Synthesis and structure-toxicity relationships of three new stable analogues of acetyl-seco-hemicholinium-3.
In order to develop and study inhibitors of neuromuscular function which act presynaptically, three stable analogues of acetyl-seco-hemicholinum-3 (AcHC-3,2) were prepared. These analogues have 2-ethoxyethyltrimethylammonium, 4-oxopentyltrimethylammonium, and n-pentyltrimethylammonium moieties substituted for the 2-acetylethyltrimethylammonium (acetylcholine) moieties of AcHC-3 (2) to form the ether 2, ketone 4, and alkane 5 analoggues of AcHC-3 (2). Although AcHC-3 (2) has been shown to undergo deesterification rapidly in basic solutions and slowly at pH 7.4, it has been found to be stable in H2O or D2O under slightly acidic conditions. All of the analogues are stable for extended time under both slightly acidic conditions and at pH 7.4 in H2O or D3O. It has been found that 2 reacts with acetylcholinesterase and butyrylcholinesterase within seconds in H2O at pH7.4. However, deesterification of 2 with subsequent cyclization to the hemiacetal form of hemicholinium-3 (HC-3, 1) is prevented at pH 7.4, possibly by an irreversible binding of 2 to the enzyme. The analogues 3-5, however, do not react under identical conditions. Mouse toxicity studies (LD50) indicate that 2 is approximately as toxic as HC-3 (1), whereas 3, 4, and 5 are 14.2, 23.8, and 43.1 times less toxic, respectively. The toxic effects of 3-5, like 1 and 2, are antagonized by choline but not by neostigmine in mice. Structure-activity relationships of 2-5 are discussed.


Heterogeneity of bone mineral density across skeletal sites and its clinical implications.
Low trauma fractures in the elderly are highly predictable by measurement of bone mineral density (BMD). Preventive measures for low BMD, such as hormone replace therapy (HRT), have potential risks. Thus, a rational decision on HRT or other therapy critically depends on an accurate diagnosis of osteopenia/osteoporosis. We assessed the degree of diagnostic heterogeneity based on spine and hip BMD for 2313 women. We found: 1. In ~30.0% of cases, the difference between spine and hip Z- and T-scores was >1.0, and in 20.8% (Z-scores) and 15.2% (T-scores) the difference was >2.0. 2. With increasing age, the proportions of women with Z- or T-scores greater at the hip than the spine generally decreased. 3. The correlation between hip and spine and Z- and T-scores ranged from 0.50 to 0.72, and generally decreased with increasing age. 4. If screened only at the hip or spine, 17.9/27.3% with osteopenia and 1.3/2.9% with osteoporosis at either site would be diagnosed as normal. Corresponding analyses of 143 men yielded similar results. Therefore, if possible, dual X-ray absorptiometry (DXA) of both the spine and hip should be performed for an accurate assessment of osteoporosis at these two most frequently fractured sites. If only one site is chosen, measurement of the hip is preferred to measurement of the spine.


[Development of mixed drink of coconut water, pineapple and acerola pulp].
The purpose of the present work was to develop a blended beverage based on green coconut (Cocos nucifera L.) water, pineapple (Ananas comosus) and acerola (Malpighia emarginata D. C.) pulps as a ready to drink product, combining the sensory acceptance, nutritional and functional compounds of these fruits. Ten formulations of mixed beverages were evaluated with regard physicochemical determinations, functional compounds and sensorial attributes. Since here was no significative change in the acceptance of here formulations, the product composed of 65% green coconut water, 15% of pineapple and 20% acerola pulp was selected based on the best combination of nutritional components. This formulation presented the required characteristics for a new commercial product.


Effect of adjunctive single dose parenteral Vitamin D supplementation in major depressive disorder with concurrent vitamin D deficiency: A double-blind randomized placebo-controlled trial.
Adjunctive vitamin D replacement is a theoretically promising strategy to improve outcomes in major depression. Our objective was to assess the efficacy of a single parenteral dose of vitamin D supplementation at baseline as an adjunct to treatment as usual on change in depression symptom ratings (primary outcome), quality of life and clinical severity of illness (secondary outcomes) at the end of 12 weeks when compared to treatment as usual in patients with major depression and concurrent Vitamin D deficiency. Eligible participants were randomized to receive either treatment as usual (TAU; n = 23) or TAU plus single parenteral dose of 3,00,000 IU of vitamin D (n = 23) at baseline. Rater-blinded assessments of depression (primary outcome), quality of life (QoL) and clinical severity of illness were obtained at baseline, and end of follow-up (12 weeks). Intent-to-treat analyses were performed on the entire randomized sample. The intervention significantly improved depression symptom ratings, quality of life and clinical severity of illness at the end of the treatment phase. These findings indicate that a single parenteral dose (3,00,000 IU) of adjunctive vitamin D replacement at baseline is an effective and well tolerated intervention in major depressive disorder with concurrent Vitamin D deficiency. Additionally, it points to a possible role for vitamin D in the pathophysiology of depression and supports personalized approaches for treatment of major depressive disorder.


Impact of Antiretroviral Therapy on Oral Health among Children Living with HIV: A Systematic Review and Meta-Analysis.
Oral health is an integral component of general health and well-being but might be undermined among children living with HIV (CLWH) due to the condition itself or the antiretroviral therapy (ART) received. This review summarises the current evidence and compares the oral health status of the CLWH who were treatment-naïve with those undergoing different ART medications. Fourteen studies were included in the final qualitative and quantitative analyses. This review identified no significant difference in the prevalence of caries, periodontal conditions, and tooth development between both groups. Orofacial opportunistic infections were more prevalent in the CLWH without ART. Children undergoing ART with a duration longer than 3 years had a significantly lower prevalence of oral candidiasis and CD4+ T-cell counts. However, due to the insufficient number of well-administered case-control studies with adequate sample size, the quality of the evidence in all outcomes was of very low certainty.


Relation of Subclinical Hypothyroidism to Acute Kidney Injury Among ST-Segment Elevation Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention.
Data suggest that subclinical hypothyroidism (SCH) is associated with progression of chronic renal disease; however, no study to date has assessed the possible relation between SCH and acute deterioration of renal function. To investigate the possible relation between SCH and acute kidney injury (AKI) in a large cohort of patients with ST-elevation myocardial infarction (STEMI) treated with primary coronary intervention (PCI). We evaluated thyroid stimulating hormone (TSH) and free T4 levels of 1591 STEMI patients with no known history of hypothyroidism or thyroid replacement treatment who were admitted to the coronary care unit (October 2007-August 2017). The presence of SCH was defined as TSH levels ≥ 5 mU/ml in the presence of normal free T4 levels. Patients were assessed for development of AKI ( 0.3 mg/dl increase in serum creatinine, according to the KDIGO criteria). The presence of SCH was demonstrated in 68/1593 (4.2%) STEMI patients. Patients presenting with SCH had more AKI complications during the course of STEMI (20.6% vs. 9.6 %; P = 0.003) and had significantly higher serum creatinine change throughout hospitalization (0.19 mg/dl vs. 0.08 mg/dl, P = 0.04). No significant difference was present in groups regarding baseline renal function and the amount of contrast volume delivered during coronary angiography. In multivariate logistic regression model, SCH was independently associated with AKI (odds ratio = 2.19, 95% confidence interval 1.05-4.54, P =0.04). Among STEMI patients treated with PCI, the presence of SCH is common and may serve as a significant marker for AKI.


Effects of epidermal growth factor and insulin on the activity of N-acetylglucosaminyltransferase V.
When quiescent rat hepatocellular carcinoma 7919 cells were treated with epidermal growth factor (EGF) or insulin (stimulators of receptor tyrosine kinase activity), the activity of N-acetylglucosaminyltransferase V was increased. The effect of EGF reached a maximum after 10 min and remained high for 30 min, while the effect of insulin reached a maximum after 5 min and decreased after 15 min. Preincubation of the cells with 1-O-octadecyl-2-O-methylglycerophosphocholine (Et18-OH3), which blocked the activation of mitogen-activated protein kinase by EGF, also blocked the activation of N-acetylglucosamyltransferase V by this hormone, whereas the activation of N-acetylglucosamyltransferase V by insulin could not be blocked by Et18-OH3. Our results suggest that N-acetylglucosamyltransferase V may be regulated by different receptor protein tyrosine kinase pathways.


Persistent problems with the Munchausen syndrome by proxy label.
After nearly 30 years of clinical and legal experience, the definition of Munchausen syndrome by proxy remains controversial. As a result, mothers who present the problems of their children in ways perceived as unusual or problematic have become entangled in legal battles that should have been resolved clinically. Re-labeling the disorder as Pediatric Condition Falsification misdirects the focus onto mistakes and misunderstandings while avoiding the more crucial issue of intentions. Experts have enflamed the fears of harm by confusing warning signs with diagnostic signs and by citing retrospective studies instead of the more optimistic outcome studies. Accused mothers need the support of multidisciplinary teams but are often forced into contentious struggles with legal professionals and child protection services.


Sulcal hyperintensity on fluid-attenuated inversion recovery imaging in acute ischemic stroke patients treated with intra-arterial thrombolysis: iodinated contrast media as its possible cause and the association with hemorrhagic transformation.
To investigate the effect of iodinated contrast medium on sulcal hyperintensity on fluid-attenuated inversion recovery (FLAIR) imaging immediately after intra-arterial thrombolysis in patients with acute ischemic stroke and to determine whether it may be associated with subsequent hemorrhagic transformation (HT). Fourteen consecutive patients with acute ischemic stroke who were treated with intra-arterial thrombolysis were enrolled. All patients underwent noncontrast computed tomography (NCT) and diffusion-weighted (DWI), perfusion-weighted, gradient-recalled echo (GRE), and gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI). Immediate follow-up NCT and MRI (T2-weighted, FLAIR, GRE, DWI, perfusion-weighted, T1-weighted, and gadolinium-enhanced T1-weighted) were obtained and evaluated to determine the presence of sulcal hyperintensity or subarachnoid hemorrhage (SAH). The same follow-up images were obtained on days 1, 3, and 7 and evaluated to determine HT. Sulcal hyperintensity was found in 8 (57.1%) of 14 patients and was seen as hyperattenuation on immediate follow-up NCT and as hyperintensity on T1-weighted images in 4 (50%) of 8 patients. It may be suggested that the sulcal hyperattenuation was responsible for the sulcal hyperintensity, considering signal intensity and follow-up imaging. All patients with sulcal hyperintensity showed enhancement in the corresponding gyri on gadolinium-enhanced T1-weighted imaging. Hemorrhagic transformation developed in 5 of 8 patients with sulcal hyperintensity and in 1 of 4 patients without (P = 0.031). In acute ischemic patients treated with intra-arterial thrombolysis, sulcal hyperintensity on FLAIR imaging may be caused by iodinated contrast medium, which should not be considered SAH. Sulcal hyperintensity is significantly associated with subsequent HT.


