Glycoengineering tobacco plants to stably express recombinant human erythropoietin with different N-glycan profiles.
Plant-based expression system has many potential advantages to produce biopharmaceuticals, but plants cannot be directly used to express human glycoproteins because of their differences in glycosylation abilities from mammals. To exploit plant-based expression system for producing recombinant human erythropoietin (rhuEPO), we glycoengineered tobacco plants by stably introducing seven to eight mammalian genes including a target human EPO into tobacco in order to generate capacities for β1,4-galactosylation, bisecting N-acetylglucosamine (GlcNAc) and sialylation. Wild type human β1,4-galactosyltransferase gene (GalT) or a chimeric GalT gene (ST/GalT) was co-expressed to produce rhuEPO bearing β1,4-galactose-extended N-glycan chains as well as compare their β1,4-galactosylation efficiencies. Five mammalian genes encoding enzymes/transporter for sialic acid biosynthesis, transport and transfer were co-expressed to build sialylation capacity in plants. The human MGAT3 was co-expressed to produce N-glycan chains with bisecting GlcNAc. Our results demonstrated that the above transgenes were incorporated into tobacco genome and transcribed. ST/GalT was found to be more efficient than GalT for β1,4-galactosylation. Furthermore, co-expressing MGAT3 generated N-glycans likely bearing bisected GlcNAc. However, our current efforts did not result in generating sialylation capacity. Created transgenic plants expressing EPO and ST/GalT could be used to produce rhuEPO with high proportion of β1,4-galactose-extended N-glycan chains for tissue protective purposes.


The use of ozone-treated blood in the therapy of HIV infection and immune disease: a pilot study of safety and efficacy.
The use of ozone therapy is reported to be effective in a variety of viral illnesses, including HIV disease. We performed a phase I study of ozone blood treatments in 10 patients in whom no significant toxicity was observed. Three patients with moderate immunodeficiency showed improvement in surrogate markers of HIV-associated immune disease. A phase II controlled and randomized double-blinded study was initiated comparing reinjection of ozone-treated blood, and reinjection of unprocessed blood for 8 weeks, followed by a 4-week observation period. Ozone had no significant effect on hematologic, biochemical or clinical toxicity when compared with placebo. CD4 cell count, interleukin-2, gamma-interferon, beta 2-microglobulin, neopterin and p24 antigen were also unaffected by both treatment arms. In conclusion, ozone therapy does not enhance parameters of immune activation nor does it diminish measureable p24 antigen in HIV-infected individuals.


Impact of covid-19 pandemic on quality of life and psychosocial difficulties among liver transplant recipients.
The first wave of the COVID-19 pandemic affected health in all domains i.e., physical, mental, and social aspects. Liver transplant (LT) recipients faced a multitude of challenges during the first wave of lockdown. The aim was to identify the psychosocial difficulties and quality of life during the first year of the pandemic. A cross-sectional survey was conducted on LT recipients with a predefined structured questionnaire that included clinical, COVID-19 anxiety scale, and Post-Transplant Quality of life questionnaire (pLTQ). A total of 109 patients were studied; with a mean age of 50.5 ± 11.1 years, with a median post-transplant follow-up of 52.4 months and a live donor transplant in the majority (79.8%). Almost all (99.1%) could come to the hospital for regular follow-up, prior to the pandemic. But during the first wave only 57% could maintain planned hospital visits and about 88% could not pursue their regular activities, and 39% missed their routine exercise because of imposed restrictions. Similarly, financial implications were responsible for 4% defaulting from treatment; while 7.3% managed by curtailing supportive drugs (on their own) leading to deranged liver tests in 4.6%; requiring immediate attention. The psychosocial difficulties raised the stress of pandemic (median score 18), and impacted quality of life (mean total pLTQ score 4.7 ± 0.9). For LT recipients, the first wave of COVID-19 pandemic affected their physical, mental, financial, and social wellbeing; in addition to the disease itself. Awareness, psychosocial support, and comprehensive care are some unmet needs for this special group; especially when it is expected that subsequent waves may continue to occur.


Mesenchymal stem cell abnormalities in patients with multiple myeloma.
Osteolytic bone lesions are common in patients with multiple myeloma (MM), a clonal plasma cell disorder, and result from increased osteoclastic bone resorption and decreased osteoblastic bone formation. Because mesenchymal stem cells (MSCs) are committed towards cells of the osteoblast lineage, we compared the in vitro characteristics of MSCs from the bone marrow of 18 MM patients (MM-MSCs) and eight normal donors (ND-MSCs). MM-MSCs displayed deficient growth that could be explained in part by the reduced expression of several growth factor receptors on the surface of MM-MSCs compared with ND-MSCs. Receptor downregulation was observed on RT-PCR analysis. A major finding was an approximately fivefold higher expression of osteoblast inhibitor DKK1 at transcript and protein levels in MM-MSCs than ND-MSCs. These data suggest that defective osteoblast function in patients with advanced MM may be related not only to factors released by tumor myeloma cells but also to MSC abnormalities.


Synthesis of Mesoporous and Hollow SiO2@ Eu(TTA)3phen with Enhanced Fluorescence Properties.
Lanthanide ions are extensively utilized in optoelectronic materials, owing to their narrow emission bandwidth, prolonged lifetime, and elevated fluorescence quantum yield. Inorganic non-metallic materials commonly serve as host matrices for lanthanide complexes, posing noteworthy challenges regarding loading quantity and fluorescence performance stability post-loading. In this investigation, an enhanced Stöber method was employed to synthesize mesoporous hollow silica, and diverse forms of SiO2@Eu(TTA)3phen (S@Eu) were successfully prepared. Transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS), Fourier-transform infrared (FTIR) spectroscopy, and X-ray photoelectron spectroscopy (XPS) outcomes revealed the effective binding of silica with Eu(TTA)3phen through both physical adsorption and chemical bonding. This includes the formation of Si-O-C bonds between silica and the ligand, as well as Si-O-Eu bonds between silica and europium ions. Fluorescence tests demonstrated that the mesoporous SiO2@Eu(TTA)3phen(MS@Eu) composite exhibited the highest fluorescence intensity among the three structured silica composites, with a notable enhancement of 46.60% compared to the normal SiO2@Eu(TTA)3phen composite. The Brunauer-Emmett-Teller (BET) analysis indicated that the specific surface area plays a crucial role in influencing the fluorescence intensity of SiO2@Eu(TTA)3phen, whereby the prepared mesoporous hollow silica further elevated the fluorescence intensity by 61.49%. Moreover, SiO2@Eu(TTA)3phen demonstrated 11.11% greater cyclic stability, heightened thermal stability, and enhanced alkaline resistance relative to SiO2@Eu(TTA)3phen.


[ZApprO versus ZÄPrO: results of a first comparative study].
More than 60 years after the enactment of the first Licensing Regulations for Dentists (ZÄPrO), a new Licensing Regulations for Dentists, the ZApprO, was implemented in 2020. The aims of this study were to evaluate and compare the "Course in Technical Propaedeutics" (TPK) with the course "Dental Propaedeutics with a Focus on Dental Technology" (ZPDT), which are based on different legal foundations. The following parameters were compared after completion of the courses: (1) theoretical and practical knowledge, (2) regular department-internal learner evaluation, and (3) special evaluation of learning conditions by the learners and (4) by the instructors. The theoretical and practical exams and the questionnaires were analyzed in terms of their test-statistical characteristics (difficulty, discrimination index, internal consistency). Group comparisons between TPK and ZPDT were conducted using t‑tests for independent groups. Significant differences were only detected in the students' evaluation of their learning conditions, with theoretical and practical knowledge transfer being rated lower in the TPK than in the ZPDT. The comparable results of the knowledge assessments and the regular learner evaluation, triangulated with the comprehensive learner and instructor evaluation, allowed a broad assessment of both courses. The significant differences identified provide opportunities for optimization of the newly implemented ZPDT course.


Oral and maxillofacial surgery--character of the specialty.
Because of its similarities to other disciplines in dentistry and to medicine, the boundaries of oral and maxillofacial surgery are not easily defined. Some of the characteristics of the specialty include depth of the medical and biological knowledge of patients required, competitive selection and extensive training, hospital training and practice, and well articulated standards and support from its professional organization, the American Association of Oral and Maxillofacial Surgeons.


Factors associated with awake bruxism according to perceptions of parents/guardians and self-reports of children.
Bruxism is a repetitive activity of the masticatory muscles that has been associated with orofacial disorders and psychosocial factors AIM: The aim of this study was to investigate associations between possible awake bruxism (PAB) and family functioning, bullying, and dental caries in children 8-10 years of age. A school-based study was conducted with 739 pairs of parents/guardians and children. The parents/guardians answered the Family Adaptability and Cohesion Evaluation Scales for the establishment of family functioning. Information on bullying due to dental conditions was collected from the children. Dental caries in the children was evaluated using International Caries Detection and Assessment System criteria. A directed acyclic graph was used to define the theoretical model and select control factors. Descriptive analysis was performed, followed by multivariate logistic regression for complex samples. Considering the parental reports, fewer years of mother's schooling, a low family income, very flexible family adaptability, and cavitated dental caries were associated with PAB. The female sex, bullying, and orofacial dysfunction were associated with self-reported PAB. Therefore, the factors associated with PAB differ according to the reports of parents/guardians or self-reports of children. Healthcare providers should consider both reports for a more effective intervention addressing PAB.


Stem cells: the pursuit of genomic stability.
Stem cells harbor significant potential for regenerative medicine as well as basic and clinical translational research. Prior to harnessing their reparative nature for degenerative diseases, concerns regarding their genetic integrity and mutation acquisition need to be addressed. Here we review pluripotent and multipotent stem cell response to DNA damage including differences in DNA repair kinetics, specific repair pathways (homologous recombination vs. non-homologous end joining), and apoptotic sensitivity. We also describe DNA damage and repair strategies during reprogramming and discuss potential genotoxic agents that can reduce the inherent risk for teratoma formation and mutation accumulation. Ensuring genomic stability in stem cell lines is required to achieve the quality control standards for safe clinical application.


