Highly Sensitive Detection and Genotyping of HPV by PCR Multiplex and Luminex Technology in a Cohort of Colombian Women with Abnormal Cytology.
Cancer of the uterine cervix (CC) is the second most common cancer in women worldwide. In Colombia, CC is the second most frequent cancer among the entire women population and the first among women aged between 15 and 44 years, with an estimated incidence of 24.9 cases/100,000 inhabitants. The main risk factor is infection with one or more high-risk human papillomavirus (HPV) types. The aim of this study was to estimate the genotype-specific prevalence of human papillomavirus (HPV) DNA in patients with cervical pathology using the multiplex PCR and Luminex xMAP technology. In addition, we compared genotyping with Luminex xMAP and with Reverse Line Blot (RLB). A cohort of 160 patients participated in the study, of which 25.6% had no cervical lesions, 35% presented cervical intraepithelial neoplasia of grade I (CIN I), 10% CIN II, 20.6% CIN III and 8.8% CC. The most frequent viral types in all lesion grades were HPV16 and HPV18. Infections by a unique virus were less frequent (19.4%) than multiple infections (80.6%). Single infections were found in 22% of women with no cervical lesions, and in 14.3% of CIN I, 18.7% CIN II, 21.2% CIN III and 28.6% of CC. Multiple infections were observed in 78.0% of cervical samples with negative histopathologic diagnosis, and in 85.7% of CIN I, 81.2% CIN II, 78.8% CIN III and 71.4% CC. All samples analyzed with Luminex xMAP were HPV-positive, while we could detect HPV in only 48.8% of cases with RLB. Of the samples positive by both methods, there was a 67.2% correlation in the viral type(s) detected. In conclusion, Luminex suspension array showed a remarkably higher sensitivity compared with RLB. Multiple infections were unexpectedly common, being HPV types 16 and 18 the most prevalent in all histopathologic grades.


Covalently Immobilized Battacin Lipopeptide Gels with Activity against Bacterial Biofilms.
Novel antibiotic treatments are in increasing demand to tackle life-threatening infections from bacterial pathogens. In this study, we report the use of a potent battacin lipopeptide as an antimicrobial gel to inhibit planktonic and mature biofilms of S. aureus and P. aeruginosa. The antimicrobial gels were made by covalently linking the N-terminal cysteine containing lipopeptide (GZ3.163) onto the polyethylene glycol polymer matrix and initiating gelation using thiol-ene click chemistry. The gels were prepared both in methanol and in water and were characterised using rheology, Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). Antibacterial and antibiofilm analyses revealed that the gels prepared in methanol have better antibacterial and antibiofilm activity. Additionally, a minimum peptide content of 0.5 wt% (relative to polymer content) is required to successfully inhibit the planktonic bacterial growth and disperse mature biofilms of P. aeruginosa and S. aureus. The antibacterial activity of these lipopeptide gels is mediated by a contact kill mechanism of action. The gels are non-haemolytic against mouse red blood cells and are non-cytotoxic against human dermal fibroblasts. Findings from this study show that battacin lipopeptide gels have the potential to be developed as novel topical antibacterial agents to combat skin infections, particularly caused by S. aureus.


Menthol smoking in relation to time to first cigarette and cotinine: results from a community-based study.
Smokers who have their first cigarette shortly after waking, an indicator of nicotine dependence, have substantially higher cotinine levels. There is controversy regarding the role of menthol in nicotine dependence. We hypothesized that menthol smokers have a shorter time to first cigarette (TTFC), and tested whether any statistical association actually reflects increased dependence by measuring nicotine uptake (e.g. cotinine) in the same group of smokers. A cross-sectional community-based study was conducted that included 495 black and white daily cigarette smokers. Results showed a trend between menthol smoking and a shorter TTFC (P < 0.04 in blacks). Menthol was not an independent predictor of cotinine or an effect modifier with TTFC on cotinine levels in blacks and whites. These results show that while menthol in tobacco is associated with an indicator of nicotine dependence in blacks, menthol was not associated with biological uptake of nicotine in black and white smokers.


Activity-based costs of blood transfusions in surgical patients at four hospitals.
Blood utilization has long been suspected to consume more health care resources than previously reported. Incomplete accounting for blood costs has the potential to misdirect programmatic decision making by health care systems. Determining the cost of supplying patients with blood transfusions requires an in-depth examination of the complex array of activities surrounding the decision to transfuse. To accurately determine the cost of blood in a surgical population from a health system perspective, an activity-based costing (ABC) model was constructed. Tasks and resource consumption (materials, labor, third-party services, capital) related to blood administration were identified prospectively at two US and two European hospitals. Process frequency (i.e., usage) data were captured retrospectively from each hospital and used to populate the ABC model. All major process steps, staff, and consumables to provide red blood cell (RBC) transfusions to surgical patients, including usage frequencies, and direct and indirect overhead costs contributed to per-RBC-unit costs between $522 and $1183 (mean, $761 +/- $294). These exceed previously reported estimates and were 3.2- to 4.8-fold higher than blood product acquisition costs. Annual expenditures on blood and transfusion-related activities, limited to surgical patients, ranged from $1.62 to $6.03 million per hospital and were largely related to the transfusion rate. Applicable to various hospital practices, the ABC model confirms that blood costs have been underestimated and that they are geographically variable and identifies opportunities for cost containment. Studies to determine whether more stringent control of blood utilization improves health care utilization and quality, and further reduces costs, are warranted.


Dying in hospital: the residents' viewpoint.
A survey of residents' (junior house officers') experiences and attitudes to the terminal care part of their work in four Glasgow teaching hospitals showed that even a month after starting work one-fifth of the respondents had not actively managed a dying patient. Sixty-four per cent thought that they had received inadequate teaching in terminal care. Depression and anxiety had been the most difficult symptoms encountered. The residents thought that the ward nursing staff contributed much more than their senior medical colleagues to both the medical and psychological aspects of terminal care. The results indicate a need for more undergraduate education in the most relevant areas, such as coping with the psychological problems of dying patients and their relatives. Newly qualified residents require more support from senior medical staff in looking after the terminally ill.


Identifying primary and recurrent cancers using a SAS-based natural language processing algorithm.
Significant limitations exist in the timely and complete identification of primary and recurrent cancers for clinical and epidemiologic research. A SAS-based coding, extraction, and nomenclature tool (SCENT) was developed to address this problem. SCENT employs hierarchical classification rules to identify and extract information from electronic pathology reports. Reports are analyzed and coded using a dictionary of clinical concepts and associated SNOMED codes. To assess the accuracy of SCENT, validation was conducted using manual review of pathology reports from a random sample of 400 breast and 400 prostate cancer patients diagnosed at Kaiser Permanente Southern California. Trained abstractors classified the malignancy status of each report. Classifications of SCENT were highly concordant with those of abstractors, achieving κ of 0.96 and 0.95 in the breast and prostate cancer groups, respectively. SCENT identified 51 of 54 new primary and 60 of 61 recurrent cancer cases across both groups, with only three false positives in 792 true benign cases. Measures of sensitivity, specificity, positive predictive value, and negative predictive value exceeded 94% in both cancer groups. Favorable validation results suggest that SCENT can be used to identify, extract, and code information from pathology report text. Consequently, SCENT has wide applicability in research and clinical care. Further assessment will be needed to validate performance with other clinical text sources, particularly those with greater linguistic variability. SCENT is proof of concept for SAS-based natural language processing applications that can be easily shared between institutions and used to support clinical and epidemiologic research.


Weight loss in adults following bariatric surgery, a systematic review of preoperative behavioural predictors.
Bariatric surgery is effective in treating obesity in many cases, yet as many as 50% of patients may not achieve the desired weight reduction. Preoperative modifiable behavioural factors could help patient selection and intervention design to improve outcomes. Medline, EMBASE, Cochrane Library and PsychINFO were searched to identify studies published between 1 January 2008 and 14 February 2019 reporting on preoperative modifiable behavioural factors associated with postoperative weight loss, with minimum 2 years follow-up. A total of 6888 articles were screened, 34 met the inclusion criteria. Maladaptive eating behaviours (MEB), preoperative weight loss (PWL), and tobacco use were reported 21, 18, and 3 times respectively. Physical activity and substance abuse were each reported once. Most articles on PWL (72.2%) and MEB (52.4%) reported no association. Positive associations were reported in 22.2% and 14.3% of articles for PWL and MEB respectively. Negative associations were reported in 5.6% and 33.3% of articles for PWL and MEB, respectively. Marked heterogeneity in outcome reporting hindered quantitative synthesis. The current paucity of evidence amenable to synthesis leads to ongoing uncertainty regarding the size and direction of association between PWL and MEB with outcomes following bariatric surgery. Long-term studies with common reporting of outcomes are needed.


Neural correlates of pragmatic language comprehension in autism spectrum disorders.
Difficulties with pragmatic aspects of communication are universal across individuals with autism spectrum disorders (ASDs). Here we focused on an aspect of pragmatic language comprehension that is relevant to social interaction in daily life: the integration of speaker characteristics inferred from the voice with the content of a message. Using functional magnetic resonance imaging (fMRI), we examined the neural correlates of the integration of voice-based inferences about the speaker's age, gender or social background, and sentence content in adults with ASD and matched control participants. Relative to the control group, the ASD group showed increased activation in right inferior frontal gyrus (RIFG; Brodmann area 47) for speaker-incongruent sentences compared to speaker-congruent sentences. Given that both groups performed behaviourally at a similar level on a debriefing interview outside the scanner, the increased activation in RIFG for the ASD group was interpreted as being compensatory in nature. It presumably reflects spill-over processing from the language dominant left hemisphere due to higher task demands faced by the participants with ASD when integrating speaker characteristics and the content of a spoken sentence. Furthermore, only the control group showed decreased activation for speaker-incongruent relative to speaker-congruent sentences in right ventral medial prefrontal cortex (vMPFC; Brodmann area 10), including right anterior cingulate cortex (ACC; Brodmann area 24/32). Since vMPFC is involved in self-referential processing related to judgments and inferences about self and others, the absence of such a modulation in vMPFC activation in the ASD group possibly points to atypical default self-referential mental activity in ASD. Our results show that in ASD compensatory mechanisms are necessary in implicit, low-level inferential processes in spoken language understanding. This indicates that pragmatic language problems in ASD are not restricted to high-level inferential processes, but encompass the most basic aspects of pragmatic language processing.