Intellectual Profile of Children with Autism Spectrum Disorder: Identification of verbal and nonverbal subscales predicting intelligence quotient.
This study aimed to explore the intelligence quotient (IQ) profile among children with autism spectrum disorder (ASD) and identify the most important subscales that predict the IQ. The analysis of an intellectual profile with age and gender differentials and the identification of a battery of subscales of intelligence are important for clinical management of ASD among children and for facilitating placement for remedial and educational services. Data were collected through an exploratory study of 100 children aged between three and 13 years, who were referred to the department of child health and development in Sultan Qaboos University Hospital, a tertiary hospital, in Oman between June 2016 and June 2019. Among the 100 participants of this study, 79% were male, resulting in a male-female ratio of 4:1. The mean of full-scale IQ was found to be 68.6 ± 18.1. Furthermore, the mean of nonverbal IQ (73.5 ± 17.5) was significantly higher than that of verbal IQ (65.5 ± 17.6). Finally, more than half (61%) of the children were observed to have had mild to moderate impairment in their IQ levels. Age and gender showed no significant association with IQ level. The regression analysis identified nonverbal fluid reasoning, nonverbal visual-spatial processing, nonverbal working memory and verbal knowledge as the significant predictors of total IQ. The crucial dimensions of verbal and nonverbal IQ identified in this study can be used to evaluate complicated cases.


[Tissue and regional distribution of activity of phenylmethylsulfonyl fluoride inhibited carboxypeptidase and other carboxypeptidases in rats].
Phenylmethylsulfonyl fluoride (PMSF)-inhibited carboxypeptidase (CP) is recently described exopeptidase, that cleaved arginine residues from C-terminal of enkephalin synthetic analogs. The highest enzyme activity was found in the adrenal gland and 40% lower one was revealed in the pituitary gland. A 2.5-fold lower than PMSF-inhibited CP activity in adrenal glands was present in testes. The enzyme activity in the brain regions, liver and spleen was about 2.3-fold lower than in the pituitary gland. Its activity in kidneys is insignificant. In the brain region the lowest PMSF-inhibited CP activity was observed in hippocamp and optic and auditory hills, the highest enzyme activity, in the olfactory bulbus and cerebral hemispheres. The differences between brain regions with the highest and the lowest PMSF-inhibited CP activity do not exceed 1.5 fold. The tissue and regional distribution of PMSF-inhibited CP correlated with that for CPH, enzyme of regulatory peptides processing, and it did not correlate with the distribution of lysosomal CPB. The results allow one to suggest the involvement of PMSF-inhibited CP in the processing of the precursors of biological active peptides and secretory proteins. The differences of distribution of PMSF-inhibited CP and CPH are probably connected with involvements of these enzymes in the processing of precursors of different regulatory peptides.


Treatment for diabetic nephropathy - a review of the recent patent literature.
Diabetic nephropathy is now the leading cause of end-stage renal disease in the Western world. Renal disease develops secondary to long-standing hyperglycemia and hemodynamic alterations, which activate a common pathway that ultimately leads to the renal damage. Current strategies to treat diabetic nephropathy include optimization of glycemic control and treatment of glomerular and systemic hypertension. Although these strategies can slow the progression of proteinuria and decline in renal function, diabetic nephropathy remains a huge clinical problem. It is anticipated that future treatment modalities for preventing and treating diabetic nephropathy will involve drugs that modulate common pathogenetic pathways, possibly acting to inhibit both metabolic and hemodynamically induced forms of renal injury. These include inhibitors of growth factor and cytokine release or action, and inhibitors of intracellular second messengers. Although most of these agents have only been investigated in vitro, in animal experiments, or in relatively short-term human studies, these studies suggest that therapeutic strategies which involve a multifactorial approach may be more successful in the treatment of diabetic kidney disease than drugs which influence only one pathway.


An Unexpected Finding of Hepatosplenomegaly in a Pediatric Patient.
Gaucher disease (GD) is a rare autosomal recessive metabolic disorder. It is characterized by a deficiency of lysosomal glucocerebrosidase, which results in the accumulation of glycosphingolipid substrates, primarily glucosylceramide, in the phagocyte system. In GD Type 1, the liver, spleen, and bone marrow are typically affected. We report the case of a 7-year-old female with GD Type 1 who presented with hepatosplenomegaly detected incidentally following a motor vehicle accident. She was found to have concomitant thrombocytopenia and Erlenmeyer flask deformities of her lower limbs. Diagnosis was made on the basis of very low leukocyte β-glucocerebrosidase activity and elevated plasma chitotriosidase. DNA mutation studies revealed both c.1226A>G and c.116_1505 deletion (exons 3-11). The patient is currently managed with biweekly intravenous imiglucerase (Cerezyme) replacement therapy. She demonstrated resolution of thrombocytopenia and hepatosplenomegaly at 2-year follow-up. Physicians must consider this rare diagnosis in children presenting with hepatosplenomegaly to prompt timely management.


Multiomics signatures of type 1 diabetes with and without albuminuria.
To identify novel pathophysiological signatures of longstanding type 1 diabetes (T1D) with and without albuminuria we investigated the gut microbiome and blood metabolome in individuals with T1D and healthy controls (HC). We also mapped the functional underpinnings of the microbiome in relation to its metabolic role. One hundred and sixty-one individuals with T1D and 50 HC were recruited at the Steno Diabetes Center Copenhagen, Denmark. T1D cases were stratified based on levels of albuminuria into normoalbuminuria, moderate and severely increased albuminuria. Shotgun sequencing of bacterial and viral microbiome in stool samples and circulating metabolites and lipids profiling using mass spectroscopy in plasma of all participants were performed. Functional mapping of microbiome into Gut Metabolic Modules (GMMs) was done using EggNog and KEGG databases. Multiomics integration was performed using MOFA tool. Measures of the gut bacterial beta diversity differed significantly between T1D and HC, either with moderately or severely increased albuminuria. Taxonomic analyses of the bacterial microbiota identified 51 species that differed in absolute abundance between T1D and HC (17 higher, 34 lower). Stratified on levels of albuminuria, 10 species were differentially abundant for the moderately increased albuminuria group, 63 for the severely increased albuminuria group while 25 were common and differentially abundant both for moderately and severely increased albuminuria groups, when compared to HC. Functional characterization of the bacteriome identified 23 differentially enriched GMMs between T1D and HC, mostly involved in sugar and amino acid metabolism. No differences in relation to albuminuria stratification was observed. Twenty-five phages were differentially abundant between T1D and HC groups. Six of these varied with albuminuria status. Plasma metabolomics indicated differences in the steroidogenesis and sugar metabolism and circulating sphingolipids in T1D individuals. We identified association between sphingolipid levels and Bacteroides sp. abundances. MOFA revealed reduced interactions between gut microbiome and plasma metabolome profiles albeit polar metabolite, lipids and bacteriome compositions contributed to the variance in albuminuria levels among T1D individuals. Individuals with T1D and progressive kidney disease stratified on levels of albuminuria show distinct signatures in their gut microbiome and blood metabolome.


Effect of boron doping on the electrical conductivity of metallicity-separated single walled carbon nanotubes.
We explored the effect of substitutional boron doping on the electrical conductivity of a metallicity-separated single walled carbon nanotube (SWCNT) assembly. Boron atoms were introduced into semiconducting (S)- and metallic (M)-SWCNT assemblies using high temperature thermal diffusion and the concentration of the doped boron atoms was controlled by the thermal treatment temperature. Depending on the conduction mechanism of the SWCNT assembly, both positive and negative effects upon boron incorporation are observed. For the S-SWCNT sheet, the electrical resistivity decreased by about 1 order on introduction of a small amount of boron atoms, due to the localized state for hopping conduction. In contrast, we observed an increase in the electrical resistivity on boron doping for M-SWCNTs. The pristine and boron doped metallic SWCNTs exhibited a tendency of decreasing electrical resistivity in the presence of an external magnetic field perpendicular to the film, which indicated two-dimensional weak localization behavior. A detailed analysis of the resistivity and the magnetoresistance implied that an increase in the inelastic scattering event at the doped boron site reduced the phase coherence length, leading to an increase in the electrical resistivity.


Cognitive and neurobehavioral features in multiple sclerosis.
Multiple sclerosis (MS) is the most common nontraumatic neurological condition of early and middle adulthood. Cognitive and neurobehavioral problems associated with this disorder are common. Approximately 50% of MS patients experience lifetime clinical depression, and at least 50% will experience significant cognitive difficulties. Fatigue is also extremely common and disabling in MS and appears to be associated with sleep problems and primary neurological features, in addition to secondary factors, including depression and pain. Quality of life is affected in MS by all of these factors and is an especially salient issue given that patients often live for many years following diagnosis. In this article, we explore the literature on cognitive and neurobehavioral features in MS, provide a commentary on the state of the literature and make suggestions for research directions over the next 5 years that would move the field forward significantly.


Guinea pig abscess/hypersensitivity model for study of adverse vaccination reactions induced by use of Q fever vaccines.
The Coxiella burnetii phase-I cellular vaccine is efficacious in humans, imparting nearly complete protection against Q fever. However, this vaccine can also induce sterile abscesses and granulomas at the inoculation site in humans previously sensitized by natural infection or vaccination. To decrease the possibility of vaccinating immune persons, vaccinees are currently screened by skin testing to detect pre-existing Q fever immunity. We developed a model of abscess hypersensitivity in Hartley guinea pigs to assess the likelihood that Q fever vaccines would induce adverse vaccination reactions in previously sensitized individuals. Guinea pigs (4 to 6/group) were sensitized to C. burnetii by immunization and aerosol challenge, or by intraperitoneal inoculation. Eight weeks later, animals were then vaccinated SC with a Q fever cellular (WCI) or chloroform:methanol residue (CMR) vaccine. Development of adverse reactions at the vaccination site was assessed histologically and by observation of increases in erythema and/or induration. The WCI vaccine caused greater magnitude and duration of erythema and induration at the vaccination sites than did the CMR vaccine. In addition, non-immune guinea pigs developed induration when given WCI, but not CMR vaccine. The CMR vaccine may prove a safe alternative to WCI vaccines for use in individuals unscreened for prior immunity to C. burnetii.