Growing Racial Disparities in the Utilization of Adult Spinal Deformity Surgery: An Analysis of Trends From 2004 to 2014.
Retrospective. The purpose of this study was to assess trends in utilization rates of adult spinal deformity (ASD) surgery, as well as perioperative surgical metrics between Black and White patients undergoing operative treatment for ASD in the United States. Racial disparities in access to care, complications, and surgical selection have been shown to exist in the field of spine surgery. However, there is a paucity of data concerning racial disparities in the management of ASD patients. Adult patients undergoing ASD surgery from 2004 to 2014 were identified in the nationwide inpatient sample (NIS). Utilization rates, major complications rates, and length of stay (LOS) for Black patients and White patients were trended over time. Utilization rates were reported per 1,000,000 people and determined using annual census data among subpopulations stratified by race. All reported complication rates and prolonged hospital stay rates are adjusted for Elixhauser Comorbidity Index, income quartile by zip code, and insurance payer status. From 2004 to 2014, ASD utilization for Black patients increased from 24.0 to 50.9 per 1,000,000 people, whereas ASD utilization for White patients increased from 29.9 to 73.1 per 1,000,000 people, indicating a significant increase in racial disparities in ASD utilization (P-trend < 0.001). There were no significant differences in complication rates or rates of prolonged hospital stay between Black and White patients across the time period studied (P > 0.05 for both). Although Black and White patients undergoing ASD surgery do not differ significantly in terms of postoperative complications and length of hospital stay, there is a growing disparity in utilization of ASD surgery between White and Black patients from 2004 to 2014 in the United States. There is need for continued focus on identifying ways to reduce racial disparities in surgical selection and perioperative management in spine deformity surgery.Level of Evidence: 3.


Image mosaicking using SURF features of line segments.
In this paper, we present a novel image mosaicking method that is based on Speeded-Up Robust Features (SURF) of line segments, aiming to achieve robustness to incident scaling, rotation, change in illumination, and significant affine distortion between images in a panoramic series. Our method involves 1) using a SURF detection operator to locate feature points; 2) rough matching using SURF features of directed line segments constructed via the feature points; and 3) eliminating incorrectly matched pairs using RANSAC (RANdom SAmple Consensus). Experimental results confirm that our method results in high-quality panoramic mosaics that are superior to state-of-the-art methods.


Clinical and electrodiagnostic abnormalities of the median nerve in US Army Dental Assistants at the onset of training.
Dental personnel including dentists, dental hygienists, and dental assistants have been reported as having a high prevalence of upper-extremity musculoskeletal disorders, including carpal tunnel syndrome. Previous research has not involved dental assistant students at the onset of dental training. Therefore, the purpose of this study was to determine the presence of median and ulnar neuropathies in US Army dental assistants at the onset of their training. Fifty-five US Army Soldiers (28 female, 27 male) enrolled in the Dental Assistant (68E) course, volunteered to participate in the study. The mean age of the dental assistant students was 24±7.2 years (range 18-41 years). There were 45 right handed dental assistant students, and the mean length of time in the Army prior to dental training was 27 months (range 3-180 months). Subjects were evaluated during the first week of their 10-week dental assistant course. Subjects completed a history form, were interviewed, and underwent a physical examination. Electrophysiological status of the median and ulnar nerves of both upper extremities was obtained by performing motor and sensory nerve conduction studies. Descriptive statistics for subject demographics and nerve conduction study variables were calculated. Six of the 55 subjects (11%) presented with abnormal electrophysiologic values suggestive of median mononeuropathy at or distal to the wrist. Five of the subjects had abnormal electrophysiologic values in both hands. Five of these 6 subjects had clinical examination findings consistent with the electrophysiological findings. The ulnar nerve electrophysiologic assessment was normal in all subjects sampled. The prevalence of median mononeuropathies in this sample of Army dental assistants at the onset of training is greater than 5% prevalence reported in previous healthy populations and is less than 26% prevalence in previous research examining Army dental assistants with dental work experience. Median neuropathy at or distal to the wrist has been reported in dental personnel including dentists, dental hygienists, and dental assistants, and is also prevalent in this sample of dental assistants at the onset of training. Further long-term prospective research involving the impact of dental practice and techniques for reducing upper extremity injuries in dental professionals appears to be warranted.


A herbicide resistance risk assessment for weeds in wheat and barley crops in New Zealand.
We estimated the risk of selecting for herbicide resistance in 101 weed species known to occur in wheat and barley crops on farms in New Zealand. A protocol was used that accounts for both the risk that different herbicides will select for resistance and each weed's propensity to develop herbicide resistance based on the number of cases worldwide. To provide context we documented current herbicide use patterns. Most weeds (55) were low-risk, 30 were medium-risk and 16 high-risk. The top ten scored weeds were Echinochloa crus-galli, Poa annua, Lolium multiflorum, Erigeron sumatrensis, Raphanus raphanistrum, Lolium perenne, Erigeron bonariensis, Avena fatua, Avena sterilis and Digitaria sanguinalis. Seven out of ten high-risk weeds were grasses. The most used herbicides were synthetic auxins, an enolpyruvylshikimate-phosphate synthase inhibitor, acetolactate synthase (ALS) inhibitors, carotenoid biosynthesis inhibitors, and long-chain fatty acid inhibitors. ALS-inhibitors were assessed as posing the greatest risk for more species than other modes-of-action. Despite pre-emergence herbicides being known to delay resistance, New Zealand farmers only applied flufenacet and terbuthlazine with high frequency. Based on our analysis, surveys for herbicide-resistant species should focus on the high-risk species we identified. Farmer extension efforts in New Zealand should address resistance evolution in cropping weeds.


The genus Gallerucida Motschulsky in Taiwan (Insecta, Coleoptera, Chrysomelidae, Galerucinae).
Species within the genus Gallerucida Motschulsky recorded in Taiwan are revised. Gallerucida bifasciata Motschulsky 1861 G. lutea Gressitt & Kimoto 1963 G. sauteri Chûjô 1938 and G. shirozui Kimoto 1969 are redescribed. Sphenoraia chujoi Lee 2014 is proposed as a junior synonym of G. flaviventris (Baly 1861). Gallerucida thoracica (Jacoby 1888) is recorded as new for Taiwan and redescribed. Lectotypes are designated for Gallerucida nigrita Chûjô 1935 G. sauteri Chûjô 1938 and Eustetha thoracica Jacoby 1888. Biological notes are given on all Taiwanese species of Gallerucida.


Identification of a Novel Myxoma Virus C7-Like Host Range Factor That Enabled a Species Leap from Rabbits to Hares.
Myxoma virus (MYXV) is naturally found in rabbit Sylvilagus species and is known to cause lethal myxomatosis in European rabbits (Oryctolagus cuniculus). In 2019, an MYXV strain (MYXV strain Toledo [MYXV-Tol]) causing myxomatosis-like disease in Iberian hares (Lepus granatensis) was identified. MYXV-Tol acquired a recombinant region of ∼2.8 kb harboring several new genes, including a novel host range gene (M159) that we show to be an orthologous member of the vaccinia virus C7 host range family. Here, to test whether M159 alone has enabled MYXV to alter its host range to Iberian hares, several recombinant viruses were generated, including an MYXV-Tol ΔM159 (knockout) strain. While MYXV-Tol underwent fully productive infection in hare HN-R cells, neither the wild-type MYXV-Lau strain (lacking M159) nor vMyxTol-ΔM159 (deleted for M159) was able to infect and replicate, showing that the ability of MYXV-Tol to infect these cells and replicate depends on the presence of M159. Similar to other C7L family members, M159 was shown to be expressed as an early/late gene but was translocated into the nucleus at later time points, indicating that further studies are needed to elucidate its role in the nucleus. Finally, in rabbit cells, the M159 protein did not contribute to increased replication but was able to upregulate the replication levels of MYXV in nonpermissive and semipermissive human cancer cells, suggesting that the M159-targeted pathway is conserved across mammalian species. Altogether, these observations demonstrate that the M159 protein plays a critical role in determining the host specificity of MYXV-Tol in hare and human cells by imparting new host range functions. IMPORTANCE The coevolution of European rabbit populations and MYXV is a textbook example of an arms race between a pathogen and a host. Recently, a recombinant MYXV (MYXV-Tol) crossed the species barrier by jumping from leporid species to another species, causing lethal myxomatosis-like disease. Given the highly pathogenic nature of this new virus in hares and the incidences of other poxvirus cross-species spillovers into other animals, including humans, it is important to understand how and why MYXV-Tol was able to become virulent in a new host species. The results presented clearly demonstrate that M159 is the key factor allowing MYXV-Tol replication in hare cells by imparting new host range functions. These results have the potential to improve current knowledge about the virulence of poxviruses and provide a platform to better understand the new MYXV-Tol, rendering the virus capable of leaping into a new host species.


The practice of nurses caring for families of pediatric inpatients in light of Jean Watson.
Objective To know the facilities and the difficulties of nurses in caring practice of hospitalized children's families in the light of Jean Watson's Theory of Human Caring. Method It was used the descriptive qualitative approach. The data collection was conducted in three stages: presentation of theoretical content; engagement with families in the light of Watson's theory; and semi-structured interview with 12 pediatric nurses. The interviews were analysed using inductive thematic analysis, being possible to form three themes: Recognizing a framework for care; Considering the institutional context; and Challenges in family's relationship. Results The theory favored reflections about self, about the institutions and about nurses' relationship with the family of the child, normalized by a consciousness toward caring attitudes. Conclusion In this process, it is imperative that nurses recognize the philosophical-theoretical foundations of care to attend the child's family in hospital.


Pediatric lung transplantation: Dynamics of the microbiome and bronchiolitis obliterans in cystic fibrosis.
Compositional changes in the microbiome are associated with the development of bronchiolitis obliterans (BO) after lung transplantation (LTx) in adults with cystic fibrosis (CF). The association between the lower airway bacterial community and BO after LTx in children with CF remains largely unexplored and is possibly influenced by frequent antibiotic therapy. The objectives of this study were to examine the relationship between bacterial community dynamics and the development of BO and analyze antibiotic resistance trends in children after LTx for CF. For 3 years from the time of transplant, 12 LTx recipients were followed longitudinally, with 5 subjects developing BO during the study period. A total of 82 longitudinal bronchoalveolar lavage samples were collected during standard of care bronchoscopies. Metagenomic shotgun sequencing was performed on the extracted microbial DNA from bronchoalveolar lavage specimens. Taxonomic profiling was constructed using WEVOTE pipeline. The longitudinal association between development of BO and temporal changes in bacterial diversity and abundance were evaluated with MetaLonDA. The analysis of antibiotic resistance genes was performed with the ARGs-OAP v2.0 pipeline. All recipients demonstrated a Proteobacteria-predominant lower airways community. Temporal reduction in bacterial diversity was significantly associated with the development of BO and associated with neutrophilia and antibiotic therapy. Conversely, an increasing abundance of the phylum Actinobacteria and the orders Neisseriales and Pseudonocardiales in the lower airways was significantly associated with resilience to BO. A more diverse bacterial community was related to a higher expression of multidrug resistance genes and increased proteobacterial abundance. Decreased diversity within bacterial communities may suggest a contribution to pediatric lung allograft rejection in CF.


