, ethidium bromide, acridine, sodium dodecyl sulfate (SDS), deoxycholate, triclosan, and cetrimide, but not ciprofloxacin or erythromycin. C. jejuni NCTC11168 and two efflux pump knockout strains, cmeB::Kan(r) and cmeF::Kan(r), were exposed to 0.5 to 1 microg of ciprofloxacin/ml in agar plates. All mutants arising from NCTC11168 were resistant to ciprofloxacin but not to other agents and contained a mutation resulting in the replacement of threonine 86 with isoleucine in the quinolone resistance-determining region of GyrA. Mutants with two distinct phenotypes were selected from the efflux pump knockout strains. Mutants with the first phenotype were resistant to ciprofloxacin only and had the same substitution within GyrA as the NCTC11168-derived mutants. Irrespective of the parent strain, mutants with the second phenotype were resistant to ciprofloxacin, chloramphenicol, tetracycline, ethidium bromide, acridine orange, and SDS and had no mutation in gyrA. These mutants expressed levels of the efflux pump genes cmeB and cmeF and the major outer membrane protein gene porA similar to those expressed by the respective parent strains. No mutations were detected in cmeF or cmeB. Accumulation assays revealed that the mutants accumulated lower concentrations of drug. These data suggest the involvement of a non-CmeB or -CmeF efflux pump or reduced uptake conferring multiple-antibiotic resistance, which can be selected after exposure to a fluoroquinolone.


Writing with Fluid: Structuring Hydrogels with Micrometer Precision by AFM in Combination with Nanofluidics.
Hydrogels have many applications in biomedical surface modification and tissue engineering. However, the structuring of hydrogels after their formation represents still a major challenge, in particular due to their softness. Here, a novel approach is presented that is based on the combination of atomic force microscopy (AFM) and nanofluidics, also referred to as FluidFM technology. Its applicability is demonstrated for supramolecular hydrogel films that are prepared from low-molecular weight hydrogelators, such as derivates of 1,3,5-benzene tricarboxamides (BTAs). BTA films can be dissolved selectively by ejecting alkaline solution through the aperture of a hollow AFM-cantilever connected to a nanofluidic controller. The AFM-based force control is essential in preventing mechanical destruction of the hydrogels. The resulting "chemical writing" process is studied in detail and the influence of various parameters, such as applied pressure and time, is validated. It is demonstrated that the achievable structuring precision is primarily limited by diffusion and the aperture dimensions. Recently, various additive techniques have been presented to pattern hydrogels. The here-presented subtractive approach can not only be applied to structure hydrogels from the large class of reversibly formed gels with superior resolution but would also allow for the selective loading of the hydrogels with active substances or nanoparticles.


Theory and practice of uncommon molecular electronic configurations.
The electronic configuration of the molecule is the foundation of its structure and reactivity. The spin state is one of the key characteristics arising from the ordering of electrons within the molecule's set of orbitals. Organic molecules that have open-shell ground states and interesting physicochemical properties, particularly those influencing their spin alignment, are of immense interest within the up-and-coming field of molecular electronics. In this advanced review, we scrutinize various qualitative rules of orbital occupation and spin alignment, viz., the aufbau principle, Hund's multiplicity rule, and dynamic spin polarization concept, through the prism of quantum mechanics. While such rules hold in selected simple cases, in general the spin state of a system depends on a combination of electronic factors that include Coulomb and Pauli repulsion, nuclear attraction, kinetic energy, orbital relaxation, and static correlation. A number of fascinating chemical systems with spin states that fluctuate between triplet and open-shell singlet, and are responsive to irradiation, pH, and other external stimuli, are highlighted. In addition, we outline a range of organic molecules with intriguing non-aufbau orbital configurations. In such quasi-closed-shell systems, the singly occupied molecular orbital (SOMO) is energetically lower than one or more doubly occupied orbitals. As a result, the SOMO is not affected by electron attachment to or removal from the molecule, and the products of such redox processes are polyradicals. These peculiar species possess attractive conductive and magnetic properties, and a number of them that have already been developed into molecular electronics applications are highlighted in this review. WIREs Comput Mol Sci 2015, 5:440-459. doi: 10.1002/wcms.1233 For further resources related to this article, please visit the WIREs website.


