Children Diagnosed with Auditory Processing Disorder and Their Parents: A Qualitative Study about Perceptions of Living with APD.
Negative psychosocial consequences have been reported for children with auditory processing disorder (APD). The current literature surrounding APD does not sufficiently address the emotional and psychological consequences of living with the disorder. It is recommended that data be collected from multiple sources, including the child living with APD. Subjective reports of the perceptions of children with APD and their families have real-life validity and can inform clinical decisions and guide future research. The aims of this study were to explore the psychosocial consequences of APD as perceived by children with the disorder and their parents. Qualitative cross-sectional study. Thirteen participants were interviewed: six children with APD, aged 10-12 yr, and one parent for each child (in one case, two parents participated in the interview). Semistructured interviews were used to examine the social, emotional, and educational well-being of children with APD. Inductive thematic analysis was conducted to develop themes that illustrated the experiences of living with APD. Three themes were identified forming a causal network conceptual framework that is reciprocal in nature: (1) external factors, (2) internal problems, and (3) coping. The themes revealed how APD impacted negatively on children's psychosocial well-being (internal problems: covert thoughts, overt behaviors) and described the basis for these outcomes (external factors: environmentally based problems, dissatisfaction with support) and the ability of children and their parent(s) to manage the impact of APD (coping: positive, negative). The three themes identified in this research provide a novel understanding of the experience of APD. The themes reflect the psychosocial consequences of external factors that are created internally through "thought" and expressed externally through "behavior." Pathways to support positive coping strategies while discouraging negative coping strategies will enable children to overcome problems and improve their psychosocial well-being.


A mutagenic screen reveals NspS residues important for regulation of Vibrio cholerae biofilm formation.
Biofilm formation in the human intestinal pathogen Vibrio cholerae is in part regulated by norspermidine, spermidine and spermine. V. cholerae senses these polyamines through a signalling pathway consisting of the periplasmic protein, NspS, and the integral membrane c-di-GMP phosphodiesterase MbaA. NspS and MbaA belong to a proposed class of novel signalling systems composed of periplasmic ligand-binding proteins and membrane-bound c-di-GMP phosphodiesterases containing both GGDEF and EAL domains. In this signal transduction pathway, NspS is hypothesized to interact with MbaA in the periplasm to regulate its phosphodiesterase activity. Polyamine binding to NspS likely alters this interaction, leading to the activation or inhibition of biofilm formation depending on the polyamine. The purpose of this study was to determine the amino acids important for NspS function. We performed random mutagenesis of the nspS gene, identified mutant clones deficient in biofilm formation, determined their responsiveness to norspermidine and mapped the location of these residues onto NspS homology models. Single mutants clustered on two lobes of the NspS model, but the majority were found on a single lobe that appeared to be more mobile upon norspermidine binding. We also identified residues in the putative ligand-binding site that may be important for norspermidine binding and interactions with MbaA. Ultimately, our results provide new insights into this novel signalling pathway in V. cholerae and highlight differences between periplasmic binding proteins involved in transport versus signal transduction.


Mutation of a single MalK subunit severely impairs maltose transport activity in Escherichia coli.
The maltose transport system of Escherichia coli, a member of the ABC transport superfamily of proteins, consists of a periplasmic maltose binding protein and a membrane-associated translocation complex that contains two copies of the ATP-binding protein MalK. To examine the need for two nucleotide-binding domains in this transport complex, one of the two MalK subunits was inactivated by site-directed mutagenesis. Complexes with mutations in a single subunit were obtained by attaching a polyhistidine tag to the mutagenized version of MalK and by coexpressing both wild-type MalK and mutant (His)6MalK in the same cell. Hybrid complexes containing one mutant (His)6MalK subunit and one wild-type MalK subunit were separated from those containing two mutant (His)6MalK proteins based on differential affinities for a metal chelate column. Purified transport complexes were reconstituted into proteoliposome vesicles and assayed for maltose transport and ATPase activities. When a conserved lysine residue at position 42 that is involved in ATP binding was replaced with asparagine in both MalK subunits, maltose transport and ATPase activities were reduced to 1% of those of the wild type. When the mutation was present in only one of the two subunits, the complex had 6% of the wild-type activities. Replacement of a conserved histidine residue at position 192 in MalK with arginine generated similar results. It is clear from these results that two functional MalK proteins are required for transport activity and that the two nucleotide-binding domains do not function independently to catalyze transport.


3D Printed Porous Methacrylate/Silica Hybrid Scaffold for Bone Substitution.
Inorganic-organic hybrid biomaterials made with star polymer poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate) and silica, which show promising mechanical properties, are 3D printed as bone substitutes for the first time, by direct ink writing of the sol. Three different inorganic:organic ratios of poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate)-star-SiO2 hybrid inks are printed with pore channels in the range of 100-200 µm. Mechanical properties of the 3D printed scaffolds fall within the range of trabecular bone, and MC3T3 pre-osteoblast cells are able to adhere to the scaffolds in vitro, regardless of their compositions. Osteogenic and angiogenic properties of the hybrid scaffolds are shown using a rat calvarial defect model. Hybrid scaffolds with 40:60 inorganic:organic composition are able to instigate new vascularized bone formation within its pore channels and polarize macrophages toward M2 phenotype. 3D printing inorganic-organic hybrids with sophisticated polymer structure opens up possibilities to produce novel bone graft materials.


Treatment of diabetic foot ulcers with Therapeutic Magnetic Resonance (TMR®) improves the quality of granulation tissue.
Diabetic foot ulcers (DFUs) often result in severely adverse outcomes, such as serious infections, hospitalization, and lower extremity amputations. In last few years, to improve the outcome of DFUs, clinicians and researchers put their attention on the application of low intensity pulsating electro-magnetic fields through Therapeutic Magnetic Resonance (TMR®). In our study, patients with DFUs have been divided into two groups: The Sham Group treated with non-functioning TMR® device, and the Active Group treated with a functioning device. Biopsies were recovered from ulcers before and after a 15-day treatment with both kind of TMR® device. To recognize signs of inflammation or healing process, the harvested biopsies were subjected to histological and molecular analyses. The histological analysis showed a change in cell population after treatment with TMR®: an increase of fibroblasts and endothelial cells with a reduction of inflammatory cells. After TMR® application, the gene expression profile analysis revealed an improvement in extracellular matrix components such as matrix metalloproteinases, collagens and integrins, a reduction in pro-inflammatory interleukins, and an increase in growth factors expression. In conclusion, our research has identified histological and molecular features of reduced inflammation and increased cell proliferation during the wound healing process in response to TMR® application.


Impact of Cannabinoid Compounds on Skin Cancer.
Drugs targeting the endocannabinoid system are of interest as potential systemic chemotherapeutic treatments and for palliative care in cancer. In this context, cannabinoid compounds have been successfully tested as a systemic therapeutic option in preclinical models over the past decades. Recent findings have suggested an essential function of the endocannabinoid system in the homeostasis of various skin functions and indicated that cannabinoids could also be considered for the treatment and prophylaxis of tumour diseases of the skin. Cannabinoids have been shown to exert their anticarcinogenic effects at different levels of skin cancer progression, such as inhibition of tumour growth, proliferation, invasion and angiogenesis, as well as inducing apoptosis and autophagy. This review provides an insight into the current literature on cannabinoid compounds as potential pharmaceuticals for the treatment of melanoma and squamous cell carcinoma.


Effects of the venom of the Brazilian scorpion (Tityus serrulatus) on the compound action potential of the rabbit vagus nerve fibres.
1 The effects of the venom of the scorpion (Tityus serrulatus) on nerve fibres of the rabbit cervical vagus were studied by the single sucrose-gap technique. Scorpion venom (1 microgram/ml) increased irreversibly the duration of the B component of the compound action potential of the vagus nerves, leaving the C component with its normal configuration. Tetrodotoxin (200 nM) suppressed the prolongation of the action potential duration in venom-treated B fibres. 2 At the same concentration (1 microgram/ml), scorpion venom reduced the amplitude and the rate constant of decay of the hyperpolarization produced by tetanic stimulation of non-myelinated nerve fibres. 3 A lower concentration (0.2 micrograms/ml) blocked completely the hyperpolarization of the potassium-activated response. After washing, the potassium-activated response partially recovered its amplitude but there was a significant increase in the time constant of the decay of hyperpolarization. 4 It is suggested that scorpion venom may modify the sodium pumping mechanism within fibres as well as affecting the passive and active sodium permeability systems.


Regulation of 11beta-hydroxysteroid dehydrogenase type II expression in the renal epithelial cells.
The regulation of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2) expression at the level of specific mRNA and 11betaHSD2 protein was investigated in primary culture of renal epithelial cells of the rat. It has been shown that treatment of the SE cells with adenylyl cyclase activator, forskolin, known to stimulate the protein kinase A (PKA) pathway, resulted in an increase in 11betaHSD2 mRNA content in these cells. Semi-quantitative RT-PCR revealed that the effect of forskolin was attenuated by the addition of phorbol ester, tetradecanoyl phorbol acetate (TPA), an activator of the protein kinase C (PKC) pathway, whereas TPA on its own slightly reduced the basal level of 11betaHSD2 expression judging from the content of specific mRNA. Measurements of [35S]-methionine incorporation into immunoprecipitable 11betaHSD2 revealed an increased synthesis of this protein in renal epithelial cells treated with forskolin. Phorbol ester TPA markedly reduced the effect of forskolin on the synthesis of 11betaHSD2 and attenuated the basal level of synthesis of this protein. It is concluded that in renal epithelial cells in primary culture, stimulation of PKA pathway results in the induction of 11betaHSD2 both at a specific mRNA and at a protein level and that this effect is markedly reduced by activation of PKC pathway.


