Transmitted HIV type 1 drug resistance among individuals with recent HIV infection in East and Southern Africa.
To characterize WHO-defined transmitted HIV drug resistance mutation (TDRM) data from recently HIV-infected African volunteers, we sequenced HIV (pol) and evaluated for TDRM the earliest available specimens from ARV-naive volunteers diagnosed within 1 year of their estimated date of infection at eight research centers in sub-Saharan Africa. TDRMs were detected in 19/408 (5%) volunteers. The prevalence of TDRMs varied by research center, from 5/26 (19%) in Entebbe, 6/78 (8%) in Kigali, 2/49 (4%) in Kilifi, to 3/106 (3%) in Lusaka. One of five volunteers from Cape Town (20%) had TDRMs. Despite small numbers, our data suggest an increase in DRMs by year of infection in Zambia (p = 0.004). The prevalence observed in Entebbe was high across the entire study. ARV history data from 12 (63%) HIV-infected sexual partners were available; 3 reported ARV use prior to transmission. Among four partners with sequence data available, transmission linkage was confirmed and two had the same TDRMs as the newly infected volunteer (both K103N). As ARV therapy continues to increase in availability throughout Africa, monitoring incident virus strains for the presence of TDRMs should be a priority. Early HIV infection cohorts provide an excellent and important platform to monitor the development of TDRMs to inform treatment guidelines, drug choices, and strategies for secondary prevention of TDRM transmission.


How well can we estimate the information carried in neuronal responses from limited samples?
It is difficult to extract the information carried by neuronal responses about a set of stimuli because limited data samples result in biased estimates. Recently two improved procedures have been developed to calculate information from experimental results: a binning-and-correcting procedure and a neural network procedure. We have used data produced from a model of the spatiotemporal receptive fields of parvocellular and magnocellular lateral geniculate neurons to study the performance of these methods as a function of the number of trials used. Both procedures yield accurate results for one-dimensional neuronal codes. They can also be used to produce a reasonable estimate of the extra information in a three-dimensional code, in this instance, within 0.05-0.1 bit of the asymptotically calculated value--about 10% of the total transmitted information. We believe that this performance is much more accurate than previous procedures.


Inert gas clearance from tissue by co-currently and counter-currently arranged microvessels.
To elucidate the clearance of dissolved inert gas from tissues, we have developed numerical models of gas transport in a cylindrical block of tissue supplied by one or two capillaries. With two capillaries, attention is given to the effects of co-current and counter-current flow on tissue gas clearance. Clearance by counter-current flow is compared with clearance by a single capillary or by two co-currently arranged capillaries. Effects of the blood velocity, solubility, and diffusivity of the gas in the tissue are investigated using parameters with physiological values. It is found that under the conditions investigated, almost identical clearances are achieved by a single capillary as by a co-current pair when the total flow per tissue volume in each unit is the same (i.e., flow velocity in the single capillary is twice that in each co-current vessel). For both co-current and counter-current arrangements, approximate linear relations exist between the tissue gas clearance rate and tissue blood perfusion rate. However, the counter-current arrangement of capillaries results in less-efficient clearance of the inert gas from tissues. Furthermore, this difference in efficiency increases at higher blood flow rates. At a given blood flow, the simple conduction-capacitance model, which has been used to estimate tissue blood perfusion rate from inert gas clearance, underestimates gas clearance rates predicted by the numerical models for single vessel or for two vessels with co-current flow. This difference is accounted for in discussion, which also considers the choice of parameters and possible effects of microvascular architecture on the interpretation of tissue inert gas clearance.