Investigation of NRXN1 deletions: clinical and molecular characterization.
Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.


Compositional time Petri nets and reduction rules.
This paper introduces compositional time Petri net (CTPN) models. A CTPN is a modularized time Petri net (TPN), which is composed of components and connectors. The paper also proposes a set of component-level reduction rules for TPNs. Each of these reduction rules transforms a TPN component to a very simple one while maintaining the net's external observable timing properties. Consequently, the proposed method works at a coarse level rather than at an individual transition level. Therefore, one requires significantly fewer applications to reduce the size of the TPN under analysis than those existing ones for TPNs. The use and benefits of CTPNs and reduction rules are illustrated by modeling and analyzing the response time of a command and control system to its external arriving messages.


Transcription factors NRF2 and NF-κB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation.
The small GTPase protein RAC1 participates in innate immunity by activating a complex program that includes cytoskeleton remodeling, chemotaxis, activation of NADPH oxidase, and modulation of gene expression. However, its role in regulating the transcriptional signatures that in term control the cellular inflammatory profiles are not well defined. Here we investigated the functional and mechanistic connection between RAC1 and the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2), master regulator of the anti-oxidant response. Lipopolysaccharide and constitutively active RAC1(Q61L) mutant induced the anti-oxidant enzyme heme-oxygenase-1 (HO-1) through activation of NRF2. The use of KEAP1-insensitive NRF2 mutants indicated that RAC1 regulation of NRF2 is KEAP1-independent. Interestingly, NRF2 overexpression inhibited, whereas a dominant-negative mutant of NRF2 exacerbated RAC1-dependent activation of nuclear factor-κB (NF-κB), suggesting that NRF2 has an antagonistic effect on the NF-κB pathway. Moreover, we found that RAC1 acts through NF-κB to induce NRF2 because either expression of a dominant negative mutant of IκBα that leads to NF-κB degradation or the use of p65-NF-κB-deficient cells demonstrated lower NRF2 protein levels and basally impaired NRF2 signature compared with control cells. In contrast, NRF2-deficient cells showed increased p65-NF-κB protein levels, although the mRNA levels remain unchanged, indicating post-translational alterations. Our results demonstrate a new mechanism of modulation of RAC1 inflammatory pathway through a cross-talk between NF-κB and NRF2.


MLcps: machine learning cumulative performance score for classification problems.
Assessing the performance of machine learning (ML) models requires careful consideration of the evaluation metrics used. It is often necessary to utilize multiple metrics to gain a comprehensive understanding of a trained model's performance, as each metric focuses on a specific aspect. However, comparing the scores of these individual metrics for each model to determine the best-performing model can be time-consuming and susceptible to subjective user preferences, potentially introducing bias. We propose the Machine Learning Cumulative Performance Score (MLcps), a novel evaluation metric for classification problems. MLcps integrates several precomputed evaluation metrics into a unified score, enabling a comprehensive assessment of the trained model's strengths and weaknesses. We tested MLcps on 4 publicly available datasets, and the results demonstrate that MLcps provides a holistic evaluation of the model's robustness, ensuring a thorough understanding of its overall performance. By utilizing MLcps, researchers and practitioners no longer need to individually examine and compare multiple metrics to identify the best-performing models. Instead, they can rely on a single MLcps value to assess the overall performance of their ML models. This streamlined evaluation process saves valuable time and effort, enhancing the efficiency of model evaluation. MLcps is available as a Python package at https://pypi.org/project/MLcps/.


Intervention effects on dietary intake among children by maternal education level: results of the Copenhagen School Child Intervention Study (CoSCIS).
Dietary intake among Danish children, in general, does not comply with the official recommendations. The objectives of the present study were to evaluate the 3-year effect of a multi-component school-based intervention on nutrient intake in children, and to examine whether an intervention effect depended on maternal education level. A total of 307 children (intervention group: n 184; comparison group: n 123) were included in the present study. All had information on dietary intake pre- and post-intervention (mean age 6·8 and 9·5 years for intervention and comparison groups, respectively) assessed by a 7-d food record. Analyses were conducted based on the daily intake of macronutrients (energy percentage (E%)), fatty acids (E%), added sugar (E%) and dietary fibre (g/d and g/MJ). Analyses were stratified by maternal education level into three categories. Changes in nutrient intake were observed in the intervention group, mainly among children of mothers with a short education ( < 10 years). Here, intake of dietary fibre increased (β = 2·1 g/d, 95 % CI 0·5, 3·6, P= 0·01). Intake of protein tended to increase (β = 0·6 E%, 95 % CI -0·01, 1·2, P= 0·05), while intake of fat (β = -1·7 E%, 95 % CI -3·8, 0·3, P= 0·09) and SFA (β = -0·9, 95 % CI -2·0, 0·2, P= 0·10) tended to decrease. Also, a significant intervention effect was observed on the intake of SFA among children of mothers with a long education (β = -0·8, 95 % CI -1·5, -0·03, P= 0·04). This multi-component school-based intervention resulted in changes in the dietary intake, particularly among children of mothers with a short education. As the dietary intake of this subgroup generally differs most from the recommendations, the results of the present study are particularly encouraging.


Fully Bayesian estimation of Gibbs hyperparameters for emission computed tomography data.
In recent years, many investigators have proposed Gibbs prior models to regularize images reconstructed from emission computed tomography data. Unfortunately, hyperparameters used to specify Gibbs priors can greatly influence the degree of regularity imposed by such priors and, as a result, numerous procedures have been proposed to estimate hyperparameter values from observed image data. Many of these procedures attempt to maximize the joint posterior distribution on the image scene. To implement these methods, approximations to the joint posterior densities are required, because the dependence of the Gibbs partition function on the hyperparameter values is unknown. In this paper, we use recent results in Markov chain Monte Carlo (MCMC) sampling to estimate the relative values of Gibbs partition functions and using these values, sample from joint posterior distributions on image scenes. This allows for a fully Bayesian procedure which does not fix the hyperparameters at some estimated or specified value, but enables uncertainty about these values to be propagated through to the estimated intensities. We utilize realizations from the posterior distribution for determining credible regions for the intensity of the emission source. We consider two different Markov random field (MRF) models-the power model and a line-site model. As applications we estimate the posterior distribution of source intensities from computer simulated data as well as data collected from a physical single photon emission computed tomography (SPECT) phantom.


The impact of a long-term reduction in dietary energy density on body weight within a randomized diet trial.
We examined the effect of dietary energy density change on body weight in participants of a randomized trial. Intervention participants markedly increased fruit and vegetable intake while reducing energy intake from fat. Participants were 2,718 breast cancer survivors, aged 26-74 yr, with baseline mean body mass index of 27.3 kg/m(2) (SD = 6.3). We assessed dietary intake by sets of four 24-h dietary recalls and validated with plasma carotenoid concentrations. Weight and height were measured at baseline, 1 yr, and 4 yr. Dietary energy density was calculated using food but excluding beverages. Intervention participants significantly reduced dietary energy density compared to controls and maintained it over 4 yr -- both in cross-sectional (P < 0.0001) and longitudinal (Group x Time interaction, P < 0.0001) analyses. Total energy intake or physical activity did not vary between groups. The intervention group had a small but significant weight loss at 1 yr (Group x Time interaction, P < 0.0001), but no between-group weight difference was observed at 4 yr. Our study showed that reducing dietary energy density did not result in a reduction in total energy intake and suggests that this strategy alone is not sufficient to promote long-term weight loss in a free-living population.


The relevance of syllable per minute measuring at the assessment of reading rate.
Purpose To verify whether there are differences in the assessment of reading rate of children at 3rd and 4th grade from elementary school using the measures of words read per minute and syllables read per minute. Methods This research counted on 29 children from 3rd grade and 28 from the 4th grade of elementary school without reading and writing disorders. All children were asked to read aloud a text according to their schooling level. The procedure was recorded and the reading rate was calculated both in words and syllables read per minute. Results Data indicated that syllable read per minute measure was more effective to calculate reading rate of children from different schooling levels since it provides a more reliable profile of reading rate. Conclusion The present study showed evidences that syllable per minute measure is more precise to characterize children's performance since it considers linguistic and textual features.


[Examination of drug addicts on methadone treatment for HIV antibodies in the county of Frederiksborg].
In November 1988, all of the general practitioners in the County of Frederiksborg were requested to examine drug addicts on methadone therapy for HIV antibodies in December 1988 and January 1989. 81.3% of the general practitioners returned the completed form of results which they had received. Twenty-eight of the drug addicts were examined for HIV antibodies. One was found to be positive, corresponding to 3.6% (95% confidence limits 0.09-18.35%). According to the official lists of patients from whom dangerous drugs were prescribed in the Danish Board of Health, 128 persons had received methadone during the two months involved. Information was thus obtained concerning 22% of the group concerned by means of this questionnaire method of investigation. This method is thus of relatively limited value for monitoring of the spread of HIV-infection among drug addicts receiving methadone therapy.


Calibration and Application of PUF Disk Passive Air Samplers To Assess Chlorinated Paraffins in Ambient Air in Australia, China, and Vietnam.
Ambient air samples were collected in Brisbane (Australia), Dalian (China), and Hanoi (Vietnam) during Mar 2013-Feb 2018 using polyurethane foam based passive air samplers. A sampling rate calibration experiment was conducted for chlorinated paraffins (CPs, i.e., short-chain, medium-chain, and long-chain CPs), where the sampling rates were 4.5 ± 0.7, 4.8 ± 0.3, and 4.8 ± 2.1 m3 day-1 for SCCPs, MCCPs, and LCCPs, respectively. The atmospheric concentration of CPs was then calculated and the medians of ∑CPs were 0.079, 1.0, and 0.89 ng m-3 in Brisbane, Dalian, and Hanoi, respectively. The concentration of CPs in Brisbane's air remained at low levels, with no significant differences observed between the city background site and the city center site, indicating limited usage and production of CPs in this city. The highest concentration of MCCPs was detected in Dalian, while the highest concentration of SCCPs was detected in Hanoi. A decrease of SCCP concentration and an increase of MCCPs' were found in Brisbane's air from 2016 to 2018, while increasing trends for both SCCPs and MCCPs were observed in Dalian. These results indicated impacts from different sources of CPs in the investigated cities.


Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus alpha-hemolysin-mediated cellular injury.
Staphylococcus aureus alpha-hemolysin (Hla), a potent cytotoxin, plays an important role in the pathogenesis of staphylococcal diseases, including those caused by methicillin-resistant epidemic strains. Hla is secreted as a water-soluble monomer that undergoes a series of conformational changes to generate a heptameric, beta-barrel structure in host membranes. Structural maturation of Hla depends on its interaction with a previously unknown proteinaceous receptor in the context of the cell membrane. It is reported here that a disintegrin and metalloprotease 10 (ADAM10) interacts with Hla and is required to initiate the sequence of events whereby the toxin is transformed into a cytolytic pore. Hla binding to the eukaryotic cell requires ADAM10 expression. Further, ADAM10 is required for Hla-mediated cytotoxicity, most notably when the toxin is present at low concentrations. These data thus implicate ADAM10 as the probable high-affinity toxin receptor. Upon Hla binding, ADAM10 relocalizes to caveolin 1-enriched lipid rafts that serve as a platform for the clustering of signaling molecules. It is demonstrated that the Hla-ADAM10 complex initiates intracellular signaling events that culminate in the disruption of focal adhesions.


[Community composition of phytoplankton in Fujian-Guangdong coastal upwelling region in summer and related affecting factors].
Based on the investigation data of 133 samples from 30 grid stations in the Fujian-Guangdong coastal upwelling region (21.6 degrees - 24.3 degrees N,115.7 degrees -118.7 degrees E) in 11-16 June 2009, this paper studied the phytoplankton species composition and cell abundance in the region in three dimensions (vertical, horizontal, and sectional), and approached their relations with major environmental factors. A total of 159 taxa belonging to 85 genera of 4 phyla were identified, among which, diatom was predominant, followed by dinoflagellate. Cyanophyceae mainly composed of Trichodesmium also occupied a greater proportion, but Chrysophyceae was only checked out in the upper 10 m water layer at coastal stations. The dominant species were Rhizosolenia alata f. gracillma, Thalassionema nitzschioides, Pseudonitzschia pungens, Skeletonema costatum, Thalassionema frauenfeldii, Paralia sulcata, Guinadia striata, Trichodesmium thiebautii, Ceratium fusus, and Gyrodinium spirale. Most of the phytoplankton taxa were cosmopolitan species, followed by warm-water species, while tropic high-salinity or oceanic eurythermal species were lesser. The cell abundance of the phytoplankton was average of 67.59 x10(2) ind x L(-1). In vertical profile, the cell abundance of the phytoplankton was the highest in surface water, and decreased with water depth. In horizontal and sectional profiles, the cell abundance had no definite patterns, but the high abundance region was in Nanao Island water area, being anastomosed with the center of upwelling region, which indicated that the weak and small intensity of deep-sea water upwelling caused lesser phytoplankton cell abundance and superposition. The comparatively high phytoplankton cell abundance in the four sections (B, C, D, E) along Nanao-Zhangpu was resulted from the upwelling from Taiwan Bank. The phytoplankton cell abundance had a significant positive correlation with the PO4(3-) concentration in the upper 10 m water layer, but no correlation with the dissolved inorganic nitrogen (DIN) concentration. Thereby, to study the eco-physiological responses of phytoplankton species to nutrient stress would be helpful to reveal the formation mechanism of algal bloom in upwelling region.


Married men who have sex with men: the bridge to HIV prevention in Mumbai, India.
The present study compared the sexual behaviours of married and unmarried men, in Mumbai, India, who have sex with men. We conducted a cross-sectional analysis (comparing socio-demographic, behavioural and clinical data) of 88 married and 423 unmarried MSM. Even though MSM are single at younger ages, they are more likely to be married later in life and carry their risky sexual behaviours to this changed social milieu. Married MSM had high-risk behaviours with both men and women; they form an important intervention group for HIV prevention. The interventions will not only reduce the transmission in the male-to-male sexual group, but will also have an effect on the male-to-female transmission of HIV.


Health-related quality of life following TAVI or cardiac surgery in patients at intermediate and low risk: a systematic review and meta-analysis.
Recent randomised trials have shown that clinical outcomes with transcatheter aortic valve implantation (TAVI) are non-inferior to surgical aortic valve replacement (SAVR) in patients with symptomatic aortic stenosis at intermediate to low risk. Health-related quality of life (HrQoL) outcomes in these patient groups remain uncertain. A systematic search of the literature was conducted that included nine trials and 11,295 patients. Kansas City Cardiomyopathy Questionnaire (KCCQ), a heart-failure-specific measure and EuroQol-5D (EQ-5D) (a generic health status tool) changes were the primary outcomes. New York Heart Association (NYHA) classification was the secondary outcome. Improvement in KCCQ scores was greater with TAVI (mean difference (MD)=13.56, 95% confidence interval (CI) 11.67-15.46, p<0.001) at 1 month, as was the improvement in EQ-5D (MD=0.07, 95% CI 0.05-0.08, p<0.001). There was no difference in KCCQ (MD=1.05, 95% CI -0.11 to 2.21, p=0.08) or EQ-5D (MD=-0.01, 95% CI -0.03 to 0.01), p=0.37) at 12 months. NYHA functional class 3/4 was lower in patients undergoing TAVI at 1 month (MD=0.51, 95% CI 0.34-0.78, p=0.002), but there was no difference at 12 months (MD=1.10; 95% CI 0.87-1.38, p=0.43). Overall, TAVI offers early benefit in HRQoL outcomes compared with SAVR, but they are equivalent at 12 months.


Studies of coagulation and platelet functions in heparin-free hemodialysis.
Hematologic and coagulation studies were carried out during 12 heparin-free hemodialysis in 9 maintenance hemodialysis patients. Treatment employed a C-DAK 4000 cellulose acetate membrane hemodialyzer. Both hemodialyzer and blood tubing were periodically flushed with physiologic saline. No significant clotting of the hemodialyzers was encountered in uneventful dialyses. Platelet counts, platelet aggregation with ADP and epinephrine, antithrombin III and fibrinogen/fibrin degradation products were not significantly changed compared with pre-dialysis values. Fibrino-peptide A levels, elevated pre-treatment, demonstrated additional rise during dialysis. These findings support clinical experience that this anticoagulation-free method can be used safely and effectively to dialyze patients at risk for bleeding.


Post-thymic selection of peripheral CD4+ T-lymphocytes on class II major histocompatibility antigen-bearing cells.
Following positive and negative selection in the thymus, mature CD4+ T-cells emigrate into peripheral lymphoid organs. Whether resting T-cells require periodic stimulation to remain viable in the absence of antigen is important for understanding peripheral T-cell homeostasis. A prerequisite for T-cell receptor (TCR)-mediated signals in maintaining peripheral CD4+ T-cell longevity has been demonstrated. Here, we show in mice expressing a mutant I-Abeta transgene on an I-Abeta knockout background that naïve CD4+ T-cells also require engagement of their CD4 coreceptors by peripheral, class II MHC-bearing cells for their survival. The transgene's product combines with endogenous Aalpha, but this mutant AalphaAbeta heterodimer cannot interact with CD4 molecules, although it efficiently presents antigens to TCRs. Resting CD4+ T-lymphocytes from mutant Abeta transgenic mice die by apoptosis at a much higher rate than do CD4+ T-cells from normal mice. Apoptosis of CD4+ T-cells in mutant Abeta transgenic mice is partially mediated by Fas. Adoptive transfer experiments revealed that the increase in apoptosis is due to a lack of interactions with mutant MHC class II rather than to an intrinsic defect in the CD4+ T-cells selected on mutant Abeta-expressing thymic epithelial cells. Thus, interactions between CD4 and MHC class II molecules contribute to the regulation of homeostasis in the peripheral immune system. Our results further suggest that thymic emigrant cells are continuously retested in the periphery for appropriate coreceptor interactions. Peripheral selection may be important in eliminating potentially autoreactive T-cells.


High-Performance Al/PDMS TENG with Novel Complex Morphology of Two-Height Microneedles Array for High-Sensitivity Force-Sensor and Self-Powered Application.
Triboelectric nanogenerators (TENGs) are widely applied to self-powered devices and force sensors. TENGs consist of the electrode-layer frequently made of high-cost conductors (Ag, Au, ITO) and the tribo-layer of rigid negative-triboelectricity fluoropolymers (PTFE, FEP). The surface morpholoy is studied for enhancing performance. Here, a high-performance Al/PDMS-TENG is proposed with a complex morphology of overlapped deep two-height microneedles (OL-DTH-MN) fabricated by the integrated process of low-cost CO2 laser ablation and PDMS casting for self-powered devices and high-sensitivity force/pressure sensors. The high open-circuit voltage and short-circuit current of the OL-DTH-MN-TENG are 167 V and 129.3 µA. Also, the sensitivity of the force/pressure sensor of the OL-DTH-MN-TENG is very high, 1.03 V N-1 and about 3.11 V kPa-1 , at an area of 30 cm2 that is much higher than the sensitivity of about 0.18-0.414 V N-1 and 0.013-0.29 V kPa-1 of conventional TENG sensors. Meanwhile, the high-performance OL-DTH-MN-TENG not only exhibits the energy storage capability of charging a 0.1 µF capacitor to 2.75 V at 1.19 s, to maximum 3.22 V, but also activates various self-powered devices including lighting colorful 226 LEDs connected in series, the "2020-ME-NCKU" advertising board, a calculator and a temperature sensor. Numerical simulation is also performed to support the experiments.