Associations between the COVID-19 pandemic and women's fertility intentions: a multi-country, cross-sectional (I-SHARE) study.
The COVID-19 pandemic, together with the subsequent social distancing measures, could lead to shifts in family and fertility planning. This study aimed to explore the associations between the COVID-19 pandemic and changes in fertility intentions among an international sample of reproductive-aged women. A multi-country, cross-sectional study based on data from 10 672 women aged 18-49 years who participated in the International Sexual Health And REproductive Health (I-SHARE) study, which organised an international online survey between July 2020 and February 2021. Factors associated with changes in fertility intentions were explored using multinomial probit regression models. Cluster-robust standard errors were used to calculate model parameters. Of 10 672 included reproductive-aged women, 14.4% reported changing their fertility intentions due to the pandemic, with 10.2% postponement and 4.2% acceleration. Women who had ever been isolated/quarantined were more likely to postpone their fertility intentions (adjusted odds ratio (AOR)=1.41; 95% CI 1.18 to 1.69) compared with those who had not; women who lived with a steady partner were more likely to want children sooner (AOR=1.57; 95% CI 1.10 to 2.23) compared with those who did not; and those who reported a higher frequency of getting angry, feeling frustrated, or worrying about their finances were more likely to postpone their fertility intentions. The main findings were robust in the sensitivity analyses. Most women who changed fertility intentions because of the pandemic have postponed intentions to expand their families. The pandemic-induced exposures were associated with these postponements.


Respiratory Failure Due to Idiopathic Pneumonia Syndrome in a Pediatric Patient After Recipient-derived Allogeneic Chimeric Antigen Receptor T-Cell Therapy.
Idiopathic pneumonia syndrome (IPS) is a life-threatening complication of hematopoietic cell transplantation, but it is not clearly described following chimeric antigen receptor (CAR) T-cell therapy. We describe a child who developed IPS after receiving tisagenlecleucel for post-hematopoietic cell transplantation relapsed acute lymphoblastic leukemia and had a remarkable improvement after treatment with corticosteroids and etanercept. We discuss the implications of cytokine signaling in IPS and immunologic considerations of allogeneic CAR T cells. We anticipate that the incidence of IPS and other allogeneic phenomena will be observed more often as allogeneic CAR T cells are employed in more varied settings with more mismatched donors.


[Verbal fluency tasks in a Spanish sample of young adults (20-49 years of age): normative data of clustering and switching strategies].
The aim of this study is to establish normative data on phonological and semantic verbal fluency tests, measuring total production of words, clusters and switching of words in a healthy young adult Spanish population. We assessed 53 healthy adults between 20-49 years old (32.8 +/- 9.5) with 8-18 years of formal education (9 +/- 3.3 years). The semantic fluency category included: animals, fruits, clothes and the initial letters F, A, S in 1 minute of time. Clustering and switching strategies were examined and scored according to a protocol elaborated ad hoc by the authors. Pearson correlations between number of "clusters", "switching" and total number of words was used and we evaluated the possible influence of age, years of schooling and gender in each one of the categories in 1 minute and in intervals of 15 seconds. The variable years of formal education was the only demographical factor that significantly influenced semantic verbal fluency (r = 0.43; p = 0.04). Switching and clustering were positively correlated with the number of words generated. Clustering was highly correlated with total number of words generated on semantic fluency (r = 0.846; p < 0.01). In contrast, switching was more highly correlated than clustering with total number of words generated on phonemic fluency (r = 0.864; p < 0.01). Rules for scoring switching and clustering in our population are provided. Optimal fluency performance requires some type of balance between clustering and switching strategies and should be taken into account in studies regarding verbal fluency.


Brain-Machine Interface Control Algorithms.
Motor brain-machine interfaces (BMI) allow subjects to control external devices by modulating their neural activity. BMIs record the neural activity, use a mathematical algorithm to estimate the subject's intended movement, actuate an external device, and provide visual feedback of the generated movement to the subject. A critical component of a BMI system is the control algorithm, termed decoder. Significant progress has been made in the design of BMI decoders in recent years resulting in proficient control in non-human primates and humans. In this review article, we discuss the decoding algorithms developed in the BMI field, with particular focus on recent designs that are informed by closed-loop control ideas. A motor BMI can be modeled as a closed-loop control system, where the controller is the brain, the plant is the prosthetic, the feedback is the biofeedback, and the control command is the neural activity. Additionally, compared to other closed-loop systems, BMIs have various unique properties. Neural activity is noisy and stochastic, and often consists of a sequence of spike trains. Neural representations of movement could be non-stationary and change over time, for example as a result of learning. We review recent decoder designs that take these unique properties into account. We also discuss the opportunities that exist at the interface of control theory, statistical inference, and neuroscience to devise a control-theoretic framework for BMI design and help develop the next-generation BMI control algorithms.


Availability bias in clinical formulation: the first idea that comes to mind.
This study tested whether initial client formulations are based simply on the ideas that come most readily to mind, irrespective of the validity of these ideas. This phenomenon is known in decision theory literature as availability bias. The study tested the influence of two possible sources of availability bias in formulation: (a) theoretical orientation; and (b) a suggestion in a referral letter. Forty-four qualified and 20 trainee clinical psychologists participated in a procedure designed to reflect clinical practice. Clinical materials consisted of a fictional referral letter describing a client with adult attachment difficulties and post-traumatic stress disorder. Participants recalled information from the referral letter, described their areas of further interest and initial hypotheses. Results showed no evidence of an availability bias in clinical formulation as a result of theoretical orientation. Theoretical orientation towards attachment did appear to influence the availability of attachment ideas and predicted clinicians taking a stronger attachment focus when discussing the client. In particular, a self-report measure of theoretical orientation demonstrated high predictive validity. However, orientation towards attachment did not predict bias in the sense of selective recall of attachment information or neglect of alternative psychological frameworks. The study provided an inadequate test of availability bias as a result of a suggestion in the referral letter, possibly due to a ceiling effect, and no conclusions can be drawn as to clinical materials as a potential source of availability bias. The discussion addresses implications for further research and for a scientist-practitioner approach to individual case formulation.


N-[4-(Di-methyl-amino)-benzyl-idene]-4-methyl-aniline.
The mol-ecules of the title compound, C16H18N2, exists in a trans conformation with respect to the C=N bond [1.270 (3) Å]. The least-squares plane of the di-methyl-amino group makes a dihedral angle of 1.3 (2)° with the ring to which it is attached. The dihedral angle between the two aromatic rings is 11.70 (2)°. The crystal structure features weak C-H⋯π inter-actions.


[Influence of disposable diaper dependence on emotional behavior and related factors of preschool-aged children].
Objective: To investigate the influence of disposable diaper dependence (DDD) on emotional behavior and related factors of preschool-aged children. Methods: A total of 3 000 preschool-aged children from 16 kindergartens in Zhengzhou of Henan Province from October 2019 to March 2020 were selected and their parents were investigated by using a basic information questionnaire (including usage of disposable diapers), Strengths and Difficulties Questionnaire (SDQ) and Children's Sleep Questionnaire (PSQ). The differences in baseline and clinical data were compared between the DDD children and normal children, and multiple linear regression models were used to analyze the factors associated with emotional behavior in DDD children. Results: A total of 3 000 questionnaires were distributed and 2 775 (92.50%) were valid. The children ranged in age from 3 to 5 years, including 1 438 boys (51.82%) and 1 337 girls (48.18%). There were 98 (3.53%) children in DDD group and 2 677 (96.47%) children in normal group. The proportion of children living in cities in the DDD group was 58.16%, significantly higher than that of 41.84% in the normal children group (P<0.001). The abnormal detection rate of various factors in SDQ in DDD children, from high to low, were hyperactivity (n=14, 14.29%), peer communication problems (n=12, 12.24%), prosocial behavior (n=11, 11.22%), emotional symptoms (n=10, 10.20%) and conduct problems (n=7, 7.14%). The detection rates of abnormal total difficulty scores in DDD group and normal children were 7.14% (7 cases) and 0.78% (21 cases), respectively, with statistically significant differences (P<0.001). The proportions of emotional symptoms and hyperactivity disorder in DDD group were higher than those in normal group, and the differences were statistically significant (P<0.05). The PSQ score of children in DDD group was 3.01±2.02 which was not significantly different from the PSQ score of the normal group (2.71±2.10, P=0.157). The multi-factor analysis showed that caregiver's education level (β=-1.135,95%CI:-1.910 to -0.359), urinary incontinence (β=2.222, 95%CI: 1.105-3.339), fecal incontinence (β=3.833, 95%CI: 2.691-4.975), urinary and fecal incontinence (β=5.522, 95%CI: 4.145-6.899), and recurrent urinary tract infections(β=3.523,95%CI: 1.798-5.248)were the independent influencing factors of emotional behavioral problems in DDD children (P<0.05). Conclusions: Children with DDD are more likely to have emotional behavioral problems than normal children. Caregiver's education level, urinary incontinence and recurrent urinary tract infections were influencing factors of emotional behavioral problems in DDD children.


Issues and trends in nursing service administration education.
The Council on Graduate Education for Administration in Nursing (CGEAN) was established to further the development and improvement of graduate education for administration in nursing. The Council seeks to identify the nature and direction of education for administration in nursing in various healthcare systems, providing guidelines for programs offering administration. A major goal of CGEAN is facilitating dialogue between nursing service administrators and graduate level educators who are engaged in teaching and research related to administration in nursing. This column, sponsored by members of the Council, will analyze and respond to position statements and trends related to the delivery of health services and graduate education for administrators in nursing.


Prospective study of polydimethylsiloxane vs dextranomer/hyaluronic acid injection for treatment of vesicoureteral reflux.
Endoscopic injection of a bulking agent is becoming a first-line treatment for low grade vesicoureteral reflux. We prospectively compared the efficacy of 2 such products commercially available in Canada. A total of 275 patients with documented grade I to V vesicoureteral reflux were prospectively enrolled in a comparative study between April 2005 and February 2011 to be randomly treated endoscopically with either polydimethylsiloxane (Macroplastique®) or dextranomer/hyaluronic acid copolymer (Deflux®). Of the ureters 202 were treated with polydimethylsiloxane and 197 with dextranomer/hyaluronic acid copolymer. Patients were followed with voiding cystourethrography at 3 months and renal ultrasonography at 3 months and at 1 year. Median followup was 4.3 years. The primary outcome was surgical success (resolution vs nonresolution), and secondary outcomes included occurrence of adverse events. Vesicoureteral reflux was fully corrected in 182 of 202 ureters (90%) treated with polydimethylsiloxane, compared to 159 of 197 (81%) treated with dextranomer/hyaluronic acid copolymer (p <0.05). Obstruction was found in 5 ureters. Univariate and multivariate analyses did not allow identification of any characteristics that could explain the significant difference in the success rates except for the type of product used. We present the largest known prospective evaluation comparing 2 bulking agents for the treatment of vesicoureteral reflux. Endoscopic injection of polydimethylsiloxane resulted in a better success rate than dextranomer/hyaluronic acid copolymer. The rate of resolution obtained with the latter is lower than those previously published due to the inclusion of high grade reflux.