A cytoskeleton-related gene, uso1, is required for intracellular protein transport in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae mutant strains blocked in the protein secretion pathway are not able to induce sexual aggregation. We have utilized the defect of aggregation to concentrate the secretion-deficient cells and identified a new gene which functions in the process of intracellular protein transport. The new mutant, uso1, is temperature sensitive for growth and protein secretion. At the restrictive temperature (37 degrees C), uso1 mutant accumulated the core-glycosylated precursor form of the exported protein invertase in the cells. Ultrastructural study of the mutant fixed by the freeze-substitution method revealed expansion of the nuclear envelope lumen and accumulation of the ER at the restrictive temperature. Abnormally oriented bundles of microtubules were often found in the nucleus. The USO1 gene was cloned by complementation of the uso1 temperature-sensitive growth defect. DNA sequence analysis revealed a hydrophilic protein of 1790 amino acids with a COOH-terminal 1,100-amino acid-long alpha-helical structure characteristic of the coiled-coil rod region of the cytoskeleton-related proteins. These observations suggest that Uso1 protein plays a role as a cytoskeletal component in the protein transport from the ER to the later secretory compartments.


Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome.
Impaired glucose transport across brain tissue barriers causes infantile seizures, developmental delay and acquired microcephaly. Since the first report in 1991 (De Vivo et al, NEJM, 1991) 17 patients have been identified with the glucose transporter protein syndrome (GTPS). The diagnostic feature of the syndrome is an unexplained hypoglycorrhachia in the clinical setting of an infantile epileptic encephalopathy. We review our clinical experience by highlighting one illustrative case: a 6-year old girl who presented at age 2 months with infantile seizures and hypoglycorrhachia. The CSF/blood glucose ratio was 0.33. DNA sequencing identified a missense mutation in exon 7 (C1108T). Erythrocyte GLUT1 immunoreactivity was normal. The time course of 3-O-methyl-glucose (3OMG) uptake by erythrocytes of the patient was 46% that of mother and father. The apparent Km was similar in all cases (2-4 mmol/L), but the apparent Vmax in the patient was only 28% that of the parents (500 versus 1,766 fmol/s/10(6)RBC; p < 0.004). In addition, a 3-month trial of oral thioctic acid also benefited the patient and increased the Vmax to 935 fmol/s/10(6) RBC (p < 3 x 10(-7)). Uptake of dehydroascorbic acid by erythrocytes of the patient was impaired to the same degree as that of 3OMG (Vmax was 38% of that of the mother's), which supports previous observations of GLUT1 being multifunctional. These studies confirm the molecular basis of the GTPS and the multifunctional role of GLUT1. The need for more effective treatment is compelling.


Effect of cyclosporin A on immunoglobulin class in patients receiving blood transfusions.
IgG antibodies detected by flow cytometry in sera from potential renal transplant recipients are associated with an increased number of rejection episodes and impaired graft function. Furthermore, cytotoxic antibodies may develop if pre-transplant blood transfusions are given to such patients. We have investigated the effect of cyclosporin A on the development of IgM and IgG antibodies detected by flow cytometry after blood transfusions in 16 previously untransfused dialysis patients. Eight (group 1) received three to five third-party blood transfusions at two weekly intervals and the remaining eight (group 2) received transfusions with concomitant cyclosporin A therapy (10 mg/kg/day). Sera obtained after each transfusion were tested using flow cytometry against lymphocytes from six normal donors. In all 462 serum/cell combinations were tested. Sera from six out of eight patients in group 1 showed IgG antibody activity following blood transfusions and none developed IgM antibodies alone. In contrast IgG antibody activity was detected in one serum sample from only one of the eight patients in group 2 (P less than 0.02); a further three patients developed IgM but not IgG antibody activity during the transfusion protocol. IgG antibodies were found in 25/228 serum/cell combinations in group 1 but in 1/234 in group 2 (P less than 0.001). The patient in group 2 who developed IgG antibodies in one serum/cell combination was known to have red cell autoantibodies. This IgG activity was removed by red cell absorption, suggesting that the autoreactive red cell antibody cross-reacted with lymphocytes. Cytotoxic antibodies were detected in two serum/cell combinations in group 1 alone.(ABSTRACT TRUNCATED AT 250 WORDS)


Over-expression of calpastatin inhibits calpain activation and attenuates post-infarction myocardial remodeling.
Calpain is activated following myocardial infarction and ablation of calpastatin (CAST), an endogenous inhibitor of calpains, promotes left ventricular remodeling after myocardial infarction (MI). The present study aimed to investigate the effect of transgenic over-expression of CAST on the post-infarction myocardial remodeling process. We established transgenic mice (TG) ubiquitously over-expressing human CAST protein and produced MI in TG mice and C57BL/6J wild-type (WT) littermates. The CAST protein expression was profoundly upregulated in the myocardial tissue of TG mice compared with WT littermates (P < 0.01). Overexpression of CAST significantly reduced the infarct size (P < 0.01) and blunted MI-induced interventricular hypertrophy, global myocardial fibrosis and collagen I and collagen III deposition, hypotension and hemodynamic disturbances at 21 days after MI. Moreover, the MI-induced up-regulation and activation of calpains were obviously attenuated in CAST TG mice. MI-induced down-regulation of CAST was partially reversed in TG mice. Additionally, the MI-caused imbalance of matrix metalloproteinases and their inhibitors was improved in TG mice. Transgenic over-expression of CAST inhibits calpain activation and attenuates post-infarction myocardial remodeling.


Opportunistic screening for heart failure with natriuretic peptides in patients with atrial fibrillation: a meta-analysis of individual participant data of four screening studies.
Heart failure (HF) often coexists in atrial fibrillation (AF) but is frequently unrecognised due to overlapping symptomatology. Furthermore, AF can cause elevated natriuretic peptide levels, impairing its diagnostic value for HF detection. We aimed to assess the prevalence of previously unknown HF in community-dwelling patients with AF, and to determine the diagnostic value of the amino-terminal pro B-type natriuretic peptide (NTproBNP) for HF screening in patients with AF. Individual participant data from four HF-screening studies in older community-dwelling persons were combined. Presence or absence of HF was in each study established by an expert panel following the criteria of the European Society of Cardiology. We performed a two-stage patient-level meta-analysis to calculate traditional diagnostic indices. Of the 1941 individuals included in the four studies, 196 (10.1%) had AF at baseline. HF was uncovered in 83 (43%) of these 196 patients with AF, versus 381 (19.7%) in those without AF at baseline. Median NTproBNP levels of patients with AF with and without HF were 744 pg/mL and 211 pg/mL, respectively. At the cut-point of 125 pg/mL, sensitivity was 93%, specificity 35%, and positive and negative predictive values 51% and 86%, respectively. Only 23% of all patients with AF had an NTproBNP level below the 125 pg/mL cut-point, with still a 13% prevalence of HF in this group. With a prevalence of nearly 50%, unrecognised HF is common among community-dwelling patients with AF. Given the high prior change, natriuretic peptides are diagnostically not helpful, and straightforward echocardiography seems to be the preferred strategy for HF screening in patients with AF.


The effects of selective schooling and self-concept on adolescents' academic aspiration: an examination of Dweck's self-theory.
Dweck has emphasized the role of pupils' implicit theories about intellectual ability in explaining variations in their engagement, persistence and achievement. She has also highlighted the role of confidence in one's intelligence as a factor influencing educational attainment. The aim of this paper is to develop a model of achievement aspiration in adolescence and to compare young people who are educated at a selective grammar school with those who attend a non-selective 'secondary modern' school. The sample consisted of 856 English secondary school pupils in years 7 and 10 from two selective and two non-selective secondary schools. Questionnaires were completed in schools. The findings are consistent with the model, showing that achievement aspiration is predicted directly by gender, school type and type of intelligence theory. Importantly, school type also affects aspirations indirectly, with effects being mediated by confidence in one's own intelligence and perceived academic performance. Intelligence theory also affects aspirations indirectly with effects being mediated by perceived academic performance, confidence and self-esteem. Additionally, intelligence theory has a stronger effect on aspirations in the selective schools than in the non-selective schools. The findings provide substantial support for Dweck's self-theory, showing that implicit theories are related to aspirations. However, the way in which theory of intelligence relates to age and gender suggests there may be important cross-cultural or contextual differences not addressed by Dweck's theory. Further research should also investigate the causal paths between aspirations, implicit theories of intelligence and the impact of school selection.


Osteoradionecrosis (ORN) of the mandible: a laser Raman spectroscopic study.
Laser Raman spectroscopy has been used in this study to characterize mandibular bone samples from patients who had undergone radiation therapy for oral cancer. The paper discusses spectral changes resulting in osteoradionecrosis (ORN) of the mandibular bone, a serious complication that may occur after radiation therapy. Histopathological studies normally reveal the radiation damage on vascular canals and loss in bone cells, but will not reveal any structural or biochemical changes. All radiation-induced side effects are attributed to this hypovascularity and hypocellularity caused by early- and/or late-delayed effects. Our Raman studies on normal and ORN bone and on bone exposed to radiation, but not in the ORN state, show that irradiation produces immediate structural changes in the inorganic bone matrix with a slight loss in cells. ORN bone, in addition to the structural changes that had already occurred on radiation exposure, shows almost complete loss of cellular components. Since bone tissue is continuously being remodeled (dissolved and rebuilt) under normal conditions, our results suggest that the immediate structural changes in the calcium hydroxy apatite mineral part is not repaired in ORN, due to loss of the highly transient osteoblasts and osteoclasts resulting from destruction of stem cells. The spectral studies also show changes in the organic matrix, which is mostly type I collagen.