Nonsexual relationships between psychotherapists and their former clients: obligations of psychologists.
This article examines the issue of nonsexual relationships between psychologists and their former therapy clients. What little research is available concerning nonsexual relationships with former clients suggests that psychologists have clear reservations about some of these relationships, especially personal ones and intentional social interactions. Relationships immediately following termination are seen as particularly suspect. Drawing on the literature dealing with multiple relationships in general, and sexual relationships with former clients in particular, a number of arguments are made outlining why psychologists should avoid significant nonsexual relationships with former clients for at least some period of time following termination.


Design of negative-regulating proteins of Rheb/mTORC1 with much-reduced sizes of the tuberous sclerosis protein complex.
The mTORC1 signaling pathway regulates cell growth and metabolism in a variety of organisms from yeast to human, and inhibition of the mTORC1 pathway has the prospect to treat cancer or achieve longevity. The tuberous sclerosis protein complex (TSCC) is a master negative regulator of the mTORC1 signaling pathway through hydrolyzing the GTP loaded on the small GTPase Rheb, which is a key activator of mTOR. However, the large size (~700 kDa) and complex structural organization of TSCC render it vulnerable to degradation and inactivation, thus limiting its potential application. In this work, based on thorough analysis and understanding of the structural mechanism of how the stabilization domain of TSC2 secures the association of TSC2-GAP with Rheb and thus enhances its GAP activity, we designed two proteins, namely SSG-MTM (short stabilization domain and GAP domain-membrane targeting motif) and SSG-TSC1N, which were able to function like TSCC to negatively regulate Rheb and mTORC1, but with much-reduced sizes (~1/15 and ~ 1/9 of the size of TSCC, respectively). Biochemical and cell biological assays demonstrated that these designed proteins indeed could promote the GTPase activity of Rheb to hydrolyze GTP, inhibit the kinase activity of mTORC1, and prevent mTORC1 from down-regulating catabolism and autophagy.


New data analysis and mining approaches identify unique proteome and transcriptome markers of susceptibility to autoimmune diabetes.
Non-obese diabetic (NOD) mice spontaneously develop autoimmunity to the insulin producing beta cells leading to insulin-dependent diabetes. In this study we developed and used new data analysis and mining approaches on combined proteome and transcriptome (molecular phenotype) data to define pathways affected by abnormalities in peripheral leukocytes of young NOD female mice. Cells were collected before mice show signs of autoimmunity (age, 2-4 weeks). We extracted both protein and RNA from NOD and C57BL/6 control mice to conduct both proteome analysis by two-dimensional gel electrophoresis and transcriptome analysis on Affymetrix expression arrays. We developed a new approach to analyze the two-dimensional gel proteome data that included two-way analysis of variance, cluster analysis, and principal component analysis. Lists of differentially expressed proteins and transcripts were subjected to pathway analysis using a commercial service. From the list of 24 proteins differentially expressed between strains we identified two highly significant and interconnected networks centered around oncogenes (Myc and Mycn) and apoptosis-related genes (Bcl2 and Casp3). The 273 genes with significant strain differences in RNA expression levels created six interconnected networks with a significant over-representation of genes related to cancer, cell cycle, and cell death. They contained many of the same genes found in the proteome networks (including Myc and Mycn). The combination of the eight, highly significant networks created one large network of 272 genes of which 82 had differential expression between strains either at the protein or the RNA level. We conclude that new proteome data analysis strategies and combined information from proteome and transcriptome can enhance the insights gained from either type of data alone. The overall systems biology of prediabetic NOD mice points toward abnormalities in regulation of the opposing processes of cell renewal and cell death even before there are any clear signatures of immune system activation.


A modular and enantioselective synthesis of the pleuromutilin antibiotics.
The tricyclic diterpene fungal metabolite (+)-pleuromutilin has served as a starting point for antibiotic development. Semisynthetic modification of its glycolic acid subunit at C14 provided the first analogs fit for human use, and derivatization at C12 led to 12-epi-pleuromutilins with extended-spectrum antibacterial activity, including activity against Gram-negative pathogens. Given the inherent limitations of semisynthesis, however, accessing derivatives of (+)-pleuromutilin with full control over their structure presents an opportunity to develop derivatives with improved antibacterial activities. Here we disclose a modular synthesis of pleuromutilins by the convergent union of an enimide with a bifunctional iodoether. We illustrate our approach through synthesis of (+)-12-epi-mutilin, (+)-11,12-di-epi-mutilin, (+)-12-epi-pleuromutilin, (+)-11,12-di-epi-pleuromutilin, and (+)-pleuromutilin itself in 17 to 20 steps.


Adherence and utilization of short-term antibiotics: Randomized controlled study.
Enhancing adherence to medication has the potential to improve clinical outcomes and decrease healthcare cost. The role of clinical pharmacist-led education on adherence to short-term antibiotic has never been investigated in Jordan. This study aimed to evaluate the impact of an educational intervention on antibiotic short-term adherence and to assess the antibiotic utilization pattern. A prospective, single blinded, randomized controlled study was conducted in a tertiary referral hospital in Jordan. Adult patients diagnosed with acute infection and prescribed a short-term antibiotic course (< 30 day) were included in the study. Recruited patients were randomly allocated into control and intervention groups. Pharmaceutical education about the correct use of antibiotic/s was provided to the intervention group. The results showed that penicillins were the most prescribed antibiotics (38.7%) followed by fluoroquinolones (23.9%) and cephalosporines (20.9%). Patients in the intervention group were more likely to be adherent to the prescribed antibiotics compared to control group (OR = 1.445, 95CI% = 1.029-2.030, p = 0.033). Employed patients, less frequent administration of antibiotic, and searching information related to the prescribed antibiotics were factors associated with better adherence to short-term antibiotic (p<0.05). The most common reasons for non-adherence were feeling better and forgetfulness to take medication. These findings highlighted that pharmacist-led educational intervention significantly enhance adherence to prescribed short-term antibiotics which is a major drive to control antibiotic resistance. Initiatives should be adopted to include patient education as a regular element in the medication dispensing process. Clinical trial registration: The trial is registered at ClinicalTrials.gov (identifier: NCT05293977).


A Retrospective Study on the Fracture Toughness of the Coronal Restorations in Endodontically Restored Teeth. An Original Research.
The best treatment for the deeply carious tooth that cannot be restored is by the root canal therapy. This method has saved many patients from the loss of tooth. The common practice is either to deliver a full crown or close the access cavity with restoration. Hence in this study, the clinical longevity of the routine practice is tested for by analyzing the fracture toughness and the survival of the teeth that were restored endodontically with various materials. The hospital records were retrospectively evaluated from 2000 to 2010 for a decade. The demographics as well as the survival and the failure rates noted and compared for the various types of the restorations. The number of the walls of the teeth was also compared. Thousand teeth were considered in the study. Less than 7% of teeth had coronal fractures. Of the 93% teeth that had survived, the most common restoration was Individual post (+ crown) followed by GIC, amalgams, and crowns. The mean survival of the crown+ bridge & gold restoration was highest. The mean survival was 10 ± 2 years for the restored teeth without any fractures at the coronal level. The failure was greatest for the GIC followed by amalgam, and the variations when compared with other restorations were significant. There was no significant difference for the number of the walls on the crown; however, the number of walls present was proportional to the survival rate. The teeth that were covered with a crown were comparatively fracture resistant and had a better survival rate compared to other restorations. GIC showed highest fracture, and the post core with crown had the best survival. Restoration of the lost crown architecture and the reinforcement are the best methods that can be followed for the survivals.


DNA switches: from principles to applications.
The base sequence of nucleic acid encodes structural and functional properties into the biopolymer. Structural information includes the formation of duplexes, G-quadruplexes, i-motif, and cooperatively stabilized assemblies. Functional information encoded in the base sequence involves the strand-displacement process, the recognition properties by aptamers, and the catalytic functions of DNAzymes. This Review addresses the implementation of the information encoded in nucleic acids to develop DNA switches. A DNA switch is a supramolecular nucleic acid assembly that undergoes cyclic, switchable, transitions between two distinct states in the presence of appropriate triggers and counter triggers, such as pH value, metal ions/ligands, photonic and electrical stimuli. Applications of switchable DNA systems to tailor switchable DNA hydrogels, for the controlled drug-release and for the activation of switchable enzyme cascades, are described, and future perspectives of the systems are addressed.