Genetic and epigenetic regulation of human lincRNA gene expression.
Large intergenic noncoding RNAs (lincRNAs) are still poorly functionally characterized. We analyzed the genetic and epigenetic regulation of human lincRNA expression in the GenCord collection by using three cell types from 195 unrelated European individuals. We detected a considerable number of cis expression quantitative trait loci (cis-eQTLs) and demonstrated that the genetic regulation of lincRNA expression is independent of the regulation of neighboring protein-coding genes. lincRNAs have relatively more cis-eQTLs than do equally expressed protein-coding genes with the same exon number. lincRNA cis-eQTLs are located closer to transcription start sites (TSSs) and their effect sizes are higher than cis-eQTLs found for protein-coding genes, suggesting that lincRNA expression levels are less constrained than that of protein-coding genes. Additionally, lincRNA cis-eQTLs can influence the expression level of nearby protein-coding genes and thus could be considered as QTLs for enhancer activity. Enrichment of expressed lincRNA promoters in enhancer marks provides an additional argument for the involvement of lincRNAs in the regulation of transcription in cis. By investigating the epigenetic regulation of lincRNAs, we observed both positive and negative correlations between DNA methylation and gene expression (expression quantitative trait methylation [eQTMs]), as expected, and found that the landscapes of passive and active roles of DNA methylation in gene regulation are similar to protein-coding genes. However, lincRNA eQTMs are located closer to TSSs than are protein-coding gene eQTMs. These similarities and differences in genetic and epigenetic regulation between lincRNAs and protein-coding genes contribute to the elucidation of potential functions of lincRNAs.


Assessing model uncertainty of bioaccumulation models by combining chemical space visualization with a process-based diagnostic approach.
As models describing human exposure to organic chemicals gain wider use in chemical risk assessment and management, it becomes important to understand their uncertainty. Although evaluation of parameter sensitivity/uncertainty is increasingly common, model uncertainty is rarely assessed. When it is, the assessment is generally limited to a handful of chemicals. In this study, a strategy for more comprehensive model uncertainty assessment was developed. A regulatory model (EUSES) was compared with a research model based on more recent science. Predicted human intake was used as the model end point. Chemical space visualization techniques showed that the extent of disagreement between the models varied strongly with chemical partitioning properties. For each region of disagreement, the primary human exposure vector was determined. The differences between the models' process algorithms describing these exposure vectors were identified and evaluated. The equilibrium assumption for root crops in EUSES caused overestimations in daily intake of superhydrophobic chemicals (log K(OW) > 11, log K(OA) > 10), whereas EUSES's approach to calculating bioaccumulation in fish prey resulted in underestimations for hydrophobic compounds (log K(OW) ∼ 6-8). Uptake of hydrophilic chemicals from soil and bioaccumulation of superhydrophobic chemicals in zooplankton were identified as important research areas to enable further reduction of model uncertainty in bioaccumulation models.


Secretion of alpha 1-proteinase inhibitor by cultured rat alveolar macrophages.
Alpha 1-proteinase inhibitor, metabolically labeled with 35S, was detected in concentrated culture medium of rat alveolar macrophages by immunoelectrophoresis autoradiography. The metabolically labeled macrophage alpha 1-proteinase inhibitor had the same electrophoretic mobility as did pure rat serum alpha 1-proteinase inhibitor. Moreover, monospecific antiserum to rat serum alpha 1-proteinase inhibitor precipitated a 35S-labeled protein from macrophage culture supernates, and this protein was shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis to have a molecular weight close to that of rat serum alpha 1-proteinase inhibitor. Cycloheximide (an inhibitor of protein synthesis) at a concentration of 0.50 micrograms/ml, inhibited secretion of labeled inhibitor. This, cultured rat alveolar macrophages secrete detectable concentrations of a proteinase inhibitor believed to play a major role in lung defense.


Comparison of static headspace, headspace solid phase microextraction, headspace sorptive extraction, and direct thermal desorption techniques on chemical composition of French olive oils.
Static headspace (SHS), headspace solid phase microextraction (HS-SPME), headspace sorptive extraction (HSSE), and direct thermal desorption (DTD) were applied to the analysis of four French virgin olive oils from Corsica. More than 60 compounds were isolated and characterized by GC-RI and GC-MS. SHS was not suited to the characterization of olive oil volatile compounds because of low sensitivity. The SPME and HSSE techniques were successfully applied to olive oil headspace analysis. Both methods allow the characterization of volatile compounds (mainly C(6) aldehydes and alcohols), which contribute significantly to the "green" flavor note of virgin olive oils. The PDMS stir bar showed a higher concentration capacity than a DVB/CAR/PDMS SPME fiber due to the higher volume of polymeric coating. DTD was a very good tool for extracting volatile and especially semivolatile compounds, such as sesquiterpenes, but requires a significant investment like that for HSSE. Finally, SPME may be a more appropriate technique for routine quality control due to its operational simplicity, repeatability, and low cost.


Nystagmus as an early ocular alteration in Machado-Joseph disease (MJD/SCA3).
Machado-Joseph disease (MJD), also named spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia worldwide. Although nystagmus is one of the most frequently reported ocular alterations in MJD patients its behaviour during the course of the disease, namely in its early stages, has only recently started to be investigated. The main goal of this work was to characterize the frequency of nystagmus in symptomatic and presymptomatic carriers of the MJD mutation, and investigate its usefulness as an early indicator of the disease. We conducted an observational study of Azorean MJD family members, comprising a total of 158 subjects which underwent neurological evaluation. Sixty eight were clinically and molecularly diagnosed with MJD, 48 were confirmed asymptomatic carriers and 42 were confirmed non-carriers of the MJD mutation. The frequency of nystagmus was calculated for the 3 groups. Nystagmus was present in 88% of the MJD patients. Seventeen percent of the at-risk subjects with a carrier result in the molecular test and none of the 42 individuals who received a non-carrier test result displayed nystagmus (p < 0.006). Although not reaching statistical significance, symptomatic subjects showing nystagmus had a tendency for a higher length of the CAG tract in the expanded allele, when compared to individuals who did not have nystagmus. The frequency of nystagmus in asymptomatic carriers and its absence in non-carriers of the mutation, suggests that nystagmus may appear before gait disturbance and can thus be considered an early sign of MJD.


Utilizing CAD/CAM to Measure Total Occlusal Convergence of Preclinical Dental Students' Crown Preparations.
Traditionally, faculty assessment of preclinical crown preparations occurs by visualizing preparation features. However, contemporary CAD/CAM tools have the ability to more precisely evaluate preparation features, which is beneficial for psychomotor development. Taper is one of the most challenging features to objectively assess. The aim of this study was twofold: first, to validate the software's ability to distinguish differences in taper, and second, to compare traditional faculty assessment with digital assessment of taper. In the study, 30 all-metal crown preparations were created on typodont teeth with varying degrees of axial reduction and placed into three groups based on amount of taper (minimum, moderate, or excessive). Each tooth was scanned with the D4D scanner, and the taper was analyzed using E4D Compare. A second experiment used 50 crown preparations of tooth #19, which were done as a formative exercise. A comparison faculty assessment with CAD/CAM assessments of taper was performed. The results showed that when the taper was varied, E4D Compare was able to distinguish those differences; the Tukey post-hoc test revealed a significant difference (p=0.001). The qualitative analysis comparing faculty grading to CAD/CAM grading demonstrated a trend for CAD/CAM to be more precise. These results suggest that E4D Compare is an effective means of quantitatively measuring the amount of total occlusal convergence or taper on a crown preparation and that digital assessment may be more precise than faculty visual grading.


[Research progress on exposure to disinfectants and chronic obstructive pulmonary disease].
Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease. In recent years, the cumulative prevalence of COPD has been increasing. There are many etiologies and predisposing factors related to COPD, among which occupational risk factors play an important role. Recent studies have found an association between exposure to disinfectants and their products and airway inflammation, respiratory symptoms, and the development of COPD. During the period of COVID-19, disinfection has become an important link in the prevention and control of COVID-19, and the use rate of disinfectants has increased significantly. Therefore, this review summarizes the effects of disinfectants and their products on COPD, discusses the possible mechanisms, and puts forward suggestions for rational use of disinfectants according to the current situation and the development status of disinfectants.


Preparation, characterization and immune response of chitosan‑gold loaded Myricaria germanica polysaccharide.
In this study, a novel nano-drug delivery system (CS-Au NPs) based on gold nanoparticles (Au NPs) and chitosan (CS) that modified Myricaria germanica polysaccharide (MGP) was developed to enhance immune responses. At a MGP to CS Au ratio of 5:1, CS-Au-MGP NPs had a loading capacity of 78.27 %. The structure of CS-Au-MGP NPs were characterized by Transmission electron microscope, TEM-energy dispersive spectroscopy mapping, Fourier transform infrared spectroscopy, X-ray photoelectron spectrometer, particle size and zeta-potential distribution analysis. Under weakly acidic conditions, in vitro CS-Au-MGP NPs release was most effective. In vivo showed that co-immunization with CS-Au-MGP NPs and PCV2 significantly increased the organ index of the thymus, spleen, and liver in mice. Additionally, CS-Au-MGP NPs significantly increased the levels of IgG, IgG1, and IgG2a antibodies, as well as IFN-γ and IL-6 levels. Furthermore, the CS-Au-MGP NPs promoted proliferation of spleen T and B lymphocytes, increased the number of CD3+, CD4+, and CD8+ cells, and increased the CD4+/CD8+ T cell ratio. Meanwhile, CS-Au-MGP NPs remarkably TLR2/IRAK4 pathway activation and mRNA levels of cytokines (IFN-γ and IL-6). These results indicated that CS-Au-MGP NPs could enhance the immune activity, and it could be potentially used as an MGP delivery system for the induction of strong immune responses.