The Effects of Prioritizing Lead or Boulder Climbing Among Intermediate Climbers.
This study compared the effects of prioritizing lead climbing or boulder climbing on climbing-specific strength and endurance, as well as climbing performance. Fourteen active climbers were randomized to a boulder climbing training group (BCT: age = 27.2 ± 4.4 years, body mass = 65.8 ± 5.5 kg, height = 173.3 ± 3.8 cm) or a lead-climbing training group (LCT: age = 27.7 ± 6.1 years, body mass = 70.2 ± 4.4 kg, height = 177.7 ± 4.4 cm). The groups participated in a 5-week training period consisting of 15 sessions, performing either two weekly bouldering sessions and one maintenance-session of lead-climbing (BCT) or two weekly lead-climbing sessions and one maintenance-session of bouldering (LCT). Pre- and post-training, maximal force and rate of force development (RFD) were measured during isometric pull-ups performed on a jug hold and a shallow rung, and during an isolated finger-strength test. Lead-climbing and bouldering performance were also measured, along with an intermittent forearm endurance test. The pre-to-post changes were not significantly different between the groups for any of the parameters (P = 0.062-0.710). However, both the BCT (ES = 0.30, P = 0.049) and LCT (ES = 0.41, P = 0.046) groups improved strength in the isometric pull-up performed using the jug, whereas neither group improved force in the rung condition (P = 0.054 and P = 0.084) or RFD (P = 0.060 and P = 0.070). Furthermore, climbing and bouldering performance remained unchanged in both groups (P = 0.210-0.895). The LCT group improved forearm endurance (ES = 0.55, P = 0.007), while the BCT group improved isolated finger strength (ES = 0.35, P = 0.015). In addition to isometric pull-up strength, bouldering can increase isolated finger strength while lead-climbing may improve forearm endurance. A 5-week period prioritizing one discipline can be safely implemented for advanced to intermediate climbers without risking declined performance in the non-prioritized discipline.


Different effects of bifeprunox, aripiprazole, and haloperidol on body weight gain, food and water intake, and locomotor activity in rats.
Following on the success of Aripiprazole with its high clinical efficacy and minimal side effects, further antipsychotic drugs (such as Bifeprunox) have been developed based on the same dopamine D2 partial agonist pharmacological profile as Aripiprazole. However clinical trials of Bifeprunox have found differing results to that of its predecessor, without the same significant clinical efficacy. This study has therefore investigated the different effects of 10 week treatment with Aripiprazole (0.75 mg/kg, 3 times per day), Bifeprunox (0.8 mg/kg, 3 times per day) and Haloperidol (0.1mg/kg, 3 times per day) on body weight gain, food and water intake, white fat mass, and 8 week treatment on locomotor activity. Treatment with Bifeprunox was found to significantly reduce all of the measured parameters except white fat mass compared to the control group. However, Aripiprazole and Haloperidol treatment reduced water intake compared to the control, without any significant effects on the other measured parameters. These findings further demonstrate the potential pharmacological differences between Aripiprazole and Bifeprunox, and identify potential weight loss side effects and increased anxiety behaviour with Bifeprunox treatment.


miR-877-5p as a Potential Link between Triple-Negative Breast Cancer Development and Metabolic Syndrome.
Metabolic syndrome (MS) is a risk factor for breast cancer (BC) that increases its aggressiveness and metastasis. The prevalence of MS is higher in triple-negative breast cancer (TNBC), which is the molecular subtype with the worst prognosis. The molecular mechanisms underlying this association have not been fully elucidated. MiRNAs are small, non-coding RNAs that regulate gene expression. Aberrant expression of miRNAs in both tissues and fluids are linked to several pathologies. The aim of this work was to identify circulating miRNAs in patients with alterations associated with MS (AAMS) that also impact on BC. Using microarray technology, we detected 23 miRNAs altered in the plasma of women with AAMS that modulate processes linked to cancer. We found that let-7b-5p and miR-28-3p were decreased in plasma from patients with AAMS and also in BC tumors, while miR-877-5p was increased. Interestingly, miR-877-5p expression was associated with lower patient survival, and its expression was higher in PAM50 basal-like BC tumors compared to the other molecular subtypes. Analyses from public databases revealed that miR-877-5p was also increased in plasma from BC patients compared to plasma from healthy donors. We identified IGF2 and TIMP3 as validated target genes of miR-877-5p whose expression was decreased in BC tissue and moreover, was negatively correlated with the levels of this miRNA in the tumors. Finally, a miRNA inhibitor against miR-877-5p diminished viability and tumor growth of the TNBC model 4T1. These results reveal that miR-877-5p inhibition could be a therapeutic option for the treatment of TNBC. Further studies are needed to investigate the role of this miRNA in TNBC progression.


The incidence, calf morbidity and mortality due to Theileria parva infections in smallholder dairy farms in Murang'a District, Kenya.
A prospective observational study was conducted among smallholder dairy farmers in Murang'a District, Kenya, to estimate the incidence of Theileria parva infections, as well as calf morbidity and mortality caused by the infection. The study was conducted between March 1995 and August 1996, in five cohorts of female calves from birth to six months of age from different agro-ecological zones (AEZs) and grazing-system strata shown previously to have varying prevalences of T. parva infection. A total of 188 smallholder dairy farms with 225 female calves were selected purposively by five AEZ-grazing strata. All recruited calves were visited within the first two weeks of life and thereafter at biweekly intervals up to the age of six months. The mean number of cattle in these smallholder farms was 2.6. Both exotic and indigenous breeds of cattle and their crosses were present, with the former predominating. The incidence (27-54%) of sero-conversion to T. parva in an ELISA test was significantly different (p < 0.05) across the five AEZ-grazing strata and increased with lower elevation and unrestricted grazing. Calf morbidity and mortality were also variable across the AEZ-grazing strata. East Coast fever (ECF) was the highest-incidence cause calf morbidity and mortality (relative to other diseases). There are great differences in the epidemiology of ECF within a small area and this implies that there is need to carefully consider different ECF control strategies in different AEZ-grazing strata.


The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.
Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.


Fractional nonablative 1540-nm laser treatment of striae distensae in Fitzpatrick skin types II to IV: clinical and histological results.
Current striae treatments are limited in their ability to deliver long-lasting improvements for all skin types. The success of fractional nonablative lasers for surgical scars has been attributed to the controlled wound-healing response stimulated by microscopic columns of epidermal and dermal thermal damage. The authors describe the safety and efficacy results of treatment with a fractional nonablative 1540-nm erbium:glass laser in patients with Fitzpatrick skin types II to IV for both striae rubra and striae alba. A 51-person clinical study was conducted on striae ranging in duration from one to 40 years. Nine different anatomical locations were treated, including the breasts, hips, and abdomen. Treatment parameters included two to three passes with the 1540-nm laser, with energy settings from 35 to 55 mJ/mb with the 10-mm optical tip or 12 to 14 mJ/mb with the 15-mm optical tip. Two to four total treatments were performed at four- to six-week intervals. Nonblinded efficacy evaluations were performed on all 51 patients; blinded evaluations were conducted by three independent clinicians on 14 randomized sets of pre- and posttreatment images on a 0% to 100% quartile improvement scale. Skin reactions were assessed by the treating physician and recorded at multiple time points, and histology was conducted with hemotoxylin and eosin as well as Orcein-Giemsa staining. Nonblinded clinical assessments rated overall improvement as 50% or greater for all patients at six months or longer after the last treatment. Blinded evaluators reported an overall mean improvement score of 51% to 75% on properly selected images taken at least three months after treatment (n = 11). In all patients examined at either 18 or 24 months after treatment, there was no recurrence of striae. Typical side effects included transient erythema and edema. A small minority of patients experienced transient cases of trace postinflammatory hyperpigmentation (PIH), which all resolved. Histologic observations showed thickening of the epidermis and dermis, neocollagenesis, and increased elastin deposition one month after the last treatment. Positive safety and efficacy results with the fractional nonablative 1540-nm erbium:glass laser for the treatment of striae rubra and striae alba ranging in maturation age from one to 40 years was demonstrated in Fitzpatrick skin types II to IV.


Incomplete recovery of myocyte contractile function despite improvement of myocardial architecture with left ventricular assist device support.
Unloading a failing heart with a left ventricular assist device (LVAD) can improve ejection fraction (EF) and LV size; however, recovery with LVAD explantation is rare. We hypothesized that evaluation of myocyte contractility and biochemistry at the sarcomere level before and after LVAD may explain organ-level changes. Paired LV tissue samples were frozen from 8 patients with nonischemic cardiomyopathy at LVAD implantation (before LVAD) and before cardiac transplantation (after LVAD). These were compared with 8 nonfailing hearts. Isolated skinned myocytes were purified and attached to a force transducer, and dimensions, maximum calcium-saturated force, calcium sensitivity, and myofilament cooperativity were assessed. Relative isoform abundance and phosphorylation levels of sarcomeric contractile proteins were measured. With LVAD support, the unloaded EF improved (10.0±1.0% to 25.6±11.0%, P=0.007), LV size decreased (LV internal dimension at end diastole, 7.6±1.2 to 4.9±1.4 cm; P<0.001), and myocyte dimensions decreased (cross-sectional area, 1247±346 to 638±254 μm(2); P=0.001). Maximum calcium-saturated force improved after LVAD (3.6±0.9 to 7.3±1.8 mN/mm(2), P<0.001) implantation but was still lower than in nonfailing hearts (7.3±1.8 versus 17.6±1.8 mN/mm(2), P<0.001). An increase in troponin I (TnI) phosphorylation after LVAD implantation was noted, but protein kinase C phosphorylation of TnI decreased. Biochemical changes of other sarcomeric proteins were not observed after LVAD. There is significant improvement in LV and myocyte size with LVAD, but there is only partial recovery of EF and myocyte contractility. LVAD support was associated only with biochemical changes in TnI, suggesting that alternate mechanisms might contribute to contractile changes after LVAD and that additional interventions may be needed to alter biochemical remodeling of the sarcomere to further enhance myofilament and organ-level recovery.