Synthesis, Optimization, and Structure-Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs).
Depletion of nicotinamide adenine dinucleotide (NAD+) is associated with aging and disease, spurring the study of dietary supplements to replenish NAD+. The catabolism of NAD+ to nicotinamide (NAM) requires the salvage of NAM to replenish cellular NAD+, which relies on the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological activation of NAMPT provides an alternative to dietary supplements. Screening for activators of NAMPT identified small molecule NAMPT positive allosteric modulators (N-PAMs). N-PAMs bind to the rear channel of NAMPT increasing enzyme activity and alleviating feedback inhibition by NAM and NAD+. Synthesis of over 70 N-PAMs provided an excellent correlation between rear channel binding affinity and potency for enzyme activation, confirming the mechanism of allosteric activation via binding to the rear channel. The mechanism accounts for higher binding affinity leading to loss of efficacy. Enzyme activation translated directly to elevation of NAD+ measured in cells. Optimization led to an orally bioavailable N-PAM.


Implementation of a Training Course Increased the Diagnosis of Histoplasmosis in Colombia.
Histoplasmosis causes a significant mortality, especially persons living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) from developing countries where access to both appropriate diagnostic methods and antiretroviral therapy are limited. A total of 81 physicians assigned to 17 Colombian departments (states) received training in the clinical, epidemiological, and diagnostic aspects of histoplasmosis. Once this training was received and during the period of October 2009-November 2012, these physicians sent biological samples for immunodiagnostic, mycological, and molecular tests from their patients with suspicion of histoplasmosis. A total of 1,536 samples from 768 patients were evaluated. Of the 768 patients studied, 463 (60%) were HIV positive, 214 (28%) HIV negative, and in 91 (12%) this diagnosis was unknown, and 538 (70%) were males. The 1,536 specimens studied comprised 722 sera, 439 blood samples, and 241 urines, which were tested by immunodiffusion (ID), culture, and antigenuria, respectively; in addition, 134 specimens were tested by performing a molecular assay. Histoplasmosis was diagnosed in 133 patients (17%). After the training, we observed more diagnoses from 27 to 44 cases per year. In this study, a significantly increased number of histoplasmosis cases reported by year were observed after implementing an educational training program.


Non-contact ultrasonic gas flow metering using air-coupled leaky Lamb waves.
This paper describes a completely non-contact ultrasonic method of gas flow metering using air-coupled leaky Lamb waves. To show proof of principle, a simplified representation of gas flow in a duct, comprising two separated thin isotropic plates with a gas flowing between them, has been modelled and investigated experimentally. An airborne compression wave emitted from an air-coupled capacitive ultrasonic transducer excited a leaky Lamb wave in the first plate in a non-contact manner. The leakage of this Lamb wave crossed the gas flow at an angle between the two plates as a compression wave, and excited a leaky Lamb wave in the second plate. An air-coupled capacitive ultrasonic transducer on the opposite side of this second plate then detected the airborne compression wave leakage from the second Lamb wave. As the gas flow shifted the wave field between the two plates, the point of Lamb wave excitation in the second plate was displaced in proportion to the gas flow rate. Two such measurements, in opposite directions, formed a completely non-contact contra-propagating Lamb wave flow meter, allowing measurement of the flow velocity between the plates. A COMSOL Multiphysics® model was used to visualize the wave fields, and accurately predicted the time differences that were then measured experimentally. Experiments using different Lamb wave frequencies and plate materials were also similarly verified. This entirely non-contact airborne approach to Lamb wave flow metering could be applied in place of clamp-on techniques in thin-walled ducts or pipes.


Retinal optical coherence tomography manifestations of intraocular lymphoma.
Primary central nervous system lymphoma (PCNSL) is a rare disease. The index report describes a patient with intraocular lymphoma secondary to recurrent PCNSL and corresponding retinal findings on spectral domain optical coherence tomography (SD-OCT). Case report. OCT changes were documented and correlated with the clinical course of intraocular lymphoma progression in the index patient. The OCT changes, manifested as hyperreflective material accumulation in the intraretinal and subretinal pigment epithelial spaces, were caused by lymphomatous infiltration. SD-OCT can be useful in diagnosing and monitoring the progression or regression of intraocular lymphoma with retinal involvement.