Short versus conventional term glucocorticoid therapy in acute exacerbation of chronic obstructive pulmonary disease - the "REDUCE" trial.
International guidelines advocate a 10 to 14-day course of systemic glucocorticoid therapy in the management of COPD exacerbations. The optimal duration of therapy is unknown and glucocorticoids have serious adverse effects. The aim of this trial is to demonstrate non-inferiority of a five-day compared to a 14-day course of systemic glucocorticoids with respect to COPD outcome, thereby significantly reducing steroid exposure and side effects in patients with COPD exacerbations. This is a randomised, placebo-controlled, non-inferiority multicentre trial. Patients with acute COPD exacerbation are randomised to receive 40 mg of prednisone-equivalent daily for 14 days (conventional arm) or glucocorticoid treatment for 5 days, followed by placebo for another 9 days (intervention arm). Follow-up is 180 days. The primary endpoint is time to next exacerbation. Secondary endpoints include cumulative glucocorticoid dose, time to open-label glucocorticoid therapy, glucocorticoid-associated side effects and complications, duration of hospital stay, death, change in FEV1, need for assisted ventilation, clinical outcome assessed by standardised questionnaires, and suppression of the hypothalamic-pituitary-adrenal axis. Mean age (± SD) of patients who finished the study was 70 ± 11 years. 12% had mild or moderate disease, whereas severe and very severe stages were found in 30 and 58%, respectively. At the time of inclusion, 20% of patients were under treatment with systemic glucocorticoids. If the strategy of significantly reducing cumulative exposure to glucocorticoids while taking advantage of their beneficial short-term effects proves to be successful, it will warrant a change in common glucocorticoid prescription practice, thereby improving the management of COPD.


An evaluation of practice-based interprofessional education initiatives involving service users.
There is little published evidence regarding the impact of service-user focused interprofessional education in the practice setting. This article reports evaluative case studies of two practice-based interprofessional initiatives, in which service users played a central role. These initiatives formed part of the Trent Universities Interprofessional Learning in Practice (TUILIP) project ( http://tuilip.hwb.shu.ac.uk ), a collaboration between Sheffield Hallam University and the University of Nottingham. Practice settings were an acute mental health service and a community organisation offering care and services to adults with learning disabilities. Interprofessional initiatives were developed by facilitators, and empirically studied at each site. Facilitators, managers, practitioners, students and service users took part in interviews and focus groups to discuss their perceptions of the initiative in their practice setting. The study revealed participants' perceptions of the projects' aims, process and outcomes, factors which facilitated success or proved challenging, and their impact upon individuals, clinical practice and the organisations involved.


Composition, structure, and function of heart teams: a joint position paper of the ACVC, EAPCI, EACTS, and EACTA focused on the management of patients with complex coronary artery disease requiring myocardial revascularization.
Contemporary cardiovascular medicine is complex, dynamic, and interactive. Therefore, multidisciplinary dialogue between different specialists is required to deliver optimal and patient-centred care. This has led to the concept of explicit collaborations of different specialists caring for patients with complex cardiovascular diseases-that is 'heart teams'. These teams are particularly valuable to minimize referral bias and improve guideline adherence as so to be responsive to patient preferences, needs, and values but may be challenging to coordinate, especially in the acute setting. This position paper-jointly developed by four cardiovascular associations-is intended to provide conceptual and practical considerations for the composition, structure, and function of multidisciplinary teams. It focuses on patients with complex coronary artery diseases in both elective and urgent setting and provide guidance on how to implement the heart team both in chronic and in acute coronary syndromes patients, including cases with mechanical complications and haemodynamic instability; it also discuss strategies for clear and transparent patient communication and provision of a patient-centric approach. Finally, gaps in evidence and research perspectives in this context are discussed.


Smoking and health implications of a change in the federal cigarette excise tax.
Cigarette excise tax changes ultimately influence the health of smokers and potential smokers. An 8-cent decrease in the federal tax is estimated to induce up to 1 million young persons, ages 12 to 25 years, to smoke, when without the tax decrease they would not. Hundreds of thousands of Americans older than 25 years would also start or continue smoking as a result of the tax decrease. Conversely, an 8- to 16-cent tax increase would encourage from 1 to 2 million young persons and 800,000 to 1.5 million adults to quit smoking or not to start. Thus, a tax increase could prevent hundreds of thousands of premature smoking-related deaths, while a tax decrease would contribute to the disease burden of tobacco. Intentionally or inadvertently, the federal cigarette excise tax is a powerful tool of public health policy.


The roles of neoadjuvant radiotherapy and lymphadenectomy in the treatment of esophageal adenocarcinoma.
Using a population-based registry, we evaluated the impact of neoadjuvant radiotherapy and lymphadenectomy on survival of patients undergoing curative-intent surgery for esophageal adenocarcinoma (EAC). Surveillance, Epidemiology, and End Results (SEER) data for patients with esophageal adenocarcinoma from 1988 to 2005 were queried. Patients undergoing curative operations were included. Treatment was stratified between no radiotherapy, neoadjuvant versus adjuvant radiotherapy, and adequate (> or = 18 lymph nodes) versus inadequate (<18 lymph nodes) lymphadenectomy. Univariate and multivariate analysis were performed to determine median survival (MST) and cause-specific survival (CSS). Overall, 4,224 patients underwent surgical extirpation with curative intent for EAC in the study period. MST and CSS for the entire cohort were 25 and 31 months, respectively. Multivariate analysis showed age <65 years, well-differentiated tumor, local disease, negative lymph node status, adequate lymphadenectomy, and neoadjuvant radiotherapy to be independent predictors of improved survival. In node-positive patients, the greatest survival benefit was seen in patients who received both neoadjuvant radiotherapy and adequate lymphadenectomy (MST = 32 months, CSS = 34 months). The lymph node ratio (LNR) for adequately dissected patients treated with neoadjuvant radiotherapy was 0.17, which is <0.2, the established LNR cutoff that is an independent predictor of improved survival. The survival benefit of neoadjuvant treatment is additive to that of adequate lymphadenectomy. There is a cooperative survival benefit for neoadjuvant radiation and adequate lymphadenectomy in patients with node-positive EAC. Both are independent predictors of improved survival. Patients who have clinically node-positive disease should undergo both neoadjuvant radiation and adequate lymphadenectomy to ensure optimal outcome.


Transforming growth factor-beta inhibits lipopolysaccharide-stimulated expression of inflammatory cytokines in mouse macrophages through downregulation of activation protein 1 and CD14 receptor expression.
The septic shock that occurs in gram-negative infections is caused by a cascade of inflammatory cytokines. Several studies showed that transforming growth factor-beta1 (TGF-beta1) inhibits this septic shock through suppression of expression of the lipopolysaccharide (LPS)-induced inflammatory cytokines. In this study, we investigated whether TGF-beta1 inhibition of LPS-induced expression of inflammatory cytokines in the septic shock results from downregulation of LPS-stimulated expression of CD14, an LPS receptor. TGF-beta1 markedly inhibited LPS stimulation of CD14 mRNA and protein levels in mouse macrophages. LPS-stimulated expression of CD14 was dramatically inhibited by addition of antisense, but not sense, c-fos and c-jun oligonucleotides. Since TGF-beta1 pretreatment inhibited LPS-stimulated expression of c-fos and c-jun genes and also the binding of nuclear proteins to the consensus sequence of the binding site for activation protein 1 (AP-1), a heterodimer of c-Fos and c-Jun, in the cells, TGF-beta1 inhibition of CD14 expression may be a consequence of downregulation of AP-1. LPS-stimulated expression of interleukin-1beta and tumor necrosis factor alpha genes in the cells was inhibited by addition of CD14 antisense oligonucleotide. Also, TGF-beta1 inhibited the LPS-stimulated production of both inflammatory cytokines by the macrophages. In addition, TGF-beta1 inhibited expression of the two cytokines in several organs of mice receiving LPS. Thus, our results suggest that TGF-beta1 inhibition of LPS-stimulated inflammatory responses resulted from downregulation of CD14 and also may be a possible mechanism of TGF-beta1 inhibition of LPS-induced septic shock.


[Understanding unsuccessful attempts to quit smoking: a social phenomenology approach].
The aim of this paper is to understand the experience of smokers in view of unsuccessful attempts to quit smoking. This study is based on social phenomenology. Between November and December of 2014, nine interviews were conducted with people that had attempted to quit smoking. The content of these interviews was analyzed and discussed based on the related literature. Unsuccessful attempts to quit smoking are related to tobacco addiction; cigarettes are seen as a support to cope with everyday stressful situations. Attempts to quit the smoking habits were based on the need of health improvement and insistence of family and friends. Smokers reported the use of habit cessation strategies learned in support groups, but they also express expectation of specialized psychological support. The study points out the need to expand the strategies of approaching smokers, and reinforcing psychological support in order to achieve success in the attempt to quit smoking.