Age differences in the association of childhood obesity with area-level and school-level deprivation: cross-classified multilevel analysis of cross-sectional data.
Evidence suggests that area-level deprivation is associated with obesity independently of individual socioeconomic status; however, although the school may also have an impact on child health, few studies have investigated the association between school-level deprivation and the body mass index (BMI) of students. The aim of this study was to assess the relationship between the BMI for children of different ages and area-level and school-level deprivation. BMI measurements were collected through the National Child Measurement Programme (NCMP) that samples from two school years: 396,171 reception year pupils (4-5-year olds) and 392,344 year 6 pupils (10-11-year olds) from 14,054 primary schools in England. Cross-classified multilevel models with four levels: individual (n=788,525), lower super output areas corresponding to area of residence (n=29,606), schools (n=14,054) and primary care trusts (PCTs, n=143), which coordinate the collection of data within a large area, were used to study the relationship between measures of deprivation at an area and school level, and childhood BMI within England. A positive association was found between the area and school measures of deprivation, and student BMI. Both the measures of deprivation explained a greater proportion of variance in BMI z-scores for year 6 students than for the reception year students, with a greater difference between the year groups found with the school-level measure of socioeconomic status than for the the area-level measure. Deprivation explains a greater proportion of the variance in BMI for older compared with younger children, perhaps reflecting the impact of deprivation as children age, highlighting the widening of health inequalities through childhood. The association with school-level deprivation illustrates the impact of the school on BMI status throughout the primary school years.


Primary care physicians' participation in managed care networks.
The study described in this article explored the relationships between primary care physician characteristics and patterns of managed care affiliation in a single region. Secondary data sources were used to investigate the affiliations of all primary care physicians in King County, Washington (Seattle and environs) with 29 managed care products in 1996. Descriptive findings indicate that specialty, board certification, and experience all are associated with the managed care affiliations held by physicians. Differences between managed care product provider lists suggest that there are different strategies for the design and management of provider networks.


The classical Ubisch bodies carry a sporophytically produced structural protein (RAFTIN) that is essential for pollen development.
Pollen fecundity is crucial to crop productivity and also to biodiversity in general. Pollen development is supported by the tapetum, a metabolically active sporophytic nurse layer that devotes itself to this process. The tapetum in cereals and a vast majority of other plants is of the nonamoeboid type. Unable to reach out to microspores, it secretes nutrients into the anther locule where the microspores reside and develop. Orbicules (Ubisch bodies), studied in various plants since their discovery approximately 140 years ago, are a hallmark of the secretory tapetum. Their significance to tapetal or pollen development has not been established. We have identified in wheat and rice an anther-specific single-copy gene (per haploid genome equivalent) whose suppression in rice by RNA interference nearly eliminated the seed set. The flowers in the transgenics were normal for female functions, but the pollen collapsed and became less viable. Further characterization of the gene product, named RAFTIN, in wheat has shown that it is present in pro-orbicule bodies and it is accumulated in Ubisch bodies. Furthermore, it is targeted to microspore exine. Although the carboxyl portion of RAFTINs shares short, dispersed amino acid sequences (BURP domain) in common with a variety of proteins of disparate biological contexts, the occurrence RAFTIN per se is limited to cereals; neither the Arabidopsis genome nor the vast collection of ESTs suggests any obvious dicot homologs. Furthermore, our results show that RAFTIN is essential for the late phase of pollen development in cereals.


Cloning of genomic DNA for tumor necrosis factor and efficient expression in CHO cells.
A genomic clone for human tumor necrosis factor (TNF-alpha) was isolated using synthetic oligonucleotide probes. The genomic DNA was cleaved to remove 5' regulatory sequences and cloned in a PSVE3 expression vector containing the SV40 early promoter. The plasmid was co-transfected with a selectable dihydrofolate reductase (DHFR) gene into DHFR-deficient Chinese hamster ovary cells. Efficient expression of TNF mRNA was established by Northern analysis. Expression of TNF protein was assayed for by cytotoxic activity for cycloheximide-treated SV80 fibroblasts. Selected transfected cultures secreted as much as 50,000 units of TNF activity/ml of culture medium. Synthesis of TNF protein was confirmed by immunofluorescence of transfected cells with a monoclonal antibody to TNF and immunoprecipitation of 17 kD protein from transfected CHO culture supernates. The efficient expression of TNF from genomic DNA in transfected mammalian cells may be advantageous for biologic uses.