Mapping of receptive language cortex in bilingual volunteers by using magnetic source imaging.
There are conflicting claims in the functional imaging literature concerning whether different languages are represented by distinct brain mechanisms in individuals who are proficient in more than one language. This interesting theoretical issue has practical implications when functional imaging methods are used for presurgical language mapping. To address this issue the authors compared the location and extent of receptive language cortex specific to English and Spanish in neurologically intact bilingual volunteers by using magnetic source imaging. Areas of the cortex that were specialized for receptive language functions were identified separately for each language in 11 healthy adults who were bilingual in English and Spanish. The authors performed exactly the same procedures used routinely for presurgical receptive language mapping. In each bilingual individual, the receptive language-specific map always encompassed the posterior portion of the superior temporal gyrus. In every case, however, substantial differences in the receptive language maps were also observed for the two languages, regardless of whether each participant's first language was English or Spanish. Although the reasons for such differences and their ultimate significance in identifying the cerebral mechanisms of language are subject to continuing investigation, their presence is noteworthy and has practical implications for the surgical management of patients with lesions in the temporal and parietal regions of the dominant hemisphere.


Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are independent risk predictors of short-term mortality in patients with acute coronary syndromes.
Cytokines play an important role in ischemic injury and repair. However, little is known about their prognostic value in cardiovascular disease. The aim of this study was to investigate the prognostic importance of chemokines CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC for the risk of future cardiovascular events in patients with acute coronary syndromes (ACS). Baseline levels of CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC were determined in ACS patients from the Bad Nauheim ACS II registry (n = 609). During the following 200 days, patients were monitored for the occurrence of fatal and non-fatal cardiovascular events. Patients with CCL3/MIP1α, CCL5/RANTES and CCL18/PARC concentrations in the highest tertile were associated with an increased risk of a fatal event during follow-up (HR: 2.19, 95%CI: 1.04-4.61 for CCL3/MIP1α, HR: 3.45, 95%CI: 1.54-7.72 for CCL5/RANTES and HR: 3.14, 95%CI: 1.33-7.46 for CCL18/PARC). This risk was highest for patients with all three biomarkers concentrations in the upper tertile (HR: 2.52, 95%CI: 1.11-5.65). Together with known risk predictors of cardiovascular events, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC combined improved the c-statistics from 0.74 to 0.81 (p = 0.007). In conclusion, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC are independently associated with the risk of short-term mortality in ACS patients. Combining all three biomarkers further increased their prognostic value.


Structural analysis of zinc substitutions in the active site of thermolysin.
Native thermolysin binds a single catalytically essential zinc ion that is tetrahedrally coordinated by three protein ligands and a water molecule. During catalysis the zinc ligation is thought to change from fourfold to fivefold. Substitution of the active-site zinc with Cd2+, Mn2+, Fe2+, and Co2+ alters the catalytic activity (Holmquist B, Vallee BL, 1974, J Biol Chem 249:4601-4607). Excess zinc inhibits the enzyme. To investigate the structural basis of these changes in activity, we have determined the structures of a series of metal-substituted thermolysins at 1.7-1.9 A resolution. The structure of the Co(2+)-substituted enzyme is shown to be very similar to that of wild type except that two solvent molecules are liganded to the metal at positions that are thought to be occupied by the two oxygens of the hydrated scissile peptide in the transition state. Thus, the enhanced activity toward some substrates of the cobalt-relative to the zinc-substituted enzyme may be due to enhanced stabilization of the transition state. The ability of Zn2+ and Co2+ to accept tetrahedral coordination in the Michaelis complex, as well as fivefold coordination in the transition state, may also contribute to their effectiveness in catalysis. The Cd(2+)- and Mn(2+)-substituted thermolysins display conformational changes that disrupt the active site to varying degrees and could explain the associated reduction of activity. The conformational changes involve not only the essential catalytic residue, Glu 143, but also concerted side-chain rotations in the adjacent residues Met 120 and Leu 144. Some of these side-chain movements are similar to adjustments that have been observed previously in association with the "hinge-bending" motion that is presumed to occur during catalysis by the zinc endoproteases. In the presence of excess zinc, a second zinc ion is observed to bind at His 231 within 3.2 A of the zinc bound to native thermolysin, explaining the inhibitory effect.


Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3.
5'-Rapid amplification of cDNA ends, done on poly(A)+ RNA from human U87 cells, was used to identify 420 bp of novel 5' sequence of a PDE4B cAMP-specific phosphodiesterase (PDE). This identified an open reading frame encoding a putative 721-residue 'long-form' PDE4B splice variant, which we term HSPDE4B3. HSPDE4B3 differs from the two known PDE4B forms by virtue of its unique 79-residue N-terminal region, compared with the unique N-terminal regions of 94 and 39 residues found in HSPDE4B1 and HSPDE4B2 respectively. In transfected COS7 cells the two long forms, HSPDE4B1 and HSPDE4B3, had molecular masses of approx. 104 and approx. 103 kDa respectively. Expressed in COS-7 cells, the three HSPDE4B isoforms were found in the high-speed supernatant (cytosol) fraction as well as both the high-speed pellet (P2) and low-speed pellet (P1) fractions. All isoforms showed similar Km values for cAMP hydrolysis (1.5-2.6 microM). The maximal activities of the soluble cytosolic activity of the two long forms were very similar, whereas that of the short form, HSPDE4B2, was approx. 4-fold higher. Particulate-associated HSPDE4B1 and HSPDE4B2 were less active (approx. 40%) than their cytosol forms, whereas particulate HSPDE4B3 was similar in activity to its cytosolic form. Particulate and cytosolic forms of HSPDE4B1 and HSPDE4B3 were similarly inhibited by rolipram {4-[3-(cyclopentoxyl)-4-methoxyphenyl]-2-pyrrolidone}, the selective inhibitor of PDE4 (IC50 0.05-0.1 microM), whereas particulate-associated HSPDE4B2 was profoundly (approx. 10-fold) more sensitive (IC50 0.02 microM) to rolipram inhibition than its cytosolic form (IC50 0.2 microM). The various particulate-associated HSPDE4B isoforms showed very different susceptibilities to solubilization with the detergent Triton X-100 and high NaCl concentration. A novel cDNA, called pRPDE74, was obtained by screening a rat olfactory lobe cDNA library. This contained an open reading frame encoding a 721-residue protein that showed approx. 96% amino acid identity with HSPDE4B3 and is proposed to reflect the rat homologue of this human enzyme and is thus called RNPDE4B3. Alternative splicing of mRNA generated from both the human and rat PDE4B genes produces long and short splice variants that have unique N-terminal splice regions. It is suggested that these alternatively spliced regions determine changes in the maximal catalytic activity of the isoforms, their susceptibility to inhibition by rolipram and mode of interaction with particulate fractions.


Diagnostic performance of visible severe wasting for identifying severe acute malnutrition in children admitted to hospital in Kenya.
To determine the diagnostic value of visible severe wasting in identifying severe acute malnutrition at two public hospitals in Kenya. This was a cross-sectional study of children aged 6 to 59.9 months admitted to one rural and one urban hospital. On admission, mid-upper arm circumference (MUAC), weight and height were measured and the presence of visible severe wasting was assessed. The diagnostic performance of visible severe wasting was evaluated against anthropometric criteria. Of 11,166 children admitted, 563 (5%) had kwashiorkor and 1406 (12.5%) were severely wasted (MUAC < 11.5 cm). The combined sensitivity and specificity of visible severe wasting at the two hospitals, as assessed against a MUAC < 11.5 cm, were 54% (95% confidence interval, CI: 51-56) and 96% (95% CI: 96-97), respectively; at one hospital, its sensitivity and specificity against a weight-for-height z-score below -3 were 44.7% (95% CI: 42-48) and 96.5% (95% CI: 96-97), respectively. Severely wasted children who were correctly identified by visible severe wasting were consistently older, more severely wasted, more often having kwashiorkor, more often positive to the human immunodeficiency virus, ill for a longer period and at greater risk of death. Visible severe wasting had lower sensitivity for determining the risk of death than the anthropometric measures. There was no evidence to support measuring both MUAC and weight-for-height z-score. Visible severe wasting failed to detect approximately half of the children admitted to hospital with severe acute malnutrition diagnosed anthropometrically. Routine screening by MUAC is quick, simple and inexpensive and should be part of the standard assessment of all paediatric hospital admissions in the study setting.


The epidemiology of eczema in children and adults in England: A population-based study using primary care data.
Whilst eczema is a common inflammatory skin condition, we lack contemporary estimates of disease incidence and prevalence across the lifespan. To estimate the incidence and prevalence of eczema in children and adults in England and variation by sociodemographic factors (sex, socio-economic status, ethnicity, and geography). We used the Royal College of General Practitioners Research and Surveillance Centre primary care research database of 3.85 million children and adults registered with participating general practitioner practices between 2009 and 2018 inclusive. Eczema incidence was defined as the first-ever diagnosis of eczema recorded in the primary care record, and eczema prevalence was defined as fulfilment of criteria for active eczema (two eczema records appearing in the primary care record within any one-year period). Eczema incidence was highest in infants younger than 1 year (15.0 per 100 person-years), lowest in adults aged 40-49 (0.35 p/100 person-years), and increased from middle age to a second smaller peak in people 80 years or older (0.79 p/100 person-years). Eczema prevalence was highest in children aged 2 (16.5%) and lowest in adults aged 30-39 (2.8%). Eczema incidence was higher in male infants (<2) and male adults older than 70; for all other ages, incidence was higher in females. Eczema was more common in Asian and black ethnic groups than in people of white ethnicity. Higher socio-economic status was associated with a greater incidence of eczema in infants younger than 2, but the reverse was seen for all other age groups. Both incidence and prevalence of eczema were greater in urban settings and in North-West England. Eczema has a bimodal distribution across the lifespan. We observed differences in incidence and prevalence of eczema by ethnicity, geography, sex, and socio-economic status, which varied in magnitude throughout life.


