CRISPR/Cas9 knockout of MTA1 enhanced RANKL-induced osteoclastogenesis in RAW264.7 cells partly via increasing ROS activities.
Metastasis-associated protein 1 (MTA1), belonging to metastasis-associated proteins (MTA) family, which are integral parts of nucleosome remodelling and histone deacetylation (NuRD) complexes. However, the effect of MTA1 on osteoclastogenesis is unknown. Currently, the regulation of MTA1 in osteoclastogenesis was reported for the first time. MTA1 knockout cells (KO) were established by CRISPR/Cas9 genome editing. RAW264.7 cells with WT and KO group were stimulated independently by RANKL to differentiate into mature osteoclasts. Further, western blotting and quantitative qRT-PCR were used to explore the effect of MTA1 on the expression of osteoclast-associated genes (including CTSK, MMP9, c-Fos and NFATc1) during osteoclastogenesis. Moreover, the effects of MTA1 on the expression of reactive oxygen species (ROS) in osteoclastogenesis was determined by 2', 7' -dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Nuclear translocation of Nrf2 was assessed by immunofluorescence staining and western blotting. Our results indicated that the MTA1 deletion group could differentiate into osteoclasts with larger volume and more TRAP positive. In addition, compared with WT group, KO group cells generated more actin rings. Mechanistically, the loss of MTA1 increased the expression of osteoclast-specific markers, including c-Fos, NFATc1, CTSK and MMP-9. Furthermore, the results of qRT-PCR and western blotting showed that MTA1 deficiency reduced basal Nrf2 expression and inhibited Nrf2-mediated expression of related antioxidant enzymes. Immunofluorescence staining demonstrated that MTA1 deficiency inhibited Nrf2 nuclear translocation. Taken together, the above increased basal and RANKL-induced intracellular ROS levels, leading to enhanced osteoclast formation.


Intracellular location of triple helix formation of collagen. Enzyme probe studies.
Primary cultures of chick embryo fibroblasts were used to study ribosomal events in the processing of procollagen. Polyribosomes from radiolabeled cells were subjected to enzyme probe analysis using collagenase and pepsin digestion to assess both the amount of procollagen present on the polyribosomes and the conformation of the molecule. The peptides rendered dialyzable by each enzyme treatment were analyzed for radioactive proline and hydroxyproline. Approximately 30% of the nascent proteins were collagenous. Although some hydroxyproline was dialyzable in the pepsin-treated material, a low ratio of hydroxyproline to proline (0.04) indicated that considerable amounts of noncollagenous proteins were digested. Polyribosomal material, previously treated with pepsin, was digested with purified collagenase. Similarly, collagenase-digested polyribosomes were treated with pepsin. The pepsin pretreatment released noncollagenous protein and served to purify the remaining ribosomally bound pepsin-resistant collagenous protein. Collagenase treatment of the pepsin-resistant ribosomally bound peptides released peptides with a hydroxyproline to proline ratio of 0.65, indicating that considerable hydroxylation of proline occurs on nascent ribosomally bound procollagen. This finding combined with the well documented stabilizing effect of hydroxyproline on the collagen triple helix and the demonstrated resistance of ribosomally bound procollagen to pepsin digestion indicates that the collagen triple helix may well form on the polyribosome.


Randomised controlled trial of the effects of increased energy intake on menstrual recovery in exercising women with menstrual disturbances: the 'REFUEL' study.
Does increased daily energy intake lead to menstrual recovery in exercising women with oligomenorrhoea (Oligo) or amenorrhoea (Amen)? A modest increase in daily energy intake (330 ± 65 kcal/day; 18 ± 4%) is sufficient to induce menstrual recovery in exercising women with Oligo/Amen. Optimal energy availability is critical for normal reproductive function, but the magnitude of increased energy intake necessary for menstrual recovery in exercising women, along with the associated metabolic changes, is not known. The REFUEL study (trial # NCT00392873) is the first randomised controlled trial to assess the effectiveness of 12 months of increased energy intake on menstrual function in 76 exercising women with menstrual disturbances. Participants were randomised (block method) to increase energy intake 20-40% above baseline energy needs (Oligo/Amen + Cal, n = 40) or maintain energy intake (Oligo/Amen Control, n = 36). The study was performed from 2006 to 2014. Participants were Amen and Oligo exercising women (age = 21.0 ± 0.3 years, BMI = 20.8 ± 0.2 kg/m2, body fat = 24.7 ± 0.6%) recruited from two universities. Detailed assessment of menstrual function was performed using logs and measures of daily urinary ovarian steroids. Body composition and metabolic outcomes were assessed every 3 months. Using an intent-to-treat analysis, the Oligo/Amen + Cal group was more likely to experience menses during the intervention than the Oligo/Amen Control group (P = 0.002; hazard ratio [CI] = 1.91 [1.27, 2.89]). In the intent-to-treat analysis, the Oligo/Amen + Cal group demonstrated a greater increase in energy intake, body weight, percent body fat and total triiodothyronine (TT3) compared to the Oligo/Amen Control group (P < 0.05). In a subgroup analysis where n = 22 participants were excluded (ambiguous baseline menstrual cycle, insufficient time in intervention for menstrual recovery classification), 64% of the Oligo/Amen + Cal group exhibited improved menstrual function compared with 19% in the Oligo/Amen Control group (χ2, P = 0.001). While we had a greater than expected dropout rate for the 12-month intervention, it was comparable to other shorter interventions of 3-6 months in duration. Menstrual recovery defined herein does not account for quality of recovery. Expanding upon findings in shorter, non-randomised studies, a modest increase in daily energy intake (330 ± 65 kcal/day; 18 ± 4%) is sufficient to induce menstrual recovery in exercising women with Oligo/Amen. Improved metabolism, as demonstrated by a modest increase in body weight (4.9%), percent body fat (13%) and TT3 (16%), was associated with menstrual recovery. This research was supported by the U.S. Department of Defense: U.S. Army Medical Research and Material Command (Grant PR054531). Additional research assistance provided by the Penn State Clinical Research Center was supported by the National Center for Advancing Translation Sciences, National Institutes of Health, through Grant UL1 TR002014. M.P.O. was supported in part by the Loretta Anne Rogers Chair in Eating Disorders at University of Toronto and University Health Network. All authors report no conflict of interest. NCT00392873. October 2006. September 2006.


Factors associated with the age of natural menopause and menopausal symptoms in Chinese women.
To investigate the factors associated with the age of natural menopause and menopausal symptoms in a large population of Chinese middle-aged women. In this cross-sectional study, a total of 20,275 women (40-65 years) attending health screening in Jiangsu Province of China were enrolled. A structured questionnaire was used to collect data of demographics, menopausal status, chronic diseases, reproductive history, etc. Also we evaluated the severity of menopausal symptoms by Kupperman menopause index (KMI). Menopausal age and scorings of Kupperman menopause index. The overall median age at natural menopause was 50 years. Lower educational level, poor economic status, lower body mass index (BMI), age at menarche less than 14 years, nulliparity and smoking were associated with earlier onset of natural menopause (P<0.05). The most frequently symptoms in postmenopausal women were sexual problems (57.05%), muscle/joint pain (53.29%) and insomnia (51.02%), while fatigue, insomnia and muscle/joint pain were predominant symptoms in pre- and peri-menopausal women. After adjusting for confounding factors, logistic regression analysis revealed that women with poor educational background, low income, divorce, higher BMI, higher parity, smoking and chronic diseases presented higher KMI scores (P<0.05). The study provided an estimate of median age at natural menopause in Chinese women. The main factors contributing to earlier onset of menopause and severity of menopausal symptoms were lower educational level, poor economic status, and smoking. Thus, this study provides important insights for physicians to prevent and treat menopause related symptoms.


Effect of Individualized Dietary Intervention on Oxidative Stress in Patients with Type 2 Diabetes Complicated by Tuberculosis in Xinjiang, China.
This study aimed to examine the effect of individual dietary intervention on nutrition and oxidative stress of patients with type 2 diabetes mellitus (T2DM) complicated by pulmonary tuberculosis (PTB) in Xinjiang. A total of 164 patients with T2DM and PTB from January 2018 to December 2018 in the Chest Hospital of Xinjiang Uyghur Autonomous Region were included. According to the random number table method, the patients were divided into an experimental group (n = 82) and control group (n = 82). The original treatments of PTB and T2DM were maintained. The control group was treated with a self-controlled diet, while the experimental group was treated with an individual quantitative dietary intervention. All patients included in our study were closely followed up for 3 months and the serum levels of variables related to nutrition, oxidative stress, and blood glucose were measured to compare each patient's nutritional and oxidative stress after the intervention. Proportions of patients with sputum testing positive for bacteria before and after the intervention were also recorded and compared between the two groups. There were no significant differences between the two groups with regard to age, sex, labor intensity, marital status, course and treatment of diabetes, and proportion of patients with sputum positive for bacteria before the intervention (P > 0.05). There were statistically significant differences between the two groups in variables to related nutrition and oxidative stress, especially SOD which was increased by 13.2% in the experimental group and 2.5% in the control group after intervention (P < 0.05). The proportion of patients with sputum positive for bacteria in the experimental group was significantly lower than that in the control group, and the difference was statistically significant (P < 0.05). A combination of individual quantitative dietary interventions can improve the nutritional status of patients with T2DM-PTB and adjust the oxidative stress. This method provides a theoretical basis for a reasonable diet in patients with T2DM-PTB. ChiCTR900025477 (Retrospectively registered).