Acupuncture Enhances Gastrointestinal Motility and Improves Autonomic Nervous Function in Patients with Septic Gastrointestinal Dysfunction.
Gastrointestinal dysfunction (GD) is a common complication after endotoxemia, which can further aggravate the progress of infection. Acupuncture uses metal needles of different shapes and techniques to stimulate specific points on the human body, which are effective in treating various diseases, including gastrointestinal diseases. We aimed at exploring the clinical effect of acupuncture on the recovery of visceral sensation, proximal gastric compliance, and autonomic nervous function in patients with septic GD. A total of 73 sepsis with GD patients were selected using modified single section ultrasonography combined with clinical symptoms in the First People's Hospital of Lanzhou City during 2019. The participants were randomly allocated to routine-treatment (control group) and study group receiving acupuncture. The indexes before and after treatment included gastric residue, gastric dilatation, pressure and volume, gastric compliance, autonomic nerve function, APACHE II score, and infection index were measured and compared. Before treatment, there was no significant difference in the basic information of the two groups, including gastric volume and pressure, gastric residue, gastric compliance, autonomic nerve function, and APACHE II score. After treatment, the maximum gastric volume and pressure, gastric residue, and APACHE II score of the two groups were significantly improved (P < 0.05). In addition, the maximum gastric volume and pressure of the study group were significantly higher, while gastric residual, autonomic nerve function, and APACHE II were significantly lower than those of the control group (P < 0.05). However, our results showed that acupuncture did not further reduce inflammatory markers, including white blood cells, C-reactive protein, and procalcitonin. To sum up, on the basis of basic treatment, the application of acupuncture can further improve the clinical symptoms of GD in patients with sepsis, enhance gastrointestinal motility, and improve autonomic nervous function, which is worthy of clinical application and promotion.


CBD: a biomarker database for colorectal cancer.
Colorectal cancer (CRC) biomarker database (CBD) was established based on 870 identified CRC biomarkers and their relevant information from 1115 original articles in PubMed published from 1986 to 2017. In this version of the CBD, CRC biomarker data were collected, sorted, displayed and analysed. The CBD with the credible contents as a powerful and time-saving tool provide more comprehensive and accurate information for further CRC biomarker research. The CBD was constructed under MySQL server. HTML, PHP and JavaScript languages have been used to implement the web interface. The Apache was selected as HTTP server. All of these web operations were implemented under the Windows system. The CBD could provide to users the multiple individual biomarker information and categorized into the biological category, source and application of biomarkers; the experiment methods, results, authors and publication resources; the research region, the average age of cohort, gender, race, the number of tumours, tumour location and stage. We only collect data from the articles with clear and credible results to prove the biomarkers are useful in the diagnosis, treatment or prognosis of CRC. The CBD can also provide a professional platform to researchers who are interested in CRC research to communicate, exchange their research ideas and further design high-quality research in CRC. They can submit their new findings to our database via the submission page and communicate with us in the CBD.Database URL: http://sysbio.suda.edu.cn/CBD/.


Polypeptide hormones and the prostate.
Results presented in this paper demonstrate that both insulin and prolactin have direct effects on the growth and functions of prostatic epithelium. They also act on the prostate indirectly by potentiating the effects of testosterone on these cells. Both are capable of inducing cell multiplication and increasing the activity of ornithine decarboxylase in cells. However, the intracellular events which follow the interaction of these hormones with the cell membrane receptors are not clearly understood. Little is known at the present time about the specific effects of insulin and prolactin on prostatic growth regulation and function and about their interactions with other protein and steroid hormones. A considerable amount of further research is needed to establish the basic influences of insulin and prolactin on the prostate. This inquiry is essential before the role of these hormones in normal and abnormal growth of the prostate can be understood.


The affected sib method. I. Statistical features of the affected sib-pair method.
The distribution of the number of HLA haplotypes shared by sibs affected with the same HLA-linked disease can be used to obtain information on the genetics of the disease. Since the inception of the use of sib-pair methods for the analysis of the HLA-associated diseases, the question has been raised of how to include families with more than two affected sibs in the sib-pair analysis. This paper presents appropriate weighting schemes. A procedure for estimating the frequency of the disease allele in the general population, under the assumptions of single-allele recessive, additive, dominant and intermediate models, with negligible recombination (theta = 0) between the disease-predisposing gene and the HLA region, and no selective disadvantage of the trait, is also given. Cluster-sampling techniques are used in the analysis.


Coverage of climate change in introductory biology textbooks, 1970-2019.
Climate change is a potent threat to human society, biodiversity, and ecosystem stability. Yet a 2021 Gallup poll found that only 43% of Americans see climate change as a serious threat over their lifetimes. In this study, we analyze college biology textbook coverage of climate change from 1970 to 2019. We focus on four aspects for content analysis: 1) the amount of coverage, determined by counting the number of sentences within the climate change passage, 2) the start location of the passage in the book, 3) the categorization of sentences as addressing a description of the greenhouse effect, impacts of global warming, or actions to ameliorate climate change, and 4) the presentation of data in figures. We analyzed 57 textbooks. Our findings show that coverage of climate change has continually increased, although the greatest increase occurred during the 1990s despite the growing threats of climate change. The position of the climate change passage moved further back in the book, from the last 15% to the last 2.5% of pages. Over time, coverage shifted from a description of the greenhouse effect to focus mostly on effects of climate change; the most addressed impact was shifting ecosystems. Sentences dedicated to actionable solutions to climate change peaked in the 1990s at over 15% of the passage, then decreased in recent decades to 3%. Data figures present only global temperatures and CO2 levels prior to the year 2000, then include photographic evidence and changes to species distributions after 2000. We hope this study will alert curriculum designers and instructors to consider implicit messages communicated in climate change lessons.


Two gamma-ray sources and ancient guest stars.
On the basis of the fact that the youngest neutron stars such as the Crab pulsar and the Vela pulsar emit strong gamma-ray radiation, it is suggested that a few gamma-ray sources may be identified with young compact sources formed in the events of guest stars. Two such sources, 2CG 353+16 and 2CG 054+01, are identified with guest stars observed in the 14th century B.C. and A.D. 1230, respectively.


Evaluation the effect of 50 and 100 mg doses of Cuminum cyminum essential oil on glycemic indices, insulin resistance and serum inflammatory factors on patients with diabetes type II: A double-blind randomized placebo-controlled clinical trial.
The purpose of this study was to evaluate the effect of 50 and 100 mg doses of green cumin essential oil on glycemic and inflammatory indices in patients with diabetes type II. In this randomized double-blind placebo-controlled clinical trial, subjects were divided into three groups after selecting them randomly according to the inclusion criteria: 1 - Cuminum cyminum capsule (100 mg/day,n = 33), 2 - C. cyminum capsule (50 mg/day, n = 33), and 3 - placebo (n = 33). Before and after 8 weeks of intervention, a blood sample was taken. The findings demonstrated that the mean of the FBS, glycosylated hemoglobin (HgA1c) and the serum levels of insulin were significantly decreased and insulin sensitivity (HOMA-IR) was significantly increased in the groups receiving the 100 mg supplement (P < 0.001) and 50 mg supplement, but these indices were increased in the placebo group. The mean serum levels of TNF-α and hsCRP were significantly decreased, and serum levels of adiponectin was significantly increased at the end of the study in the groups receiving 100 mg (P < 0.001) and 50 mg (P = 0.008) supplement as well as in the group who received the placebo. There were no significant change in HOMA-B and QUICKI as insulin resistance parameters. Administering C. cyminum supplement in patients with diabetes type II may decrease the serum levels of insulin, FBS, and glycosylated hemoglobin and also the inflammatory indices of TNF-α and hsCRP and increased the serum levels of adiponectin. In addition it may control the complications of diabetes type II in these patients.


The associations between physical activity, screen time and weight from 6 to 14 yrs: the Raine Study.
To examine the strength and direction of the relationship between physical activity level, screen use and BMI in a cohort at ages 6, 8, 10 and 14 yrs as part of a prospective longitudinal cohort study. The sample comprised 1403 males and females who participated in the follow-up survey at 14 yrs of age between 2003 and 2005. Exploratory structural equation modelling was used to examine the interrelationships between physical activity level, BMI and screen time at 6, 8, 10 and 14 yrs. Predictors of BMI at 6, 8, 10 and 14 yrs explained 1.3, 76.1, 80.1 and 73.1 percent of the variances, respectively, with previous BMI the largest predictor [χ(2)=43.082, df=36, p=194]. Increased screen time predicted higher BMI and lower physical activity at 8 and 10 yrs but not 14 yrs. At 14 yrs, physical activity predicted BMI. Sedentary patterns of behaviour in early childhood were predictive of later and concurrent obesity, whereas physical activity was predictive of obesity in adolescence. Different intervention targets are required for children and adolescents.


Radiosynthesis and in vivo evaluation of 11C-labeled BMS-193885 and its desmethyl analog as PET tracers for neuropeptide Y1 receptors.
Neuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms. NPY Yl receptor (NPY Y1-R) is the most widely studied NPY receptor, and is involved in many of these processes. BMS-193885 (1) was previously developed as a potent and selective NPY Y1-R antagonist, which has good systemic bioavailability and brain penetration. To evaluate the characteristics of 1 in vivo, we developed 11C-labeled BMS-193885 ([11C]1) and its desmethyl analog ([11C]2) for potential use as two new positron emission tomography (PET) tracers. [11C]1 was synthesized from [11C]methyl iodide using 2. [11C]2 was synthesized from [11C]phosgene using its aniline and amine derivatives. The mean ± S.D. decay-corrected radiochemical yields of [11C]1 and [11C]2 from 11CO2 at the end of radionuclide production were 23 ± 3.2% (n = 6) and 24 ± 1.5% (n = 4), respectively. In biodistribution on mice, radioactivity levels for both tracers were relatively high in the kidney, small intestine, and liver at 60 min post-injection. The radioactivity levels in the kidney, lung, and spleen of mice at 30 min post-injection with [11C]1 were significantly reduced by pretreatment with 1 (10 mg/kg), and levels of [11C]1 in the brain of mice were significantly increased by pretreatment with the P-glycoprotein and breast cancer resistance protein inhibitor elacridar (10 mg/kg). In metabolite analysis using mouse plasma, [11C]1 and [11C]2 were rapidly metabolized within 30 min post-injection, and [11C]1 was mainly metabolized into unlabeled 2 and radiolabeled components. [11C]1 and [11C]2 were successfully synthesized with sufficient amount of radioactivity and high quality for use in vivo. Our study of [11C]1 and its desmethyl analog [11C]2 was useful in that it helped to elucidate the in vivo characteristics of 1.