Vav3, a GEF for RhoA, Plays a Critical Role under High Glucose Conditions.
The role of small GTPase molecules is poorly understood under high glucose conditions. We analyzed the expression pattern of Vav3 in skeletal muscle C2C12 cells under high glucose culture condition with reverse transcription-polymerase chain reaction and Western blot analysis. We also measured glucose uptake using isotope-labelled glucose. We showed that expression of Vav3 (a guanine nucleotide exchange factor for RhoA) increased. mRNA and protein levels in skeletal muscle C2C12 cells under high glucose conditions. The AMP-activated protein kinase (AMPK) activator AMPK agonist 5-aminoimidazole-4-carboxy-amide-1-d-ribofuranoside (AICAR) suppressed high glucose-induced Vav3 induction. In addition, exposure of cells to high glucose concentration increased the phosphorylation of PAK-1, a molecule downstream of RhoA. The phosphorylation of paxillin, a downstream molecule of PAK-1, was also increased by exposure to high glucose. Phosphorylation of these molecules was not observed in the presence of AICAR, indicating that AMPK is involved in the RhoA signal pathway under high glucose conditions. Knock down of Vav3 enhances metformin-mediated glucose uptake. Inhibition of AMPK blocked the increases of Vav3 knock down-induced glucose uptake. Metformin-mediated Glut4 translocation was also increased by Vav3 knock-down, suggesting that Vav3 is involved in metformin-mediated glucose uptake. These results demonstrate that Vav3 is involved in the process of metformin-mediated glucose regulation.


The diversity and anti-microbial activity of endophytic actinomycetes isolated from medicinal plants in Panxi plateau, China.
Traditional Chinese medicinal plants are sources of biologically active compounds, providing raw material for pharmaceutical, cosmetic and fragrance industries. The endophytes of medicinal plants participate in biochemical pathways and produce analogous or novel bioactive compounds. Panxi plateau in South-west Sichuan in China with its unique geographical and climatological characteristics is a habitat of a great variety of medicinal plants. In this study, 560 endophytic actinomycetes were isolated from 26 medicinal plant species in Panxi plateau. 60 isolates were selected for 16S rDNA-RFLP analysis and 14 representative strains were chosen for 16S rDNA sequencing. According to the phylogenetic analysis, seven isolates were Streptomyces sp., while the remainder belonged to genera Micromonospora, Oerskovia, Nonomuraea, Promicromonospora and Rhodococcus. Antimicrobial activity analysis combined with the results of amplifying genes coding for polyketide synthetase (PKS-I, PKS-II) and nonribosomal peptide synthetase (NRPS) showed that endophytic actinomycetes isolated from medicinal plants in Panxi plateau had broad-spectrum antimicrobial activity and potential natural product diversity, which further proved that endophytic actinomycetes are valuable reservoirs of novel bioactive compounds.


Renal function monitoring in heart failure - what is the optimal frequency? A narrative review.
The second most common cause of hospitalization due to adverse drug reactions in the UK is renal dysfunction due to diuretics, particularly in patients with heart failure, where diuretic therapy is a mainstay of treatment regimens. Therefore, the optimal frequency for monitoring renal function in these patients is an important consideration for preventing renal failure and hospitalization. This review looks at the current evidence for optimal monitoring practices of renal function in patients with heart failure according to national and international guidelines on the management of heart failure (AHA/NICE/ESC/SIGN). Current guidance of renal function monitoring is in large part based on expert opinion, with a lack of clinical studies that have specifically evaluated the optimal frequency of renal function monitoring in patients with heart failure. Furthermore, there is variability between guidelines, and recommendations are typically nonspecific. Safer prescribing of diuretics in combination with other antiheart failure treatments requires better evidence for frequency of renal function monitoring. We suggest developing more personalized monitoring rather than from the current medication-based guidance. Such flexible clinical guidelines could be implemented using intelligent clinical decision support systems. Personalized renal function monitoring would be more effective in preventing renal decline, rather than reacting to it.


Analyzing repeated data collected by mobile phones and frequent text messages. An example of low back pain measured weekly for 18 weeks.
Repeated data collection is desirable when monitoring fluctuating conditions. Mobile phones can be used to gather such data from large groups of respondents by sending and receiving frequently repeated short questions and answers as text messages.The analysis of repeated data involves some challenges. Vital issues to consider are the within-subject correlation, the between measurement occasion correlation and the presence of missing values.The overall aim of this commentary is to describe different methods of analyzing repeated data. It is meant to give an overview for the clinical researcher in order for complex outcome measures to be interpreted in a clinically meaningful way. A model data set was formed using data from two clinical studies, where patients with low back pain were followed with weekly text messages for 18 weeks. Different research questions and analytic approaches were illustrated and discussed, as well as the handling of missing data. In the applications the weekly outcome "number of days with pain" was analyzed in relation to the patients' "previous duration of pain" (categorized as more or less than 30 days in the previous year).Research questions with appropriate analytical methods 1: How many days with pain do patients experience? This question was answered with data summaries. 2: What is the proportion of participants "recovered" at a specific time point? This question was answered using logistic regression analysis. 3: What is the time to recovery? This question was answered using survival analysis, illustrated in Kaplan-Meier curves, Proportional Hazard regression analyses and spline regression analyses. 4: How is the repeatedly measured data associated with baseline (predictor) variables? This question was answered using generalized Estimating Equations, Poisson regression and Mixed linear models analyses. 5: Are there subgroups of patients with similar courses of pain within the studied population? A visual approach and hierarchical cluster analyses revealed different subgroups using subsets of the model data. We have illustrated several ways of analysing repeated measures with both traditional analytic approaches using standard statistical packages, as well as recently developed statistical methods that will utilize all the vital features inherent in the data.


Absorption and peak blood alcohol concentration after drinking beer, wine, or spirits.
Both the amount and the rate of absorption of ethanol (EtOH) from alcoholic beverages are key determinants of the peak blood alcohol concentration (BAC) and exposure of organs other than gut and liver. Previous studies suggest EtOH is absorbed more rapidly in the fasting than in the postprandial state. The concentration of EtOH and the type of beverage may determine gastric emptying/absorption of EtOH. The pharmacokinetics of EtOH were measured in 15 healthy men after consumption of 0.5 g of EtOH/kg body weight. During this 3-session crossover study, subjects consumed in separate sessions, beer (5.1% v/v), white wine (12.5% v/v), or vodka/tonic (20% v/v) over 20 minutes following an overnight fast. BAC was measured by gas chromatography at multiple points after consumption. Peak BAC (Cmax ) was significantly higher (p < 0.001) after vodka/tonic (77.4 ± 17.0 mg/dl) than after wine (61.7 ± 10.8 mg/dl) or beer (50.3 ± 9.8 mg/dl) and was significantly higher (p < 0.001) after wine than beer. The time to Cmax occurred significantly earlier (p < 0.01) after vodka/tonic (36 ± 10 minutes) compared to wine (54 ± 14 minutes) or beer (62 ± 23 minutes). Six subjects exceeded a Cmax of 80 mg/dl after vodka/tonic, but none exceeded this limit after beer or wine. The area under the concentration-time curve (AUC) was significantly greater after drinking vodka/tonic (p < 0.001) than after wine or beer. Comparison of AUCs indicated the relative bioavailability of EtOH was lower after drinking beer. Findings indicate that BAC is higher after drinking vodka/tonic than beer or wine after fasting. A binge pattern is significantly more likely to result in BAC above 80 mg/dl after drinking vodka/tonic than beer or wine. Men drinking on an empty stomach should know BAC will vary depending on beverage type and the rate and amount of EtOH.


High efficiency diffusion molecular retention tumor targeting.
Here we introduce diffusion molecular retention (DMR) tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT) injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding) and RAD (control) probes were synthesized bearing DOTA (for (111) In(3+)), a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or i.v. methods was assessed by surface fluorescence, biodistribution of [(111)In] RGD and [(111)In] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [(111)In] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352%ID/g tumor obtained by DMR (vs 4.14%ID/g by i.v.). The high efficiency molecular targeting of DMR employed low probe doses (e.g. 25 ng as RGD peptide), which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e.g. toxic, short range alpha emitters) for radiotherapy, or the delivery of photosensitizers to tumors accessible to light.


B lymphocyte responses in Parkinson's disease and their possible significance in disease progression.
Inflammation contributes to Parkinson's disease pathogenesis. We hypothesized that B lymphocytes are involved in Parkinson's disease progression. We measured antibodies to alpha-synuclein and tau in serum from patients with rapid eye movement sleep behaviour disorder (n = 79), early Parkinson's disease (n = 50) and matched controls (n = 50). Rapid eye movement sleep behaviour disorder cases were stratified by risk of progression to Parkinson's disease (low risk = 30, high risk = 49). We also measured B-cell activating factor of the tumour necrosis factor receptor family, C-reactive protein and total immunoglobulin G. We found elevated levels of antibodies to alpha-synuclein fibrils in rapid eye movement sleep behaviour disorder patients at high risk of Parkinson's disease conversion (ANOVA, P < 0.001) and lower S129D peptide-specific antibodies in those at low risk (ANOVA, P < 0.001). An early humoral response to alpha-synuclein is therefore detectable prior to the development of Parkinson's disease. Peripheral B lymphocyte phenotyping using flow cytometry in early Parkinson's disease patients and matched controls (n = 41 per group) revealed reduced B cells in Parkinson's disease, particularly in those at higher risk of developing an early dementia [t(3) = 2.87, P = 0.01]. Patients with a greater proportion of regulatory B cells had better motor scores [F(4,24) = 3.612, P = 0.019], suggesting they have a protective role in Parkinson's disease. In contrast, B cells isolated from Parkinson's disease patients at higher risk of dementia had greater cytokine (interleukin 6 and interleukin 10) responses following in vitro stimulation. We assessed peripheral blood lymphocytes in alpha-synuclein transgenic mouse models of Parkinson's disease: they also had reduced B cells, suggesting this is related to alpha-synuclein pathology. In a toxin-based mouse model of Parkinson's disease, B-cell deficiency or depletion resulted in worse pathological and behavioural outcomes, supporting the conclusion that B cells play an early protective role in dopaminergic cell loss. In conclusion, we found changes in the B-cell compartment associated with risk of disease progression in rapid eye movement sleep behaviour disorder (higher alpha-synuclein antibodies) and early Parkinson's disease (lower levels of B lymphocytes that were more reactive to stimulation). Regulatory B cells play a protective role in a mouse model, potentially by attenuating inflammation and dopaminergic cell loss. B cells are therefore likely to be involved in the pathogenesis of Parkinson's disease, albeit in a complex way, and thus warrant consideration as a therapeutic target.