Systematic review of arthroscopic versus open repair for recurrent anterior shoulder dislocations.
It remains unknown if arthroscopic repair of recurrent anterior shoulder instability is as effective as open repair. The purpose of this study is to analyze the literature to provide clinical recommendations regarding the most appropriate therapeutic intervention for recurrent anterior shoulder instability. Systematic review of level I and II studies. PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and secondary references from 1967 to March 2010 were appraised for studies that met the inclusion criteria. Inclusion criteria were English-language level I or level II trials involving the treatment of recurrent anterior shoulder instability. Exclusion criteria included non-English-language studies; level III, IV, or V studies; and trials examining treatment of first-time shoulder dislocation, posterior shoulder dislocation, or diagnoses other than recurrent anterior shoulder dislocations. Included studies underwent quality appraisal independently by each author identifying strengths, weaknesses, and biases. Four randomized controlled trials compared the use of arthroscopic and open repair for recurrent anterior shoulder dislocations. These studies show no statistically significant difference between the 2 operative approaches. No long-term follow-up data describing the effects of either surgical approach are available at this time. Each investigation had weaknesses in study design that decreased the validity of its findings. While limited, the available evidence from randomized controlled trials does not show a statistically significant difference in redislocation rates, return to activity, and functional outcomes between the arthroscopic and open repair groups. Range of motion is marginally better following arthroscopic treatment when compared with open repair. Recommendations on the optimal surgical intervention cannot be provided.


Identifying Unique Contributions of the Coach-Athlete Working Alliance, Psychological Resilience and Perceived Stress on Athlete Burnout among Norwegian Junior Athletes.
The main purpose of the current study was to examine how the coach-athlete working alliance, psychological resilience and perceived stress are uniquely associated with burnout among junior athletes in sport. A sample of 670 Norwegian junior athletes practicing a variety of sports participated in the study. A hierarchical multiple regression analysis showed that the bond dimension of the working alliance, the protective factors 'planned future' and 'structured style', as well as perceived stress, all contributed uniquely to the explanation of athlete burnout. A dominance analysis identified perceived stress to have the strongest relative influence on athlete burnout among the set of variables investigated in this study. The findings are discussed in terms of applied implications and possible future research.


A fatal case of early prosthetic valve endocarditis caused by multidrug-resistant (MDR) - Sphingomonas paucimobilis.
Sphyngomonas paucimobilis (S. paucimobilis) is a low-pathogenicity, gram-negative bacilli (GNB) that are previously known as an opportunist microorganism. Recent studies have shown that S. paucimobilis is an emerging pathogen causing various infections. Multidrug-resistant GNB has emerged as a major clinical and therapeutic dilemma in various hospital-associated infections. Although rare, S. paucimobilis could be associated with infective endocarditis (IE). Prosthetic valve endocarditis (PVE) is the most severe type of IE, which has high mortality rates despite diagnostic and treatment advances. We report a fatal case of early PVE associated with multidrug-resistant (MDR) - S. paucimobilis complicated with perivalvular abscess, complete heart block, valve detachment, and septic arthritis.


Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience.
The simultaneous use of deferoxamine (DFO) and deferiprone (DFP) has an additive effect in iron excretion in transfusion-dependent thalassemic patients. To evaluate the efficacy and safety of a prospective alternating therapy with DFO and DFP in patients with beta-thalassemia major (TM) and increased serum ferritin with DFO monotherapy alone. Sixty patients with beta-TM (mean age +/- SD, 13.05 +/- 6.1, range 10-20 years) with iron overload (serum ferritin > 2000 ng/ml) were studied. They received DFO at a daily dose of 40 mg/kg/day for 5-7 nights/week for the past several years. These patients were randomly assigned either to continue treatment with DFO alone (DFO group, n = 30) or prospectively receive additional alternating therapy with DFP at 75 mg/kg/day for 4 days/week and DFO for the other 2 days/week (alternating therapy group, n = 30). The efficacy of both groups was assessed by measurements of serum ferritin, echocardiography, and 24 h urine iron excretion (UIE) levels throughout 1 year follow-up. In the 60 evaluable patients, the mean serum ferritin ( +/- SD) fell dramatically from 4500 ( +/- 1250) ng/ml at the start of the study to 1250 ( +/- 750) ng/ml (alternate therapy group; P < 0.001) at the end of the study. There was also a significant improvement in the myocardial function as assessed by the ejection fraction (P < 0.002) and fractional shortening (P < 0.01) in those patients on alternate therapy for 1 year. Their mean urinary iron excretion elevated from 0.41 +/- 0.27 to 0.76 +/- 0.49 mg/kg/24 h (P < 0.003). There was a significant difference between both groups as regard the studied parameters at the end of the study. Whereas, there was no statistical difference as regard the studied parameters at the start and the end of the study in the DFO group. No significant adverse effects had occurred in both groups that necessitated withdrawal from the study. beta-Thalassemic major patients with transfusional iron overload can be safely and effectively treated with an alternate therapy of DFO/DFP with a progressive fall in the mean serum ferritin and significant improvement of myocardial performance.


Fisetin Protects PC12 Cells from Tunicamycin-Mediated Cell Death via Reactive Oxygen Species Scavenging and Modulation of Nrf2-Driven Gene Expression, SIRT1 and MAPK Signaling in PC12 Cells.
Fisetin (3,7,3',4'-tetrahydroxyflavone) is a dietary flavonol and exhibits antioxidant, anti-inflammatory, and neuroprotective activities. However, high concentration of fisetin is reported to produce reactive oxygen species (ROS), induce endoplasmic reticulum (ER) stress and cause cytotoxicity in cancer cells. The aim of this study is to investigate the cytoprotective effects of low concentration of fisetin against tunicamycin (Tm)-mediated cytotoxicity in neuronal-like catecholaminergic PC12 cells. Cell viability was assayed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and apoptotic and autophagic markers were analyzed by Western blot. Gene expression of unfolded protein response (UPR) and Phase II enzymes was further investigated using RT-Q-PCR or Western blotting. Intracellular ROS level was measured using 2',7'-dichlorodihydrofluorescein diacetate (H₂DCFDA) by a fluorometer. The effects of fisetin on mitogen activated protein kinases (MAPKs) and SIRT1 (Sirtuin 1) signaling pathways were examined using Western blotting and specific inhibitors. Fisetin (<20 µM) restored cell viability and repressed apoptosis, autophagy and ROS production in Tm-treated cells. Fisetin attenuated Tm-mediated expression of ER stress genes, such as glucose-regulated proteins 78 (GRP78), C/EBP homologous protein (CHOP also known as GADD153) and Tribbles homolog 3 (TRB3), but induced the expression of nuclear E2 related factor (Nrf)2-targeted heme oxygenase (HO)-1, glutamate cysteine ligase (GCL) and cystine/glutamate transporter (xCT/SLC7A11), in both the presence and absence of Tm. Moreover, fisetin enhanced phosphorylation of ERK (extracellular signal-regulated kinase), JNK (c-JUN NH₂-terminal protein kinase), and p38 MAPK. Addition of JNK and p38 MAPK inhibitor significantly antagonized its cytoprotective activity and modulatory effects on UPR. Fisetin also restored Tm-inhibited SIRT1 expression and addition of sirtinol (SIRT1 activation inhibitor) significantly blocked fisetin-mediated cytoprotection. In conclusion, this result shows that fisetin activates Nrf2, MAPK and SIRT1, which may elicit adaptive cellular stress response pathways so as to protect cells from Tm-induced cytotoxicity.


Delivery technologies to engineer natural killer cells for cancer immunotherapy.
In recent years, immune cell-based cancer therapeutics have been utilized broadly in the clinic. Through advances in cellular engineering, chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial success in treating hematological tumors and have become the most prominent cell-based therapy with three commercialized products in the market. However, T-cell-based immunotherapies have certain limitations, including a restriction to autologous cell sources to avoid severe side-effects caused by human leukocyte antigen (HLA) mismatch. This necessity for personalized treatment inevitably results in tremendous manufacturing and time costs, reducing accessibility for many patients. As an alternative strategy, natural killer (NK) cells have emerged as potential candidates for improved cell-based immunotherapies. NK cells are capable of killing cancer cells directly without requiring HLA matching. Furthermore, NK cell-based therapies can use various allogeneic cell sources, allowing for the possibility of "off-the-shelf" immunotherapies with reduced side-effects and shortened manufacturing times. Here we provide an overview of the use of NK cells in cancer immunotherapy, their current status in clinical trials, as well as the design and implementation of delivery technologies-including viral, non-viral, and nanoparticle-based approaches-for engineering NK cell-based immunotherapies.


Single-Particle Tracking Method in Fluorescence Microscopy to Monitor Bioenergetic Responses of Individual Mitochondria.
The spectroscopic methods commonly used to study mitochondria bioenergetics do not show the diversity of responses within a population of mitochondria (isolated or in a cell), and/or cannot measure individual dynamics. New methodological developments are necessary in order to improve quantitative and kinetic resolutions and eventually gain further insights on individual mitochondrial responses, such as studying activities of the mitochondrial permeability transition pore (mPTP ). The work reported herein is devoted to study responses of single mitochondria within a large population after isolation from cardiomyocytes. Mitochondria were preloaded with a commonly used membrane potential sensitive dye (TMRM), they are then deposited on a plasma-treated glass coverslip and subsequently energized or inhibited by additions of usual bioenergetics effectors. Responses were analyzed by fluorescence microscopy over few thousands of mitochondria simultaneously with a single organelle resolution. We report an automatic method to analyze each image of time-lapse stacks based on the TrackMate-ImageJ plug-in and specially made Python scripts. Images are processed to eliminate defects of illumination inhomogeneity, improving by at least two orders of magnitude the signal/noise ratio. This method enables us to follow the track of each mitochondrion within the observed field and monitor its fluorescence changes, with a time resolution of 400 ms, uninterrupted over the course of the experiment. Such methodological improvement is a prerequisite to further study the role of mPTP in single mitochondria during calcium transient loading.


WEEE treatment and system management in Italy and Serbia: A comparison.
Waste electrical and electronic equipment (WEEE) represent one of the growing waste streams in Europe, whose content of hazardous substances and valuable materials focus on how it is handled. However, there are differences between countries regarding e-waste management system in Europe. This paper analyses and presents data regarding the e-waste management system in Italy, one of the founding countries of the EU and Serbia - EU candidate country. Within this work, the following aspects were considered: legislative framework and EU directive goals in terms of e-waste, institutional setup, collection system, and existing recycling and treatment technologies. In addition, material flow analysis is used to model mass balance within WEEE treatment plants in both countries. Finally, through assessment and comparison of current systems in both countries, problems and shortages of Serbia's e-waste management system are addressed.