Comparative sensitivity evaluation for 122 CE-marked rapid diagnostic tests for SARS-CoV-2 antigen, Germany, September 2020 to April 2021.
IntroductionNumerous CE-marked SARS-CoV-2 antigen rapid diagnostic tests (Ag RDT) are offered in Europe, several of them with unconfirmed quality claims.AimWe performed an independent head-to-head evaluation of the sensitivity of SARS-CoV-2 Ag RDT offered in Germany.MethodsWe addressed the sensitivity of 122 Ag RDT in direct comparison using a common evaluation panel comprised of 50 specimens. Minimum sensitivity of 75% for panel specimens with a PCR quantification cycle (Cq) ≤ 25 was used to identify Ag RDT eligible for reimbursement in the German healthcare system.ResultsThe sensitivity of different SARS-CoV-2 Ag RDT varied over a wide range. The sensitivity limit of 75% for panel members with Cq ≤ 25 was met by 96 of the 122 tests evaluated; 26 tests exhibited lower sensitivity, few of which failed completely. Some RDT exhibited high sensitivity, e.g. 97.5 % for Cq < 30.ConclusionsThis comparative evaluation succeeded in distinguishing less sensitive from better performing Ag RDT. Most of the evaluated Ag RDT appeared to be suitable for fast identification of acute infections associated with high viral loads. Market access of SARS-CoV-2 Ag RDT should be based on minimal requirements for sensitivity and specificity.


Single-vessel coronary artery stenosis: myocardial perfusion imaging with Gadomer-17 first-pass MR imaging in a swine model of comparison with gadopentetate dimeglumine.
To evaluate the ability of Gadomer-17 to depict perfusion defects in a closed-chest swine model of single-vessel coronary artery disease. Twelve pigs underwent closed-chest placement of a flow reducer for 70%-90% luminal stenosis in the proximal left anterior coronary artery. Magnetic resonance (MR) perfusion imaging with Gadomer-17 and gadopentetate dimeglumine, microsphere blood flow (MBF) testing, and technetium 99m ((99m)Tc) 2 methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) were performed during dipyridamole vasodilation. Comparisons of percentage signal intensity (SI) increase (PSIC) in remote and ischemic myocardium were made with repeated measurements analysis of variance after injection of both tracers. Perfusion defects and reduced PSIC in the anterior ischemic versus the inferior remote myocardium could be identified after injection of both Gadomer-17 (PSIC, 66% +/- 30 [mean +/- SD] vs 100% +/- 32, respectively; P <.001) and gadopentetate dimeglumine (PSIC, 49% +/- 31 vs 81% +/- 43, respectively; P <.005). The size of perfusion defect depicted with both tracers was highly correlated with defect size at (99m)Tc MIBI SPECT (r = 0.69, P <.05 for Gadomer-17 and r = 0.60, P =.05 for gadopentetate dimeglumine) and with areas of reduced MBF (r = 0.70, P <.05 for Gadomer-17 and r = 0.80, P <.05 for gadopentetate dimeglumine). PSIC also correlated with MBF (r = 0.89, P <.001 for Gadomer-17 and r = 0.75, P <.001 for gadopentetate dimeglumine). Gadomer-17 allowed differentiation of ischemic from nonischemic myocardium, as demonstrated by reduced PSIC (PSIC, 48% +/- 38 vs 72% +/- 31, respectively; P <.001) until 20 minutes after contrast material injection. In contrast, differentiation of ischemic from nonischemic myocardium was possible only until 55 seconds after injection of gadopentetate dimeglumine (PSIC, 36% +/- 24 vs 56% +/- 27, respectively; P <.005) but not at any time point thereafter. With the study conditions, Gadomer-17 provided more prolonged differentiation of ischemic from remote myocardium than that with gadopentetate dimeglumine.