Image collection of 3D-printed prototypes and non-3D-printed prototypes.
Image processing refers to the use of computer algorithms to manipulate and enhance digital images to improve their quality or to make them more suitable for tasks such as classification. Common benchmarking datasets in this field include the imagenet, CIFAR-100, and MNIST datasets. This dataset is a collection of images that are particularly relevant to engineering and design, consisting of two categories: 3D-printed prototypes, and non-3D-printed prototypes This data was collected through a hybrid approach that entailed both web scraping and direct collection from engineering labs and workspaces at Penn State University. The initial data was then augmented using several data augmentation techniques including rotation, noise, blur, and color shifting. This dataset is potentially useful to train image classification algorithms or attentional mapping approaches. This data can be used either by itself or used to bolster an existing image classification dataset.


Flavones: From Biosynthesis to Health Benefits.
Flavones correspond to a flavonoid subgroup that is widely distributed in the plants, and which can be synthesized by different pathways, depending on whether they contain C- or O-glycosylation and hydroxylated B-ring. Flavones are emerging as very important specialized metabolites involved in plant signaling and defense, as well as key ingredients of the human diet, with significant health benefits. Here, we appraise flavone formation in plants, emphasizing the emerging theme that biosynthesis pathway determines flavone chemistry. Additionally, we briefly review the biological activities of flavones, both from the perspective of the functions that they play in biotic and abiotic plant interactions, as well as their roles as nutraceutical components of the human and animal diet.


[Treatment results of intermittent and cyclic regimen with ATRA and chemotherapy in childhood acute promyelocytic leukemia. Children's Cancer and Leukemia Study Group].
An intermittent and cyclic regimen with All-Trans Retinoic Acid (ATRA) and intensive chemotherapy was conducted due to pharmacokinetic studies on ATRA for acute promyelocytic leukemia (APL) in children. We have treated 17 children with APL using ATRA for remission induction followed by an intermittent schedule of ATRA plus intensive chemotherapy (APL-ATRA protocol). There were 10 males and 7 females. The median age was 9.0 years old. The median baseline white blood cell count was 12.1 x 10(3)/microliter, hemoglobin 7.8 g/dl, platelet 4.5 x 10(4) microliters at diagnosis. Sixteen patients showed t(15; 17) translocation. RT-PCR analysis was available in 15 patients and showed PML/RAR alpha rearrangement in all patients. Overall, 13 or 17 newly diagnosed patients (88%) achieved complete remission and EFS was 67%. Compared to the control (same chemotherapy without ATRA regimen), remission induction and EFS were significantly increased. The toxicity of ATRA consisted of retinoic acid syndrome in 1 and pseudotumor cerebli in another. Other toxicities included headache, chelitis, gastrointestinal trouble and bone pain. These results suggest that intermittent and cyclic regimen with ATRA and intensive chemotherapy (APL-ATRA protocol) is highly effective for APL patients.


One-Minute Walk Test in Children with Cerebral Palsy GMFCS Level 1 and 2: Reference Values to Identify Therapeutic Effects after Rehabilitation.
Background: Children with cerebral palsy (CP) show age-driven development and individual fluctuations in walking capacity.Aim: 1. To precisely quantify 1MWT changes in children with CP, GMFCS level 1 and 2, generating 1MWT percentiles, depicting expected development over 6 months; 2. to assess the effect of a 6-month rehabilitation using whole-body vibration (WBV).Methods: Retrospective data analysis in 210 children with CP, GMFCS 1 and 2 who received standardized rehabilitation (DRKS00011331). 1MWT was assessed before (M0) and after treatment (M6), and at a 6-month follow-up (M12). Centiles were created using the lambda-mu-sigma method. Cohen's d was used to assess effect size.Results: We created 1MWT percentiles using data of all 210 children (M0 data). A small treatment effect size (d = 0.46) was found (M6 and M12 data).Conclusions: Using the generated centiles clinicians may monitor 1MWT changes over 6 months. Combining WBV and conventional physiotherapy may improve 1MWT in children with CP.Abbreviations: 1MWT: One-Minute Walk Test; 6MWT: Six-Minute Walk Test; CP: Cerebral palsy; ES: effect size; GMFCS: Gross Motor Function Classification System; GMFM-66: Gross Motor Function Measure 66; LOESS: Locally Estimated Scatterplot Smoothing; LMS: lambda-mu-sigma; SD: standard deviation; WBV: whole-body-vibration.


Insights into metal-ligand hydrogen transfer: a square-planar ruthenate complex supported by a tetradentate amino-amido-diolefin ligand.
A four-coordinate, sixteen-electron Ru(0) complex containing the tetradentate diamino-diolefin ligand (±)-trans-N,N-bis(5H-dibenzo[a,d]cyclohepten-5-yl)-1,2-diaminocyclohexane (trop2dach) has been synthesised. Deprotonation of one amino N-H functional group generates an unprecedented four-coordinate ruthenate species which has been characterised in solution and in the solid state. The newly formed ruthenate complex undergoes intramolecular metal-ligand N-H addition/elimination in solution to generate a transient diamido ruthenium hydride species, as supported by NMR spectroscopy and density functional theory.


Evidence for differential modulation of primary and nonprimary auditory cortex by forward masking in tinnitus.
It has been proposed that tinnitus is generated by aberrant neural activity that develops among neurons in tonotopic of regions of primary auditory cortex (A1) affected by hearing loss, which is also the frequency region where tinnitus percepts localize (Eggermont and Roberts 2004; Roberts et al., 2010, 2013). These models suggest (1) that differences between tinnitus and control groups of similar age and audiometric function should depend on whether A1 is probed in tinnitus frequency region (TFR) or below it, and (2) that brain responses evoked from A1 should track changes in the tinnitus percept when residual inhibition (RI) is induced by forward masking. We tested these predictions by measuring (128-channel EEG) the sound-evoked 40-Hz auditory steady-state response (ASSR) known to localize tonotopically to neural sources in A1. For comparison the N1 transient response localizing to distributed neural sources in nonprimary cortex (A2) was also studied. When tested under baseline conditions where tinnitus subjects would have heard their tinnitus, ASSR responses were larger in a tinnitus group than in controls when evoked by 500 Hz probes while the reverse was true for tinnitus and control groups tested with 5 kHz probes, confirming frequency-dependent group differences in this measure. On subsequent trials where RI was induced by masking (narrow band noise centered at 5 kHz), ASSR amplitude increased in the tinnitus group probed at 5 kHz but not in the tinnitus group probed at 500 Hz. When collapsed into a single sample tinnitus subjects reporting comparatively greater RI depth and duration showed comparatively larger ASSR increases after masking regardless of probe frequency. Effects of masking on ASSR amplitude in the control groups were completely reversed from those in the tinnitus groups, with no change seen to 5 kHz probes but ASSR increases to 500 Hz probes even though the masking sound contained no energy at 500 Hz (an "off-frequency" masking effect). In contrast to these findings for the ASSR, N1 amplitude was larger in tinnitus than control groups at both probe frequencies under baseline conditions, decreased after masking in all conditions, and did not relate to RI. These results suggest that aberrant neural activity occurring in the TFR of A1 underlies tinnitus and its modulation during RI. They indicate further that while neural changes occur in A2 in tinnitus, these changes do not reflect the tinnitus percept. Models for tinnitus and forward masking are described that integrate these findings within a common framework.


High-resolution 1.5-Tesla magnetic resonance imaging for tissue-engineered constructs: a noninvasive tool to assess three-dimensional scaffold architecture and cell seeding.
Tissue-engineered scaffolds are made of biocompatible polymers with various structures, allowing cell seeding, growth, and differentiation. Noninvasive imaging methods are needed to study tissue-engineered constructs before and after implantation. Here, we show that high-resolution magnetic resonance imaging (MRI) performed on a clinical 1.5-T device is a reliable technique to assess three-dimensional structures of porous scaffolds and to validate cell-seeding procedures. A high-temperature superconducting detection coil was used to achieve a resolution of 30 x 30 x 30 microm(3) when imaging the scaffolds. Three types of structures with tuneable architectures were prepared from naturally derived polysaccharides and evaluated as scaffolds for mesenchymal stem cell (MSC) culture. To monitor cell seeding, MSCs were magnetically labeled using simple incubation with anionic citrate-coated iron-oxide nanoparticles for 30 min. Iron uptake was quantified using single-cell magnetophoresis, and cell proliferation was checked for 7 days after labeling. Three-dimensional (3D) microstructures of scaffolds were assessed using MRI, revealing lamellar or globular porous organization according to the scaffold preparation process. MSCs with different iron load (5, 12 and 31 pg of iron per cell) were seeded on scaffolds at low density (132 cells/mm(3)) and detected on 3D gradient-echo MR images according to phase distortions and areas of intensely low signal, whose size increased with cell iron load and echo time. Overall signal loss in the scaffold correlated with the number of seeded cells and their iron load. Different organizations of cells were observed depending on the scaffold architecture. After subcutaneous implantation in mice, scaffolds seeded with labeled cells could be distinguished in vivo from scaffold with nonlabeled cells by observation of signal and phase heterogeneities and by measuring the global signal loss. High-resolution 1.5-T MRI combined with efficient intracellular contrast agents shows promise for noninvasive 3D visualization of tissue-engineered constructs before and after in vivo implantation.


Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence.
We assessed association between prior cytomegalovirus (CMV) infection, proinflammatory status and effectiveness of the anti-influenza vaccination. We examined 154 individuals during the epidemic season dividing them according to the age, response to the vaccine and the Senieur Protocol (SP). The anti-hemagglutinins (HI), tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6, IL10, ACTH/cortisol axis, anti-CMV antibodies and CD28+CD57- lymphocytes were assessed. Non-responders of both ages we characterised by higher levels of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes (known to be associated with CMV carrier status) together with increased concentrations of TNFalpha and IL6 and decreased levels of cortisol. The anti-influenza vaccine induced increase in TNFalpha and IL10 in the all non-responders, while cortisol increased only in the young. Concluding, CMV carrier status eliciting elevated proinflammatory potential could contribute to unresponsiveness to the anti-influenza vaccine.