A mechanism for P-glycoprotein-mediated apoptosis as revealed by verapamil hypersensitivity.
Selection of tumor cell lines with anticancer drugs has led to the appearance of multidrug-resistant (MDR) subclones with P-glycoprotein 1 (P-gp1) expression. These cells are cross-resistant to several structurally and functionally dissimilar drugs. Interestingly, in the process of gaining resistance, MDR cells become hypersensitive or collaterally sensitive to membrane-active agents, such as calcium channel blockers, steroids, and local anaesthetics. In this report, hypersensitivity to the calcium channel blocker, verapamil, was analyzed in sensitive and resistant CHO cell lines. Our results show that treatment with verapamil preferentially induced apoptosis in MDR cells compared to drug-sensitive cells. This effect was independent of p53 activity and could be inhibited by overexpression of the Bcl-2 gene. The induction of apoptosis by verapamil had a biphasic trend in which maximum cell death occurred at 10 microM, followed by improved cell survival at higher concentrations (50 microM). We correlated this effect to a similar biphasic trend in P-gp1 ATPase activation by verapamil in which low concentrations of verapamil (10 microM) activated ATPase, followed by inhibition at higher concentrations. To confirm the relationship between apoptosis and ATPase activity, we used two inhibitors of P-gp1 ATPase, PSC 833 and ivermectin. These ATPase inhibitors reduced hypersensitivity to verapamil in MDR cells. In addition, low concentrations of verapamil resulted in the production of reactive oxygen species (ROS) in MDR cells. Taken together, these results show that apoptosis was preferentially induced by P-gp1 expressing cells exposed to verapamil, an effect that was mediated by ROS, produced in response the high ATP demand by P-gp1.


A pragmatic approach for implementation of value-based healthcare in Amsterdam UMC, the Netherlands.
The emphasis on implementation of value-based healthcare (VBHC) has increased in the Dutch healthcare system. Yet, the translation of the theoretical principles of VBHC towards actual implementation in daily practice has been rarely described. Our aim is to present a pragmatic step-by-step approach for VBHC implementation, developed and applied in Amsterdam UMC, to share our key elements. The approach may inspire others and can be used as a template for implementing VBHC principles in other hospitals. The local approach is developed in a major academic hospital in the Netherlands, based at two locations with 15,000 employees in total. Experience-based co-design is used, building on our learning experiences from implementing VBHC for 14 specific patient groups. The described steps and activities devolved from iterative and participative co-design sessions with various experienced stakeholders involved in the implementation of one or more VBHC pathways. The approach includes five phases; preparation, design (team introduction, outcome selection, action agenda), building (outcome set integration in daily practice), implementation (training, outcome registration and implementation) and the continuous improvement cycle. We described two cases for illustration of the approach; the Cleft Lip and Palate and the Chronic Kidney Disease patient groups. For a good start, involvement of a clinical leader as driving force, ensuring participation of patient representatives and sufficient resources are needed. We have experienced that several defining features of the development and implementation of this approach may have contributed to its completeness and applicability. Key elements for success have been organisational readiness and clinical leadership. In conclusion, the approach has provided a first step towards VBHC in our hospital. Further research is needed for evaluation of its effectiveness including impact on value for patients.


Synthesis of 2,3-dihydro-1H-pyrroles by intramolecular cyclization of N-(3-butynyl)-sulfonamides.
Hydroamination of 3-butynamine derivatives to give non-aromatic 2,3-dihydropyrroles was achieved by using PdCl2 or AuCl as the catalyst. With microwave-assisted heating, up to 92% isolated yield was obtained from this intramolecular 5-endo-dig cyclisation. The cyclopentane- and cyclohexane-fused 2,3-dihydropyrroles were transformed into the corresponding N-tosyl-pyrrolidine-2-carboxylic acids.


AzoCholine Enables Optical Control of Alpha 7 Nicotinic Acetylcholine Receptors in Neural Networks.
Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and re-evaluated the known photochromic ligand, BisQ. Using electrophysiology, we found that one of our new compounds, AzoCholine, is an excellent photoswitchable agonist for neuronal α7 nAChRs, whereas BisQ was confirmed to be an agonist for the muscle-type nAChR. AzoCholine could be used to modulate cholinergic activity in a brain slice and in dorsal root ganglion neurons. In addition, we demonstrate light-dependent perturbation of behavior in the nematode, Caenorhabditis elegans.


Can exposure to coalmine dust cause a severe impairment of lung function?
It is well recognised that exposure to respirable coalmine dust causes a reduction in lung function but it has not been clear whether the impairment of function is sufficient to cause disability, unless progressive massive fibrosis occurs. From a study of 4059 men without progressive massive fibrosis who worked in the coal industry for at least ten years from the 1950s, and who were followed up and re-examined medically more than 20 years later, a subgroup was selected using criteria intended to favour those who may have suffered greater than average effects of dust exposure. These 199 men had left the coal industry before normal retiral age, had taken other jobs, and had reported symptoms of chronic bronchitis at follow up. The inverse relation between dust exposure and FEV1 among these 199 men was much more severe than the average effects previously shown among more representative groups of coalminers. The effect of exposure to respirable dust was estimated conservatively as an impairment of about 2 ml FEV1 per unit of dust exposure (gh/m3). The estimated effect among ex-smokers was more severe. These compare with a previous estimate, based on a less selected population, of 0.6 ml FEV1 per gh/m3. The new estimate in this group of 199 men corresponds to an average loss of 600 ml FEV1 in response to a moderately high dust exposure to 300 gh/m3, with correspondingly higher losses in the ex-smokers. These findings show that among a group of men intentionally selected to include those who may have suffered greater than average effects of dust exposure, the relation between exposure and FEV1 is consistent with the view that in some men even moderately high exposure to dust causes severe impairment of lung function.


Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants.
The tumour necrosis factor family member TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of cancer cells through the activation of death receptors 4 (DR4) and 5 (DR5) and is considered a promising anticancer therapeutic agent. As apoptosis seems to occur primarily via only one of the two death receptors in many cancer cells, the introduction of DR selectivity is thought to create more potent TRAIL agonists with superior therapeutic properties. By use of a computer-aided structure-based design followed by rational combination of mutations, we obtained variants that signal exclusively via DR4. Besides an enhanced selectivity, these TRAIL-DR4 agonists show superior affinity to DR4, and a high apoptosis-inducing activity against several TRAIL-sensitive and -resistant cancer cell lines in vitro. Intriguingly, combined treatment of the DR4-selective variant and a DR5-selective TRAIL variant in cancer cell lines signalling by both death receptors leads to a significant increase in activity when compared with wild-type rhTRAIL or each single rhTRAIL variant. Our results suggest that TRAIL induced apoptosis via high-affinity and rapid-selective homotrimerization of each DR represent an important step towards an efficient cancer treatment.


Mixed (neutrophil-rich) interstitial pneumonitis in biopsy specimens of lung allografts: a clinicopathologic evaluation.
Mixed interstitial pneumonitis (MIP), defined herein as a diffuse neutrophil-rich inflammatory infiltrate within the interstitial tissues, is an uncommon finding that is not a standard manifestation of acute or chronic rejection. This study examines the clinical significance of MIP in lung allograft recipients at St. Louis University Hospital. We retrospectively reviewed surgical pathology reports from a selected 50-month period, and identified MIP reported in 13 transbronchial biopsy specimens in lung transplant recipients, representing 4.7% of all lung allograft biopsy specimens seen during this 4-year period. Biopsy specimens with MIP were examined to confirm the presence of a neutrophil-rich interstitial infiltrate and other associated histopathologic findings. The culture results, cytopathologic findings, and clinical charts of the affected patients were also reviewed. The detection of MIP at some point in a patient's posttransplant course was found to be associated with a significantly shorter (p < 0.01) survival, when compared to lung allograft recipients who did not show this finding. A total of seven lung allograft recipients (23% of total) showed MIP at some point in their posttransplant course. Four of the seven (57%) were actively smoking following lung transplantation, compared to 0 of 22 patients who did not show MIP. Six of the 13 MIP biopsy specimens were associated with positive cultures. In no case did MIP coexist with the conventional histologic patterns of acute or chronic rejection. MIP also did not correlate with levels of immunosuppressive therapy or with the incidence of rejection at other times in the patients' posttransplant courses. We found no evidence that MIP represents an unusual form of acute or chronic rejection. Instead, it appears to represent a response to acute injury, similar to other injury patterns (hyaline membranes, organizing pneumonia) in transplant recipients. Exposure to tobacco smoke is likely to have played a role in the development of MIP in at least some cases. Because patients with MIP had a significantly shorter posttransplant survival, MIP may usefully identify lung allograft recipients at risk for an adverse outcome.


Coronary vasodilatory action after a single dose of nicorandil.
Coronary hemodynamics and vasodilatory effects on major epicardial arteries were investigated after a single dose of nicorandil in 22 patients undergoing cardiac catheterization for suspected coronary artery disease. Nicorandil, 20 mg, was administered sublingually to 11 consecutive patients and 40 mg to 11 others. Systemic blood pressure decreased significantly without affecting the heart rate. Coronary sinus blood flow did not change significantly. As the mean aortic pressure decreased significantly by 13% after 20 mg and 21% after 40 mg of nicorandil, the calculated coronary vascular resistance decreased but did not reach statistical significance. There was a decrease in myocardial oxygen consumption (-14% and -22%, respectively), and this was consistent with a significant decrease in the calculated pressure-rate product of 19% and 24%, respectively. A total of 103 selected coronary segments, including 17 stenotic segments, were analyzed quantitatively using a computer-assisted coronary angiography analysis system. After 20 or 40 mg of nicorandil, a significant increase of the mean diameter was observed in the proximal (+9% and +7%), midportion (+10% and +11%) and distal (+15% and +13%) parts of the left anterior descending coronary artery. Corresponding values for the proximal (+13% and +10%) and distal (+10% and +15%) segments of the circumflex artery were observed. An increase in the obstruction diameter was also observed in all but 3 of the analyzed stenotic segments. The results demonstrate that nicorandil, in the route and doses used, causes a significant vasodilation in the major epicardial coronary segments, including most stenotic segments, and decreases the myocardial oxygen demand with little effect on the resistance vessels.