Earliest Human Presence in North America Dated to the Last Glacial Maximum: New Radiocarbon Dates from Bluefish Caves, Canada.
The timing of the first entry of humans into North America is still hotly debated within the scientific community. Excavations conducted at Bluefish Caves (Yukon Territory) from 1977 to 1987 yielded a series of radiocarbon dates that led archaeologists to propose that the initial dispersal of human groups into Eastern Beringia (Alaska and the Yukon Territory) occurred during the Last Glacial Maximum (LGM). This hypothesis proved highly controversial in the absence of other sites of similar age and concerns about the stratigraphy and anthropogenic signature of the bone assemblages that yielded the dates. The weight of the available archaeological evidence suggests that the first peopling of North America occurred ca. 14,000 cal BP (calibrated years Before Present), i.e., well after the LGM. Here, we report new AMS radiocarbon dates obtained on cut-marked bone samples identified during a comprehensive taphonomic analysis of the Bluefish Caves fauna. Our results demonstrate that humans occupied the site as early as 24,000 cal BP (19,650 ± 130 14C BP). In addition to proving that Bluefish Caves is the oldest known archaeological site in North America, the results offer archaeological support for the "Beringian standstill hypothesis", which proposes that a genetically isolated human population persisted in Beringia during the LGM and dispersed from there to North and South America during the post-LGM period.


Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene.
Congenital hypothyroidism due to impaired thyroid response to TSH was originally described by Stanbury. A diagnosis of congenital hypothyroidism with thyroid unresponsiveness to TSH is accepted if the patient has congenital hypothyroidism, the thyroid gland is in the normal position in the neck, the size of the thyroid is either normal or atrophic, the serum TSH level is increased, the bioactivity of TSH is intact, and the response of the thyroid gland to TSH stimulation is decreased. In all originally described cases serum thyroglobulin was undetectable. We describe a 22-yr-old female patient who was severely hypothyroid and mentally retarded. Serum T4 and T3 concentrations were below the sensitivity of the methods, with elevated serum TSH levels. Serum thyroglobulin was undetectable. A normally shaped hypoplastic gland located in the appropriate anatomical position in the neck was found at scintiscan. The gland did not respond after administration of bovine TSH in terms of 131I uptake, serum thyroid hormones, and thyroglobulin secretion. A diagnosis of congenital hypothyroidism due to TSH unresponsiveness was formulated. Genetic analysis in the propositus showed a homozygous inactivating mutation of the TSH receptor that had not been previously described. The mutation consisted of the substitution of an isoleucine in place of a highly conserved threonine at position 477 in the first extracellular loop of the receptor (T477I). The brother, one sister of the father (whose DNA was not available), the mother of the propositus, one sister, and the brother were heterozygous for T477I. All the heterozygous persons were unaffected. After transfection in COS-7 cells, the mutant receptor displayed an extremely low expression at cell surface. At variance with cells transfected with the wild-type TSH receptor, cells transfected with the mutant T477I did not show constitutive activity for the adenylyl cyclase pathway. A dramatic reduction in the amount of cAMP accumulation after bovine TSH challenge was observed in cells transfected with the mutant T477I receptor. A structural defect in the mutant TSH receptor protein was probably responsible for the poor routing of the receptor to the cell membrane. This is the first time that a loss of function mutation of the TSH receptor is described in a patient with severe congenital hypothyroidism and absent circulating thyroglobulin due to TSH unresponsiveness and the first time that an inactivating mutation of the TSH receptor is described in the first extracellular loop.


Use of advisers in the diagnosis and management of abdominal pain in accident and emergency departments.
The performance of senior house officers (SHOs) and their advisers in accident and emergency departments was compared in the diagnosis of abdominal pain in 711 patients. Accuracy of diagnosis was 63 per cent for advisers and 54 per cent for SHOs. Overall, the adviser improves the diagnosis of the SHO in only 6 per cent of cases. The SHOs refer accurately in 94 per cent of cases, and the advisers improve the SHO referrals in only 1 per cent of patients. It is argued that the time-consuming process of calling a surgeon away from a ward or theatre to advise in the receiving room is of little value, and avoidance of this step would enable patients to be admitted more rapidly.