Pea3 expression promotes the invasive and metastatic potential of colorectal carcinoma.
To investigate the function of Pea3 in colorectal carcinoma (CRC) invasion and metastatic potential. The expression of Pea3 during clinical progression of human CRC was investigated using Oncomine Research Edition. To assay Pea3 expression in established CRC cell lines, we performed western blotting of cell lysates. We employed shRNA-mediated knockdown of Pea3 in HCT116 (HCT) and LS174T CRC cells which was confirmed by real-time quantitative PCR (qPCR) and western blotting. Transwell invasion assays, MTS proliferation assays, anoikis assays, and fluorometric matrix metalloprotease (MMP) assays were performed to determine the effects of Pea3 knockdown on invasion, proliferation, anoikis and MMP activity in CRC cells in vitro. Alterations in epithelial-mesenchymal transition (EMT) and matrix metalloprotease (MMP) mRNA levels were determined by qPCR. CRC cells were injected into the flanks of nude mice to generate xenografts and tumor growth monitored with serial calliper measurements. To assay metastatic potential, CRC cells were injected into the spleen of nude mice, and histological analysis performed on the livers 21 d later. We demonstrated that reduction of Pea3 expression in CRC cells significantly impaired their invasive capacity (HCT.shPea3, 0.28 ± 0.04 fold, P < 0.01; LS.shPea3, 0.15 ± 0.04 fold; SW.shPea3, 0.23 ± 0.03, P < 0.01), reduced anoikis resistance (HCT.shPea3 75.4% ± 1.9% viable cells vs HCT.shCtrl 88.6% ± 0.6% viable cells, P < 0.01; LS.shPea3 71.7% ± 0.5% viable cells vs LS.Ctrl 89.6% ± 0.3% viable cells, P < 0.005, but had no effect on proliferation (HCT.shCtrl AUC 5098 ± 123 vs HCT.shPea3 5689 ± 151, P < 0.05; LS.shCtrl AUC 5600 ± 324.1 vs LS.shPea3 6423 ± 400, P < 0.05). In vivo, HCT.shPea3 and HCT.shCtrl tumour xenografts grew at a similar rate (HCT.shPea3 2.64 ± 0.82 fold vs HCT.shCtrl 2.88 ± 0.80 fold, P > 0.05). In keeping with a pro-metastatic function for Pea3 in CRC, several EMT markers and MMPs were downregulated in shPea3-expressing cells, suggesting that Pea3 may exert its effects through these processes. A reduction in overall MMP activity was observed in HCT.shPea3 cells compared to their control counterparts (HCT.shPea3 0.61 ± 0.04 fold, P < 0.005). This translated in vivo to the complete absence of metastases in the livers of mice that were grafted with CRC cells lacking Pea3. Conversely, CRC cells expressing Pea3 formed liver metastases in all mice. Our study implicates Pea3 as a mediator of metastases, and provides a biological rationale for the adverse prognosis associated with elevated Pea3 expression in human CRC.


Technology assessment. A framework for generating questions useful in evaluating nursing information systems.
Nursing information systems are computer systems that enable nurses to collect, manipulate, store, retrieve, display, and communicate data to administer nursing services and resources, manage nursing practice to improve patient care, and advance nursing knowledge. Selection and implementation of a nursing information system require a clear vision of the need for the system, careful planning, and astute forward thinking. Technology assessment provides a framework for generating pragmatic questions that can be used in systematically evaluating nursing information systems. This article provides a brief overview of nursing information systems, explains the technology assessment framework, and gives examples of questions useful in evaluating a nursing information system.


Clinical Assessment of Short (> 6 mm and ≤ 8.5 mm) Implants in Posterior Sites with an Average Follow-Up of 74 Months: A Retrospective Study.
To evaluate the survival and success rates of short (> 6 mm and ≤ 8.5 mm) implants after at least 2 years of functional loading. Implants were assessed using clinical parameters such as marginal bone loss (MBL), pocket depth (PD), keratinized mucosa width (KMW), bleeding on probing (BoP), and the peri-implant condition (mucositis or peri-implantitis). Any correlations between clinical parameters were analyzed. This observational and retrospective study included 114 posterior maxillary and mandibular implants placed in 27 women and 38 men with a mean age of 68.04 ± 9.07 years. Patients included in the study had received at least one short implant between 2001 and 2013, such that each implant was in occlusal function for at least 2 years by 2015. Patients with only long (≥ 10 mm) implants, patients with any systemic condition, and smokers were excluded from the study. PD, KMW, peri-implant condition, BoP, and MBL were the clinical parameters assessed in the study. Data on prosthesis type (single or splinted) and implant features were also obtained. All data were submitted to analysis via Mann-Whitney unpaired test, with a significance level of P < .05. Spearman correlation coefficient was also measured to verify the negative or positive correlation. The mean follow-up time was 74.08 months, and mean implant success and survival rates were 87.63% and 94.74%, respectively. There were 6 implant failures (5.26%). A total of 66 (59.46%) prostheses were screw-retained implant-supported restorations, and 45 (40.54%) were cemented. A total of 93 (86.49%) short implants were splinted to another implant, and 15 out of 111 (13.51%) restorations were single implants. Keratinized mucosa was missing around 43 (39%) implants, whereas PD was measured to be between 0 and 3 mm in 64.86% of implants and ≥ 4 mm in 31.53% of implants. MBL was ≤ 1.5 mm in 71.17% of cases and > two-thirds the length of the implant in 2.71% of cases. Mucositis and peri-implantitis were found in 22.52% and 7.21% of implants, respectively. The correlation coefficient showed a positive result for PD and MBL (0.11; P = .368) and negative results for PD and KMW (-0.42; P = .002) and KMW and MBL (-0.19; P = .183). Within the limitations of this study, it is possible to conclude that short implants are a feasible treatment option for dental rehabilitation. They are considered an excellent alternative to complex procedures and have high survival rates after at least 2 years of follow-up, with compatible peri-implant local tissue response. Moreover, a significant negative correlation between KMW and PD was observed.


Genome-wide investigation of bHLH genes and expression analysis under different biotic and abiotic stresses in Helianthus annuus L.
The basic helix-loop-helix (bHLH) transcription factors play important roles in many processes such as plant growth, metabolism and response to biotic/abiotic stresses. Sunflower (Helianthus annuus) is a major oil crop, cultivated throughout the world. However, no systematic characterization of bHLH gene members in sunflower (HabHLH) and their functions involved in drought, cadmium tolerance and Orobanche cumana resistance has been reported yet. In this study, 183 HabHLH genes were identified and named according to their chromosomal locations. We classified these proteins into 21 subfamilies by phylogenetic tree analysis. Subsequently, DNA-binding patterns, sequence analysis, duplication analysis and gene structures were analyzed. All of the HabHLH genes were randomly distributed on 17 chromosomes, and 10 pairs of tandem duplicated genes and one pair of segmental duplicated genes were detected in the HabHLH family. Among the duplicated gene pairs, eight pairs of HabHLH genes suffer from positive selection. Moreover, qRT-PCR results revealed significant up-regulated expression of HabHLH024 gene in response to both abiotic (cadmium, drought) and biotic (Orobanche cumana) stresses, suggesting its important functions in response to different stresses. Therefore, HabHLH024 would be the potential candidate gene for the sunflower tolerance breeding.


Hypnotherapeutic ego strengthening with male South African coronary artery bypass patients.
Morbidity (i.e., elevated anxiety and depression) is a common feature of coronary artery bypass surgery (CABS) patients, pre- and postoperatively. Since hypnotherapy can possibly reduce morbidity in CABS patients, the aim of this study was to determine the feasibility of hypnotherapeutic ego strengthening (HES) to facilitate patient coping with concomitant anxiety and depression. Fifty patients were randomly assigned to a non-intervention control group (n = 25) and an experimental group (n = 25) and exposed to a pre- and postoperative HES intervention. Anxiety and depression were assessed with the Beck Depression Inventory and Profile of Mood States, administered preoperatively, at discharge, and at 6-week follow-up. Findings confirmed large practical reductions of anxiety and depression in the experimental group and were maintained at follow-up, while a trend towards increased depression levels occurred in the control group. Although not generalizable, results suggest broadened applications of hypnotherapy with patients in cardiac centers.


Momentary intentions and perceived behavioral control are within-person predictors of sedentary leisure time: preliminary findings from an ecological momentary assessment study in adolescents.
Previous studies among adolescents conceptualize behavioral cognitions [e.g., intentions and perceived behavioral control (PBC)] as stable trait-like factors despite evidence suggesting they vary momentarily. We examined whether intentions and PBC momentarily relate to subsequent sedentary time during non-school periods. Healthy adolescents (N = 15, ages 11-15) reported their intentions and PBC regarding sedentary leisure behaviors via ecological momentary assessment (EMA) up to seven times/day for 14 days. Sedentary time in the two hours following each EMA prompt was measured by ActivPAL accelerometers. When participants reported greater sedentary intentions (within-person β = 1.1, 95% CI 0.2, 2.1, p = 0.0213) and sedentary PBC (within-person β = 1.7, 95% CI 0.6, 2.8, p = 0.0029), they accumulated greater sedentary time. This demonstrates that sedentary intentions and PBC are acutely associated with sedentary time among adolescents. Our findings highlight the potential for implementing just-in-time activity interventions among adolescents during at-risk periods within the day, characterized by deviations from one's usual intentions and PBC levels.


Locked intramedullary nail: metacarpal geometry study in adults.
Ideal fixation for metacarpal fracture should provide immediate stability to allow early rehabilitation. Locked intramedullary nail may fulfill the need. Metecarpal geometry has to be studied in order to design the locked intramedullaly nail. To study metacarpal geometry in adult cadaver for locked intramedullary nail design. Radiographs of metacarpals taken from 50 embalmed adult cadavers were measured for essential parameters for locked intramedullary nail design. Total length, proximal metaphyseal width, distal metaphyseal width, isthmus width and medullary canal width were measured. The parameters were analyzed by descriptive statistic. The average total lengths were rangedfrom 44.53 to 65.42 mm. The average metaphyseal widths ofmetacarpal bone were between 11.42 to 16.42 mm. The average medullary canal widths were between 3.05 to 6.74 mm. The extreme small (less than 3 mm) medullary canals were found in index, middle, ring and small metacarpals. The results of our study provide crucial preliminary data for locked metacarpal nail design for adult patient.


HIV mother-to-child transmission, mode of delivery, and duration of rupture of membranes: experience in the current era.
To evaluate whether the length of time of rupture of membranes (ROM) in optimally managed HIV-positive women on highly active antiretroviral therapy (HAART) with low viral loads (VL) is predictive of the risk of mother to child transmission (MTCT) of the human immunodeficiency virus (HIV). A retrospective case series of all HIV-positive women who delivered at two academic tertiary centers in Toronto, Canada from January 2000 to November 2010 was completed. Two hundred and ten HIV-positive women with viral loads <1,000 copies/ml delivered during the study period. VL was undetectable (<50 copies/mL) for the majority of the women (167, 80%), and <1,000 copies/mL for all women. Mode of delivery was vaginal in 107 (51%) and cesarean in 103 (49%). The median length of time of ROM was 0.63 hours (range 0 to 77.87 hours) for the entire group and 2.56 hours (range 0 to 53.90 hours) for those who had a vaginal birth. Among women with undetectable VL, 90 (54%) had a vaginal birth and 77 (46%) had a cesarean birth. Among the women in this cohort there were no cases of MTCT of HIV. There was no association between duration of ROM or mode of delivery and MTCT in this cohort of 210 virally suppressed HIV-positive pregnant women.