Erdheim Chester disease: cerebral involvement in childhood.
Erdheim Chester disease (ECD) is an uncommon, non-Langerhans form of histiocytosis, characterized by long bone sclerosis. To date, only approximately some 100 cases have been reported. The diagnosis is based on its peculiar radiological and pathological features. ECD disease is rarely expected preoperatively. Although the ECD is an adult illness it can rarely be seen in the childhood period. We reported the case of a 10-year-old boy who presented headache, paraparesis and with diabetes inspidus for 6 years. As far as we know, the case presented here is the first published report of intracranial involvement and unilateral bone sclerosis with ECD in childhood.


Psychometric evaluation of the Heart Failure Somatic Perception Scale in a European heart failure population.
The Heart Failure Somatic Perception Scale (HFSPS) is a four-factor instrument used to assess how bothersome are 18 physical signs and symptoms of heart failure. To date, construct validity and reliability of the HFSPS have been evaluated in only one American study and never in a European population. To evaluate psychometric properties (validity and reliability) of the HFSPS in a European heart failure population. This was an Italian multicentre study in which the HFSPS factorial structure was assessed using confirmatory factor analysis. Criterion related validity of the HFSPS was evaluated by correlating its factor scores with the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores using Pearson's r. The HFSPS internal consistency reliability was evaluated using the factor score determinacy coefficient, Cronbach's α and model-based internal consistency index. Most of the participants (n=321) were male (56.6%), with a mean age of 71.48 years (SD, 12.75) and in New York Heart Association class II (61.8%). The confirmatory factor analysis, testing the original HFSPS four-factor structure (dyspnoea, chest discomfort, early and subtle, and oedema), resulted in the following supportive fit indices: χ2 (126, N=321)=337.612, p<0.001, comparative fit index =0.920, Tucker-Lewis index =0.903, root mean square error of approximation =0.072 and standardized root mean square residual =0.045. With regard to the criterion related validity, all the correlations with the KCCQ were statistically significant. The HFSPS reliability resulted in factor score determinacy coefficients ⩾ 0.87 and Cronbach's α ⩾ 0.75, with the exception of the two-item chest discomfort subscale; the model-based reliability coefficient was 0.914. The validity and reliability of the HFSPS were supportive in this European sample. The HFSPS can be used to assess how bothersome heart failure signs and symptoms are in order to improve their management.


Short and long telomeres increase risk of amnestic mild cognitive impairment.
Peripheral blood telomere length has been associated with age-related conditions including Alzheimer's disease (AD). This suggests that telomere length may identify subjects at increased risk of AD. Thus, we investigated the associations of peripheral blood telomere length with amnestic mild cognitive impairment (aMCI), a putative precursor of AD, among Mayo Clinic Study of Aging participants who were prospectively followed for incident aMCI. We matched 137 incident aMCI cases (mean age 81.1 years, [range 70.9-90.8]; 49.6% men) by age and sex to 137 cognitively normal controls. We measured telomere length (T/S ratio) at baseline using quantitative PCR. Compared to the middle T/S quintile (Q3), the risk of aMCI was elevated for subjects with the shortest (Q1: HR, 2.85, 95% Confidence interval [CI] 0.98, 8.25; p=0.05) and the longest telomere lengths (Q5: HR, 5.58, 95%CI, 2.21, 14.11; p=0.0003). In this elderly cohort, short and long telomeres were associated with increased risk of aMCI. Our findings suggest that both long and short telomere lengths may play a role in the pathogenesis of aMCI, and may be markers of increased risk of aMCI.


The potential for community-based health information exchange systems to reduce hospital readmissions.
Hospital readmissions are common, costly, and offer opportunities for utilization reduction. Electronic health information exchange (HIE) systems may help prevent readmissions by improving access to clinical data by ambulatory providers after discharge from the hospital. We sought to determine the association between HIE system usage and 30-day same-cause hospital readmissions among patients who consented and participated in an operational community-wide HIE during a 6-month period in 2009-2010. We identified a retrospective cohort of hospital readmissions among adult patients in the Rochester, New York area. We analyzed claims files from two health plans that insure more than 60% of the area population. To be included in the dataset, patients needed to be continuously enrolled in the health plan with at least one encounter with a participating provider in the 6 months following consent to be included in the HIE system. Each patient appeared in the dataset only once and each discharge could be followed for at least 30 days. We found that accessing patient information in the HIE system in the 30 days after discharge was associated with a 57% lower adjusted odds of readmission (OR 0.43; 95% CI 0.27 to 0.70). The estimated annual savings in the sample from averted readmissions associated with HIE usage was $605 000. These findings indicate that usage of an electronic HIE system in the ambulatory setting within 30 days after hospital discharge may effectively prevent hospital readmissions, thereby supporting the need for ongoing HIE efforts.


Ball/dumbbell-like structured micrometer-sized Sb₂S₃ particles as a scattering layer in dye-sensitized solar cells.
To improve the light harvesting efficiency in dye-sensitized solar cells (DSSC) the light scattering layer is important. In this Letter, we present ball/dumbbell-like structured micrometer-sized Sb2S3 particles for photon propagation in DSSCs and demonstrate their effective usage in photoelectrodes. The analysis of the photoelectrode by a UV-vis spectrophotometer indicates that the absorption wavelength of an electrode with scattering layer can be obviously promoted from ultraviolet to visible light. The synthesized Sb2S3 particle structures were also characterized by x-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The photovoltaic performance of the ball/dumbbell-like structured Sb2S3 based cell exhibits excellent power conversion efficiency.


The Efficacy of Acupuncture for the Treatment of Sciatica: A Systematic Review and Meta-Analysis.
Background. Sciatica is one of the most frequently reported complaints; it affects quality of life and reduces social and economic efficacy. Clinical studies on the efficacy of acupuncture therapy in sciatica are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This study aims to assess the effectiveness of acupuncture therapy for sciatica. Methods. Comprehensive searches of 8 databases were conducted up until April 2015. Outcomes included effectiveness (proportion of patients who improved totally or partly in clinical symptoms), pain intensity, and pain threshold. Effect sizes were presented as risk ratio (RR) and mean difference (MD). Pooled effect sizes were calculated by fixed effects or random effects model. Results. A total of 12 studies (involving 1842 participants) were included. Results showed that acupuncture was more effective than conventional Western medicine (CWM) in outcomes effectiveness (RR 1.21, 95% CI: 1.16-1.25), pain intensity (MD -1.25, 95% CI: -1.63 to -0.86), and pain threshold (MD: 1.08, 95% CI: 0.98-1.17). Subgroup and sensitivity analysis found that the results did not change in different treatment method and drug categories substantially. The reported adverse effects were acceptable. Conclusions. Acupuncture may be effective in treating the pain associated with sciatica.


Cytogenetic and molecular characterization of Y isochromosome in a 63XO/64Xi(Yq) mosaic karyotype of an intersex horse.
Sex chromosome aberrations commonly lead to abnormal sexual development. Here we cytogenetically and molecularly characterized Y isochromosome in an intersex horse. Blood lymphocyte analysis showed a mosaic karyotype with 96% 63,XO and 4% 64,Xi(Y) cells. Molecular analysis of the isochromosome was carried out by fluorescence in situ hybridization and polymerase chain reaction with male-specific and pseudoautosomal markers from the horse Y chromosome. We found that the isochromosome was monocentric, composed of 2 long arms, carrying 2 sets of genes of the pseudoautosomal region (PAR) and the male-specific region of the Y (MSY), including the SRY - thus being genetically equivalent to Y disomy. Sequence analysis of a 1,955-bp region including the SRY exon, the promoter and the UTRs, revealed no mutations in the aberrant Y. The presence of an intact SRY in a small proportion of cells is the proposed cause for the intersex phenotype. Given that the i(Yq) was present in a mosaic form, both post-zygotic and meiotic mechanisms of its origin were proposed. We speculated that nonmosaic 64,Xi(Yq) karyotypes might be rare or absent because of the likely instability of the i(Yq) during cell division. Genetic and phenotypic implications of Y isochromosome formation in other mammals are discussed in the light of the diversity of Y chromosome organization between species.


Purification of centrosomes from mammalian cell lines.
Centrosomes act as the main microtubule-organizing centre of animal cells and play critical roles in the cell, such as mitotic spindle organization, cell polarity, and motility. They are composed of two barrel-shaped structures, the centrioles, surrounded by the pericentriolar matrix. In mammalian cells, the two centrioles differ structurally due to generational difference, the oldest one bearing appendages which allow the transient docking of the centriole at the plasma membrane in order to grow a primary cilium. Centrosome components are highly conserved throughout evolution and several pathologies have been associated with centrosomal defects. The understanding of such a complex organelle has therefore been a challenge for many researchers and has led to the development of centrosomal purification procedures to assess molecular composition, biological function, and structural organization of centrosomes. In this paper, we detail a step-by-step procedure to generate high yield of purified centrosome obtained from various mammalian cell lines.


Health Data Entanglement and artificial intelligence-based analysis: a brand new methodology to improve the effectiveness of healthcare services.
Healthcare expenses will be the most relevant policy issue for most governments in the EU and in the USA. This expenditure can be associated with two major key categories: demographic and economic drivers. Factors driving healthcare expenditure were rarely recognised, measured and comprehended. An improvement of health data generation and analysis is mandatory, and in order to tackle healthcare spending growth, it may be useful to design and implement an effective, advanced system to generate and analyse these data. A methodological approach relied upon the Health Data Entanglement (HDE) can be a suitable option. By definition, in the HDE a large amount of data sets having several sources are functionally interconnected and computed through learning machines that generate patterns of highly probable future health conditions of a population. Entanglement concept is borrowed from quantum physics and means that multiple particles (information) are linked together in a way such that the measurement of one particle's quantum state (individual health conditions and related economic requirements) determines the possible quantum states of other particles (population health forecasts to predict their impact). The value created by the HDE is based on the combined evaluation of clinical, economic and social effects generated by health interventions. To predict the future health conditions of a population, analyses of data are performed using self-learning AI, in which sequential decisions are based on Bayesian algorithmic probabilities. HDE and AI-based analysis can be adopted to improve the effectiveness of the health governance system in ways that also lead to better quality of care.