Atomic resolution imaging of a carbon nanotube from diffraction intensities.
Atomic imaging of three-dimensional structures has required a crystal in diffraction or a lens in electron imaging. Whereas diffraction achieves very high resolution by averaging over many cells, imaging gives localized structural information, such as the position of a single dopant atom. However, lens aberrations limit electron imaging resolution to about 1 angstrom. Resolution is reduced further by low contrast from weakscattering or from the limitations on electron dose for radiation-sensitive molecules. We show that both high resolution and high contrast can be achieved by imaging from diffraction with a nanometer-sized coherent electron beam. The phase problem is solved by oversampling and iterative phase retrieval. We apply this technique to image a double-wall carbon nanotube at 1-angstrom resolution, revealing the structure of two tubes of different helicities. Because the only requirement for imaging is a diffraction pattern sampled below the Nyquist frequency, our technique has the potential to image nonperiodic nanostructures, including biological macromolecules, at diffraction intensity-limited resolutions.


ReAl-LiFE: Accelerating the Discovery of Individualized Brain Connectomes on GPUs.
Diffusion imaging and tractography enable mapping structural connections in the human brain, in-vivo. Linear Fascicle Evaluation (LiFE) is a state-of-the-art approach for pruning spurious connections in the estimated structural connectome, by optimizing its fit to the measured diffusion data. Yet, LiFE imposes heavy demands on computing time, precluding its use in analyses of large connectome databases. Here, we introduce a GPU-based implementation of LiFE that achieves 50-100x speedups over conventional CPU-based implementations for connectome sizes of up to several million fibers. Briefly, the algorithm accelerates generalized matrix multiplications on a compressed tensor through efficient GPU kernels, while ensuring favorable memory access patterns. Leveraging these speedups, we advance LiFE's algorithm by imposing a regularization constraint on estimated fiber weights during connectome pruning. Our regularized, accelerated, LiFE algorithm ("ReAl-LiFE") estimates sparser connectomes that also provide more accurate fits to the underlying diffusion signal. We demonstrate the utility of our approach by classifying pathological signatures of structural connectivity in patients with Alzheimer's Disease (AD). We estimated million fiber whole-brain connectomes, followed by pruning with ReAl-LiFE, for 90 individuals (45 AD patients and 45 healthy controls). Linear classifiers, based on support vector machines, achieved over 80% accuracy in classifying AD patients from healthy controls based on their ReAl-LiFE pruned structural connectomes alone. Moreover, classification based on the ReAl-LiFE pruned connectome outperformed both the unpruned connectome, as well as the LiFE pruned connectome, in terms of accuracy. We propose our GPU-accelerated approach as a widely relevant tool for non-negative least squares optimization, across many domains.


Exploring the Genetic Patterns of Complex Diseases via the Integrative Genome-Wide Approach.
Genome-wide association studies (GWASs), which assay more than a million single nucleotide polymorphisms (SNPs) in thousands of individuals, have been widely used to identify genetic risk variants for complex diseases. However, most of the variants that have been identified contribute relatively small increments of risk and only explain a small portion of the genetic variation in complex diseases. This is the so-called missing heritability problem. Evidence has indicated that many complex diseases are genetically related, meaning these diseases share common genetic risk variants. Therefore, exploring the genetic correlations across multiple related studies could be a promising strategy for removing spurious associations and identifying underlying genetic risk variants, and thereby uncovering the mystery of missing heritability in complex diseases. We present a general and robust method to identify genetic patterns from multiple large-scale genomic datasets. We treat the summary statistics as a matrix and demonstrate that genetic patterns will form a low-rank matrix plus a sparse component. Hence, we formulate the problem as a matrix recovering problem, where we aim to discover risk variants shared by multiple diseases/traits and those for each individual disease/trait. We propose a convex formulation for matrix recovery and an efficient algorithm to solve the problem. We demonstrate the advantages of our method using both synthesized datasets and real datasets. The experimental results show that our method can successfully reconstruct both the shared and the individual genetic patterns from summary statistics and achieve comparable performances compared with alternative methods under a wide range of scenarios. The MATLAB code is available at: http://www.comp.hkbu.edu.hk/~xwan/iga.zip.