Genome Sequence of Streptomyces violaceusniger Strain SPC6, a Halotolerant Streptomycete That Exhibits Rapid Growth and Development.
Streptomyces violaceusniger strain SPC6 is a halotolerant streptomycete isolated from the Linze desert in China. The strain has a very high growth rate and a short life cycle for a streptomycete. For surface-grown cultures, the period from spore germination to formation of colonies with mature spore chains is only 2 days at 37°C. Additionally, the strain is remarkably resistant to osmotic, heat, and UV stress compared with other streptomycetes. Analysis of the draft genome sequence indicates that the strain has the smallest reported genome (6.4 Mb) of any streptomycete. The availability of this genome sequence allows us to investigate the genetic basis of adaptation for growth in an extremely arid environment.


Genetically encoded biosensors for visualizing live-cell biochemical activity at super-resolution.
Compartmentalized biochemical activities are essential to all cellular processes, but there is no generalizable method to visualize dynamic protein activities in living cells at a resolution commensurate with cellular compartmentalization. Here, we introduce a new class of fluorescent biosensors that detect biochemical activities in living cells at a resolution up to threefold better than the diffraction limit. These 'FLINC' biosensors use binding-induced changes in protein fluorescence dynamics to translate kinase activities or protein-protein interactions into changes in fluorescence fluctuations, which are quantifiable through stochastic optical fluctuation imaging. A protein kinase A (PKA) biosensor allowed us to resolve minute PKA activity microdomains on the plasma membranes of living cells and to uncover the role of clustered anchoring proteins in organizing these activity microdomains. Together, these findings suggest that biochemical activities of the cell are spatially organized into an activity architecture whose structural and functional characteristics can be revealed by these new biosensors.


Telomere Length in Human Spermatogenic Cells as a New Potential Predictor of Clinical Outcomes in ART Treatment with Intracytoplasmic Injection of Testicular Spermatozoa.
Predicting the clinical outcomes of intracytoplasmic sperm injection (ICSI) cycles that use the testicular spermatozoa of azoospermic patients presents a challenge. Thus, the development of additional approaches to assessing the competence of a testicular-sperm-derived embryo without causing damage to gametes or the embryo is necessary. One of the key parameters in determining such developmental competence is telomere length (TL). We aimed to analyze TLs in spermatogenic cells from the testicular biopsy samples of azoospermic patients and determine how this parameter influences embryo competence for pre- and post-implantation development. Using Q-FISH, we studied the TL of the chromosomes in spermatogonia and spermatocytes I from the TESE biopsy samples of 30 azoospermic patients. An increase in TL was detected during the differentiation from spermatogonia to spermatocytes I. The patients' testicular spermatozoa were used in 37 ICSI cycles that resulted in 22 embryo transfers. Nine pregnancies resulted, of which, one was ectopic and eight ended in birth. The analysis of embryological outcomes revealed a dependence between embryo competence for development to the blastocyst stage and the TL in spermatogenic cells. The TLs in spermatogonia and spermatocytes I in the testicular biopsy samples were found to be higher in patients whose testicular sperm ICSI cycles resulted in a birth. Therefore, the length of telomeres in spermatogenic cells can be considered as a potential prognostic criterion in assessing the competence of testicular-sperm-derived embryos for pre- and post-implantation development. The results of this study provide the basis for the development of a laboratory test for the prediction of testicular sperm ICSI cycle outcomes.


TAVR in Cancer Patients: Comprehensive Review, Meta-Analysis, and Meta-Regression.
Objectives: This study sought to systematically analyze the available clinical evidence on TAVR therapy in cancer patients with symptomatic severe AS. Background: Aortic stenosis is the most common valvular heart disease in the world. TAVR has expanded the treatment options for this lethal disease process. The safety and efficacy of TAVR in cancer patients has not yet been reliably established. We thus conducted the largest known multi-center meta-analysis on TAVR and cancer status. Methods: We performed a literature search using PubMed, EMBASE, and Cochrane Central Register of Controlled Trials from January 2015 to 2020. Studies that compared the use of TAVR in patients with severe symptomatic aortic stenosis and cancer against patients without cancer were included. Meta-regression was also conducted to determine if common clinical factors modified the possible association between cancer status and TAVR mortality. Results: Five studies with 11,129 patients in the cancer group and 41,706 patients in the control group met inclusion criteria. The short-term mortality in the cancer group was 2.4% compared with 3.3% in the control group (odds ratio: 0.72, 95% confidence interval: 0.63-0.82; p < 0.0001). The frequency of stroke was 2.4% compared with 2.7% (odds ratio of 0.87, 95% confidence interval: 0.76-0.99; p < 0.04). The frequency of AKI was 14.2% in cancer patients vs. 16.4% (odds ratio of 0.81, 95% confidence interval: 0.76-0.85; p < 0.04). The rates of bleeding and need for new pacemaker implantation were not significantly different. Meta-regression demonstrated there was no significant association modifying. Conclusions: On the basis of the results of this meta-analysis TAVR may be a safe and effective therapeutic option for patients with cancer and symptomatic severe aortic stenosis. Larger, longer, and randomized trials are required to adequately test this above hypothesis.


Mitochondrial translation in absence of local tRNA aminoacylation and methionyl tRNA Met formylation in Apicomplexa.
Apicomplexans possess three translationally active compartments: the cytosol, a single tubular mitochondrion, and a vestigial plastid organelle called apicoplast. Mitochondrion and apicoplast are of bacterial evolutionary origin and therefore depend on a bacterial-like translation machinery. The minimal mitochondrial genome contains only three ORFs, and in Toxoplasma gondii the absence of mitochondrial tRNA genes is compensated for by the import of cytosolic eukaryotic tRNAs. Although all compartments require a complete set of charged tRNAs, the apicomplexan nuclear genomes do not hold sufficient aminoacyl-tRNA synthetase (aaRSs) genes to be targeted individually to each compartment. This study reveals that aaRSs are either cytosolic, apicoplastic or shared between the two compartments by dual targeting but are absent from the mitochondrion. Consequently, tRNAs are very likely imported in their aminoacylated form. Furthermore, the unexpected absence of tRNA(Met) formyltransferase and peptide deformylase implies that the requirement for a specialized formylmethionyl-tRNA(Met) for translation initiation is bypassed in the mitochondrion of Apicomplexa.


The distinct role of guanine nucleotide exchange factor Vav1 in Bcl-2 transcription and apoptosis inhibition in Jurkat leukemia T cells.
To investigate a novel function of proto-oncogene Vav1 in the apoptosis of human leukemia Jurkat cells. Jurkat cells, Jurkat-derived vav1-null cells (J.Vav1) and Vav1-reconstituted J.WT cells were treated with a Fas agonist antibody, IgM clone CH11. Apoptosis was determined using propidium iodide (PI) staining, Annexin-V staining, DNA fragmentation, cleavage of caspase 3/caspase 8, and poly (ADP-ribose) polymerase (PARP). Mitochondria transmembrane potential (ΔΨ(m)) was measured using DiOC(6)(3) staining. Transcription and expression of the Bcl-2 family of proteins were evaluated using semi-quantitative RT-PCR and Western blot, respectively. Bcl-2 promoter activity was analyzed using luciferase reporter assays. Cells lacking Vav1 were more sensitive to Fas-mediated apoptosis than Jurkat and J.WT cells. J.Vav1 cells lost mitochondria transmembrane potential (ΔΨ(m)) more rapidly upon Fas induction. These phenotypes could be rescued by re-expression of Vav1 in J.Vav1 cells. The expression of Vav1 increased the transcription of pro-survival Bcl-2. The guanine nucleotide exchange activity of Vav1 was required for enhancing Bcl-2 promoter activity, and the Vav1 downstream substrate, small GTPase Rac2, was likely involved in the control of Bcl-2 expression. Vav1 protects Jurkat cells from Fas-mediated apoptosis by promoting Bcl-2 transcription through its GEF activity.


Three-Dimensional Crumpled Graphene-Based Nanosheets with Ultrahigh NO2 Gas Sensibility.
It is well-established that the structures dominate the properties. Inspired by the highly contorted and crumpled maxilloturbinate inside dog nose, herein an artificial nanostructure, i.e., 3D crumpled graphene-based nanosheets, is reported with the simple fabrication, detailed characterizations, and efficient gas-sensing applications. A facile supramolecular noncovalent assembly is introduced to modify graphene with functional molecules, followed with a lyophilization process to massively transform 2D plane graphene-based nanosheets to 3D crumpled structure. The detailed morphological characterizations reveal that the bioinspired nanosheets exhibit full consistency with maxilloturbinate. The fabricated 3D crumpled graphene-based sensors exhibit ultrahigh response (Ra/Rg = 3.8) toward 10 ppm of NO2, which is mainly attributed to the specific maxilloturbinate-mimic structure. The sensors also exhibit excellent selectivity and sensing linearity, reliable repeatability, and stability. Interestingly, it is observed that only 4 mg of graphene oxide (GO) raw materials can produce more than 1000 gas sensors, which provides a new insight for developing novel 3D biomimetic materials in large-scale gas sensor production.


A place called LIFE: exploring the advance care planning of African-American PACE enrollees.
The goals of this exploratory study were (a) to describe, among African-American PACE (Program of All-Inclusive Care for the Elderly) enrollees, verbalized preferences for end-of-life care as compared to preferences for care as documented in their medical record and (b) to explore the personal values that inform end-of-life decision making among these frail elders. Medical record review and semi-structured interviews generated descriptive and qualitative data for 18 African-American enrollees in a PACE program located in a large eastern city of the United States. Review of verbalized and documented preferences for end-of-life care among participants indicated that most preferred life-sustaining treatments. In addition, findings suggest that these PACE enrollees had limited information or understanding of the interventions and terminology associated with advance directives. Content analysis of interviews indicated that end-of-life decision making was influenced by the desire to maintain usual activities of daily living; to avoid burdening caregivers; and to remain in control of personal health care. Furthermore, these African-American elders relied on faith in God as central to medical decision making, believing ultimately that God controls the end of life. This research may enhance the ability of social workers, in collaboration with other members of PACE or similar interdisciplinary teams, to understand the values and attitudes associated with the preferences of older African Americans for care at the end of life. These findings suggest future research is needed to ensure advance care planning acknowledges and responds to the values and preferences of African-American PACE enrollees for the end of life.