A variational framework for multiregion pairwise-similarity-based image segmentation.
Variational cost functions that are based on pairwise similarity between pixels can be minimized within level set framework resulting in a binary image segmentation. In this paper we extend such cost functions and address multi-region image segmentation problem by employing a multi-phase level set framework. For multi-modal images cost functions become more complicated and relatively difficult to minimize. We extend our previous work, proposed for background/foreground separation, to the segmentation of images in more than two regions. We also demonstrate an efficient implementation of the curve evolution, which reduces the computational time significantly. Finally, we validate the proposed method on the Berkeley Segmentation Data Set by comparing its performance with other segmentation techniques.


Singlet oxygen luminescence dosimetry (SOLD) for photodynamic therapy: current status, challenges and future prospects.
As photodynamic therapy (PDT) continues to develop and find new clinical indications, robust individualized dosimetry is warranted to achieve effective treatments. We posit that the most direct PDT dosimetry is achieved by monitoring singlet oxygen (1O2), the major cytotoxic species generated photochemically during PDT. Its detection and quantification during PDT have been long-term goals for PDT dosimetry and the development of techniques for this, based on detection of its near-infrared luminescence emission (1270 nm), is at a noteworthy stage of development. We begin by discussing the theory behind singlet-oxygen luminescence dosimetry (SOLD) and the seminal contributions that have brought SOLD to its current status. Subsequently, technology developments that could potentially improve SOLD are discussed, together with future areas of research, as well as the potential limitations of this method. We conclude by examining the major thrusts for future SOLD applications: as a tool for quantitative photobiological studies, a point of reference to evaluate other PDT dosimetry techniques, the optimal means to evaluate new photosensitizers and delivery methods and, potentially, a direct and robust clinical dosimetry system.


Reconstruction of orbital exenteration defects by primary closure using cheek advancement.
Orbital exenteration is a highly disfiguring procedure which, although providing local control of invasive orbital malignancy also results in marked visual, psychological and social disability. We present three consecutive total exenteration cases over 1 year where all 3, including extended exenteration defects, were repaired by primary closure by way of cheek advancement. This technique may be considered where succinct management with minimal follow-up is required and maybe preferable if considering rapidity of rehabilitation with a short time to fitting definitive prostheses. Retrospective review of three consecutive patients who presented with neglected basal cell carcinoma with orbital invasion and subsequently underwent total orbital exenteration with repair by cheek advancement flap. All underwent repair with primary skin closure using a cheek advancement flap. Patient 2 developed a small area of central flap dehiscence noted at 2 months with almost complete granulation of the orbital cavity at 3 months. Patients 1, 2 and 3 were fitted with final prosthesis at 7, 6 and 12 months, respectively. Reconstruction of the exenterated orbit using cheek advancement represents an evolution of the cervico-facial flap repair. The cheek advancement avoids creating a secondary defect and because it involves less dissection and additional skin incisions, is an easier procedure to perform with fewer facial scars. It does not preclude osseointegration if required at a later date and as such we recommend it as an option in repairing the exenterated orbit.


Catharanthus roseus genes regulated differentially by mollicute infections.
A differential display of mRNAs was used to isolate periwinkle cDNAs differentially expressed following infection with one of three mollicutes: Spiroplasma citri, Candidatus Phytoplasma aurantifolia, and stolbur phytoplasma. Twenty-four differentially expressed cDNAs were characterized by Northern blots and sequence analysis. Eight of them had homologies with genes in databanks coding for proteins involved in photosynthesis, sugar transport, response to stress, or pathways of phytosterol synthesis. The regulation of these genes in periwinkle plants infected by additional phloem-restricted bacteria showed that they were not specific to a given mollicute, but correlations with particular symptoms could be established. Expression of transketolase was down regulated following infection with a pathogenic strain of S. citri. No down regulation was observed for the nonphytopathogenic mutant GMT553, which is deficient for fructose utilization.


Primary health care in Canada: systems in motion.
During the 1980s and 1990s, innovations in the organization, funding, and delivery of primary health care in Canada were at the periphery of the system rather than at its core. In the early 2000s, a new policy environment emerged. This policy analysis examines primary health care reform efforts in Canada during the last decade, drawing on descriptive information from published and gray literature and from a series of semistructured interviews with informed observers of primary health care in Canada. Primary health care in Canada has entered a period of potentially transformative change. Key initiatives include support for interprofessional primary health care teams, group practices and networks, patient enrollment with a primary care provider, financial incentives and blended-payment schemes, development of primary health care governance mechanisms, expansion of the primary health care provider pool, implementation of electronic medical records, and quality improvement training and support. Canada's experience suggests that primary health care transformation can be achieved voluntarily in a pluralistic system of private health care delivery, given strong government and professional leadership working in concert.


Photoactivatable oligonucleotide probes to trap single-stranded DNA binding proteins: Updating the potential of 4-thiothymidine from a comparative study.
Photoaffinity labeling (PAL) in combination with recent developments in mass spectrometry is a powerful tool for studying nucleic acid-protein interactions, enabling crosslinking of both partners through covalent bond formation. Such a strategy requires a preliminary study of the most judicious photoreactive group to crosslink efficiently with the target protein. In this study, we report a survey of three different photoreactive nucleobases (including a guanine functionalized with a benzophenone or a diazirine and the zero-length agent 4-thiothymine) incorporated in 30-mer oligonucleotides (ODN) containing a biotin moiety for selective trapping and enrichment of single-stranded DNA binding proteins (SSB). First, the conditions and efficiency of the photochemical reaction with a purified protein using human replication protein A as the relevant model was studied. Secondly, the ability of the probe as bait to photocrosslink and enrich SSB in cell lysate was addressed. Among the different ODN probes studied, we showed that 4-thiothymine was the most relevant: i) it allows efficient and specific trapping of SSB in whole cell extracts in a similar extent as the widely used diazirine, ii) it features the advantages of a zero-length agent thus retaining the physicochemical properties of the ODN bait; iii) ODN including this photochemical agent are easily accessible. In combination with mass spectrometry, the probes incorporating this nucleobase are powerful tools for PAL strategies and can be added in the toolbox of the traditional photocrosslinkers for studying DNA-protein interactions.


Early dexamethasone therapy in preterm infants: a follow-up study.
To study the outcome at 2-year corrected age of infants who participated in a double-blind controlled trial of early (<12 hours) dexamethasone therapy for the prevention of chronic lung disease (CLD). A total of 133 children (70 in the control group, 63 in the dexamethasone-treated group) who survived the initial study period and lived to 2 years of age were studied. All infants had birth weights of 500 to 1999 g and had severe respiratory distress syndrome requiring mechanical ventilation within 6 hours after birth. For infants in the treatment group, dexamethasone was started at a mean age of 8.1 hours and given 0.25 mg/kg every 12 hours for 1 week and then tapered off gradually over a 3-week period. The following variables were evaluated: interim medical history, socioeconomic background, physical growth, neurologic examinations, mental and psychomotor development index score (MDI and PDI), pulmonary function, electroencephalogram, and auditory and visual evoked potential. Infants in the control group tended to have a higher incidence of upper respiratory infection and rehospitalization than did the dexamethasone-treated group because of respiratory problems. Although there was no difference between the groups in somatic growth in girls, the dexamethasone-treated boys had significantly lower body weight and shorter height than the control boys (10.7 +/- 3.0 vs 11.9 +/- 2.0 kg; 84.9 +/- 5.7 vs 87.5 +/- 4.8 cm). The dexamethasone-treated group had a significantly higher incidence of neuromotor dysfunction (25/63 vs 12/70) than did the control group. The dexamethasone-treated infants also had a lower PDI score (79 +/- 26) than did the control group (87 +/- 23), but the difference was not statistically significant. Both groups were comparable in MDI, incidence of vision impairment, and auditory and visual evoked potential. Significant handicap, defined as severe neurologic defect and/or intellectual defect (MDI and/or PDI </= 69), was seen in 22 children (31.4%) in the control group and 26 (41.2%) in the dexamethasone-treated group. Although early postnatal dexamethasone therapy for 4 weeks significantly reduces the incidence of CLD, this therapeutic regimen cannot be recommended at present because of its adverse effects on neuromotor function and somatic growth in male infants, detected at 2 years of age. A longer follow-up is needed. If early dexamethasone therapy is to be used for the prevention of CLD, the therapeutic regimen should be modified. The proper route of administration, the critical time to initiate the therapy, and the dosage and duration of therapy remain to be defined further.


Transbilayer movement of fluorescent and spin-labeled phospholipids in the plasma membrane of human fibroblasts: a quantitative approach.
All phospholipids in the plasma membrane of eukaryotic cells are subject to a slow passive transbilayer movement. In addition, aminophospholipids are recognized by the so-called aminophospholipid translocase, and are rapidly moved from the exoplasmic to the cytoplasmic leaflet of the plasma membrane at the expense of ATP hydrolysis. Though these principal pathways of transbilayer movement of phospholipids probably apply to all eukaryotic plasma membranes, studies of the actual kinetics of phospholipid redistribution have been largely confined to non-nucleated cells (erythrocytes). Experiments on nucleated cells are complicated by endocytosis and metabolism of the lipid probes inserted into the plasma membrane. Taking these complicating factors into account, we performed a detailed kinetic study of the transbilayer movement of short-chain fluorescent (N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl); NBD) and, for the first time, spin-labeled analogues of phosphatidylcholine (PC), -ethanolamine (PE), -serine (PS), and sphingomyelin (SM) in the plasma membrane of cultured human gingival fibroblasts. At 20 degrees C, the passive transbilayer diffusion of NBD analogues was very slow, and the choline-containing NBD analogues were internalized predominantly by endocytosis. Spin-labeled analogues of PC and SM showed higher passive transbilayer diffusion rates, and probably entered the cell by both passive transbilayer movement and endocytosis. In contrast, the rapid uptake of NBD- and spin-labeled aminophospholipid analogues could be mainly ascribed to the action of the aminophospholipid translocase, since it was inhibited by ATP depletion and N-ethylmaleimide pretreatment. The initial velocity of NBD-aminophospholipid translocation was eight to ten times slower than that of the corresponding spin-labeled lipid, and the half-times of redistribution of NBD-PS and spin-labeled PS were 7.2 and 3.6 minutes, respectively. Our data indicate that in human fibroblasts the initial velocity of aminophospholipid translocation is at least one order of magnitude higher than that in human erythrocytes, which should be sufficient to maintain the phospholipid asymmetry in the plasma membrane.