Zac1 is a histone acetylation-regulated NF-κB suppressor that mediates histone deacetylase inhibitor-induced apoptosis.
Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-κB (NF-κB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-κB activity. Further investigation showed that Zac1 inhibits NF-κB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-κB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis.


MiR-24-3p Conservatively Regulates Muscle Cell Proliferation and Apoptosis by Targeting Common Gene CAMK2B in Rat and Cattle.
Skeletal muscle plays an important role in the growth and development of meat animals. MicroRNAs (miRNAs) can participate in the regulation of muscle development-related functions; however, there have been few reports on whether there are related miRNAs that conservatively regulate muscle development among different species. In this study, the miRNA transcriptome sequencing data of the muscle tissue of cattle, rat, goat, and pig showed that miR-24-3p may conservatively regulate muscle development in these species. Furthermore, mmu-miR-24-3p can positively regulate C2C12 cell proliferation and apoptosis by regulating key proliferation and apoptosis genes in muscle development, which was verified by CCK-8 and RT-qPCR. Bta-miR-24-3p can also positively regulate the proliferation and apoptosis of bovine muscle primary cells by regulating key proliferation and apoptosis genes in the process of muscle development, as verified by CCK-8 and RT-qPCR. The target genes of miR-24-3p in cattle, rat, goat, and pig, which include a large proportion of target genes shared among the four species, are enriched in multiple cell functions and signal pathways that are closely related to muscle development, as revealed by GO and KEGG enrichment analysis. A double luciferase test showed that the shared target genes WNT4, CAMK2B, and TCF7 were targeted by mmu-miR-24-3p in rat and bta-miR-24-3p in cattle. These three shared target genes WNT4, CAMK2B, and TCF7 are involved in the Wnt signaling pathway, which showed that miR-24-3p plays an important role in rat and cattle. The shared target gene (CAMK2B) in rat and cattle increased significantly after the inhibition of miR-24-3p by RT-qPCR. The findings of this study contribute to a better understanding of the role of miR-24-3p in the regulation of muscle development.


Gender and ethnic differences in formal and informal help seeking among Israeli adolescents.
This study examines the willingness of Jewish and Arab Israeli adolescents to look for help in times of distress and explores the factors that are associated with the willingness of these adolescents to look for help from formal vs. informal sources. The sample consisted of 6017 randomly selected respondents, 14-18 years old, attending secondary schools. Multiple regression analyses were used in order to explore what predicts formal vs. informal help seeking. Results indicate that satisfaction with school, family and friends, and ethnicity are all important predictors that are associated with the willingness of Israeli adolescents to ask for formal and informal help. The interaction between gender and ethnicity was also examined. The findings present the specific differences between formal and informal help seeking and are discussed in the Israeli context.


The effect of intra-oral LED device and low-level laser therapy on orthodontic tooth movement in young adults: A randomized controlled trial.
This randomized controlled clinical trial aimed to assess the effect of LED5 and LLLT6 in a three-arm parallel setting. Sixty patients who needed the maxillary first premolar extraction were allocated to three groups using the stratified block randomization method. In the LED group, a custom-made device with a wavelength of 640nm and a power density of 40 mW/cm2 was used 5min/day. In the laser group, Ga Al As7 laser with a wavelength of 810nm and a power of 100 mW was used on days 0, 3, 30, and 60 each time for 18seconds. Patients in the control group received placebo treatment as the laser group protocol, using a coated light cure device. Models were made at baseline and monthly until the end of the retraction. The rate of canine retraction was the primary outcome, while canine rotation and pain were secondary outcomes. The final data were anonymous for the outcome assessor and statistical consultant. Data were analyzed per protocol using a linear mixed model. The rate of canine retraction significantly increased by 60.8% in the laser group, while it increased not significantly by 26% in the LED group compared with the control group. There was no significant difference among the groups in terms of tooth rotation and pain. LLLT can accelerate orthodontic tooth movement (OTM). LED with the present setting couldn't increase the rate of OTM. LLLT and LED did not affect canine rotation or pain. IRCT20120220009086N4. On 1 June 2019 was retrospectively registered.


Current status and recent advances on the use of ultrasonography in pediatric rheumatic diseases.
Ultrasonography has become a useful tool in the clinical rheumatology settings in the last two decades, but its use has only recently been explored by pediatric rheumatologists. The aim of this article is to review the literature on the current status and recent advances on the use of ultrasound in pediatric rheumatic diseases. We have retrieved and reviewed the relevant articles from MEDLINE/PubMed databases published so far, on the applications of ultrasound in juvenile idiopathic arthritis (JIA), systemic lupus erythematosus, dermatomyositis, enthesitis, Sjogren's syndrome, and other rheumatic diseases. In addition, articles on novel ultrasound imaging technology of potential use in pediatric rheumatology are also reviewed. In JIA, ultrasound can be used to detect subclinical synovitis, to improve the classification of patients in JIA subtypes, to capture early articular damage, to monitor treatment response, and to guide intraarticular injections. Ultrasound is also considered useful in other rheumatic disorders for the evaluation of musculoskeletal symptoms, assessment of parotid gland pathology, and measurement of skin thickness and pathology. Novel ultrasound techniques developed to augment the functionality of ultrasonography may also be applicable in pediatric rheumatic disorders. Ultrasound shows great promise in the assessment and management of children with rheumatologic disorders. However, standardization and validation of ultrasound in healthy children and in patients with rheumatic diseases are still needed.


Measuring actual scope of nursing practice: a new tool for nurse leaders.
: This project describes the development and testing of the actual scope of nursing practice questionnaire. : Underutilization of the skill sets of registered nurses (RNs) is a widespread concern. Cost-effective, safe, and efficient care requires support by management to facilitate the implementation of nursing practice at the full scope. : Literature review, expert consultation, and face validity testing were used in item development. The instrument was tested with 285 nurses in 22 medical units in 11 hospitals in Canada. : The 26-item, 6-dimension questionnaire demonstrated validity and reliability. The responses suggest that nurses practice at less than their optimal scope, with key dimensions of professional practice being implemented infrequently. : This instrument can help nurse leaders increase the effective use of RN time in carrying out the full scope of their professional practice.


Huangqi-Honghua combination and its main components ameliorate cerebral infarction with Qi deficiency and blood stasis syndrome by antioxidant action in rats.
Combination of Radix Astragali (Huangqi) and Carthamus tinctorius L. (Honghua) has been extensively used as traditional herb medicine in China for the treatment of stroke and myocardial ischemia diseases with Qi deficiency and blood stasis (QDBS) syndrome. To investigate the effect of Huangqi-Honghua combination (HH) and its main components astragaloside IV (AS-IV) and Hydroxysafflor yellow A (HSYA) on cerebral ischemia-reperfusion (IR) with QDBS in rat model. Male rats were randomly divided into the following six groups: sham group, QDBS+I/R model group and treatment group including AS-IV, HSYA, AS-IV+HSYA and HH. The whole blood viscosity (WBV), plasma viscosity (PV), neurological examination, infarct volume, histopathology changes and some oxidative stress markers were assessed after 24h of reperfusion. HH and its main components AS-IV+HSYA could significantly decrease WBV, PV, and also significantly ameliorate neurological examination and infarct volume after 24h of reperfusion. They also significantly increased expression of Nuclear factor erythroid 2-related factor 2 (Nrf2), activities of antioxidants, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px), led to decrease levels of malondialdehyde (MDA) and reactive oxygen species (ROS). AS-IV and HSYA are responsible for the main curative effects of HH. The study may provide scientific information to further understanding the mechanism(s) of HH and its main components in removing blood stasis and ameliorating cerebral infarction. Additionally, AS-IV and HSYA appear to have synergistic effects on neuroprotection.


Effect of preexcisional heparin anticoagulation on excised canine vein and artery prostanoid production.
The effect of heparin, administered prior to vessel dissection and excision, on the luminal release of prostanoids from an excised vessel was assessed. Eight adult mongrel dogs underwent removal of the jugular vein and carotid artery on one side, followed by intravenous administration of heparin sodium (150 IU/kg) and subsequent removal of these same vessels from the contralateral neck. The excised vessels were perfused in an ex vivo system with Hanks' balanced salt solution for five consecutive 15-min periods. Prostacyclin release (measured as 6-keto-PGF1 alpha) and thromboxane A2 (measured as thromboxane B2) release into the perfusate were quantitated by radioimmunoassay. Vessel segments were studied with and without first period thrombin stimulation (2 U/ml) and with arachidonic acid (4 micrograms/ml) stimulation during the last perfusion period. Vein segments following heparin administration exhibited greater prostacyclin production than veins not exposed to heparin. This effect did not occur in arteries. Heparin did not influence thromboxane A2 release. Luminal endothelial cell coverage was not affected by the presence or absence of heparin. Thus heparin anticoagulation prior to dissection and excision of a vein, may enhance early preservation of its endothelial cell function as evident by increased luminal release of prostacyclin.


The hierarchical folding dynamics of topologically associating domains are closely related to transcriptional abnormalities in cancers.
Recent studies have shown that the three-dimensional (3D) structure of chromatin is associated with cancer progression. However, the roles of the 3D genome structure and its dynamics in cancer remains largely unknown. In this study, we investigated hierarchical topologically associating domain (TAD) structures in cancers and defined a "TAD hierarchical score (TH score)" for genes, which allowed us to assess the TAD nesting level of all genes in a simplified way. We demonstrated that the TAD nesting levels of genes in a tumor differ from those in normal tissue. Furthermore, the hierarchical TAD level dynamics were related to transcriptional changes in cancer, and some of the genes in which the hierarchical level was altered were significantly related to the prognosis of cancer patients. Overall, the results of this study suggest that the folding dynamics of TADs are closely related to transcriptional abnormalities in cancers, emphasizing that the function of hierarchical chromatin organization goes beyond simple chromatin packaging efficiency.