Self-reported symptoms and risk factors for digital ischaemia among international world-class beach volleyball players.
The prevalence of ischaemia-related symptoms is remarkably high among elite indoor volleyball players. Since the exposure to sport-specific demands may be higher in beach volleyball compared to indoor volleyball, the aim of this study was to assess the prevalence of ischaemia-related symptoms and associated risk factors among world-class beach volleyball players. Therefore, a questionnaire survey was performed among beach volleyball players active during the 2013 Grand Slam Beach Volleyball in the Netherlands. In total, 60 of the 128 beach volleyball players (47%) participated: 26 males and 34 females from 17 countries. The self-reported prevalence of cold or blue or pale digits in the dominant hand during or immediately after practice or competition was 38% (n = 23). Two risk factors were independently associated with symptoms of blue or pale digits: more than 14 years playing volleyball (odds ratio (OR) 4.42, 90% confidence interval (90% CI) 1.30-15.07) and sex (female) (OR 4.62, 90% CI 1.15-18.57). In conclusion, the prevalence of symptoms associated with digital ischaemia is high among international world-class beach volleyball players. Female sex and the length of the volleyball career were independently associated with an increased risk of ischaemia-related symptoms. The high prevalence of these seemingly innocuous symptoms and possible associated risk factors warrant regular monitoring since early detection can potentially prevent thromboembolic complications and irreversible tissue damage.


Status of genomic imprinting in human embryonic stem cells as revealed by a large cohort of independently derived and maintained lines.
Investigation of the epigenetic stability of human embryonic stem cells (hESCs) is a crucial step for their use in cell-replacement therapies, as well as for assessing whether hESCs model epigenetic regulation in human pre-implantation cell types. To address these issues, we have examined the expression of imprinted genes in a previous study and more recently in 46 individual hESC lines as part of the International Stem Cell Initiative. Our results show that nearly all hESC lines examined possessed a substantial degree of epigenetic stability, despite differences in genetic background and in their derivation and initial propagation conditions. However, some hESCs did show loss of allele-specific expression, which could have implications for hESC differentiation and epigenetic stability (both in vitro and after clinical transplantation). A benefit of our and other recent studies of genomic imprinting in hESCs was the identification of imprinted genes that provide a useful indication of epigenetic stability. SNRPN, IPW and KCNQ1OT1 were highly stable and thus appeared insensitive to perturbation; in contrast, H19, IGF2 and MEG3 were more variable and thus could potentially provide a sensitive indication of epigenetic status. In this review, we examine the differences between imprinted genes in their susceptibility to perturbation and discuss the potential molecular basis for these differences. This examination provides insight into the regulation of genomic imprinting in hESCs and the corresponding peri-implantation stages of human development.


Study on Machine Tool Positioning Uncertainty Due to Volumetric Verification.
Volumetric verification is based on the machine tool (MT) kinematic model, along with its geometric errors. Although users often ignore the uncertainty of verification, the use of the MT as a traceable measurement system in the manufacturing process has increased the need for professionals to be aware of it. This paper presents an improvement in the MT kinematic model, introducing in it the influence of verification uncertainty sources. These sources have been classified into four groups: the MT, the measurement system itself, the measurement strategy, and the optimization strategy. As the developed model exhibits non-linear behavior, the Monte Carlo method was used to determine the influence of the measurement system on verification uncertainty using synthetic tests. In this manner, an improved estimation of the MT uncertainty can be obtained. Therefore, if the MT is used as a traceable measurement system, its accuracy should not be higher than the laser tracker (LT) verification influence. It hence shows the importance of LT influence.


Spatial-Temporal Pattern of Human-Induced Land Degradation in Northern China in the Past 3 Decades-RESTREND Approach.
Land degradation is one of the world's most serious environmental issues. Human activities play an important role in it. Therefore, human-induced land degradation monitoring is of crucial scientific significance in revealing the evolution of land degradation and guiding its governance. Based on the residual trend (RESTREND) approach and using Global Inventory Modeling and Mapping Studies (GIMMS) normalized difference vegetation index (NDVI) 3g and monthly precipitation as data sources, a quantitative evaluation is conducted on the conditions of human-induced land degradation during 1982-2012 in northern China. The results indicate that (1) the "optimal cumulative precipitation-NDVImax" regression model constructed herein can improve the capability of recognizing human-induced land degradation of arid and semiarid areas in the RESTREND approach. Moreover, long time-series NDVI and precipitation data may reduce the uncertainty of quantifying human-induced land degradation. (2) In the past 3 decades, northern China has experienced three stages of human-induced land degradation, i.e., rapid development, overall reversal with local development, and continuous reversion. Human-induced land degradation in the agro-pastoral ecotone of northern China has shown a rapid restoration trend since the 1990s. (3) It is believed that the dominant factor of land degradation has a significant spatial-temporal scale effect and spatial heterogeneity. Therefore, concrete issues should be specifically analyzed to improve our understanding of land degradation development and reversal, the spatial-temporal pattern and the driving forces of land degradation in the past 3 decades in northern China. Climate change may be the main driving force of land degradation. However, the influence of human activities on the development and reversal of land degradation in small areas and in a short time is more remarkable.


The psychological assessment of candidates for spinal cord stimulation for chronic pain management.
It is known that, in spite of meeting appropriate clinical criteria for spinal cord stimulation (SCS) and having undergone flawless procedures, a significant number of patients who fail the therapy continues to exist. It is the purpose of this article to focus on the development of psychosocial indicators of success for SCS, if any. Referring to specialist literature authors present a review of what is known, what is not known, and what remains controversial on this topic. After reading this article we hope the reader will understand the importance of a psychological evaluation as part of the development of standards for identifying appropriate patients for this therapy. To improve treatment outcomes of SCS, seems to be essential to perform psychosocial evaluations on all persons clinically indicated for SCS to exclude those patients, who most probably, on a psychosocial level, will fail the procedure. To maximize treatment efficacy, authors believe spinal cord stimulation for chronic pain control must be part of a comprehensive program. An accurate preoperative psychosocial assessment and a course of psychological assistance both before and after therapy seems to be crucial for improving outcomes.


Absorption kinetics of insulin after subcutaneous administration.
Many diabetic patients depend on regular and well-controlled administration of insulin to avoid unacceptable excursions in plasma glucose. A complicating factor is that the absorption of insulin shows a considerable variability, both between patients, and from administration to administration for the same patient. To understand the mechanisms that influence this variability we present a quantitative description of the absorption kinetics for both soluble insulin and insulin crystals. The concentration dependent distribution of insulin between different oligomers is first analysed and described. Next, the disappearance of soluble and crystalline insulin from subcutis is described and explained as a function of the administered dose, the insulin concentration and crystal specific parameters, but without diffusion. The effect of diffusion is then included, and the appearance of insulin in plasma following subcutaneous administration is simulated and discussed. Our results not only explain the observed variability, but they also explain how dose size, insulin concentration, insulin crystals etc. influence the absorption kinetics.


Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer.
Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression of coding and non-coding transcripts with an oncogenic or tumour suppressor role. These natural agents are currently exploited for the development of therapeutic strategies alone or in tandem with conventional treatments for cancer. The aim of this paper is to review the recent studies regarding the role of these natural phytochemicals in different processes related to cancer inhibition, including apoptosis activation, angiogenesis and metastasis suppression. From the large palette of phytochemicals we selected epigallocatechin gallate (EGCG), caffeic acid phenethyl ester (CAPE), genistein, morin and kaempferol, due to their increased activity in modulating multiple coding and non-coding genes, targeting the main hallmarks of cancer.


Skin type and optimistic bias in relation to the sun protection and suntanning behaviors of young adults.
The study examined the roles of general and personal beliefs and skin type in relation to suntanning and sun protection, by assessing various perceptions of risk of skin cancer both for the self and for the average person. A sample of 355 people aged 16 to 25 years was selected randomly from the telephone directory of a coastal provincial city. Highly structured interviews were conducted over the telephone. The findings were presented in relation to three research questions. First, skin type, classified as burn only, burn then tan, or tan without burning, influenced both general and personal beliefs. Compared to the tan-only group, the burn-only group perceived earlier age at onset, greater number of years of life lost, and greater severity of skin cancer, for both the average person and the self, and greater susceptibility to skin cancer for the average person. Second, differences were found between personally relevant and population-relevant beliefs on susceptibility to skin cancer, time of onset, and years of life lost due to skin cancer but not for perceptions of severity and curability. Finally, skin cancer beliefs were poor correlates of tanning and protecting behaviors. The factor explaining the greatest proportion of variance in both behaviors was skin type.


Cardiovascular pharmacotherapy update for the intensive care unit.
Pharmacologic agents including vasodilators, inotropes, and vasopressors are frequently used in the critical care setting for management of the unstable cardiac patient. These medications are used to elicit varying effects on vascular resistance, myocardial contractility, and heart rate to help achieve desired hemodynamic and clinical endpoints. Therefore, it is important for the critical care nurse to have a practical understanding and working knowledge of cardiovascular pharmacotherapy in the intensive care unit setting. This article reviews the pharmacology and clinical utility of commonly used intravenous "vasoactive" medications encountered in the intensive care unit. We also highlight innovations in pharmacotherapy for this patient population, and provide practical considerations for the most appropriate and safe use of these medications.


Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme.
Climacostol, a compound produced by the ciliated protozoan Climacostomum virens, displayed cytotoxic properties in vitro. This study demonstrates that it has anti-tumour potential. Climacostol caused a reduction of viability/proliferation of B16-F10 mouse melanoma cells, a rapidly occurring DNA damage, and induced the intrinsic apoptotic pathway characterised by the dissipation of the mitochondrial membrane potential, the translocation of Bax to the mitochondria, the release of Cytochrome c from the mitochondria, and the activation of Caspase 9-dependent cleavage of Caspase 3. The apoptotic mechanism of climacostol was found to rely on the up-regulation of p53 and its targets Noxa and Puma. In vivo analysis of B16-F10 allografts revealed a persistent inhibition of tumour growth rate when melanomas were treated with intra-tumoural injections of climacostol. In addition, it significantly improved the survival of transplanted mice, decreased tumour weight, induced a remarkable reduction of viable cells inside the tumour, activated apoptosis and up-regulated the p53 signalling network. Importantly, climacostol toxicity was more selective against tumour than non-tumour cells. The anti-tumour properties of climacostol and the molecular events associated with its action indicate that it is a powerful agent that may be considered for the design of pro-apoptotic drugs for melanoma therapy.