Locally Adaptive Bayes Nonparametric Regression via Nested Gaussian Processes.
We propose a nested Gaussian process (nGP) as a locally adaptive prior for Bayesian nonparametric regression. Specified through a set of stochastic differential equations (SDEs), the nGP imposes a Gaussian process prior for the function's mth-order derivative. The nesting comes in through including a local instantaneous mean function, which is drawn from another Gaussian process inducing adaptivity to locally-varying smoothness. We discuss the support of the nGP prior in terms of the closure of a reproducing kernel Hilbert space, and consider theoretical properties of the posterior. The posterior mean under the nGP prior is shown to be equivalent to the minimizer of a nested penalized sum-of-squares involving penalties for both the global and local roughness of the function. Using highly-efficient Markov chain Monte Carlo for posterior inference, the proposed method performs well in simulation studies compared to several alternatives, and is scalable to massive data, illustrated through a proteomics application.


Wet and dry extraction of coconut oil: impact on lipid metabolic and antioxidant status in cholesterol coadministered rats.
Because coconut oil extracted by wet process (virgin coconut oil, VCO) is gaining popularity among consumers, this study was conducted to evaluate VCO compared with coconut oil extracted by dry process (copra oil, CO) for their influence on lipid parameters, lipid peroxidation, and antioxidant status in rats coadministered with cholesterol. VCO, CO, and cholesterol were fed in a semi-synthetic diet to 24 male Sprague-Dawley rats for 45 days. After the experimental period, lipid and lipid peroxide levels and antioxidant enzyme activities were observed. Chemical composition and antioxidant properties of the polyphenolic fraction from VCO and CO were also analyzed. The results showed that lipid and lipid peroxide levels were lower in VCO-fed animals than in animals fed either CO or cholesterol alone. Antioxidant enzyme activities in VCO-fed animals were comparable with those in control animals. Although the fatty acid profiles of both oils were similar, a significantly higher level of unsaponifiable components was observed in VCO. Polyphenols from VCO also showed significant radical-scavenging activity compared with those from CO. This study clearly indicates the potential benefits of VCO over CO in maintaining lipid metabolism and antioxidant status. These effects may be attributed in part to the presence of biologically active minor unsaponifiable components.


Psychoeducation for schizophrenia.
Schizophrenia can be a severe and chronic illness characterised by lack of insight and poor compliance with treatment. Psychoeducational approaches have been developed to increase patients' knowledge of, and insight into, their illness and its treatment. It is supposed that this increased knowledge and insight will enable people with schizophrenia to cope in a more effective way with their illness, thereby improving prognosis. To assess the effects of psychoeducational interventions compared with standard levels of knowledge provision. We searched the Cochrane Schizophrenia Group Trials Register (February 2010). All relevant randomised controlled trials focusing on psychoeducation for schizophrenia and/or related serious mental illnesses involving individuals or groups. We excluded quasi-randomised trials. At least two review authors extracted data independently from included papers. We contacted authors of trials for additional and missing data. We calculated risk ratios (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data. We used a fixed-effects model for heterogeneous dichotomous data. Where possible we also calculated the numbers needed to treat (NNT), as well as weighted means for continuous data. This review includes a total of 5142 participants (mostly inpatients) from 44 trials conducted between 1988 and 2009 (median study duration ˜ 12 weeks, risk of bias - moderate). We found that incidences of non-compliance were lower in the psychoeducation group in the short term (n = 1400, RR 0.52 CI 0.40 to 0.67, NNT 11 CI 9 to 16). This finding holds for the medium and long term. Relapse appeared to be lower in psychoeducation group (n = 1214, RR 0.70 CI 0.61 to 0.81, NNT 9 CI 7 to 14) and this also applied to readmission (n = 206, RR 0.71 CI 0.56 to 0.89, NNT 5 CI 4 to 13). Scale-derived data also suggested that psychoeducation promotes better social and global functioning. In the medium term, treating four people with schizophrenia with psychoeducation instead of standard care resulted in one additional person showing a clinical improvement. Evidence suggests that participants receiving psychoeducation are more likely to be satisfied with mental health services (n = 236, RR 0.24 CI 0.12 to 0.50, NNT 5 CI 5 to 8) and have improved quality of life. Psychoeducation does seem to reduce relapse, readmission and encourage medication compliance, as well as reduce the length of hospital stay in these hospital-based studies of limited quality. The true size of effect is likely to be less than demonstrated in this review - but, nevertheless, some sort of psychoeducation could be clinically effective and potentially cost beneficial. It is not difficult to justify better, more applicable, research in this area aimed at fully investigating the effects of this promising approach.