Effect of L-arginine on collagen of high flow-induced pulmonary arterial remodeling.
Pulmonary hypertension (PH) is a common complication of congenital heart disease and pulmonary vascular structural remodeling due to the high pulmonary blood flow is considered as the key pathologic process. In the present study the effects of L-arginine on the collagen metabolism of pulmonary arteries in rats with high pulmonary blood flow-induced PH were investigated to elucidate its mechanism. The rat model of PH was established with an abdominal aorta and inferior vena cava shunt. L-arginine (1 g/kg per day) was given directly into the stomachs of the rats with the shunt (L-arginine+shunt group) and 11 weeks later, the pulmonary hemodynamics were studied. Collagen I and collagen III expressions were detected by immunohistochemical assay. The expressions of procollagen I mRNA, procollagen III mRNA, the tissue inhibitor of metalloproteinase-1 mRNA and the matrix metalloproteinase-1 mRNA were detected by in situ hybridization. The expressions of pulmonary artery collagen I, collagen III, procollagen I mRNA and procollagen III mRNA in the shunt rats were obviously elevated compared with the control rats (p<0.01). The positive signals were mainly located in the media and adventitia of median and small pulmonary arteries. The expressions of the pulmonary artery tissue inhibitor of metalloproteinase-1 mRNA, metalloproteinase-1 mRNA and the ratio of tissue inhibitor of metalloproteinase-1/metalloproteinase-1 were elevated in the shunt rats (p<0.01). However, the expressions of pulmonary artery collagen I, collagen III, procollagen I mRNA and procollagen III mRNA were significantly reduced in the shunt rats of the L-arginine group (p<0.01). L-arginine also downregulated the expressions of tissue inhibitor of metalloproteinase-1 mRNA and metalloproteinase-1 mRNA, as well as the ratio of tissue inhibitor of metalloproteinase-1/metalloproteinase-1 (p<0.05). L-arginine can reduce the synthesis of extracellular matrix-collagen and increase its degradation, thus having an important modulating effect on pulmonary vascular matrix remodeling induced by high pulmonary blood flow.


S-amlodipine plus chlorthalidone vs. S-amlodipine plus telmisartan in hypertensive patients unresponsive to amlodipine monotherapy: study protocol for a randomized controlled trial.
The efficacy of a combination of a calcium channel blocker (CCB) plus chlorthalidone (diuretic) versus a CCB plus an angiotensin receptor blocker (ARB) in patients not responding to CCB monotherapy has not been evaluated previously. We plan to compare the efficacy and safety of S-amlodipine (CCB) plus chlorthalidone versus S-amlodipine plus telmisartan (ARB) combinations among hypertension patients unresponsive to amlodipine monotherapy. This study is a prospective, randomized, double-blind, multicenter, parallel, non-inferiority phase 4 study. Hypertension patients who have been treated with amlodipine (5 mg) or S-amlodipine (2.5 mg) monotherapy for ≥2 weeks and whose mean diastolic blood pressure (DBP) is greater than 90 mmHg will be randomized to either S-amlodipine (2.5 mg) plus chlorthalidone (25 mg) or S-amlodipine (2.5 mg) plus telmisartan (40 mg) therapy. The primary efficacy endpoint is mean sitting DBP change after 12 weeks of treatment. The study objective is to prove the non-inferiority of the former combination (test drug) as compared to the latter one (control) with a non-inferiority margin of 3 mmHg in mean DBP change. The secondary endpoints are 6-week DBP change, 6- and 12-week sitting systolic BP (SBP) change, and the attainment of the target BP (SBP < 140 mmHg or DBP < 90 mmHg). Urine albumin, albumin/creatinine ratio (ACR), pulse wave velocity, central BP, 24-h ambulatory BP monitoring, and body fluid composition analysis will be performed at each hospital's discretion. The sample size was estimated as 170 in total with 1:1 randomization. This is the first study comparing the efficacy of a CCB plus chlorthalidone versus a CCB plus an ARB in patients who are not responding to CCB single therapy. The study result will help clinicians to choose between chlorthalidone and telmisartan in CCB-unresponsive patients. ClinicalTrials.gov , NCT03226340. Registered on 2 December 2015.


Healthspan Maintenance and Prevention of Parkinson's-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans.
Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer's and Parkinson's disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.


Maternal perceptions of supervision in pre-school-aged children: a qualitative approach to understanding differences between families living in affluent and disadvantaged areas.
To explore maternal perceptions of supervision and childhood unintentional injury in order to develop understanding and explanation for differences in unintentional injury rates between an advantaged and disadvantaged area. Unintentional injury is the second cause of mortality and a significant cause of morbidity in the zero to four year age group. Children living in socio-economic disadvantage are at a greater risk of unintentional injury than their more affluent counter-parts. Qualitative study using semi-structured interviews; content data analysis was undertaken. Participants included 37 mothers with a child aged less than five years; 16 living in an area of disadvantage (and high rate of childhood unintentional injury) and 21 living in an advantaged area (and low rate of childhood unintentional injury). Parents in both areas described the importance of parental supervision in reducing child unintentional injury risks. Parents in both areas used listening as a supervision strategy. Parents in both areas described how 'when the child goes quiet' that is a cue for them to make a visual check on the child. Listening was used more for boys than girls in both areas, but parents in the advantaged area used listening as a supervision strategy more frequently than those in the disadvantaged area. Parents described supervision strategies as being shaped by child character and age rather than child gender. Parents in both areas described similar strategies for managing distractions. An important difference was found with regard to older siblings; parents living in the advantaged area described older siblings as an injury risk to younger children. Parents in the disadvantaged area described older siblings as providing some supervision for younger children. Parents living in disadvantaged circumstances may face greater challenges with regard to supervision than parents living in advantaged circumstances and this may partly explain differences in injury risk.


Voronoi deformation density (VDD) charges: Assessment of the Mulliken, Bader, Hirshfeld, Weinhold, and VDD methods for charge analysis.
We present the Voronoi Deformation Density (VDD) method for computing atomic charges. The VDD method does not explicitly use the basis functions but calculates the amount of electronic density that flows to or from a certain atom due to bond formation by spatial integration of the deformation density over the atomic Voronoi cell. We compare our method to the well-known Mulliken, Hirshfeld, Bader, and Weinhold [Natural Population Analysis (NPA)] charges for a variety of biological, organic, and inorganic molecules. The Mulliken charges are (again) shown to be useless due to heavy basis set dependency, and the Bader charges (and often also the NPA charges) are not realistic, yielding too extreme values that suggest much ionic character even in the case of covalent bonds. The Hirshfeld and VDD charges, which prove to be numerically very similar, are to be recommended because they yield chemically meaningful charges. We stress the need to use spatial integration over an atomic domain to get rid of basis set dependency, and the need to integrate the deformation density in order to obtain a realistic picture of the charge rearrangement upon bonding. An asset of the VDD charges is the transparency of the approach owing to the simple geometric partitioning of space. The deformation density based charges prove to conform to chemical experience.


A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride in humans.
(+)-Cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) is a newly developed drug as a platelet-activating factor receptor antagonist. The disposition of SM-12502 was investigated in plasma from 28 healthy Japanese volunteers after a single i.v. administration of SM-12502. Three of 28 subjects were phenotyped as poor metabolizers (PMs). Genomic DNAs from three extensive metabolizers or three PMs of SM-12502 were analyzed by Southern blot analysis with CYP2A6 cDNA as a probe. DNAs from three PMs digested with SacI and SphI showed novel restriction fragment length polymorphisms (RFLPs); one type without 4.5- and 2.6-kb fragments and a weak density of a 6.4-kb fragment (E-type), and the other type without 7.1- and 5.5-kb restriction fragments (C'-type) as compared with three extensive metabolizers, respectively. The deletional restriction fragments specific to three PMs in SacI- and SphI-RFLPs were identified as CYP2A6. Using polymerase chain reaction-RFLP analyses of the gene from the three PMs, we found that the exon 1, exon 8, and exon 9 in CYP2A6 were absent. A new RFLP characterized by SacI and SphI was found to be due to the entire gene deletion of the three exons and was associated with the decreased metabolism of SM-12502. This study demonstrates a new deletional allele in the human CYP2A6 gene responsible for the poor metabolic phenotype of SM-12502.


Zebrafish Cxcr4a determines the proliferative response to Hedgehog signalling.
The Hedgehog (Hh) pathway plays dual roles in proliferation and patterning during embryonic development, but the mechanism(s) that distinguish the mitogenic and patterning activities of Hh signalling are not fully understood. An additional level of complexity is provided by the observation that Hh signalling can both promote and inhibit cell proliferation. One model to account for this apparent paradox is that Hh signalling primarily regulates cell cycle kinetics, such that activation of Hh signalling promotes fast cycling and an earlier cell cycle exit. Here we report that activation of Hh signalling promotes endodermal cell proliferation but inhibits proliferation in neighbouring non-endodermal cells, suggesting that the cell cycle kinetics model is insufficient to account for the opposing proliferative responses to Hh signalling. We show that expression of the chemokine receptor Cxcr4a is a critical parameter that determines the proliferative response to Hh signalling, and that loss of Cxcr4a function attenuates the transcription of cell cycle regulator targets of Hh signalling without affecting general transcriptional targets. We show that Cxcr4a inhibits PKA activity independently of Hh signalling, and propose that Cxcr4a enhances Hh-dependent proliferation by promoting the activity of Gli1. Our results indicate that Cxcr4a is required for Hh-dependent cell proliferation but not for Hh-dependent patterning, and suggest that the parallel activation of Cxcr4a is required to modulate the Hh pathway to distinguish between patterning and proliferation.