Intravenous Thrombolysis for Acute Ischemic Stroke After Recent Myocardial Infarction: Case Series and Systematic Review.
Background and Purpose- The safety of IV r-tPA (intravenous tissue-type plasminogen activator) for acute ischemic stroke (AIS) treatment after recent myocardial infarction (MI) is still a matter of debate. We studied the safety of delivering IV r-tPA to AIS patients with a MI within the preceding 3 months. Methods- Retrospective review of consecutive AIS admitted to 2 tertiary university hospitals' and systematic literature review for AIS patients with history of MI in the previous 3 months. Patients were divided into 2 groups: treated or not treated with standard IV r-tPA dose for AIS. Cardiac complications (cardiac rupture/tamponade, intracardiac thrombus embolization, or life-threatening arrhythmias) were compared between groups and assessed by type of MI (non-ST-segment-elevation myocardial infarction [STEMI], or STEMI) and time elapsed between vascular events. Results- One hundred and two patients were included; 46 (45.1%) were derived from literature review. Median age (interquartile range) was 64 (53-75) years old, and 69 (67.6%) were men. Forty-seven (46.1%) received IV r-tPA. In the treated group, 25 (53.2%) and 23 (48.9%) patients had, respectively, concurrent AIS and MI and STEMI, in comparison with 12 (21.8%; P=0.002) and 36 (65.5%; P=0.110) patients in the nontreated. Four (8.5%) IV r-tPA-treated patients died from confirmed or presumed cardiac rupture/ tamponade, all with a STEMI in the week preceding stroke. This complication occurred in 1 (1.8%) patients in the nontreated group (P=0.178). There were no differences in thrombus embolization (1 [2.1%) versus 2 [3.6]; P=1.000) and life-threatening arrhythmias (3 [6.4%) versus 7 [12.7]; P=0.335). No non-STEMI patients receiving IV r-tPA had cardiac complications. Conclusions- In patients with AIS and recent or concurrent MI, MI type and the time elapsed between the 2 events should be taken into consideration when deciding to deliver IV r-tPA. Although recent non-STEMI or concurrent events seem safe, STEMI in the week preceding stroke should prompt caution. The low number of events and publication bias may have influenced our conclusions.


What we don't know can hurt us: Nonresponse bias assessment in birth defects research.
Nonresponse bias assessment is an important and underutilized tool in survey research to assess potential bias due to incomplete participation. This study illustrates a nonresponse bias sensitivity assessment using a survey on perceived barriers to care for children with orofacial clefts in North Carolina. Children born in North Carolina between 2001 and 2004 with an orofacial cleft were eligible for inclusion. Vital statistics data, including maternal and child characteristics, were available on all eligible subjects. Missing 'responses' from nonparticipants were imputed using assumptions based on the distribution of responses, survey method (mail or phone), and participant maternal demographics. Overall, 245 of 475 subjects (51.6%) responded to either a mail or phone survey. Cost as a barrier to care was reported by 25.0% of participants. When stratified by survey type, 28.3% of mail respondents and 17.2% of phone respondents reported cost as a barrier. Under various assumptions, the bias-adjusted estimated prevalence of cost as barrier to care ranged from 16.1% to 30.0%. Maternal age, education, race, and marital status at time of birth were not associated with subjects reporting cost as a barrier. As survey response rates continue to decline, the importance of assessing the potential impact of nonresponse bias has become more critical. Birth defects research is particularly conducive to nonresponse bias analysis, especially when birth defect registries and birth certificate records are used. Future birth defect studies which use population-based surveillance data and have incomplete participation could benefit from this type of nonresponse bias assessment. Birth Defects Research (Part A) 103:603-609, 2015. © 2015 Wiley Periodicals, Inc.


The Case for Brachytherapy: Why It Deserves a Renaissance.
The recent global events related to the coronavirus disease of 2019 pandemic have significantly changed the medical landscape and led to a shift in oncologic treatment perspectives. There is a renewed focus on preserving treatment outcomes while maintaining medical accessibility and decreasing medical resource utilization. Brachytherapy, which is a vital part of the treatment course of many cancers (particularly prostate and gynecologic cancers), has the ability to deliver hypofractionated radiation and thus shorten treatment time. Studies in the early 2000s demonstrated a decline in brachytherapy usage despite data showing equivalent or even superior treatment outcomes for brachytherapy in disease sites, such as the prostate and cervix. However, newer data suggest that this trend may be reversing. The renewed call for shorter radiation courses based on data showing equivalent outcomes will likely establish hypofractionated radiation as the standard of care across multiple disease sites. With shifting reimbursement, brachytherapy represents the pinnacle in hypofractionated, conformal radiation therapy, and with extensive long-term data in support of the treatment modality brachytherapy is primed for a renaissance.


Uptake of the glutathione conjugate S-(1,2-dichlorovinyl)glutathione by renal basal-lateral membrane vesicles and isolated kidney cells.
Transport of the glutathione S-conjugate, S-(1,2-dichlorovinyl)glutathione (DCVG), was studied in renal basal-lateral membrane vesicles and isolated rat kidney cells. The time course of S-(1,2-dichlorovinyl)glutathione uptake in membrane vesicles exhibited an overshoot in the presence of sodium, indicating transport against a concentration gradient. The initial rate of uptake with membrane potential clamped at 0 mV was stimulated 2.5-fold by an inwardly directed gradient of 100 mM sodium chloride. Hyperpolarization of the membrane potential to -60 mV in the presence of sodium stimulated uptake another 2.7-fold, indicating that cotransport of sodium and S-(1,2-dichlorovinyl)glutathione is electrogenic. Sodium-dependent DCVG uptake was inhibited by glutathione, glutathione disulfide, and gamma-glutamylglutamate, but not by the corresponding cysteine S-conjugate, S-(1,2-dichlorovinyl)cysteine, indicating that the transport system is specific for the gamma-glutamyl moiety. Probenecid was also a potent inhibitor of sodium-dependent uptake. S-(1,2-dichlorovinyl)glutathione inhibited sodium-dependent uptake of glutathione in a concentration-dependent manner. Thus, these results show that uptake of DCVG and glutathione is mediated by the same sodium-coupled system. Uptake of S-(1,2-dichlorovinyl)glutathione was also demonstrated in isolated kidney cells; in the presence of sodium, cells accumulated approximately 4-fold more DCVG than in the absence of sodium. This basal-lateral membrane transport system can enable efficient delivery of circulating S-(1,2-dichlorovinyl)glutathione to kidney cells and may, therefore, contribute to its potent and selective nephrotoxicity. In addition, it suggests that renal clearance of glutathione conjugates may include transport from the blood through epithelial cells into the lumen as well as direct filtration through the glomerulus.


3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release.
We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defined. Here we show that the amplitude of excitatory postsynaptic currents (EPSCs) was reversibly reduced by the NO donors 3-morpholinylsydnoneimine (SIN-1) (1 mM) and spermine NONOate (1 mM). This effect was antagonized by an active peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride, G(i/o)-coupled receptor blockers, N-ethylmaleimide and pertussis toxin, A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, or adenosine deaminase. However, NO-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), or cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on the inhibitory action of SIN-1 on EPSCs. Perfusion of adenosine mimicked and subsequently occluded the action of SIN-1. Inhibition of EPSC amplitude by SIN-1 was associated with an increase in the paired-pulse ratio of EPSCs. Furthermore, SIN reduced the frequency of spontaneous EPSCs without altering their amplitude of distribution. Pretreatment with N-type Ca(2+)-channel blocker omega-conotoxin GVIA selectively blocked SIN-1-induced inhibition of EPSCs. These results suggest that a higher dose of SIN-1 acts presynaptically to elicit a synaptic depression on the RVLM neurons through an inhibition of presynaptic N-type Ca(2+)-channel activity, leading to reduced glutamate release. The presynaptic action of SIN-1 is mediated by the formation of peroxynitrite, which subsequently acts to release adenosine to activate A(1) adenosine receptors.


Differential relieving effects of shikonin and its derivatives on inflammation and mucosal barrier damage caused by ulcerative colitis.
Ulcerative colitis (UC) is one of the most challenging human diseases. Natural shikonin (SK) and its derivatives (with have higher accumulation) isolated from the root of Lithospermum erythrorhizon have numerous beneficial effects, such as wound healing and anti-inflammatory activities. Some researchers have reported that hydroxynaphthoquinone mixture (HM) and SK attenuate the acute UC induced by dextran sulfate sodium (DSS). However, no existing study has systemically investigated the effectiveness of SK and other hydroxynaphthoquinone natural derivative monomers on UC. In this study, mice were treated with SK and its derivatives (25 mg/kg) and mesalazine (200 mg/kg) after DSS administration daily for one week. Disease progression was monitored daily by observing the changes in clinical signs and body weight. Intragastric administration natural single naphthoquinone attenuated the malignant symptoms induced by DSS. SK or its derivatives remarkably suppressed the serum levels of pro-inflammatory cytokines while increasing the inflammatory cytokine interleukin (IL)-10 . Additionally, both SK and alkanin restrained the activities of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) in serum and colonic tissues. SK and its derivatives inhibited the activation of nucleotide binding oligomerization domain-like receptors (NLRP3) inflammasome and NF-κB signaling pathway, thereby relieving the DSS-induced disruption of epithelial tight junction (TJ) in colonic tissues. Our findings shed more lights on the pharmacological efficacy of SK and its derivatives in UC against inflammation and mucosal barrier damage.


Frequency of and risk factors for carbapenem-resistant Enterobacteriaceae.
Introduction. Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent threat in the USA and are associated with adverse clinical and economic outcomes. Several studies have evaluated risk factors for acquiring CRE versus carbapenem-susceptible Enterobacteriaceae, identifying antibiotic use and length of hospital stay as major players. However, no studies have compared risk factors for CRE colonization versus infection.Hypothesis/Gap Statement. Patients with CRE infection will have different risk factors and worse clinical outcomes than patients with CRE colonization.Aim. To assess clinical outcomes in patients with CRE infection versus CRE colonization.Methodology. A retrospective cohort of adult patients admitted between 1 June 2013 and 31 July 2018 with the first positive CRE culture from any source was performed. Patients were divided into two groups: CRE infection versus CRE colonization. Data collected included demographics, comorbidities, past antimicrobial usage and clinical outcomes (length of stay, in-hospital mortality). The primary outcome was infection-related length of stay. Data analysis was performed utilizing SPSS with a two-sided P value of less than 0.05 considered statistically significant.Results. A total of 56 patients were included (32 with infection; 24 with colonization). Baseline characteristics were similar between both groups. Infected patients were more likely to have higher actual body weight compared to colonized patients (P=0.03). CRE-infected patients had a longer infection-related hospital stay [12 days (5-20) and 7.5 days (1-13), respectively; P=0.08], but in-hospital mortality was similar between infected and colonized patients (37.5 and 29.2 %, respectively; P=0.30). Patients with infection were more likely to have previous exposure to levofloxacin (P=0.02) and trimethoprim/sulfamethoxazole (P=0.03) for a median of 9 days compared to those with colonization. The most common source of CRE in infected patients was the blood compared to respiratory sources in colonized patients.Conclusion. CRE infection as opposed to colonization was more common in patients with previous exposure to levofloxacin and trimethoprim/sulfamethoxazole and those with higher actual body weight.