In-depth analysis of a plasma or serum proteome using a 4D protein profiling method.
Comprehensive proteomic analysis of human plasma or serum has been a major strategy used to identify biomarkers that serve as indicators of disease. However, such in-depth proteomic analyses are challenging due to the complexity and extremely large dynamic range of protein concentrations in plasma. Therefore, reduction in sample complexity through multidimensional pre-fractionation strategies is critical, particularly for the detection of low-abundance proteins that have the potential to be the most specific disease biomarkers. We describe here a 4D protein profiling method that we developed for comprehensive proteomic analyses of both plasma and serum. Our method consists of abundant protein depletion coupled with separation strategies - microscale solution isoelectrofocusing and 1D SDS-PAGE - followed by reversed-phase separation of tryptic peptides prior to LC-MS/MS. Using this profiling strategy, we routinely identify a large number of proteins over nine orders of magnitude, including a substantial number of proteins at the low ng/mL or lower levels from approximately 300 μL of plasma sample.


Planning your cancer service line three steps to success.
One Midwest health system found that by using a three-step approach to bolster the success of its lung cancer program, the program exceeded patient volume targets within its first year of operation. The program now serves as a business model for other investment opportunities in site-specific cancer programs at the health system.


Audiometric findings of patients with migraine-associated dizziness.
The objective of this study was to determine whether the audiometric findings of migraine-associated dizziness could be used to better distinguish migraine-associated dizziness from Meniere's disease. A retrospective chart review. Tertiary, otology/neurotology practice. Two groups of patients were studied, a migraine-associated dizziness and a Meniere's disease group. There were 76 and 34 patients in the migraine-associated dizziness and Meniere's disease groups, respectively. None. Initial and follow-up pure-tone average and low-frequency pure-tone average were recorded for both groups. Independent samples t tests were used to test for mean differences in pure-tone average and low-frequency pure-tone average. Pure-tone average and low-frequency pure-tone average were significantly worse for patients in the Meniere's disease group at both the initial and follow-up assessments. Three patients in the migraine-associated dizziness group had an elevated pure-tone average (>/=26 dB) and/or low-frequency pure-tone average at initial and/or follow-up assessment. The remaining 73 migraine-associated dizziness patients had normal hearing. In the Meniere's disease group, only two patients had a normal pure-tone average and low-frequency pure-tone average at both initial and follow-up evaluations. The hearing difference between the two groups was significant even when controlling for age and duration of dizziness symptoms. Audiometric findings of patients with migraine-associated dizziness are most often normal. Unlike Meniere's disease, the sensorineural hearing loss in migraine-associated dizziness rarely progresses. These audiometric findings may help to distinguish migraine-associated dizziness from Meniere's disease when diagnostic ambiguity exists between these two diagnoses.


RNA independent fragment partition method based on deep learning for RNA secondary structure prediction.
The non-coding RNA secondary structure largely determines its function. Hence, accuracy in structure acquisition is of great importance. Currently, this acquisition primarily relies on various computational methods. The prediction of the structures of long RNA sequences with high precision and reasonable computational cost remains challenging. Here, we propose a deep learning model, RNA-par, which could partition an RNA sequence into several independent fragments (i-fragments) based on its exterior loops. Each i-fragment secondary structure predicted individually could be further assembled to acquire the complete RNA secondary structure. In the examination of our independent test set, the average length of the predicted i-fragments was 453 nt, which was considerably shorter than that of complete RNA sequences (848 nt). The accuracy of the assembled structures was higher than that of the structures predicted directly using the state-of-the-art RNA secondary structure prediction methods. This proposed model could serve as a preprocessing step for RNA secondary structure prediction for enhancing the predictive performance (especially for long RNA sequences) and reducing the computational cost. In the future, predicting the secondary structure of long-sequence RNA with high accuracy can be enabled by developing a framework combining RNA-par with various existing RNA secondary structure prediction algorithms. Our models, test codes and test data are provided at https://github.com/mianfei71/RNAPar .


Recent progress of drug nanoformulations targeting to brain.
Most of the potential therapeutic agents capable to modulate the pathophysiology or treat the neurological disorders and brain tumors are useless in the current modern and advanced era of neuroscience due to the impeding action of biological barriers. Among various therapeutic strategies applied for translocation of drug delivery across the blood-brain barrier (BBB), nanoformulations set an excellent platform for brain targeting by overcoming the biological and chemical barriers and protecting drug from efflux to promote the optimum therapeutic drug concentration in brain parenchyma tissues. Nanocarriers are the most widely studied delivery vehicles for BBB translocation with the efficiency of selectively targeting or exploiting inherent biological molecules, receptors, carriers or mechanisms of the brain. Nearly all of the available drug delivery nanocarriers explored in recent years for brain therapeutics and theranostics are based on lipid or polymeric materials. Polymeric nanoparticles (NPs) and lipid based nanocarriers including liposomes, solid lipid NPs (SLNs) and micelles, etc. are under the direct focus of neuroscientists due to the promising attributes and vast applications in neurological disorders. Surface modification of nanovehicles with proper targeting moiety or coating with surfactants promotes the interaction with endothelial cells and passage of nanocarriers to the brain. This review comprehensively depicts challenges to the brain targeted drug delivery, mechanisms of drug transportation across the BBB, and potential contributions of endogenous cells as NPs delivery cells and novel targeting ligands decorated nanoformulations in imaging, treating and controlling neurological disorders.


Spatial position is a key determinant of N-glycan functionality of the scavenger receptor cysteine-rich domain of human hepsin.
The scavenger receptor cysteine-rich (SRCR) domain is a key constituent in diverse proteins. N-glycosylation is important in protein expression and function. In the SRCR domain of different proteins, N-glycosylation sites and functionality vary substantially. In this study, we examined the importance of N-glycosylation site positions in the SRCR domain of hepsin, a type II transmembrane serine protease involved in many pathophysiological processes. We analysed hepsin mutants with alternative N-glycosylation sites in the SRCR and protease domains using three-dimensional modelling, site-directed mutagenesis, HepG2 cell expression, immunostaining, and western blotting. We found that the N-glycan function in the SRCR domain in promoting hepsin expression and activation on the cell surface cannot be replaced by alternatively created N-glycans in the protease domain. Within the SRCR domain, the presence of an N-glycan in a confined surface area was essential for calnexin-assisted protein folding, endoplasmic reticulum (ER) exiting, and zymogen activation of hepsin on the cell surface. Hepsin mutants with alternative N-glycosylation sites on the opposite side of the SRCR domain were trapped by ER chaperones, resulting in the activation of the unfolded protein response in HepG2 cells. These results indicate that the spatial N-glycan positioning in the SRCR domain is a key determinant in the interaction with calnexin and subsequent cell surface expression of hepsin. These findings may help to understand the conservation and functionality of N-glycosylation sites in the SRCR domains of different proteins.


Modification of spintronic terahertz emitter performance through defect engineering.
Spintronic ferromagnetic/non-magnetic heterostructures are novel sources for the generation of THz radiation based on spin-to-charge conversion in the layers. The key technological and scientific challenge of THz spintronic emitters is to increase their intensity and frequency bandwidth. Our work reveals the factors to engineer spintronic Terahertz generation by introducing the scattering lifetime and the interface transmission for spin polarized, non-equilibrium electrons. We clarify the influence of the electron-defect scattering lifetime on the spectral shape and the interface transmission on the THz amplitude, and how this is linked to structural defects of bilayer emitters. The results of our study define a roadmap of the properties of emitted as well as detected THz-pulse shapes and spectra that is essential for future applications of metallic spintronic THz emitters.


Susceptibility of mononuclear phagocytes to influenza A virus infection and possible role in the antiviral response.
Among leukocytes, only monocytes and macrophages were found to be highly susceptible to an infection by influenza A virus. After infection, de novo viral protein synthesis was initiated but then interrupted after 4-6 h. Most macrophages died by apoptosis within 25-30 h. Before cell death, however, macrophages responded to influenza A virus with a high cytokine gene transcription and subsequent release of tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, interferon (IFN)-alpha/beta, and CC-chemokines. The basic mechanisms of virus-induced cytokine expression are still unknown and appear to involve transcription factors such as nuclear factor-kappaB and AP-1 which, however, were only activated for 2 h and declined below control values thereafter. After influenza A virus infection, only the mononuclear cell attracting CC-chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES were produced while the prototype neutrophil CXC-chemoattractants IL-8 and GRO-alpha were entirely suppressed. This selective induction of CC-chemokines may explain the preferential influx of mononuclear leukocytes into virus-infected tissue. Our data show that monocytes and macrophages represent a primary target for an influenza A virus infection. Thus, the mononuclear phagocyte response leads to a rapid proinflammatory reaction and an enhanced immigration of mononuclear leukocytes, which may condition the infected host for the subsequent virus antigen-specific defense.


The psychosocial treatment of parental alienation.
Parental alienation occurs in divorces when one parent indoctrinates the child to dislike, fear, and avoid contact with the other parent. Mental health professionals who treat children and adolescents are likely to encounter victims of parental alienation in clinical practice, and it is important to identify and treat these youngsters earlier, when the condition is mild, rather than later, when the parental alienation is almost intractable. This article presents an overview of the treatment of parental alienation, which is called reunification therapy. All the parties involved in the case have a role in the prevention and treatment of parental alienation.