Composite pre-heating: effects on marginal adaptation, degree of conversion and mechanical properties.
This study evaluated the effect of composite pre-polymerization temperature and energy density on the marginal adaptation (MA), degree of conversion (DC), flexural strength (FS), and polymer cross-linking (PCL) of a resin composite (Filtek Z350, 3M/ESPE). For MA, class V cavities (4 mm x 2 mm x 2 mm) were prepared in 40 bovine incisors. The adhesive system Adper Single Bond 2 (3M/ESPE) was applied. Before being placed in the cavities, the resin composite was either kept at room-temperature (25 degrees C) or previously pre-heated to 68 degrees C in the Calset device (AdDent Inc., Danbury, CT, USA). The composite was then light polymerized for 20 or 40s at 600 mW/cm(2) (12 or 24 J/cm(2), respectively). The percentage of gaps was analyzed by scanning electron microscopy, after sectioning the restorations and preparing epoxy resin replicas. DC (n=3) was obtained by FT-Raman spectroscopy on irradiated and non-irradiated composite surfaces. FS (n=10) was measured by the three-point-bending test. KHN (n=6) was measured after 24 h dry storage and again after immersion in 100% ethanol solution for 24h, to calculate PCL density. Data were analyzed by appropriate statistical analyses. The pre-heated composite showed better MA than the room-temperature groups. A higher number of gaps were observed in the room-temperature groups, irrespective of the energy density, mainly in the axial wall (p<0.05). Composite pre-heating and energy density did not affect the DC, FS and PCL (p>0.05). Pre-heating the composite prior to light polymerization similar in a clinical situation did not alter the mechanical properties and monomer conversion of the composite, but provided enhanced composite adaptation to cavity walls.


Modulation of lipid polymorphism by the feline leukemia virus fusion peptide: implications for the fusion mechanism.
The structural effects of the fusion peptide of feline leukemia virus (FeLV) on lipid polymorphism were studied, using differential scanning calorimetry (DSC), 31P nuclear magnetic resonance (NMR), and time-resolved X-ray diffraction. This peptide lowers the bilayer to inverted hexagonal phase transition temperature, TH, of dipalmitoleoylphosphatidylethanolamine (DiPoPE) at peptide mole fractions of up to 1.5 x 10(-3) at pH 5.0 and at pH 7.4. The temperature at which isotropic 31P NMR signals for monomethyldioleoylphosphatidylethanolamine (MeDOPE) first occurred is lowered by the FeLV peptide. The amount of isotropic signal seen at 40 degrees C is directly correlated to the peptide:lipid molar ratio. In the peptide-containing samples, more lipid remains in the isotropic state over the whole recorded temperature range. Isotropic 31P NMR signals were observed for DiPoPE in the presence of the FeLV peptide for the entire recorded temperature range of 35-50 degrees C, while pure DiPoPE showed no significant amount of isotropic signal. X-ray studies of DiPoPE show the formation of a new lipid phase with peptide, which is not seen in the pure lipid samples. Disordering of the Lalpha phase is evidenced by broadening of the diffraction peaks, and the hexagonal cell parameter is decreased with peptide present. Our results suggest that the FeLV peptide is increasing the negative curvature of the lipid system, which is thought to be crucial to the formation of highly bent, high-energy structural fusion intermediates, such as the "stalk" model. Fusion activity for this putative fusogenic peptide was also demonstrated, using a resonance energy transfer (RET) lipid mixing assay. To our knowledge, this work provides the first published experimental evidence of both fusogenic activity and effects on lipid polymorphism for the FeLV fusion peptide.


Calcium content and distribution as a function of growth and transformation in the mouse 3T3 cell.
Total Ca content and that fraction of Ca sensitive to removal by the chelator ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetraacetate (EGTA) have been investigated in the mouse 3T3 cell as a function of growth stage, transformation with SV40 virus, and serum levels of the media. Cells were allowed to grow through several doublings in media containing (45)Ca. The cellular content of (45)Ca was used to access total cell Ca. That fraction of (45)Ca removed by EGTA was presumed to represent primarily surface-localized Ca. The data are expressed on a per cell volume basis to compensate for size differences as a function of growth stage and transformation. During exponential growth phase, the 3T3 cell contains 525pmol Ca/mul cell volume. Of this, approx. 457 pmol/mul is not removable by EGTA and, presumably, is cytoplasmically located. This value is in close agreement with previous studies on the HeLa cell (470 pmol Ca/mul cell water after the removal of the surface Ca). The low level of EGTA- removable Ca present in the 3T3 cell during early exponential growth (68 pmol Ca/mul cell volume) increases progressively with increasing cell density, and upon quiescence it is sevenfold greater. In contrast, SV40- transformed 3T3 cells growing exponentially possess total levels of Ca which are approximately two-thirds the levels of the normal 3T3 cell. However, their EGTA-sensitive Ca is not significantly different from that of exponentially growing, normal 3T3 cells. As the transformed cells continue to grow at high density, their total ca and their sensitivity to EGTA do not change, in contrast to the normal 3T3 cell. Thus, an increase in Ca associated with the cell surface appears to be correlated with growth inhibition. This has been investigated further by regulating growth of the normal and transformed cell with alterations in the serum level of the media. In 4 percent calf serum the normal cell is stopped from continued proliferation. Growth stoppage under these conditions is characterized by a nearly fourfold increase in EGTA-removable Ca, similar to the increase observed upon quiescence in depleted 10 percent serum. Similar treatment of the transformed cell does not reduce its growth rate, nor does it significantly alter Ca distribution. However, at 0.5 percent medium serum levels, the SV40 3T3 growth rate is substantially reduced and, under these conditions, EGTA-removable Ca increases twofold.


Efficacy outcomes in patients using alefacept in the AWARE study.
Alefacept has demonstrated efficacy in clinical trials of patients with chronic plaque psoriasis, either as monotherapy or combined with other treatment modalities such as phototherapy. AWARE (Amevive Wisdom Acquired from Real-World Evidence) is a multicenter, observational, phase IV Canadian registry of psoriasis patients treated with alefacept. Patients with chronic plaque psoriasis were treated with at least one course of alefacept, either alone or added on to their existing antipsoriatic treatment regimen. Each course of alefacept was followed by a period of at least 12 weeks off treatment. Efficacy outcomes included physicians' and patients' assessments of response at week 18, as well as change in percent body surface area (BSA) involvement with psoriasis. The time to retreatment was assessed in patients receiving a second course of alefacept during at least 60 weeks of prospective follow-up. The majority of patients received alefacept in combination with other antipsoriatic therapies. Physicians' and patients' assessments of response at 18 weeks showed that 42% and 41% of patients, respectively, had a "cleared to marked response" and a further 42% had a "moderate to some response." Among those patients whose psoriasis was moderately controlled or not controlled at baseline, 49 to 51% and 33 to 36%, respectively, improved to "cleared to marked response" at 18 weeks. A substantial shift in percent BSA involvement with psoriasis was observed at 18 weeks, with 55% of patients having a BSA involvement of < 10% at week 18 compared to only 20% having this level of BSA involvement at baseline. The mean time to retreatment among the 60% of patients who received a second course of alefacept was 19.3 weeks (range 2-47 weeks). A single course of alefacept therapy improved outcomes in this broad population of real-world chronic plaque psoriasis patients. The limitations of this study include its nonrandomized, noncontrolled, noncomparative design, which allowed multiple different treatment approaches across all patients. The rating scales used in this study have not been previously validated, and ranges were assigned to baseline control and response data that are not specifically defined. Clinicians did not receive specific training in using these scales; therefore, interrater variability could not be assessed.


Cranial bone histology of Metoposaurus krasiejowensis (Amphibia, Temnospondyli) from the Late Triassic of Poland.
In this study, 21 skull bones of Metoposaurus krasiejowensis from the Late Triassic of Poland were investigated histologically. Dermal bones show a diploë structure, with an ornamented external surface. The ridges consist of mostly well vascularized parallel-fibered bone; the valleys are built of an avascular layer of lamellar bone. The thick middle region consists of cancellous bone, with varying porosity. The thin and less vascularized internal cortex consists of parallel-fibered bone. The numerous Sharpey's fibers and ISF are present in all bones. The cyclicity of growth is manifested as an alternation of thick, avascular annuli and high vascularized zones as well as a sequence of resting lines. The detailed histological framework of dermal bones varies even within a single bone; this seems to be related to the local biomechanical loading of the particular part of the skull. The dynamic processes observed during the ornamentation creation indicate that the positions of the ridges and grooves change during growth and could be a specific adaptation to changing biomechanical conditions and stress distribution during bone development. In the supratemporal, the cementing lines show that the remodeling process could be involved in the creations of sculpture. The common occurrence of ISF suggests that metaplastic ossification plays an important role during cranial development. Endochondral bones preserved the numerous remains of calcified cartilage. This indicates that ossification follows a pattern known for stereospondyl intercentra, with relatively slow ossification of the trabecular part and late development of the periosteal cortex. The large accumulation of Sharpey's fibers in the occipital condyles indicates the presence of strong muscles and ligaments connecting the skull to the vertebral column.


Discoid lateral meniscus: evaluation and treatment.
Although the etiology of the discoid lateral meniscus (DLM) has been the subject of debate, the entity is now believed to result from abnormal development secondary to a deficiency in normal attachments. In children younger than 10 years, snapping knee syndrome is pathognomonic for an unstable DLM. In adolescents, clinical presentation varies and often includes symptoms typically found with meniscal tears. The asymptomatic DLM does not require surgery. Treatment for the symptomatic stable DLM is directed toward arthroscopic saucerization with preservation of enough meniscus to maintain some biomechanical function. Recent reports of meniscal repair for the unstable Wrisberg meniscus have been encouraging. Optimal treatment for DLM requires a high index of suspicion in the appropriate clinical setting and up-to-date knowledge of available therapeutic modalities.