Successful pregnancy in a kidney transplant recipient with chronic hepatitis B virus infection.
Overall success rate of pregnancies in kidney transplant recipients is higher than 90% if pregnancy goes beyond the 1st trimester. Risks to mother include hypertension, preeclampsia, infections, and worsening proteinuria, and those to the fetus are prematurity, intrauterine growth retardation, and low birth weight. Hepatitis B infection is associated with progressive liver disease and diminished survival in kidney transplant recipients. A 32-year-old woman had undergone living unrelated donor kidney transplant. Two years after transplantation, she presented with live gestation of 6 weeks. She was also found positive for hepatitis B surface antigen and extracellular antigen. Liver enzymes were normal and ultrasonography findings were normal. Cyclosporine dose was reduced and lamivudine was started. She was monitored closely until 33 weeks, when she gave birth to a healthy female baby through spontaneous vaginal delivery. The newborn received vaccination and immunoglobulins for hepatitis B virus. Mother's kidney allograft function remained stable throughout pregnancy.


Association Between Echocardiography Laboratory Accreditation and the Quality of Imaging and Reporting for Valvular Heart Disease.
It is presumed that echocardiographic laboratory accreditation leads to improved quality, but there are few data. We sought to compare the quality of echocardiographic examinations performed at accredited versus nonaccredited laboratories for the evaluation of valvular heart disease. We enrolled 335 consecutive valvular heart disease subjects who underwent echocardiography at our institution and an external accredited or nonaccredited institution within 6 months. Completeness and quality of echocardiographic reports and images were assessed by investigators blinded to the external laboratory accreditation status and echocardiographic results. Compared with nonaccredited laboratories, accredited sites more frequently reported patient sex (94% versus 78%; P<0.001), height and weight (96% versus 63%; P<0.001), blood pressure (86% versus 39%; P<0.001), left ventricular size (96% versus 83%; P<0.001), right ventricular size (94% versus 80%; P=0.001), and right ventricular function (87% versus 73%; P=0.006). Accredited laboratories had higher rates of complete and diagnostic color (58% versus 35%; P=0.002) and spectral Doppler imaging (45% versus 21%; P<0.0001). Concordance between external and internal grading of external studies was improved when diagnostic quantification was performed (85% versus 69%; P=0.003), and in patients with mitral regurgitation, reproducibility was improved with higher quality color Doppler imaging. Accredited echocardiographic laboratories had more complete reporting and better image quality, while echocardiographic quantification and color Doppler image quality were associated with improved concordance in grading valvular heart disease. Future quality improvement initiatives should highlight the importance of high-quality color Doppler imaging and echocardiographic quantification to improve the accuracy, reproducibility, and quality of echocardiographic studies for valvular heart disease.


Beta-cell function improved by supplementing basal insulin secretion in mild diabetes.
Insulin supplements, predominantly as a constant basal fish insulin infusion, were given to patients with mild diabetes to reduce the overnight fasting glucose level to normal. The basal plasma human insulin levels were reduced to subnormal levels by the infusion, and the insulin response to intravenous glucose was enhanced. The beta-cell in diabetes seems to be in a vicious circle in which an impaired insulin response to glucose produces hyperglycaemia, which stresses beta-cell function, making it more inefficient. A constant basal insulin supplement to induce basal normoglycaemia may benefit beta-cell function in diabetes.


Social context affects how rhesus monkeys explore their environment.
This study reports on social modulation of exploratory behavior and response to novelty by members of a captive rhesus monkey colony. The group was trained to split in half, with one subgroup composed of dominant members only, the other of subordinates. The animals were then presented the same initially novel stimuli (i.e., sand-filled metal boxes containing hidden food items) in two social contexts differing in hierarchical composition. In a combined context, all group members (i.e., both subgroups together) were simultaneously presented the stimuli. In a split context, only members of the top or bottom half of the group (i.e., each subgroup in turn) was independently presented the stimuli. Subordinates responded similarly to dominant animals in the combined context but differently in the split context, where they were far more hesitant. Rank-related differences were evident in the way animals used their home compound and in their approach and responsiveness toward the stimuli. These findings show that social context influences how animals explore novel situations, possibly reflecting different social roles or status effects on the perception of social structure. Also, despite the complexity of primate social relationships, the separation technique produced no permanent or adverse effects on the social integrity of the group. This study shows that manipulating the social environment through separation training can be a powerful tool for assessing contextual influences on behavior.