Co-culture of dedifferentiated and primary human chondrocytes obtained from cadaveric donor enhance the histological quality of repair tissue: an in-vivo animal study.
To compare the quality of the repair tissue in three-dimensional co-culture of human chondrocytes implanted in an in vivo model. Six cadaveric and five live human donors were included. Osteochondral biopsies from the donor knees were harvested for chondrocyte isolation. Fifty percent of cadaveric chondrocytes were expanded until passage-2 (P2) while the remaining cells were cryopreserved in passage-0 (P0). Fresh primary chondrocytes (P0f) obtained from live human donors were co-cultured. Three-dimensional constructs were prepared with a monolayer of passage-2 chondrocytes, collagen membrane (Geistlich Bio-Gide®), and pellet of non-co-cultured (P2) or co-cultured chondrocytes (P2 + P0c, P2 + P0f). Constructs were implanted in the subcutaneous tissue of athymic mice and left for 3 months growth. Safranin-O and Alcian blue staining were used to glycosaminoglycan content assessment. Aggrecan and type-II collagen were evaluated by immunohistochemistry. New-formed tissue quality was evaluated with an adaptation of the modified O'Driscoll score. Histological quality of non-co-cultured group was 4.37 (SD ±4.71), while co-cultured groups had a mean score of 8.71 (SD ±3.98) for the fresh primary chondrocytes and 9.57 (SD ±1.27) in the cryopreserved chondrocytes. In immunohistochemistry, Co-culture groups were strongly stained for type-II and aggrecan not seen in the non-co-cultured group. It is possible to isolate viable chondrocytes from cadaveric human donors in samples processed in the first 48-h of dead. There is non-significant difference between the numbers of chondrocytes isolated from live or cadaveric donors. Cryopreservation of cadaveric primary chondrocytes does not alter the capability to form cartilage like tissue. Co-culture of primary and passaged chondrocytes enhances the histological quality of new-formed tissue compared to non-co-cultured cells.


Legal and regulatory concerns about transgenic plants in Brazil.
Brazil has a biosafety law that was approved in 1995. This law provides for a horizontal type of regulation that coordinates other existing regulatory frameworks in the areas of agriculture, health and environment. Various federal government departments are responsible for implementing the law. The National Technical Biosafety Commission is the national competent authority on biosafety with overall responsibility. In the case of Bt plants or any insecticidal organism, the Agrochemical Law also applies and authorization for laboratory, greenhouse and field studies must be obtained from the Plant Protection Secretariat, the Brazilian Institute of Environment and the National Agency of Health. Furthermore, the National Environmental Council must issue a license for commercialization of any GMO. There is pressure needed for capacity building and to harmonize the regulatory and administrative frameworks among the different federal departments involved. Some perspectives and challenges for the commercial registration of transgenic crops are discussed.


Radiographically occult fracture of the tibial epiphysis: sonographic findings with CT correlation.
We report the case of a radiographically occult tibial fracture diagnosed sonographically and confirmed with CT. Ultrasound signs of cortical discontinuity and a three-layered fluid accumulation in the deep infrapatellar bursa were demonstrated.


Surgical complications after implant placement.
Placement of dental implants in the maxillofacial region is routine and considered safe. However, as with any surgical procedure, complications occur. Many issues that arise at surgery can be traced to the preoperative evaluation of the patient and assessment of the underlying anatomy. In this article, the authors review some common and uncommon complications that can occur during and shortly after implant placement. The emphasis of each section is on the management and prevention of complications that may occur during implant placement.


Anticoagulant activity of apixaban can be estimated by multiple regression analysis.
Information on apixaban anticoagulant activity is required to prevent major bleeding or thrombosis during its use. We enrolled 194 patients with nonvalvular atrial fibrillation (NVAF) in whom warfarin was replaced with apixaban: 105 (54.1%) received the standard dose of apixaban (5 mg twice daily [BID]; 5 mg group) and 89 (45.9%) received a reduced dose (2.5 mg BID; 2.5 mg group). Multiple regression analysis was performed to predict the prothrombin time of apixaban (PTa) based on factors including age, body weight (BW), serum creatinine, and CHA2DS2-VASc score. PTa and PT of warfarin (PTw) were significantly correlated in both groups (correlation coefficient R = 0.239 [P = .014] in the 5 mg group; R = 0.248 [P = .019] in the 2.5 mg group). PTa in the 5 mg group was predicted as follows: 16.952-0.036 × BW +0.299 × CHA2DS2-VASc score (P < .0004; R = 0.378). However, in the 2.5 mg group, PTa could not be predicted. The mean of the predicted and measured PTa values in the 5 mg group was 15.6 s, which was similar to the mean measured PTa of 15.5 s in the 2.5 mg group. PT can be predicted by a formula including simple clinical parameters in patients receiving the standard dose of apixaban. This simple predictive formula may help to stratify bleeding and thrombosis risks in patients treated with apixaban.


Risk factors for saphenous vein recanalization after endovenous radiofrequency ablation.
Target vein recanalization is defined as the postoperative detection of blood flow in a venous segment previously ablated. It can be occurred after thermal-tumescent procedures, as radiofrequency (RFA) and endovenous laser (EVLA) ablation techniques. Despite several papers described and analyzed incidence and consequences of recanalization, limited data are published on risk factors for this condition. The aim of this general review is to investigate clinical and instrumental risk factors for great and small saphenous veins recanalization after RFA, indicating their impact in the follow-up period. Articles were obtained through a detailed search of the scientific journal databases (PubMed, Scopus, Web of Science) for those published between January 1, 2011 to December 31, 2020. The term "radiofrequency venous ablation" was combined with "risk factors", "recanalization" and "recurrence", to obtain the first article cluster. Risk factors analysis for saphenous vein recanalization after ablation is not a well-studied problem. Although several studies have analyzed recanalization patterns and anatomical causes of ablation failure, few and disaggregate data are available regarding clinical preoperative risk factors. BMI and saphenous trunk diameter seem to be the only two recognized characteristics that may affect short and long-term recanalization rate, though CVI status, sex, target vein treatment length and others factors may be taken into account. Physicians should consider risk factors for recanalization in patient selection and treatment recommendations, but also recognize that not all "ablation failures" are of clinical relevance.


Detection of Markers in Green Beans and Roasted Beans of Kalosi-Enrekang Arabica Coffee with Different Postharvest Processing Using LC-MS/MS.
Our study is aimed at evaluating the effect of postharvest processing (natural, honey, and fully washed) on the compounds profile in green beans and roasted beans of Kalosi-Enrekang Arabica coffee and determining the marker compounds for each process. These beans were extracted using boiling water, and the extract was analyzed using LC-MS/MS. The results of this work confirmed the significant impact of postharvest processing on compounds in the coffee beans, and each process has a marker compound. Green beans by natural processing have 3 marker compounds, honey processing has 6 marker compounds, and fully washed processing has 2 marker compounds. Meanwhile, roasted beans by natural processing have 4 marker compounds, honey processing has 5 marker compounds, and fully washed processing has 7 marker compounds. In addition, our research identified caffeoyl tyrosine in green beans from natural and honey processing, which was previously only identified in Robusta coffee. These marker compounds can differentiate postharvest processing (natural, honey, and fully washed). These results can also help understand the effect of postharvest processing on the chemical composition of green and roasted beans.


Values in practice and practising values.
This paper first explores evidence that speech-language pathologists are experiencing dissatisfaction with their roles and then argues that one source of dissatisfaction may be in a mismatch between personal and organisational values. In order to clarify their notion of values, the authors next present a model that outlines various levels at which values operate in therapy and show how values pervade all aspects of practice. The paper then offers some practical examples of how a new organisation has tried to address overtly the implementation of values in practice, with suggestions for how other practitioners might go about making their own personal and organisational values more explicit. The paper ends with a few caveats about the difficulties and dangers of attending to values and conclude with why it is a beneficial endeavour. Participants will be able to (1) understand issues and practices that contribute to professional burnout; (2) describe a values-based framework for clinical practice; (3) understand the importance of concerning oneself with values, despite the difficulties in so doing; (4) explore some difficulties in adopting a medical model.


Nifedipine for the treatment of preterm labor in twin and singleton pregnancies.
To investigate the outcomes of singleton and twin pregnancies that were complicated by spontaneous preterm labor and received nifedipine tocolysis. We identified the following subjects from a computerized, hospital database: 58 singleton and 32 twin pregnancies that were between 24 and 34 weeks of gestation, admitted for spontaneous preterm labor without rupture of the membranes, and receiving tocolysis with nifedipine. Data were analyzed using the Chi-square test, the Mann-Whitney test, and the Kaplan-Meier survival analysis. Spontaneous, preterm delivery occurred in 31.1% cases of singleton and 81.3% of twin pregnancies. Although the 22% of the mothers of twins did not have cervical changes upon admission, 37% of twins were delivered within 48 h. Mean for delivery weeks from admission to 36 weeks was significantly less for twin than it was for singleton gestations (32.3 ± 1.0 vs. 35.0 ± 0.5 weeks, respectively; Mantel-Cox X (2) = 41.118; p < 0.001). The maternal side effects were not significantly different between the groups. No serious cardiovascular complication had been found in either group. Tocolysis with nifedipine is effective and safe for use in both singleton and twin gestations.


Paradigms in tick evolution.
The study of tick evolution may be classified into disciplines such as taxonomy and systematics, biogeography, evolution and development (evo-devo), ecology, and hematophagy. These disciplines overlap and impact each other to various extents. Advances in one field may lead to paradigm shifts in our understanding of tick evolution not apparent to other fields. The current study considers paradigm shifts that occurred, are in the process, or may occur in future for the disciplines that study tick evolution. Some disciplines have undergone significant changes, while others may still be developing their own paradigms. Integration of these various disciplines is essential to come to a holistic view of tick evolution; however, maturation of paradigms may be necessary before this vision can be attained.