Cophylogenetic analyses of Trachymyrmex ant-fungal specificity: "One to one with some exceptions".
Over the past few decades, large-scale phylogenetic analyses of fungus-gardening ants and their symbiotic fungi have depicted strong concordance among major clades of ants and their symbiotic fungi, yet within clades, fungus sharing is widespread among unrelated ant lineages. Sharing has been explained using a diffuse coevolution model within major clades. Understanding horizontal exchange within clades has been limited by conventional genetic markers that lack both interspecific and geographic variation. To examine whether reports of horizontal exchange were indeed due to symbiont sharing or the result of employing relatively uninformative molecular markers, samples of Trachymyrmex arizonensis and Trachymyrmex pomonae and their fungi were collected from native populations in Arizona and genotyped using conventional marker genes and genome-wide single nucleotide polymorphisms (SNPs). Conventional markers of the fungal symbionts generally exhibited cophylogenetic patterns that were consistent with some symbiont sharing, but most fungal clades had low support. SNP analysis, in contrast, indicated that each ant species exhibited fidelity to its own fungal subclade with only one instance of a colony growing a fungus that was otherwise associated with a different ant species. This evidence supports a pattern of codivergence between Trachymyrmex species and their fungi, and thus a diffuse coevolutionary model may not accurately predict symbiont exchange. These results suggest that fungal sharing across host species in these symbioses may be less extensive than previously thought.


Using a biocompatible diazidecrosslinker to fabricate a robust polyelectrolyte multilayer film with enhanced effects on cell proliferation.
Due to the noncovalent interactions between the layers of polyelectrolyte films, the layer-by-layer assembled multilayered films always face the challenge of low film stiffness and chemical stability under extreme conditions. To handle this issue, we incorporated 4,4'-diazostilbene-2,2'-disulfonic acid disodium salt (DAS) as a crosslinker and subsequently photocrosslinked the layers of a poly(allylamine hydrochloride)/catalase multilayered film. The results showed that DAS could stabilize the prepared film in a manner similar to the traditional cross-linker glutaraldehyde. The multilayered film showed good biocompatibility with a positive effect on cell proliferation. Therefore, by using the commercially available DAS crosslinker, we provide a synthesis-free and biocompatible method to stabilize polyelectrolyte multilayers for broad and significant applications in biological fields, e.g., varying crosslinking density to adjust the mechanical strength of biomaterials, stabilizing susceptible biofilms, or introducing functional groups onto cell membranes.


Trapping single human osteoblast-like cells from a heterogeneous population using a dielectrophoretic microfluidic device.
We describe a system for the isolation, concentration, separation, and recovery of human osteoblast-like cells from a heterogeneous population using dielectrophoretic ring traps. Cells flowing in a microfluidic channel are immobilized inside an electric field cage using negative dielectrophoresis. A planar ring electrode creates a closed trap while repelling surrounding cells. Target cells are identified by fluorescent labeling, and are trapped as they pass across a ring electrode by an automated system. We demonstrate recovery of small populations of human osteoblast-like cells with a purity of 100%, which in turn demonstrates the potential of such a device for cell selection from a heterogeneous population.


[Efficacy and Prognostic Factors of Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia].
To retrospectively analyze the efficacy and complications of our institution's modified nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) in treating intermediate-risk acute myeloid leukemia (AML) - first complete remission (CR1) and prognostic factors. Clinical data of 50 intermediate-risk AML-CR1 patients who underwent matched related NST at the Fifth Medical Center of Chinese People's Liberation Army General Hospital from August 2004 to April 2021 were collected, the hematopoietic recovery, donor engraftment and complications were observed, and overall survival (OS) rate, leukemia-free survival (LFS) rate, treatment-related mortality (TRM), and cumulative relapse rate were calculated. Statistical analysis of factors affecting prognosis was also preformed. The median times for neutrophil and platelet recovery after transplantation were 10 (6-16) and 13 (6-33) days, respectively. One month after transplantation, 22 patients (44%) achieved full donor chimerism (FDC), and 22 patients (44%) achieved mixed chimerism (MC), among whom 18 cases gradually transited to FDC during 1-11 months, 4 cases maintained MC status. The overall incidence of acute graft-versus-host disease (aGVHD) was 36%, with a rate of 18% for grade II-IV aGVHD and a median onset time of 45 (20-70) days after transplantation. The overall incidence of chronic GVHD (cGVHD) was 34%, with 20% and 14% of patients having limited or extensive cGVHD, respectively. The incidence rates of infections, interstitial pneumonia, and hemorrhagic cystitis were 30%, 10%, and 16%, respectively. The 5-year OS rate, LFS rate, TRM, and cumulative relapse rate were 68%, 64%, 16%, and 20%, respectively. The increase of the number of CD34+ cells infused had shortened the recovery time for neutrophils and platelets (r =0.563, r =0.350). The number of CD34+ cells infused significantly influenced the occurrence of extensive cGVHD (OR =1.36, 95%CI : 1.06-1.84, P =0.024). Modified NST is effective in treating intermediate-risk AML-CR1 patients, however, further expansion of sample size is needed to study prognostic factors.


5α-cyprinol sulfate, a bile salt from fish, induces diel vertical migration in Daphnia.
Prey are under selection to minimize predation losses. In aquatic environments, many prey use chemical cues released by predators, which initiate predator avoidance. A prominent example of behavioral predator-avoidance constitutes diel vertical migration (DVM) in the freshwater microcrustacean Daphnia spp., which is induced by chemical cues (kairomones) released by planktivorous fish. In a bioassay-guided approach using liquid chromatography and mass spectrometry, we identified the kairomone from fish incubation water as 5α-cyprinol sulfate inducing DVM in Daphnia at picomolar concentrations. The role of 5α-cyprinol sulfate in lipid digestion in fish explains why from an evolutionary perspective fish has not stopped releasing 5α-cyprinol sulfate despite the disadvantages for the releaser. The identification of the DVM-inducing kairomone enables investigating its spatial and temporal distribution and the underlying molecular mechanism of its perception. Furthermore, it allows to test if fish-mediated inducible defenses in other aquatic invertebrates are triggered by the same compound.


A comparison of three methods to estimate baseline creatinine for RIFLE classification.
A pre-morbid 'baseline' creatinine is required in order to diagnose and stage acute kidney injury (AKI) using the RIFLE classification. Estimation of baseline creatinine by solving the Modification of Diet in Renal Disease (MDRD) equation assuming a glomerular filtration rate of 75 ml/min/1.73 m(2) has been widely used but never validated. We analysed four cohorts of intensive care unit (ICU) patients from three centres (two from Pittsburgh and one from Mayo and Austin). Three cohorts consisted of preselected patients without AKI (Pittsburgh 1 n = 1048, Mayo n = 737, Austin n = 333), and measured creatinine values in these cohorts were taken to represent baseline creatinine values. The last cohort (Pittsburgh 2 n = 468) consisted of unselected ICU patients with baseline creatinine values recorded within 1 year before ICU admission. Using the Pittsburgh 1 cohort, we derived an equation using the same anthropometric variables as the MDRD equation: baseline creatinine = 0.74 - 0.2 (if female) + 0.08 (if black) + 0.003 × age (in years). We then compared measured creatinine in the Mayo and Austin cohorts and recorded creatinine in the Pittsburgh 2 cohort to the estimated creatinine from: (i) the MDRD equation; (ii) our new equation; (iii) a gender-fixed creatinine of 0.8 mg/dl for females and 1.0 mg/dl for males. Using any of the three methods, the median absolute error of the estimates was of the order of 0.1-0.2 mg/dl, and overall accuracy was similar. When the definition of AKI was limited to the severity grades of Injury and Failure, all three methods were able to generate 78-90% reliable results for preselected normal range cohorts, and 63-70% for the unselected cohort of ICU patients. Estimates of incidence of AKI in the critically ill using RIFLE classification can be affected by the bias and limited accuracy of methods to estimate baseline creatinine. Whenever possible, recorded creatinine values should be used as a reference of baseline. The use of the MDRD equation to estimate baseline creatinine when it is unknown may over- or underestimate some mild (Risk) AKI cases but is unlikely to misclassify patients in Injury and Failure.


Acute Type B Dissection Causing Collapse of EVAR Endograft and Iliac Limb Occlusion.
We describe a rare case of acute type B dissection (ATBDs) causing collapse of a previously placed infrarenal stent graft, resulting in acute limb ischemia due to left iliac limb thrombosis in a 59-year-old male. The patient presented with acute back and abdominal discomfort radiating to his back, bilateral buttock stabbing discomfort and left > right thigh and calf rest pain. CT angiography showed a spiral type B dissection with collapse of the proximal portion of the endovascular repair of aortic aneurysm (EVAR) device and left limb occlusion. Urgent treatment with thoracic endovascular aortic repair distal to the left subclavian covered the entry tear and redirected the majority of the flow to the true lumen leading to near immediate expansion of the proximal portion of the EVAR device. After surgical femoral control, balloon embolectomy of the occluded iliac limb was performed and the limb relined. His lower extremity ischemic symptoms resolved, and his abdominal and back pain dissipated. At latest 6-month follow-up, CT angiography shows an intact thoracic endovascular aortic repair stent graft and a widely patent EVAR stent graft, and the patient has no further abdominal, back, or leg symptoms. ATBD causing proximal abdominal EVAR collapse is an extremely rare presentation of false lumen pressurization and can be treated similarly to complicated type B dissection with the goal of restoring true lumen patency.