Early effects of caffeinated and decaffeinated coffee on subjective state and gender differences.
Some previous studies have demonstrated an early effect of caffeine administration on subjective state, but none of them has explored its existence after the administration of decaffeinated coffee, or the possible differences depending on the gender and circadian typology of the subjects. The aim of the present work is to investigate the early effects (10-30 min post-consumption) of a single low dose of caffeine (100 mg) and decaffeinated coffee on sleepiness, subjective activation and affect using a realistic design. The influence of gender and circadian typology is also explored. A randomized double-blind informed placebo controlled procedure was applied to 688 healthy undergraduate volunteers, mean age 22.03+/-2.21 years, 238 men and 450 women. Measures were recorded before and after beverage consumption (10, 20 and 30 min), in two experimental sessions: morning 11:00-13:00 h or afternoon 16:00-18:00 h. Caffeine administration induced arousing effects (lesser somnolence and greater activation) in all post-consumption records, while the effects of decaffeinated drink were only apparent at 10 min. Caffeine effects were greater in men, and the decaffeinated beverage produced greater effects in women. Circadian typology only showed effects for time of day (morning/afternoon) related with rhythmic expression. Future works should study more accurately the early effect of coffee beverages and the influence of gender, using other parameters which have proven to be sensitive to their administration. The effect of several caffeine doses should also be studied.


Comparison of the effectiveness of intravenous fentanyl versus caudal epidural in neonates undergoing tracheoesophageal fistula surgeries.
Caudal epidural has become an inseparable part of pediatric pain relief as it depresses the stress response better than any other form of analgesia, resulting in the reduction in the need for systemic opioids; in addition, it facilitates early recovery and promotes good postoperative respiratory functions. To evaluate the effectiveness of epidural analgesia in neonates undergoing tracheoesophageal fistula repair in terms of requirement of perioperative fentanyl opioid, postoperative neonatal infant pain score (NIPS), on-table extubation, duration of intubation, reintubation, perioperative hemodynamic response, and any other side effects. A comparative, prospective, single-blind, randomized trial on 30 neonates scheduled for tracheoesophageal surgeries were randomly allocated to two groups: group I: neonates receiving caudal epidural block with ropivacaine 0.2%, 1 mg/kg bolus followed by infusion 0.1 mg/kg/h; group II: neonates receiving initial intravenous [IV] fentanyl 1 ug/kg and maintenance with 0.5 μg/kg/h IV bolus. None of the neonates received opioids in group I. There were statistically significant differences in the mean NIPS at 30, 60, 90, 120 150, and 240-min intervals between group I and group II. Further, 80% of neonates were extubated in group 1 compared to 50% in group II, which was statistically significant (P = 0.025). The duration of intubation was more in group II compared to group I, with a suggestive significance of P = 0.093. Caudal epidural infusion provides adequate perioperative analgesia, promotes rapid weaning from the ventilator, and contributes to a successful outcome.


Internalization of rabies virus glycoprotein differs between pathogenic and attenuated virus strains.
The zoonotic rabies virus (RABV) is a non-segmented negative-sense RNA virus classified within the family Rhabdoviridae, and is the most common aetiological agent responsible for fatal rabies disease. The RABV glycoprotein (G) forms trimeric spikes that protrude from RABV virions and mediate virus attachment, entry and spread, and is a major determinant of RABV pathogenesis. A range of RABV strains exist that are highly pathogenic in part due to their ability to evade host immune detection. However, some strains are disease-attenuated and can be cleared by host defences. A detailed molecular understanding of how strain variation relates to pathogenesis is currently lacking. Here, we reveal key differences in the trafficking profiles of RABV-G proteins from the challenge virus standard strain (CVS-11) and a highly attenuated vaccine strain SAD-B19 (SAD). We show that CVS-G traffics to the cell surface and undergoes rapid internalization through both clathrin- and cholesterol-dependent endocytic pathways. In contrast, SAD-G remains resident at the plasma membrane and internalizes at a significantly slower rate. Through engineering hybrids of CVS-G and SAD-G, we show that the cytoplasmic tail of CVS-G is the key determinant of these different internalization profiles. Alanine scanning further revealed that mutation of Y497 in CVS-G (H497 in SAD-G) could reduce the rate of internalization to SAD-G levels. Together, these data reveal new phenotypic differences between CVS-G and SAD-G proteins that may contribute to altered in vivo pathogenicity.


Can e-mail messages between patients and physicians be patient-centered?
This study explores the extent to which e-mail messages between patients and physicians mimic the communication dynamics of traditional medical dialogue and its fulfillment of communication functions. Eight volunteers drawn from a larger study of e-mail users agreed to supply copies of their last 5 e-mail messages with their physicians and the physician replies. Seventy-four e-mail messages (40 patient and 34 physician) were provided and coded using the Roter Interactive Analysis System. The study found that physicians' e-mails are shorter and more direct than those of patients, averaging half the number of statements (7 vs. 14; p < .02) and words (62 vs. 121; p < .02). Whereas 72% of physician and 59% of patient statements were devoted to information exchange, the remaining communication is characterized as expressing and responding to emotions and acting to build a therapeutic partnership. Comparisons between e-mail and with face-to-face communication show many similarities in the address of these tasks. The authors concluded that e-mail accomplishes informational tasks but is also a vehicle for emotional support and partnership. The patterns of e-mail exchange appear similar to those of in-person visits and can be used by physicians in a patient-centered manner. E-mail has the potential to support the doctor-patient relationship by providing a medium through which patients can express worries and concerns and physicians can be patient-centered in response.


Hemoglobin levels and clinical outcomes after extracorporeal circulation auxiliary to open heart surgery: a retrospective cohort study.
Extracorporeal circulation auxiliary to open heart surgery is a common procedure used to treat heart diseases. However, the optimal transfusion strategy for patients undergoing this surgery remains a subject of debate. This study aims to investigate the association between hemoglobin levels and clinical outcomes in patients undergoing extracorporeal circulation auxiliary to open heart surgery, with the ultimate goal of improving surgical success rates and enhancing patients' quality of life. A retrospective analysis was conducted on data from the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2) database, including 4144 patients. The patients were categorized into five groups based on their minimum hemoglobin levels during hospitalization. Baseline characteristics, clinical scores, laboratory results, and clinical outcome data were collected. Statistical analyses utilized descriptive statistics, ANOVA or Kruskal-Wallis tests, Kaplan-Meier method, and Log-rank test. The results revealed a significant correlation between hemoglobin levels and in-hospital mortality, as well as mortality rates at 30 days, 60 days, and 180 days (p < 0.001). Patients with lower hemoglobin levels exhibited higher mortality rates. However, once hemoglobin levels exceeded 7g/dL, no significant difference in mortality rates was observed (p = 0.557). Additionally, lower hemoglobin levels were associated with prolonged hospital stay, ICU admission time, and mechanical ventilation time (p < 0.001). Furthermore, hemoglobin levels were significantly correlated with complication risk, norepinephrine dosage, and red blood cell transfusion volume (p < 0.001). However, there was no significant difference among the groups in terms of major complications, specifically sepsis (p > 0.05). The study highlights the importance of managing hemoglobin levels in patients undergoing heart surgery with extracorporeal circulation. Hemoglobin levels can serve as valuable indicators for predicting clinical outcomes and guiding treatment decisions. Physicians should carefully consider hemoglobin levels to optimize transfusion strategies and improve postoperative patient outcomes. Further research and intervention studies are warranted to validate and implement these findings in clinical practice.


Left ventricular function and remodeling after myocardial infarction in aging rats.
Adaptations of the aging left ventricle (LV) to hemodynamic overload are functionally and structurally distinct from those of the young organism. This study describes the influence of aging on LV hemodynamics and remodeling late after myocardial infarction (MI) in Fischer 344 Brown Norway rats. In sham rats at 23 mo, LV weight, myocyte cross-sectional area (CSA), and myocardial fibrosis were increased, whereas LV dP/dt, LV relaxation, and maximal LV systolic function declined with respect to younger rats (7, 12, and 18 mo of age). Isometric myocardial function was evaluated in papillary muscles of 12- and 23-mo-old sham rats. Myocardial systolic function was decreased in older rats. To determine how aging affects LV function and remodeling after MI, rats were infarcted at 7 and 18 mo of age and were studied 5 mo later. Infarct size was similar in each group. Right ventricular weight, LV end-diastolic pressure, and volume index were increased, whereas LV dP/dt, peak cardiac index, and peak developed LV pressure declined after MI. However, there were no significant differences between young and older rats in any variable of LV systolic function or remodeling after MI. Myocyte CSA increased in younger rats after MI but was unchanged in 23-mo-old rats. After MI, myocardial fibrosis was significantly increased from baseline only in younger rats. The negative interaction of aging and MI on myocyte hypertrophy and fibrosis was highly significant. The findings indicate that baseline LV and myocradial function decline with age. In the aging rat after MI, despite limited compensatory hypertrophy and more advanced baseline myocardial fibrosis, the long-term functional and structural adaptations to MI are similar to those of the mature adult heart.


Ejaculatory strategies associated with experience of losing.
Modulation of behaviours as a result of fighting experience has been observed in many animals and can influence pre-copulatory sexual selection. This study investigated how fighting experience affects ejaculatory strategies. In male flour beetles, Gnatocerus cornutus, experience of losing a fight decreases a male's aggressiveness for up to 4 days. We found that males losing a fight show increased ejaculatory investment, but there was no ejaculatory modulation owing to winning. However, the increase in ejaculate investment following a loss was no longer observed after 5 days. These results indicate that males adjust their investment in sperm competition according to their experience, and that fighting experience can significantly influence pre- and post-copulatory reproductive tactics.


Hypertension and atherosclerosis.
Membrane phospholipase C (PLC) activation is induced by the interaction of numerous vasoactive hormones and growth factors with their receptors. Two products are liberated: inositol triphosphate (IP3) and diacyglycerol (DG). The first product liberates intracellular calcium from its stores in the sarcoplasmic reticulum and the second one activates a phosphokinase, which triggers a transmembrane Na+/H+ exchange. A cascade of metabolic events secondary to these chemical changes impinges on the expression of nuclear proto-oncogenes, which determines cell growth. Studies conducted in spontaneously hypertensive rats (SHRs) have shown that PLC is hyperreactive to various agonists and that the phenomenon is present within a variety of cells, fibroblasts, platelets, and myocytes. Therefore, it is likely that hypertension in SHRs is characterized by a diffuse and intrinsic cellular defect that cannot be considered a consequence of the hemodynamic changes of hypertension. On the one hand, enhanced intracellular calcium mobilization may play a role in arterial tone and contraction whereas, on the other hand, enhanced activation of proto-oncogenes, myc, fos, and jun, may be involved in the mechanisms of arteriosclerosis. The pattern of an evolution towards arterial cell proliferation with acquisition of a secretory phenotype with collagen production was indeed observed in cultured cells from the arterial wall.