Clinical implications of small bowel diverticula.
Small bowel diverticula are usually asymptomatic and rare. Their importance is based on the fact that they carry the risk of serious complications. To study the implications and the therapeutic approach regarding small bowel diverticulosis. The medical records of 54 patients with diverticular disease of the small bowel, including Meckel's and duodenum diverticula, were retrospectively reviewed. The mean age of the 32 male and 22 female patients was 53.2 years. Diverticula were found in the duodenum in 11 cases, in the jejunum and ileum in 21 cases, and with Meckel's diverticula in 22 cases. In 24% of the patients the diverticula were multiple. The most common clinical symptom was abdominal pain, in 44.4%. Most of the duodenum diverticula were asymptomatic; 47.6% of the patients with diverticular disease located in the jejunum and ileum presented with chronic symptoms. The overall diagnostic rate for symptomatic diverticula before surgery was 52.7%; in 33.3% diverticula were found incidentally during other diagnostic or therapeutic procedures. Forty-one patients were managed surgically. 15 patients were operated on urgently because of infection or rupture, 4 patients for bleeding, 5 patients for intestinal obstruction, and one patient for jaundice. The incidence of asymptomatic small bowel diverticula is difficult to ascertain. Patients with Meckel's and duodenal diverticula are usually asymptomatic, while the majority of jejunal and ileal diverticula patients present with chronic symptoms. The pre-operative diagnostic rate is higher for duodenal diverticula. Small bowel diverticula do not require surgical treatment unless refractory symptoms or complications occur.


Using electron paramagnetic resonance to map N@C₆₀ during high throughput processing.
The endohedral fullerene molecule, N@C60, is a candidate for molecular spin qubits (quantum bits) and spin probes owing to its exceptional electron spin properties. Advancements in the processing of N@C60 are key to obtaining samples of high purity on a reasonable timescale. We investigate enrichment by high throughput processing (flow rate of 18 L h(-1) and operating pressure of 1.5-2 MPa) using high performance liquid chromatography (HPLC) as a means of scaling N@C60 production. We use detection by electron paramagnetic resonance (EPR) spectroscopy to map N@C60 during processing, and through the reconstruction of the peak position in the chromatogram, we are able to determine the retention time and relative purity of N@C60 without the need for its isolation. Based on this, we establish a procedure for time-efficient, high throughput processing to isolate N@C60 in high purity.


Multisensory calibration is independent of cue reliability.
Multisensory calibration is fundamental for proficient interaction within a changing environment. Initial studies suggested a visual-dominant mechanism. More recently, a cue-reliability-based model, similar to optimal cue integration, has been proposed. However, a more general, reliability-independent model of fixed-ratio adaptation (of which visual dominance is a subcase) has never been tested. Here, we studied behavior of both humans and monkeys performing a heading-discrimination task. Subjects were presented with either visual (optic-flow), vestibular (motion-platform), or combined (visual-vestibular) stimuli and required to report whether self-motion was to the right/left of straight ahead. A systematic heading discrepancy was introduced between the visual and vestibular cues, without external feedback. Cue calibration was measured by the resulting sensory adaptation. Both visual and vestibular cues significantly adapted in the direction required to reduce cue conflict. However, unlike multisensory cue integration, cue calibration was not reliability based. Rather, a model of fixed-ratio adaptation best described the data, whereby vestibular adaptation was greater than visual adaptation, regardless of relative cue reliability. The average ratio of vestibular to visual adaptation was 1.75 and 2.30 for the human and monkey data, respectively. Furthermore, only through modeling fixed-ratio adaptation (using the ratio extracted from the data) were we able to account for reliability-based cue integration during the adaptation process. The finding that cue calibration does not depend on cue reliability is consistent with the notion that it follows an underlying estimate of cue accuracy. Cue accuracy is generally independent of cue reliability, and its estimate may change with a much slower time constant. Thus, greater vestibular versus visual (fixed-ratio) adaptation suggests lower vestibular versus visual cue accuracy.


Pre-Implantation Genetic Screening Techniques: Implications for Clinical Prenatal Diagnosis.
Chromosomal aneuploidy is responsible for a significant proportion of pregnancy failures, whether conceived naturally or through in vitro fertilization (IVF). In an effort to improve the success rate of IVF, screening embryos for aneuploidy - or pre-implantation genetic screening (PGS) - has been proposed as a means of ensuring only euploid embryos are selected for transfer. Early PGS approaches were based on fluorescence in situ hybridization testing, and have been shown not to improve live birth rates. Recent developments in genetic testing technologies - such as next-generation sequencing and quantitative polymerase chain reaction, coupled with embryo biopsy at the blastocyst stage - have shown promise in improving IVF outcomes, but they remain to be validated in adequately powered, prospective randomized trials. The extent to which IVF with PGS lowers the a priori risk of aneuploidy in ongoing pregnancies so conceived has been poorly described, rendering it difficult to incorporate the potential benefit of PGS into existing prenatal aneuploidy screening regimens such as cell-free DNA testing or conventional combined nuchal translucency and maternal biochemistry assessment. Further data on the sensitivity and specificity of various forms of molecular PGS testing would improve our understanding of the effectiveness and accuracy of these technologies. This, in addition to further research into methods of risk combination and assessment, would allow us to help our patients make better- informed decisions about whether or not to proceed with invasive diagnostic tests.


Paediatric intensive care nurses' and doctors' perceptions on nurse-led protocol-directed ventilation weaning and extubation.
Nurse-led (protocol-directed) ventilation weaning (NLVW) is utilized in adult intensive care and has shown to be safe and reduce ventilation times. Our paediatric intensive care unit (PICU) implemented a NLVW (and extubation) protocol in 2004, yet it was observed that some NLVW-trained nurses were not undertaking the role in practice. To explore PICU nurses' and doctors' perceptions of and barriers to NLVW on a UK PICU, with the aim of facilitating more NLVW on our PICU by reducing these barriers. A cross-sectional electronic survey was used to collect data from both nurse ventilation weaners and all medical staff and advanced nurse practitioners (ANPs) on one PICU. Our survey response rates were 90% (36/40) nursing and 54% (20/37) medical. The four top reasons cited for nurses not being able to wean by protocol were not being allocated to a 'weanable' patient, being in an in-charge or runner role, high clinical workload and a perceived lack of support from medical staff/ANPs. The restrictive nature of our protocol also emerged as a key issue by all staff. The medical survey revealed an overwhelming positive response to NLVW with 90% believing that experienced PICU nurses should be allowed to wean ventilation. In contrast to the nurses perceived lack of support or encouragement for NLVW, medical staff rated their encouragement for the nurses to undertake this role as high. NLVW is a complex process, and factors that impair or facilitate this process relate not only to the weaning protocol itself, but also organizational processes and structural factors in a PICU. This paper highlights the complexities involved in instituting and establishing a nurse-led, protocol-driven ventilation weaning process within a PICU. Further, in depth research is required to examine both PICU nurses and doctors attitudes to NLVW both in the UK and across Europe.


Supertaskers: Profiles in extraordinary multitasking ability.
Theory suggests that driving should be impaired for any motorist who is concurrently talking on a cell phone. But is everybody impaired by this dual-task combination? We tested 200 participants in a high-fidelity driving simulator in both single- and dual-task conditions. The dual task involved driving while performing a demanding auditory version of the operation span (OSPAN) task. Whereas the vast majority of participants showed significant performance decrements in dual-task conditions (compared with single-task conditions for either driving or OSPAN tasks), 2.5% of the sample showed absolutely no performance decrements with respect to performing single and dual tasks. In single-task conditions, these "supertaskers" scored in the top quartile on all dependent measures associated with driving and OSPAN tasks, and Monte Carlo simulations indicated that the frequency of supertaskers was significantly greater than chance. These individual differences help to sharpen our theoretical understanding of attention and cognitive control in naturalistic settings.


Internet information sources for the identification of emerging health technologies. A starting point.
The basis of an early warning system for new and emerging health technologies is information, and in particular, information that has been selectively extracted from the huge quantity of data in the fields of medicine, science, and biobusiness. The information will be useful only if presented in a format suitable to the needs of health care decision makers and produced at the time most likely to influence the introduction or diffusion of new technologies. In 1997 the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) began a one-year pilot project to identify and provide information on developments in medical technologies that may have a significant impact on health care in Canada. We began by examining the information available to us through the Internet, based on the assumption that electronic sources can offer more timely access to a greater range of information, often with little or no cost involved. It was important to identify the sites that offered the most relevant information in the least amount of time.


Graphene and mobile ions: the key to all-plastic, solution-processed light-emitting devices.
The emerging field of "organic" or "plastic" electronics has brought low-voltage, ultrathin, and energy-efficient lighting and displays to market as organic light-emitting diode (OLED) televisions and displays in cameras and mobile phones. Despite using carbon-based materials as the light-emitting layer, previous efficient organic electronic light-emitting devices have required at least one metal electrode. Here, we utilize chemically derived graphene for the transparent cathode in an all-plastic sandwich-structure device, similar to an OLED, called a light-emitting electrochemical cell (LEC). Using a screen-printable conducting polymer as a partially transparent anode and a micrometer-thick active layer solution-deposited from a blend of a light-emitting polymer and a polymer electrolyte, we demonstrate a light-emitting device based solely on solution-processable carbon-based materials. Our results demonstrate that low-voltage, inexpensive, and efficient light-emitting devices can be made without using metals. In other words, electronics can truly be "organic".


Rucaparib and Niraparib in Advanced Ovarian Cancer.
Rucaparib and niraparib are two of the newest U.S. Food and Drug Administration-approved PARP inhibitors, joining olaparib with indications in ovarian cancer. Both drugs have led to meaningful responses when used as monotherapy in previously treated ovarian cancers, with niraparib demonstrating activity in both BRCA-mutated and BRCA wild-type tumors. Both rucaparib and niraparib have remarkably increased progression-free survival as maintenance therapy for patients with relapsed, platinum-sensitive epithelial ovarian cancer who responded to their most recent platinum-based regimen. In this setting, these drugs appear to be similar in efficacy but have distinct pharmacokinetic and adverse effect profiles. This article will guide the advanced practitioner through the efficacy, safety, and pharmacologic profiles of rucaparib and niraparib, while benchmarking them against olaparib for the treatment of ovarian cancer.