A hybrid of cells and pancreatic islets toward a new bioartificial pancreas.
Cell surface engineering using single-stranded DNA-poly(ethylene glycol)-conjugated phospholipid (ssDNA-PEG-lipid) is useful for inducing cell-cell attachment two and three dimensionally. In this review, we summarize our recent techniques for cell surface engineering and their applications to islet transplantation. Because any DNA sequence can be immobilized onto the cell surface by hydrophobic interactions between ssDNA-PEG-lipid and the cellular membrane without impairing cell function, a cell-cell hybrid can be formed through the DNA hybridization. With this technique, it would be possible to create three-dimensional hybrid structures of pancreatic islets coated with various accessory cells, such as patients' own cells, mesenchymal and adipose-derived stem cells, endothelial progenitor cells, neural crest stem cells or regulatory T cells, which might significantly improve the outcome of islet transplantation in diabetic patients.


Evolution of coronary vascular tone in vasospastic angina.
In general, anginal symptoms diminish with time in patients with vasospastic angina. We assessed changes in coronary vascular tone (CVT) in patients with vasospastic angina over a 4-year period to evaluate the time course of spastic activity. Vasospastic angina was evaluated in 39 patients in whom occlusive spasm was evoked by selective intracoronary injection of ergonovine maleate (ERG-S) 48 h after stopping all coronary vasodilator drugs. These patients had no organic coronary stenosis and developed no stenosis during follow-up. ERG-S was repeated 3 times at 2-year intervals. CVT was determined at each ERG-S study using the equation: CVT = 1-(coronary artery diameter before ERG-S/coronary artery diameter after intracoronary injection of isosorbide dinitrate). Thirty-four patients (87%) had no angina pectoris at the second ERG-S study and 28 (72%) had none at the third. Coronary spasm was induced in 25 patients at the second ERG-S study and in 20 at the third. The overall CVT was shown to decrease at each successive ERG-S study (p < 0.01). There was no correlation between changes in CVT and anginal symptoms or the coronary spasm induction rate. These results demonstrate that CVT decreases over time in patients with vasospastic angina, suggesting that myocardial ischemia may improve spontaneously.


Perinatal maternal undernutrition programs the offspring hypothalamo-pituitary-adrenal (HPA) axis.
There is now compelling evidence, coming both from animal and human studies that an early exposure to undernutrition is frequently associated with low birth weight and programs HPA axis alterations throughout the lifespan. Although animal models have reported conflicting findings arising from differences in experimental paradigms and species, they have clearly demonstrated that such programming not only affects the brain but also the pituitary corticotrophs and the adrenal cortex. In fetuses, maternal undernutrition reduces HPA axis function and implicates a reduction of placental 11beta-HSD2 activity and a greater transplacental transfer of glucocorticoids (GRs). In young adults, usually only fine HPA axis alterations were observed, whereas in older ones, maternal undernutrition was frequently associated with chronic hyperactivity of this neuroendocrine axis. In humans, evidence of HPA axis dysregulation in people who were small at birth has recently emerged. Thus, we suggest that such alterations in adults may be implicated in the aetiology of several disorders related to the metabolic syndrome as well as to immune or inflammatory diseases. To reverse such programming, recent experimental reports have shown that postnatal environmental interventions, dietary modifications and the use of agents modulating the epigenomic state could partly restore physiological functions and thus open new therapeutic strategies.


Substance P signaling mediates BMP-dependent heterotopic ossification.
Heterotopic ossification (HO) is a disabling condition associated with neurologic injury, inflammation, and overactive bone morphogenetic protein (BMP) signaling. The inductive factors involved in lesion formation are unknown. We found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and in three independent mouse models of HO. In Nse-BMP4, a mouse model of HO, robust HO forms in response to tissue injury; however, null mutations of the preprotachykinin (PPT) gene encoding SP prevent HO. Importantly, ablation of SP(+) sensory neurons, treatment with an antagonist of SP receptor NK1r, deletion of NK1r gene, or genetic down-regulation of NK1r-expressing mast cells also profoundly inhibit injury-induced HO. These observations establish a potent neuro-inflammatory induction and amplification circuit for BMP-dependent HO lesion formation, and identify novel molecular targets for prevention of HO.


Adult T-cell leukemia/lymphoma in a Peruvian hospital in human T-lymphotropic virus type 1 (HTLV-1) positive patients.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive neoplasm of T-lymphocytes associated with human T-lymphotropic virus type I (HTLV-1) infection. As HTLV-1 is endemic in native ethnics in South America, and its infection leads to several chronic diseases as ATLL with poor prognosis, we aimed to present three ATLL cases and to review current literature. Two cases were from the mountains of Peru, while one was from an endemic harbor of the country. An acute ATLL patient presented with multipapular infiltration of the skin and died 2 weeks after admission because of septic shock. The two chronic ATLL patients presented with erythematous plaques and erythroderma. They had swollen lymph nodes, lymphocytosis, and atypical lymphocytes on blood smear, with normal biochemical results. They both passed away a few months after diagnosis. ATLL is developed after years of HTLV-1 carrier status; therefore, physicians should know the principal clinical and laboratory findings in order to make prompt diagnosis. Prognosis is still poor in aggressive and indolent variants, with survival rates from months to a few years. Treatment based on chemotherapy, antiretroviral, and allogeneic stem cell transplantation are improving survival rates but with limited results.


[The plasma levels and diagnostic utility of stem cell factor and macrophage--colony stimulating factor in endometrial cancer patients].
We have investigated the plasma levels of SCF and M-CSF and commonly accepted tumor markers, such as CA 125 and SCC-Ag in endometrial cancer patients. The plasma levels of cytokines were measured in 25 patients and in 25 healthy subjects. SCF and M-CSF were determined using enzyme-linked immunosorbent assay (ELISA). CA 125 and SCC-Ag were measured by microparticle enzyme immunoassay (MEIA). SCF and CA 125 plasma levels were significantly higher in endometrial cancer patients when compared to the control group. The diagnostic specificity was high and equal for all tested parameters, similarly to tested tumour markers. The diagnostic sensitivity was the highest when SCF, M-CSF and CA 125 or all parameters were combined. Positive and negative predictive values were so high for tested cytokines, as for compared markers. Our study suggests that both tested hematopoietic cytokines can be clinically useful in endometrial cancer diagnostics, but further investigation and confirmation in a prospective study is necessary.


The role of the urologist in treating patients with hormone-refractory prostate cancer.
To ascertain what percentage of urologists' oncology practice is dedicated to the care of prostate cancer patients and to determine urologists' attitudes towards the treatment of patients with metastatic and hormone-refractory prostate cancer (HRPC). An additional objective is to determine urologists' interest in administering various types of chemotherapy in HRPC patients. The American Urological Association (AUA) directory of practicing urologists was obtained, and 3000 randomly selected members of the AUA, as well as the complete list of 168 Society of Urologic Oncology (SUO) members, were chosen for the mailing of a 16-item questionnaire. The urologists were asked about how many of their patients have prostate cancer, how many have metastatic disease, and how many have HRPC and are currently receiving intravenous (IV) chemotherapy. In addition, the urologists were queried regarding their level of interest in learning about chemotherapy options as well as learning how to administer chemotherapy. A total of 654 survey questionnaires were completed and returned for tabulation, resulting in a 21% effective response rate. Sixty-four percent of the responding urologists' cancer patients had prostate cancer, 21% had metastatic disease, and 19% had HRPC; only 4% of the urologists currently administer IV chemotherapy themselves. When asked to describe their interest in learning how to deliver and be reimbursed for IV chemotherapy, 26% expressed an extremely low level of interest, 23% a low level of interest, 31% a high level of interest, and 17% an extremely high level of interest. The results of other questions are presented and correlated with the number of years the urologists have been in practice and other demographic data. The management of prostate cancer comprises a major portion of urologists' practices. Almost one half (48%) of the urologists in this survey were interested in administering and being reimbursed for IV chemotherapy. Several chemotherapy regimens have been shown to improve quality of life in patients with HRPC, yet only about 30% of these patients were referred for chemotherapy. If more urologists were able to deliver these drugs, then the number of patients referred for chemotherapy would likely increase, as would accrual to important clinical trials in HRPC. The results of this survey suggest that methods to implement the training and reimbursement of urologists in the use of chemotherapy regimens should be investigated.


Plasma functionalization procedure for antibody immobilization for SU-8 based sensor.
In this paper, we report the study on a new protocol for the immobilization process of antigen/antibody assay on SU-8 layers by oxygen plasma treatment. Plasma treatments, at different plasma powers and for different duration times, are performed and their effects on immobilization efficiency are studied. The chemical properties and the surface morphology of SU-8 before and after the functionalization and immobilization of (IgG) are then verified by Raman spectroscopy and atomic force microscopy (AFM). An increase of the surface roughness of SU-8 layers is observed after the oxygen plasma treatment and an intensity variation of functional groups is also evidenced. To demonstrate the validity of the process the distribution of IgG immobilized on SU-8 surfaces is detected by fluorescence microscopy measurement after incubation with fluorescein isothiocyanate (FITC)-tagged anti-human IgG. An increase of the amount of the adsorbed protein of about 20% and a good repeatability on antigen/antibody distribution on the surface are detected for IgG on plasma treated substrates. Finally, label free measurements are performed by SU-8 optical ring resonators reaching detection limits of 0.86ngcm(-2). The proposed approach offers a smart protocol for IgG immobilization on SU-8 substrate that can be easily extended to different antigen/antibody assay and polymeric materials for the realization of high performance immunosensors.


Cobalt-catalyzed highly enantioselective hydrogenation of α,β-unsaturated carboxylic acids.
Asymmetric hydrogenation of α,β-unsaturated acids catalyzed by noble metals has been well established, whereas, the asymmetric hydrogenation with earth-abundant-metal was rarely reported. Here, we describe a cobalt-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids. By using chiral cobalt catalyst bearing electron-donating diphosphine ligand, high activity (up to 1860 TON) and excellent enantioselectivity (up to >99% ee) are observed. Furthermore, the cobalt-catalyzed asymmetric hydrogenation is successfully applied to a broad spectrum of α,β-unsaturated carboxylic acids, such as various α-aryl and α-alkyl cinnamic acid derivatives, α-oxy-functionalized α,β-unsaturated acids, α-substituted acrylic acids and heterocyclic α,β-unsaturated acids (30 examples). The synthetic utility of the protocol is highlighted by the synthesis of key intermediates for chiral drugs (6 cases). Preliminary mechanistic studies reveal that the carboxy group may be involved in the control of the reactivity and enantioselectivity through an interaction with the metal centre.