MIRROR DISPLAY IN THE SQUIRREL MONKEY, SAIMIRI SCIUREUS.
Male squirrel monkeys may display the erect phallus under various conditions of courtship, aggression, and salutation. One variety will display consistently to its reflection in a mirror. Such display has a typical pattern and can sometimes be triggered by reflection of but one eye. A mirror display test has beenz designed for experimentation on the brain.


Experimental obstruction to aqueous outflow by pigment particles in living monkeys.
Pigment particles (1 X 10(6)/microliters) isolated from the iris and ciliary body of enucleated cynomolgus monkey eyes were infused into the anterior chamber of seven living cynomolgus monkeys and aqueous humor outflow facility determined by the two-step constant-pressure perfusion technique. Outflow facility acutely decreased 64% in the experimental pigment perfused eyes compared to a 76% increase in the sham-manipulated fellow eyes (P less than 0.001). However, when next measured 1 wk later, facility in the pigment perfused eyes had returned to baseline levels. Repetitive pigment perfusions similarly failed to produce any long-term abnormality in outflow facility. Gonioscopically, a well-defined band of pigment was observed in the trabecular meshwork, which decreased in density with time. Scanning and transmission electron microscopy documented pigment particle phagocytosis by trabecular endothelial cells and macrophages. Forty-two and 105 days after pigment infusion the trabecular meshwork was normal morphologically, and, despite an observed decrease in trabecular pigmentation, morphometry failed to reveal a decrease in trabecular meshwork cellularity in experimental compared to control eyes. These results suggest that factors other than, or in addition to, pigment particle accumulation in the trabecular meshwork must be involved in the mechanism of human pigmentary glaucoma.


PD-L1 Expression in Ampullary Adenocarcinoma.
Ampullary adenocarcinoma is a rare neoplasm often treated by the complex Whipple's procedure. Several histological factors predict poor prognosis including pancreatobiliary morphology, presence of lymphovascular, perineural invasion and local or distant metastasis. Systemic therapy with gemcitabine, 5-fluorouracil regimens are given with variable benefits. Immunotherapy checkpoint inhibitors have shown beneficial anti-tumor effects in several carcinomas, the most remarkable being in non-small cell lung cancer. Administration of these novel drugs is based on immunohistochemical expression (which may or may not be indicative of response to therapy) along with meticulous decision making by the multidisciplinary team. Immunohistochemistry (IHC) is an effective means of immune marker demonstration and has been used in various tumor types for predictive and prognostic purposes. PD-L1 IHC (clone E1L3N) was applied in 101 cases of ampullary adenocarcinoma. Tumor infiltrating lymphocytes were also evaluated. The immunoreactivity was assessed and categorized into following staining thresholds: <1%, <5%, <10% and ≥10% for tumor cells (membranous and/or cytoplasmic staining pattern), and 5% and 10% cut-offs for immune cells. We found that at a 10% cut-off, 73.3% (74/101) patients were men (P = .006) older than 50 years of age (P < .001) presenting with a tumor measuring <3 cm (P = .001). It was significantly associated with intestinal differentiation (P = .004) and grade 1 tumors (P = .001). Twelve patients presented with recurrence as well (P = .03). In the context of ampullary adenocarcinoma, this study highlights the positivity observed with the PD-L1 IHC clone E1L3N at different thresholds, with the particularly stronger associations being evident at a 10% cut-off.


Use of injectable calcium phosphate cement for fracture fixation: a review.
Injectable osteoconductive calcium phosphate cements have been introduced as an adjunct to internal fixation for treating selected fractures. These cements harden without producing much heat, develop compressive strength, and are remodeled slowly in vivo. The main purpose of the cement is to fill voids in metaphyseal bone, thereby reducing the need for bone graft, but cements also may improve the holding strength around metal devices in osteoporotic bone. Several bioactive cements are being developed. One of these cements, Skeletal Repair System, is available in Europe and has been approved by the United States Food and Drug Administration for use in selected distal radius fractures. Cadaveric studies have shown that using Skeletal Repair System cement with conventional metal fixation in certain fractures of the distal radius, tibial plateau, proximal femur, and calcaneus can produce better stability, stiffness, and strength than metal fixation alone. Early clinical results have shown reduced time to full weightbearing when cement has been used for augmentation of tibial plateau and calcaneal fractures, more rapid gain of strength and range of motion when used in distal radius fractures, and improved stability in certain hip fractures. Bioactive cements in general also may prove useful in vertebroplasty.


Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator.
Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male and female subjects (50-79 years of age) were randomized in a placebo- and active-controlled, four-way cross-over study. Each subject received evening administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in separate treatment phases of 4 days. Simulated driving performance was assessed after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard deviation of the lateral position (SDLP) was the main outcome. On both days, with zopiclone, SDLP increased significantly compared with placebo, which confirmed sensitivity of the simulator. With daridorexant, on day 2, the placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm (0.46-3.93) and 4.43 cm (2.72-6.15) for 50 and 100 mg, respectively. On day 5, SDLP values for both daridorexant doses were significantly below the prespecified threshold of impairment (2.6 cm) and statistically not different from placebo. Daridorexant showed a lower self-rated driving quality and higher effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects, daridorexant impaired simulated driving after initial but not after repeated dosing. Subjects should be cautioned about driving until they know how daridorexant affects them.


Mechanisms of inactivation of p14ARF, p15INK4b, and p16INK4a genes in human esophageal squamous cell carcinoma.
The 9p21 gene cluster, harboring growth suppressive genes p14ARF, p15INK4b, and p16INK4a, is one of the major aberration hotspots in human cancers. It was shown that p14ARF and p16INK4a play active roles in the p53 and Rb tumor suppressive pathways, respectively, and p15INK4b is a mediator of the extracellular growth inhibition signals. To elucidate specific targets and aberrations affecting this subchromosomal region, we constructed a detailed alteration map of the 9p21 gene cluster by analyzing homozygous deletion, hypermethylation, and mutation of the p14ARF, p15INK4b, and p16INK4a genes individually in 40 esophageal squamous cell carcinomas (ESCCs) and compared the genetic alterations with mRNA expression in 18 of these samples. We detected aberrant promoter methylation of the p16INK4a gene in 16 (40%), of p14ARF in 6 (15%), and of p15INK4b in 5 (12.5%) tumor samples. Most p16INK4a methylations were exclusive, whereas all but one of the p14ARF/p15INK4b methylations were accompanied by concomitant p16INK4a methylation. We detected homozygous deletion of p16INK4a in 7 (17.5%), of p14ARF-E1beta in 13 (33%), and of p15INK4b in 16 (40%) tumor samples. Most deletions occurred exclusively on the E1beta-p15INK4b loci. Two samples contained p14ARF deletion but with p16INK4a and p15INK4b intact. No mutation was detected in the p14ARF and p16INK4a genes. Comparative RT-PCR showed good concordance between suppressed mRNA expression and genetic alteration for p15INK4b and p16INK4a genes in the 18 frozen samples, whereas 5 of the 13 cases with suppressed p14ARF mRNA expression contained no detectable E1beta alteration but aberrations in the p16INK4a locus. Our results show that in human ESCCs, p14ARF is a primary target of homozygous deletion along with p15INK4b, whereas p16INK4a is the hotspot of hypermethylation of the 9p21 gene cluster. The frequent inactivation of the p14ARF and p16INK4a genes may be an important mechanism for the dysfunction of both the Rb and p53 growth regulation pathways during ESCC development.


Development of employment indicators to advance the quality of spinal cord injury rehabilitation care: SCI-High Project.
Employment and Return to Work (RTW) rates following spinal cord injury/disease (SCI/D) are low due to individual and impairments characteristics, secondary health conditions, social and environmental barriers, prior work experience, workplace supports and resources, and physical or psychosocial work demands. To improve RTW, the SCI-High Project team developed a set of Employment structure, process, and outcome indicators for adults with SCI/D in the first 18 months after rehabilitation admission. A pan-Canadian Working Group of diverse stakeholders: (1) defined the Employment construct; (2) conducted a systematic search of available outcomes measures; (3) constructed a Driver diagram summarizing factors associated with employment. Subsequent facilitated meetings allowed for the creation of structure and process indicators, and the selection of outcome indicators. The structure indicator is the proportion of SCI/D rehabilitation programs with an employment resource center. The process indicator is the proportion of SCI/D rehabilitation inpatients who receive an employment assessment during inpatient rehabilitation. The intermediary and final outcome measures are the Readiness for Return-to-Work Scale (RRTW) and Work Productivity and Activity Impairment (WPAI). Scale A of the RRTW for those who are unemployed and Scale B of RRTW and WPAI will be used for those who are employed. This framework of Employment indicators intends to support the RTW needs of persons with SCI/D by ensuring that rehabilitation professionals provide opportunities to explore RTW within the first 18 months after rehab admission. Increased employment rates have the potential to enhance the wellbeing, health, and longevity of individuals with SCI/D.


Scientific Problem Solving and Brain Symmetry Index: An exploratory EEG study.
Scientific problem solving has recently attracted fixation in the field of cognitive neuroscience and science education. Until now, there is very little evidence on the brain dynamics of scientific problem-solving processes. In this study, we were interested in exploring whether Brain Symmetry Index (BSI) would be an EEG index to reveal neural information. The present EEG study used two levels of complexity physics problems to research the neural mechanism of problem solving. Results indicated that relatively greater BSI found during difficult problem solving on the prefrontal theta and beta band. However, smaller BSI on the occipital alpha was found when solving difficult problems. There was no significant relationship between BSI and self-effort evaluation. The current study proposes an EEG index - BSI to reflect underlying brain functional characteristic.