Submissions to the Australian and New Zealand Review of Food Labelling Law and Policy support traffic light nutrition labelling.
Food labels to support healthier choices are an important potential intervention for improving population health by reducing obesity and diet-related disease. This study examines the use of research evidence about traffic light nutrition labelling in submissions to the Review of Food Labelling Law and Policy conducted in Australia and New Zealand. Content analysis of final submissions to the Review and a literature review of documents reporting research evidence about traffic light labelling. Sixty-two submitters to the Review were categorised as 'supporters' of traffic light labelling and 29 as 'opponents'. Supporters focused on studies showing traffic light labels were better than other systems at helping consumers identify healthier food options. Opponents cited evidence that traffic light labels were no better than other systems in this respect and noted a lack of evidence that they led to changes in food consumption. A literature review demonstrated that, as a group, submitters had drawn attention to most of the relevant research evidence on traffic light labelling. Both supporters and opponents were, however, selective in their use of evidence. The weight of evidence suggested that traffic light labelling has strengths in helping consumers to identify healthier food options. Further research would be valuable in informing the development of an interpretive front-of-pack labelling system. The findings have significant implications for the development of front-of-pack nutrition labelling currently being considered in Australia and New Zealand.


Transitioning to online learning in higher education: Influence of Awareness of COVID-19 and Self-Efficacy on Perceived Net Benefits and Intention.
The COVID-19 pandemic has disrupted existing educational systems worldwide. Due to lockdowns in several countries, the educational institutions have been directed by governments to move towards online learning. The challenge for educational institutions and faculty members is to assess the influence of various factors that would enable adoption of online learning by students in higher education. This study investigates the influence of awareness of COVID-19 (AOC19), computer & internet self-efficacy (CISE), and online communication self-efficacy (OCSE) on perceived net benefits (NB) of the students and their intention towards the online learning (INT). The study further analyzes the mediating role of students' attitude towards online learning (ATOL). Data of 1023 students of higher education across multiple universities in India were collected and analyzed using structural equation modelling through AMOS 24 and mediation analysis through 'PROCESS' macro for SPSS. The findings revealed that, AOC19 positively influenced students' NB and INT; CISE had a significant inverse relationship with NB, and partially significant positive relationship with INT; OCSE was observed to be a significant predictor of NB with positive direct relationship; ATOL had a significant full mediation among CISE and NB, and acted as significant partial mediator between CISE and INT, AOC19 and NB, AO19 and INT, OCSE and NB, and OCSE and INT. This paper would be useful for the faculty members, institutions and education technology companies in the higher education domain by enabling an understanding of the attitude, perception and intention of the students towards online learning during the COVID-19 scenario.


Impact of chronic obstructive pulmonary disease with pulmonary hypertension on both left ventricular systolic and diastolic performance.
The effects of chronic obstructive pulmonary disease (COPD) on right ventricular (RV) systolic and diastolic functions and left ventricular (LV) diastolic function have been shown. Whereas LV myocardial performance index (LVMPI), which incorporates ejection and isovolumic relaxation and contraction times and is an index of global ventricular function, has not yet been evaluated in COPD. Our study population consisted of 24 age-matched control subjects (group 1), 24 patients with COPD without pulmonary hypertension (group 2), and 20 patients with COPD with pulmonary hypertension (group 3). Pulmonary function tests, analyses of arterial blood gases, and transthoracic echocardiographic examination were performed. RV myocardial performance index (RVMPI) and LVMPI were obtained by pulsed wave Doppler tissue. RVMPI was higher in both group 2 (0.61 +/- 0.15) and group 3 (0.94 +/- 0.27) than group 1 (0.41 +/- 0.08) (P = .038 and P< .001, respectively), and was higher for group 3 than in group 2 (P = .018). LVMPI was higher for group 3 (0.77 +/- 0.25) than in both group 1 (0.49 +/- 0.08) and group 2 (0.59 +/- 0.10) (P = .001 and P = .037, respectively). However, difference between groups 1 and 2 was not significant (P > .05). For patients with COPD, LVMPI was positively correlated with age, heart rate, pulmonary arterial systolic pressure, RVMPI, and partial pressure of carbon dioxide, and negatively correlated with tricuspid annular plane systolic excursion, forced expiratory volume in 1 second, and partial pressure of oxygen. In multiple linear regression analysis (R2 = 0.676), LVMPI was independently associated with forced expiratory volume in 1 second (Beta = 0.549, P = .017), pulmonary arterial systolic pressure (Beta = 0.488, P = .014), and RVMPI (Beta = 0.278, P = .042). Both LV systolic and diastolic functions are impaired in COPD, especially in patients with pulmonary hypertension. This impairment is independently associated with pulmonary arterial systolic pressure, RVMPI, and forced expiratory volume in 1 second.


Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates.
211At is a most promising radionuclide for targeted alpha therapy. However, its limited availability and poorly known basic chemistry hamper its use. Based on the analogy with iodine, labelling is performed via astatobenzoate conjugates, but in vivo deastatination occurs, particularly when the conjugates are internalized in cells. Actually, the chemical or biological mechanism responsible for deastatination is unknown. In this work, we show that the C-At "organometalloid" bond can be cleaved by oxidative dehalogenation induced by oxidants such as permanganates, peroxides or hydroxyl radicals. Quantum mechanical calculations demonstrate that astatobenzoates are more sensitive to oxidation than iodobenzoates, and the oxidative deastatination rate is estimated to be about 6 × 106 faster at 37 °C than the oxidative deiodination one. Therefore, we attribute the "internal" deastatination mechanism to oxidative dehalogenation in biological compartments, in particular lysosomes.


Distribution of identity of Thy-1-bearing cells during ontogeny in rat hemopoietic and lymphoid tissues.
The distribution and identity of Thy-1+ cells during ontogeny in the rat were examined by immunofluorescent and histologic techniques, and the relative amount of Thy-1 antigen on different cell types was assessed by quantitative absorption. Thy-1+ cells were subsequently studied by dual immunofluorescence for the simultaneous expression of either T or B lymphocyte markers. The results indicate that the Thy-1 antigen is present on hemopoietic precursors and on at least some of their lymphoid (both T and B) and nonlymphoid descendants. In addition, six serologically distinct subpopulations of lymphoid cells were identified, and their position in T and B cell maturational pathways is discussed.


Peripheral blood accessory cells modulate committed colony-forming units but not 5-week cobblestone-area-forming cell outgrowth from CD34+ cells.
While cellular modulation in vitro of committed hematopoietic stem cell (HSC) growth has been known for some time, less is known about the effect of accessory cells (AC) on the growth of more immature HSC. We have examined the effect of peripheral blood (PB) AC on hematopoiesis by coculturing enriched PB CD34+ cells (>96% pure) with different quantities of CD34 cells (<1% contamination) harvested from 10 breast cancer patients. As expected colony growth was predominantly present in the CD34+ fractions, in which colony forming units granulocyte-macrophage (CFU-GM) varied between 89-3289/10(5) (median 1422/10(5) seeded cells) and week 5 cobblestone area forming cells (CAFC) between 64-1330/10(5) (median 427/10(5) seeded cells). Few CFU-GM (0-27/10(5) seeded cells) and no week 5 CAFC (0-1/10(5) seeded cells) were present in the CD34 fractions. The addition of PB CD34 cells to cultures of CD34+ cells resulted in a considerable variation in the cloning efficiency at the CFU-GM level, and the extent of modulation within the single patient was inconsistent between the different CD34+/CD34 cell mixtures. Overall the stimulatory effect was more pronounced than inhibition and on average the CFU-GM formation per CD34+ cell seeded increased 3 fold (stimulatory effect ranged between 3-17 fold and decreases between 2-10 fold). In contrast, the cloning efficiency at the week 5 CAFC level of differentiation remained unaffected by the addition of different amounts of CD34 cells (the stimulatory effect was maximally 3-fold and inhibition 3-fold). We conclude that while the CFU assay is modulated by the presence of AC, the CAFC assay is more robust and can be employed as a reliable and reproducible tool for HSC measurement.


Typical and atypical development of basic numerical skills in elementary school.
Deficits in basic numerical processing have been identified as a central and potentially causal problem in developmental dyscalculia; however, so far not much is known about the typical and atypical development of such skills. This study assessed basic number skills cross-sectionally in 262 typically developing and 51 dyscalculic children in Grades 2, 3, and 4. Findings indicate that the efficiency of number processing improves over time and that dyscalculic children are generally less efficient than children with typical development. For children with typical arithmetic development, robust effects of numerical distance, size congruity, and compatibility of ten and unit digits in two-digit numbers could be identified as early as the end of Grade 2. Only the distance effect for comparing symbolic representations of numerosities changed developmentally. Dyscalculic children did not show a size congruity effect but showed a more marked compatibility effect for two-digit numbers. We did not find strong evidence that dyscalculic children process numbers qualitatively differently from children with typical arithmetic development.


Individual choices and universal rights for drinking water in rural Africa.
More than 500 million rural Africans lack safe drinking water. The human right to water and United Nations Sustainable Development Goal SDG6.1 promote a policy shift from building water infrastructure to sustaining water services. However, the financial calculus is bleak with the costs of "safely managed"' or "basic" water services in rural Africa beyond current government budgets and donor funds. The funding shortfall is compounded by the disappointing results of earlier policy initiatives in Africa. This is partly because of a failure to understand which attributes of water services rural people value. We model more than 11,000 choice observations in rural Kenya by attributes of drinking water quality, price, reliability, and proximity. Aggregate analysis disguises alternative user priorities in three choice classes. The two larger choice classes tolerate lower service levels with higher payments. A higher water service level reflects the smallest choice class favored by women and the lower wealth group. For the lower wealth group, slower repair times are accepted in preference to a lower payment. Some people discount potable water and proximity, and most people choose faster repair times and lower payments. We argue policy progress needs to chart common ground between individual choices and universal rights. Guaranteeing repair times may provide a policy lever to unlock individual payments to complement public investment in water quality and waterpoint proximity to support progressive realization of a universal right.


Synthesis and biological evaluation of novel pyrrolo[2,1-c][1,4]benzodiazepine prodrugs for use in antibody-directed enzyme prodrug therapy.
The design, synthesis and evaluation of four novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) prodrugs (1a,b and 2a,b; ) for potential use in carboxypeptidase G2 (CPG2)-based antibody-directed enzyme prodrug therapy (ADEPT) is reported. Although all four prodrugs were shown to be less cytotoxic than the released parent PBDs 3 and 4, the urea prodrugs 1b and 2b were found to be too unstable for use in ADEPT, whereas carbamates 1a and 2a are both stable in an aqueous environment and are good substrates for CPG2.