Microfilaria in cervicovaginal Pap smears: A common parasite hiding in an unusual site: Short series of four cases with literature review.
In India, filariasis is a severe and significant public health problem. It has been reported to be present in any potential site. However, cervicovaginal Pap smear cytology rarely contains microfilariae despite the widespread occurrence. The occurrence of microfilariae in cervicovaginal smears has seldom been reported, even as an accidental finding. In our retrospective study, four cases of clinically asymptomatic filariasis were diagnosed on a routine cervicovaginal Pap smear from January 2019 to July 2022. All microfilariae were characterized as Wuchereria bancrofti. In the present study, the majority of the cases present vaginal discharge, and the diagnosis was made by cytopathology. Therefore, it is crucial to consider and look for microfilariae in areas where they are not endemic.


Attentional modulation of SSVEP power depends on the network tagged by the flicker frequency.
Modulation of the steady-state visual evoked potential (SSVEP) by attention was studied in detail using 15 'tag' frequencies in the range of 2.5-20 Hz. The stimuli were two series of random disc search arrays superimposed on two concentric color-marked annuli respectively. Two series of arrays were updated independently; one updated at one fixed frequency (flicker) and the other updated randomly according to a white noise distribution (random broadband flicker, rbbf). On each trial, the observer was instructed to attend one annulus and to detect a target (a triangle) that occasionally appeared in a random disc array in the attended annulus. The SSVEP results show that the choice of flicker frequency selects which cortical network synchronizes to the flicker two distinct cortical networks showed different effects of attention. SSVEP power and the effects of attention on SSVEP power strongly depend on both flicker frequency and radial position of rbbf annulus. At flicker frequencies in the delta band (2-4 Hz), and in the upper alpha band (10-11 Hz), an occipital-frontal network appears to phase-lock to the flicker when attending to the flicker, increasing the magnitude of the SSVEP. At flicker frequencies in the lower alpha band (8-10 Hz), a global response to a peripheral flickering stimulus, that includes parietal cortex and posterior frontal cortex, has higher amplitude when attention is directed away from the flickering peripheral stimulus and towards a competing rbbf stimulus in the fovea. Increases in SSVEP power when attention is directed to peripheral flicker are always associated with increases in phase locking. By contrast, at frequencies in the lower alpha band, increases in SSVEP power when attention is directed away from the flicker and towards foveal stimuli are not associated with changes in phase-locking. Thus, whether attention to a flicker stimulus increases or decreases SSVEP amplitude and phase locking depends on which of two cortical networks, which have distinct spatial and dynamic properties, is selected by the flicker frequency.


Implementing practice management strategies to improve patient care: the EPIC project.
Healthcare gaps, the difference between usual care and best care, are evident in Canada, particularly with respect to our aging, ailing population. Primary care practitioners are challenged to identify, prevent and close care gaps in their practice environment given the competing demands of informed, litigious patients with complex medical needs, ever-evolving scientific evidence with new treatment recommendations across many disciplines and an enhanced emphasis on quality and accountability in healthcare. Patient-centred health and disease management partnerships using measurement, feedback and communication of practice patterns and outcomes have been shown to narrow care gaps. Practice management strategies such as the use of patient registries and recall systems have also been used to help practitioners better understand, follow and proactively manage populations of patients in their practice. The Enhancing Practice to Improve Care project was initiated to determine the impact of a patient-centred health and disease management partnership using practice management strategies to improve patient care and outcomes for patients with chronic kidney disease (CKD). Forty-four general practices from four regions of British Columbia participated and, indeed, demonstrated that care and outcomes for patients with CKD could be improved via the implementation of practice management strategies in a patient-centred partnership measurement model of health and disease management.


Integrin dependent migration of lung cancer cells to extracellular matrix components.
Since tumour progression is dependent on the ability of malignant cells to interact with the extracellular matrix (ECM), we have investigated the significance of beta1 and beta3 integrins for migration of lung cancer cells to components of the ECM. In an in vitro hapto- and chemotactic assay system, five cell lines representing the major types of lung cancer were examined: adenocarcinoma (WART); squamous cell carcinoma (U-1752); small cell lung cancer (SCLC) (U-1906, 054 A) and large cell lung cancer (LCLC) (U-1810). Flow cytometric analyses were performed to characterize their integrin expression. U-1906, 054 A, WART and U-1752 all expressed beta1 integrins whereas U-1810 did not. However, U-1810 and U-1752 expressed beta3 integrins. All cell lines except U-1810 and U-1752 showed hapto- and chemotactic motility to fibronectin, laminin and type IV collagen and this motility was beta1 integrin-dependent except in the case of U-1810. However, the hapto- and chemotactic responses differed markedly between the separate cell lines and there was no distinct pattern to separate non-small cell lung cancer (NSCLC) from SCLC. No or very little migration was seen in control experiments with bovine serum albumin (BSA) or serum-free medium alone, indicating that the migration of the lung cancer cells require adhesion molecules, soluble or substratum bound. We have found the involvement of beta1 integrins in lung cancer cell migration in vitro towards fibronectin, laminin and type IV collagen except in the case of U-1810. The U-1810 cell line clearly differed from the rest of the cell lines by lacking expression of beta1 integrins.


Core-Shell C@Sb Nanoparticles as a Nucleation Layer for High-Performance Sodium Metal Anodes.
Sodium metal anode (SMA) is one of the most favored choices for the next-generation rechargeable battery technologies owing to its low cost and natural abundance. However, the poor reversibility resulted from dendrite growth and formation of unstable solid electrolyte interphase has significantly hindered the practical application of SMAs. Herein, we report that a nucleation buffer layer comprising elaborately designed core-shell C@Sb nanoparticles (NPs) enables the homogeneous electrochemical deposition of sodium metal for long-term cycling. These C@Sb NPs can increase active sites for initial sodium nucleation through Sb-Na alloy cores and keep these cores stable through carbon shells. The assembled cells with this nucleation layer can deliver continuously repeated sodium plating/stripping cycles for nearly 6000 h at a high areal capacity of 4 mA h cm-2 with an average Coulombic efficiency 99.7%. This ingenious structure design of alloy-based nucleation agent opens up a promising avenue to stabilize sodium metal with targeted properties.


An electrochemical biosensor for sensitive detection of microRNA-155: combining target recycling with cascade catalysis for signal amplification.
In this work, a new electrochemical biosensor based on catalyzed hairpin assembly target recycling and cascade electrocatalysis (cytochrome c (Cyt c) and alcohol oxidase (AOx)) for signal amplification was constructed for highly sensitive detection of microRNA (miRNA). It is worth pointing out that target recycling was achieved only based on strand displacement process without the help of nuclease. Moreover, porous TiO2 nanosphere was synthesized, which could offer more surface area for Pt nanoparticles (PtNPs) enwrapping and enhance the amount of immobilized DNA strand 1 (S1) and Cyt c accordingly. With the mimicking sandwich-type reaction, the cascade catalysis amplification strategy was carried out by AOx catalyzing ethanol to acetaldehyde with the concomitant formation of high concentration of H2O2, which was further electrocatalyzed by PtNPs and Cyt c. This newly designed biosensor provided a sensitive detection of miRNA-155 from 0.8 fM to 1 nM with a relatively low detection limit of 0.35 fM.


Key issues in end point selection for heart failure trials: composite end points.
Composite outcomes are commonly used in heart failure trials. The aim of this article is to discuss the advantages and disadvantages of composite outcomes and recommend guidelines for reporting them. Examples are used to illustrate key points. A workshop jointly planned by the Heart Failure Society of America and the US Food and Drug Administration was convened in April 2004. One of the panel discussions concerned the use of composite outcomes in heart failure trials. With use of composite outcomes, event rates are higher and if it is reasonable to assume that the treatment effect is similar for each component of the composite outcome, sample size will be smaller than using one of the components as the primary end point. Composites end points are difficult to interpret if effects are not similar for all components or if the effect of treatment is primarily on a more common, less serious component of the composite. Composite outcomes typically only focus on the first occurring event. This can lead to a substantial loss of information in some trials. When composite end points are used, data collection for all components should continue until the end of the trial so that each component can be separately evaluated. Composite end points should be used with caution. Additional research is need on optimally weighting components of composite outcomes and to better using the entire event history of patients in heart failure trials. Further analyses of completed trials could be useful in this respect.


Broadly cross-reactive mimotope of hypervariable region 1 of hepatitis C virus derived from DNA shuffling and screened by phage display library.
The hypervariable region 1 (HVR1) is the target of neutralizing antibodies but with isolate specificity. The aim of this study was to obtain immunogenic mimotopes of HVR1, which can react broadly with different HVR1 antibodies and could be one of the candidate immunogens in an effective vaccine against HCV. Thirty-one HVR1 cDNA fragments were digested by DNase I into a pool of random fragments and reassembled by repeated cycles of annealing in the presence of DNA polymerase to their original size. The shuffled HVR1 was then inserted into the gene III phagemid vector pCANTAB-5E and displayed on the surface of the phage. Eight individual phages were selected after four rounds of biopanning against anti-HVR1. ELISA was carried out on immobilized purified phages, respectively, to detect their reactivity with a panel of sera. DNA sequences of the inserts were analyzed and compared with the consensus sequences defined by Puntoriero et al. [(1998) EMBO J 17:3521-3533]. The reactivity of the eight selected clones to the 30 sera were from 53.3 to 80%. Among these, phage 13 (ETYVSGGSAARNAYGLTSLFTVGPAQK, aa 384-410) reacted most broadly. None of the selected sequences encoded for peptides corresponded to known HVR1 from original viral isolates. The two high reactive phages had the similar amino acid sequences with the consensus, which might play a particular role in determining the frequency of reactivity. In conclusion, this study has used effectively DNA shuffling combined with phage display technology to identify broadly cross-reactive mimotopes recognized by human polyclonal antibodies. Mimotope 13 and 23 appeared to be most reactive immunologically and could be candidate immunogens. Efforts are now underway to identify their neutralizing antibodies by immunization of animals.