An asymptomatic double aortic arch with separate right vertebral artery and left subclavian artery originating from Kommerell Diverticulum combined with congenital asplenia and absence of celiac trunk.
This report describes the unique case of a completely patent Double Aortic Arch (DAA) combined with Kommerell Diverticulum (KD), absence of celiac trunk and congenital asplenia. The anatomical variants described were identified and assessed in a 51-year old female from a computed-tomography angiography (CTA) images with 3D-volume rendered reconstructions during her follow-up after hysterectomy. The reconstructed CTA images showed a DAA with the left common carotid artery stemming from the hypoplastic left aortic arch while the left subclavian artery originated from a KD in the descending thoracic aorta. A symmetric arrangement of the aortic arch branches was demonstrated, comprising a full vascular ring. Since the patient had been completely asymptomatic and with no symptoms of compression of the esophagus or trachea, no surgical management was advised. The abdomen CTA imaging revealed absence of the celiac trunk with direct origin of the common hepatic and the left gastric artery from the superior mesenteric artery as well as asplenia. We presented a case of asymptomatic DAA of completely patent arches with the right vertebral artery branching separately of and the left SCA originating from KD in the descending aorta. The term KD can be identified also in other arch anomalies than the one originally described. Since anatomical anomalies can be frequently combined, thorough imaging inspection with CTA of both thorax and abdomen is suggested.


Synthesis and evaluation of the in vitro and in vivo antitrypanosomal activity of 2-styrylquinolines.
In this study, we report the synthesis and evaluation of in vitro and in vivo antitrypanosomal activity of styrylquinoline-like compounds (SQ) 3a-h. Synthesis was carried out by using quinaldine and 8- hydroxyquinaldine with a variety of aromatic aldehydes. The structure of SQs was corroborated by one and two-dimension NMR spectroscopy. In vitro antitrypanosomal activity on T. cruzi Talahuen strain was evaluated using β-galactosidase enzymatic method; cytotoxicity on U-937 cells was assessed by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] method. On the other hand, in vivo therapeutical response to 3a-f compounds was evaluated in BALB/c mice (Mus musculus) experimentally infected with T. cruzi blood trypomastigotes and then orally administered with 100 mg/kg weight day for 20 days. All of the compounds showed in vitro activity with EC50 values ranging between 4.6 ± 0.1 μg/mL (14.4 μM) and 36.6 ± 6.1 μg/mL (91 μM). Furthermore, treatment with 3a-f compounds for 20 days resulted in improvement in all of the mice, with a 83-96% decrease in parasitic load at day 90 post-treatment. Treatment with benznidazol (BZ) managed to cure 100% of the mice at the end of treatment. None of the treatments affected the weight of the animals or alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine levels in serum. These results suggest a therapeutic potential of 3a-f compounds as treatment for the infection.


HER2 Molecular Marker Scoring Using Transfer Learning and Decision Level Fusion.
In prognostic evaluation of breast cancer, immunohistochemical (IHC) marker human epidermal growth factor receptor 2 (HER2) is used for prognostic evaluation. Accurate assessment of HER2-stained tissue sample is essential in therapeutic decision making for the patients. In regular clinical settings, expert pathologists assess the HER2-stained tissue slide under microscope for manual scoring based on prior experience. Manual scoring is time consuming, tedious, and often prone to inter-observer variation among group of pathologists. With the recent advancement in the area of computer vision and deep learning, medical image analysis has got significant attention. A number of deep learning architectures have been proposed for classification of different image groups. These networks are also used for transfer learning to classify other image classes. In the presented study, a number of transfer learning architectures are used for HER2 scoring. Five pre-trained architectures viz. VGG16, VGG19, ResNet50, MobileNetV2, and NASNetMobile with decimating the fully connected layers to get 3-class classification have been used for the comparative assessment of the networks as well as further scoring of stained tissue sample image based on statistical voting using mode operator. HER2 Challenge dataset from Warwick University is used in this study. A total of 2130 image patches were extracted to generate the training dataset from 300 training images corresponding to 30 training cases. The output model is then tested on 800 new test image patches from 100 test images acquired from 10 test cases (different from training cases) to report the outcome results. The transfer learning models have shown significant accuracy with VGG19 showing the best accuracy for the test images. The accuracy is found to be 93%, which increases to 98% on the image-based scoring using statistical voting mechanism. The output shows a capable quantification pipeline in automated HER2 score generation.


Comparison of characteristics and care-needs certification proportion between participants and non-participants in a geriatric health examination over a 3-year follow-up.
The purpose of this study was to compare the care-needs certification proportion of participants and non-participants in a geriatric health examination targeting community-dwelling seniors aged 70 years and older over 3 years. We implemented a geriatric health examination for 1347 community-dwelling adults aged 70 years and older in a local region of Japan in 2004. We followed the occurrence of new care-needs certification for 3 years in 443 subjects who participated in the health examination and in the 395 non-participants. Among the 838 subjects, there were 94 new certifications (11%) during the observation period. Non-participants had a significantly higher proportion of dependent, required assistance with walking and bathing, a history of stroke, poor self-reported health, tendency for depression and outdoors less than once a week than participants. Non-participants had a significantly lower average score of the motor fitness scale (MFS), their standing time from a long sitting position on the floor and the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG Index of Competence). The proportion of care-needs certification over 3 years was significantly higher for non-participants (63/395, 16%) than for participants (31/443, 7%, p<0.05). Non-participants have a higher risk of care-needs certification. It is necessary to investigate current data gathering methods for seniors who do not undergo these examinations.


Effective in vivo therapeutic IgG antibody against VP3 of enterovirus 71 with receptor-competing activity.
Passive immunization is an effective option for treatment against hand, foot and mouth disease caused by EV71, especially with cross-neutralizing IgG monoclonal antibodies. In this study, an EV71-specific IgG2a antibody designated 5H7 was identified and characterized. 5H7 efficiently neutralizes the major EV71 genogroups (A, B4, C2, C4). The conformational epitope of 5H7 was mapped to the highly conserved amino acid position 74 on VP3 capsid protein using escape mutants. Neutralization with 5H7 is mediated by the inhibition of viral attachment, as revealed by virus-binding and post-attachment assays. In a competitive pull-down assay with SCARB2, 5H7 blocks the receptor-binding site on EV71 for virus neutralization. Passive immunization of chimeric 5H7 protected 100% of two-week-old AG129 mice from lethal challenge with an EV71 B4 strain for both prophylactic and therapeutic treatments. In contrast, 10D3, a previously reported neutralizing antibody that takes effect after virus attachment, could only confer prophylactic protection. These results indicate that efficient interruption of viral attachment is critical for effective therapeutic activity with 5H7. This report documents a novel universal neutralizing IgG antibody for EV71 therapeutics and reveals the underlying mechanism.


Dismal outcome of relapsed or primary refractory adult T-cell lymphoblastic lymphoma: A retrospective study from China.
Little is known about the outcome and prognostic factors of relapsed or refractory T-cell lymphoblastic lymphoma (T-LBL), especially in adult patients. The aim of this study was to analyze the characteristics, outcome and prognostic factors for this patient population. Between January 2006 and December 2017, we retrospectively analyzed 84 adult patients with T-LBL, and 44 relapsed or primary refractory patients were included in this analysis. Clinical features, treatment and follow-up information were collected. For all 44 patients, the median time to disease progression or relapse was 9.5 months after diagnosis. At a median follow-up of 19.6 months, 40 (90.9%) patients died. The 3- and 5-year overall survival (OS) rates after disease progression or relapse were 7.8% and 5.2%, respectively. Among 30 patients who had detailed information of second-line treatment, only eight achieved a second complete remission (CR). Two of these eight patients subsequently underwent autologous or allogeneic stem cell transplantation (SCT), of whom one died from disease progression after autologous SCT, and one was free of event at 84 months after allogeneic SCT. Three of the rest six patients in second CR were still alive after chemotherapy alone. All the remaining patients who failed to gain second CR eventually died. In univariate analysis, only the achievement of second CR was positively predictive of OS (hazard ratio (HR) = 0.307; 95% confidence interval (CI), 0.104-0.905; P = 0.032). The outcome of adult patients with relapsed or refractory T-LBL is extremely dismal. Patients with relapsed or refractory T-LBL should be encouraged to participate in clinical trials where novel therapeutic approaches are available.


Lupus Recipe inhibits cGVHD-induced lupus nephritis in mice and promote renal LC3-associated autophagy.
Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). The chronic graft versus host disease (cGVHD) mouse model is a well-established model of SLE. LC3-associated autophagy plays a critical role in extracellular particle clearance, including pathogens and apoptotic cells. Lupus Recipe (LR) is a Chinese herbal compound that has been proven to be effective in treating SLE. In the study, we investigated the protective effects of LR or LR combined with prednisone on cGVHD mouse model and LC3-associated autophagy in the kidney. The mice were subjected to six groups. The LR treatment group received LR at the dosage of 1.15 and 2.3 g/kg/day, respectively. The corticosteroid treatment group received prednisone at a dosage of 5 mg/kg/day. The combination treatment group received LR at a dosage of 2.3 g/kg/day, and prednisone at 2.5 mg/kg/day. LR treatment reduced proteinuria and serum triglyceride levels, as well as spleen weight. LR also alleviated pathologic damage and immunoglobulin G deposition in the kidney. LR combined with a low dose of prednisone significantly improved kidney function and decreased serum triglyceride, total cholesterol, and spleen weight. In addition, combination treatment relieved kidney injury more effectively than LR alone. Western blot revealed that LR treatment or LR combined with prednisone increased the LC3-associated autophagy protein of Rubicon and Nox2, as well as LC3I levels in the kidney tissues. In conclusion, LR inhibited the manifestation of cGVHD-induced LN, which may attribute to the increased levels of LC3-associated autophagy.


Lectin-resistant variants of mouse Lewis lung carcinoma cells. II. Altered glycosylation of membrane glycoproteins.
Lectin-resistant variants of mouse Lewis lung carcinoma LL2 cell line, selected with wheat germ agglutinin (WGAR), Ricinus communis agglutinin II (RCA IIR) and Aleuria aurantia agglutinin (AAAR) were studied. Total cellular glycopeptides of the parent LL2 line and of the five lectin-resistant variants were analyzed by gel filtration and affinity chromatography on immobilized concanavalin A and Lens culinaris agglutinin. The results revealed that low-metastatic WGAR and RCA IIR variants possessed less highly branched tri- and tetra-antennary N-acetyllactosaminic type glycans with a simultaneous increase in biantennary N-acetyllactosaminic type, oligomannosidic type or hybrid type glycans, as compared to the parent metastasizing LL2 cell line. These findings imply that cell surface carbohydrate changes may possibly be relevant for metastasis. However, the AAAR variant, which possessed reduced spontaneous metastatic ability after s.c. administration, but increased experimental metastatic ability after i.v. inoculation, exhibited apparently the same glycan pattern than the parent LL2 line. This particular variant is under investigation in order to find specific modification(s) of glycan(s) which could play a specific role in the metastatic process.


A randomised controlled trial of computerised interpretation bias modification for health anxiety.
Health anxiety is characterised by a tendency to interpret benign bodily sensations as a sign of serious illness. This study aimed to examine whether computerised cognitive bias modification (CBM-I) training to facilitate benign interpretations of bodily symptoms could reduce these negative interpretations of bodily symptoms, health anxiety and comorbid symptoms. Participants (N = 89) with clinical levels of health anxiety (Short Health Anxiety Inventory [SHAI] scores ≥20) were randomised to receive two internet-delivered 30-min sessions of either CBM-I interpretation training (Intervention) or control CBM-I training over 1-week. Participants were assessed at pre-treatment, post-treatment and 2-weeks follow-up on self-reported health anxiety, cognitions and attributions of bodily symptoms, and comorbid symptoms (e.g., depression). Results showed significantly reduced catastrophic attributions, health anxiety and related symptoms at post-treatment in both groups, which were maintained at 2-week follow-up. Although there were no significant group differences at post-treatment or follow-up, we found small non-significant effect sizes in favour of the CBM-I Intervention group on health anxiety and cognitions (Cohen's d's between-group effect sizes of 0.28 at post-treatment and d = 0.35 at follow-up on the 18-item Short Health Anxiety Inventory). The study was conducted online, limiting control over the setting in which participants completed training. Additionally, training was not tailored to the specific symptoms or diseases that participants feared. This study is the first to evaluate the effect of internet-delivered CBM-I training targeting benign interpretations of bodily symptoms on health anxiety. Further research is needed before this intervention is disseminated.


A time-of-flight-based reconstruction for real-time prompt-gamma imaging in proton therapy.
We propose a novel prompt-gamma (PG) imaging modality for real-time monitoring in proton therapy: PG time imaging (PGTI). By measuring the time-of-flight (TOF) between a beam monitor and a PG detector, our goal is to reconstruct the PG vertex distribution in 3D. In this paper, a dedicated, non-iterative reconstruction strategy is proposed (PGTI reconstruction). Here, it was resolved under a 1D approximation to measure a proton range shift along the beam direction. In order to show the potential of PGTI in the transverse plane, a second method, based on the calculation of the centre of gravity (COG) of the TIARA pixel detectors' counts was also explored. The feasibility of PGTI was evaluated in two different scenarios. Under the assumption of a 100 ps (rms) time resolution (achievable in single proton regime), MC simulations showed that a millimetric proton range shift is detectable at 2σwith 108incident protons in simplified simulation settings. With the same proton statistics, a potential 2 mm sensitivity (at 2σwith 108incident protons) to beam displacements in the transverse plane was found using the COG method. This level of precision would allow to act in real-time if the treatment does not conform to the treatment plan. A worst case scenario of a 1 ns (rms) TOF resolution was also considered to demonstrate that a degraded timing information can be compensated by increasing the acquisition statistics: in this case, a 2 mm range shift would be detectable at 2σwith 109incident protons. By showing the feasibility of a time-based algorithm for the reconstruction of the PG vertex distribution for a simplified anatomy, this work poses a theoretical basis for the future development of a PG imaging detector based on the measurement of particle TOF.


Mortality and severe morbidity of very preterm infants: comparison of two French cohort studies.
In Reunion Island, a French overseas department, the burden of preterm birth and perinatal mortality exceed those observed in mainland France, despite similar access to standard perinatal care. The purpose of the study was to compare the outcome of two cohorts of NICU-admitted very preterm infants born between 24 and 31 weeks of gestation (WG): the registry-based OGP (Observatoire de la Grande Prématurité, Reunion Island, 2008-2013) cohort, and the nationwide EPIPAGE-2 (mainland France, 2011) observational cohort. The primary outcome was adverse neonatal outcomes defined as a composite indicator of in-hospital mortality or any of three following severe morbidities: bronchopulmonary dysplasia (BPD), necrotising enterocolitis, or severe neurological injury (periventricular leukomalacia or grade III-IV intraventricular haemorrhages). Logistic regression modelling adjusting for confounders was performed. A total of 1272 very preterm infants from the Reunionese OGP cohort and 3669 peers from the mainland EPIPAGE-2 cohort were compared. Adverse neonatal outcomes were more likely observed in the OGP cohort (32.6% versus 26.6%, p < 0.001), as result of both increased in-hospital mortality across all gestational age strata and increased BPD among the survivors of the 29-31 WG stratum. After adjusting for gestational age, gender and multiple perinatal factors, the risk of adverse neonatal outcomes was higher in the OGP cohort than in the EPIPAGE-2 cohort across all gestational age strata. Despite similar guidelines for standard perinatal care, very preterm infants born in Reunion Island have a higher risk for death or severe morbidity compared with those born in mainland France.


The operation of the visual system in relation to action.
Neurophysiologists studying the visual representation of the world in the parietal lobe generally find that it is based in a gaze-centred (retinotopic) frame. Students of orientation, however, find that the brain also contains a more panoramic egocentric representation that allows appropriate motor actions to take place independent of the orientation of the eyes and head. This representation can operate temporarily without visual input, but is updated from the vestibular system and from other modalities. In this minireview, I shall consider how these two representations are kept aligned with each other, and how they relate to the organisation of motor actions and to the phenomenal world that we see.


Does possession of apolipoprotein E ɛ4 benefit cognitive function in healthy young adults?
There is considerable evidence that the apolipoprotein E (APOE) ɛ4 allele is associated with cognitive deficits in older persons, and is a risk factor for dementia. However, it has recently been suggested that possession of the ɛ4 allele may benefit cognition in early adulthood. We tested this possibility in 5445 community-dwelling persons aged 20-24, 40-44, and 60-64 years using a comprehensive battery of cognitive measures. As the APOE ɛ2 allele may offer protection against cognitive deficits, in order to robustly test the hypothesis, we removed persons carrying this allele from the analyses. Older persons with possible dementia were also removed. We found no evidence of higher cognitive performance in young ɛ4 carriers, or cognitive deficits in older ɛ4 carriers. This did not change when a range of health variables were taken into account. We conclude that it is premature to suppose ɛ4-related benefits to cognition in healthy young adulthood and findings consistent with this hypothesis may have been related to methodological issues, or the pathology of the sample investigated.


Comparison of long-term outcome of two endoscopic transtympanic myringoplasty without tympanomeatal flap elevating for repairing large chronic perforations.
We compare the long-term efficacy of the cartilage-perichondrium modified over-underlay technique and transtympanic underlay alone technique using endoscopic myringoplasty without tympanomeatal flap elevating for repairing large chronic perforations. Nine chronic large perforations with mucosal chronic otitis media were recruited and randomly allocated to endoscopic cartilage-perichondrium modified over-underlay myringoplasty (MOUM, n = 55) and endoscopic cartilage-perichondrium transtympanic underlay alone myringoplasty (TUAM, n = 54). The graft success rate, hearing gain, mean operation time and postoperative complications were compared between the groups at 6 and 24 months. In total, 99 patients were finally analysed. The graft success rates 6 months after surgery between MOUM and TUAM groups were not significantly different (100.0% vs 96.0%, p = 0.484). However, the MOUM group had a significantly higher success rate 24 months after surgery than the TUAM group (93.9% vs 76.0%, p = 0.028). In addition, postoperative ABG < 10 dB was 73.5% patients in the MOUM group and 76.0% in the TUAM group, the difference wasn't significant (p = 0.953). CT examination revealed well-pneumatised middle ears 24 months after surgery in both groups, and no middle ear cholesteatoma was observed. Endoscopic modified cartilage-perichondrium over-underlay myringoplasty without tympanomeatal flap elevating is reliable and effective for repairing large perforations. It improves the long-term graft success rate compared to the endoscopic cartilage-perichondrium transtympanic underlay alone technique. The risk for iatrogenic cholesteatoma is minimal.


Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana.
Cognitive performance was examined in 145 thirteen- to sixteen-year-old adolescents for whom prenatal exposure to marihuana and cigarettes had been ascertained. The subjects were from a low-risk, predominantly middle-class sample participating in an ongoing, longitudinal study. The assessment battery included tests of general intelligence, achievement, memory, and aspects of executive functioning (EF). Consistent with results obtained at earlier ages, the strongest relationship between prenatal maternal cigarette smoking and cognitive variables was seen with overall intelligence and aspects of auditory functioning whereas prenatal exposure to marihuana was negatively associated with tasks that required visual memory, analysis, and integration. The interpretation of the results is discussed in terms of the differential observations related to in utero exposure to cigarettes and marihuana and the nature of the cognitive variables associated with the two drugs.


Using neuroimaging genomics to investigate the evolution of human brain structure.
Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past.