Clinical utility of enhanced recovery after surgery pathways in pediatric spinal deformity surgery: systematic review of the literature.
More than 7500 children undergo surgery for scoliosis each year, at an estimated annual cost to the health system of $1.1 billion. There is significant interest among patients, parents, providers, and payors in identifying methods for delivering quality outcomes at lower costs. Enhanced recovery after surgery (ERAS) protocols have been suggested as one possible solution. Here the authors conducted a systematic review of the literature describing the clinical and economic benefits of ERAS protocols in pediatric spinal deformity surgery. The authors identified all English-language articles on ERAS protocol use in pediatric spinal deformity surgery by using the following databases: PubMed/MEDLINE, Web of Science, Cochrane Reviews, EMBASE, CINAHL, and OVID MEDLINE. Quantitative analyses of comparative articles using random effects were performed for the following clinical outcomes: 1) length of stay (LOS); 2) complication rate; 3) wound infection rate; 4) 30-day readmission rate; 5) reoperation rate; and 6) postoperative pain scores. Of 950 articles reviewed, 7 were included in the qualitative analysis and 6 were included in the quantitative analysis. The most frequently cited benefits of ERAS protocols were shorter LOS, earlier urinary catheter removal, and earlier discontinuation of patient-controlled analgesia pumps. Quantitative analyses showed ERAS protocols to be associated with shorter LOS (mean difference -1.12 days; 95% CI -1.51, -0.74; p < 0.001), fewer postoperative complications (OR 0.37; 95% CI 0.20, 0.68; p = 0.001), and lower pain scores on postoperative day (POD) 0 (mean -0.92; 95% CI -1.29, -0.56; p < 0.001) and POD 2 (-0.61; 95% CI -0.75, -0.47; p < 0.001). There were no differences in reoperation rate or POD 1 pain scores. ERAS-treated patients had a trend toward higher 30-day readmission rates and earlier discontinuation of patient-controlled analgesia (both p = 0.06). Insufficient data existed to reach a conclusion about cost differences. The results of this systematic review suggest that ERAS protocols may shorten hospitalizations, reduce postoperative complication rates, and reduce postoperative pain scores in children undergoing scoliosis surgery. Publication biases exist, and therefore larger, prospective, multicenter data are needed to validate these results.


CDK2 regulates HIV-1 transcription by phosphorylation of CDK9 on serine 90.
HIV-1 transcription is activated by the viral Tat protein that recruits host positive transcription elongation factor-b (P-TEFb) containing CDK9/cyclin T1 to the HIV-1 promoter. P-TEFb in the cells exists as a lower molecular weight CDK9/cyclin T1 dimer and a high molecular weight complex of 7SK RNA, CDK9/cyclin T1, HEXIM1 dimer and several additional proteins. Our previous studies implicated CDK2 in HIV-1 transcription regulation. We also found that inhibition of CDK2 by iron chelators leads to the inhibition of CDK9 activity, suggesting a functional link between CDK2 and CDK9. Here, we investigate whether CDK2 phosphorylates CDK9 and regulates its activity. The siRNA-mediated knockdown of CDK2 inhibited CDK9 kinase activity and reduced CDK9 phosphorylation. Stable shRNA-mediated CDK2 knockdown inhibited HIV-1 transcription, but also increased the overall level of 7SK RNA. CDK9 contains a motif (90SPYNR94) that is consensus CDK2 phosphorylation site. CDK9 was phosphorylated on Ser90 by CDK2 in vitro. In cultured cells, CDK9 phosphorylation was reduced when Ser90 was mutated to an Ala. Phosphorylation of CDK9 on Ser90 was also detected with phospho-specific antibodies and it was reduced after the knockdown of CDK2. CDK9 expression decreased in the large complex for the CDK9-S90A mutant and was correlated with a reduced activity and an inhibition of HIV-1 transcription. In contrast, the CDK9-S90D mutant showed a slight decrease in CDK9 expression in both the large and small complexes but induced Tat-dependent HIV-1 transcription. Molecular modeling showed that Ser 90 of CDK9 is located on a flexible loop exposed to solvent, suggesting its availability for phosphorylation. Our data indicate that CDK2 phosphorylates CDK9 on Ser 90 and thereby contributes to HIV-1 transcription. The phosphorylation of Ser90 by CDK2 represents a novel mechanism of HIV-1 regulated transcription and provides a new strategy for activation of latent HIV-1 provirus.


GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease.
Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation.


Central benzodiazepine receptors: in vitro efficacies and potencies of 3-substituted 1,4-benzodiazepine stereoisomers.
3-Acyloxy-, 3-methoxy-, and 3-alkyl-substituted derivatives of the benzodiazepine (BZ) agonist desmethyl-diazepam (DMD) were resolved, and the stereochemical properties of binding to central BZ receptors were investigated in synaptosomal membrane preparations of rat brain. Decreasing potency and stereoselectivity of 3-methyl, 3-ethyl, and 3-isopropyl derivatives in displacement of [3H]diazepam binding can be attributed to differential susceptibilities for steric hindrance of 3-axial versus 3-equatorial substituents of the binding conformation M. Chirality in the alpha-methyl-beta-phenyl-propionic acyl moiety of oxazepam, the 3-OH-derivative of DMD, was noncritical in binding, whereas the beta-phenyl substituent selectively increased the binding of the 3S-stereoisomer. Changing the pH from 7.4 to 5.6 significantly increased the IC50 of (3R)-oxazepam acetate but not those of (3R)-methyl-DMD and diazepam. Binding data led to a steric model of the BZ binding site with the postulation of an additional hydrogen-bond-donating moiety, probably histidine in the "ceiling" of the receptor cavity, that binds the 3-carbonyloxy groups and hinders the 3-alkyl ones. In vitro efficacies of 3-substituted BZs were estimated by allosteric binding interactions within the gamma-aminobutyric acidA (GABAA) receptor-ionophore complex. Non-equilibrium enhancement of t-butyl-bicyclophosphoro[35S]thionate binding by the BZ agonist oxazepam was stereoselectively antagonized by (3S)-oxazepam-(S)-alpha-methyl-beta-phenyl-propionate, suggesting a mixed agonist-antagonist character. GABA enhanced the [3H]diazepam-displacing potencies of the 3S-enantiomers of the acetate, hemisuccinate, and (S)-alpha-methyl-beta-phenyl-propionate esters of oxazepam by a factor of about 1.5-1.6, whereas the GABA shifts for 3R-esters were about 1.2. UV affinity labeling with flunitrazepam resulted in a significantly smaller decrease in the displacing potency of (3R)-oxazepam acetate than in that of the 3S-enantiomer. GABA shifts of successively 3-methylated DMD derivatives were also compared. The GABA shifts of DMD and its (3S)-methyl and 3,3-dimethyl derivatives were all characteristic of full agonists (2.4-2.7), whereas that of (3R)-methyl-DMD was 1.5. The 3-methoxy enantiomers of DMD displayed stereoselectivity and GABA shift values intermediate between those of 3-methyl and 3-acetoxy derivatives. These allosteric interactions suggest that 3-carbonyloxy derivatives in general, as well as (3R)-BZ enantiomers bound with axial 3-alkyl and 3-alkyloxy groups, decrease the agonist efficacies of 1,4-BZs to modulate the GABAA receptor complex.


Randomized trial of $20 versus $50 incentives to increase physician survey response rates.
Recent experiences of survey researchers suggest that physicians are becoming less willing to complete surveys. To compare response rates to a mailed physician survey with a prepaid check incentive of $20 versus $50. Randomized controlled trial. Five hundred seventy-eight physicians caring for patients with lung or colorectal cancer in northern California. Proportion of physicians responding to the survey. Overall, 60.0% of physicians responded to the survey. The response rate was 52.1% for physicians who received a $20 check versus 67.8% for physicians who received a $50 check (P < 0.001). Similar differences in response rates were seen in strata by physician sex, year graduated from medical school, and survey version (all P < 0.001). More than 42% of physicians who received a $50 check responded to the first mailing, compared with only 30.8% of those who received a $20 check (P < 0.001). Among physicians caring for patients with lung cancer or colorectal cancer in northern California, a $50 check incentive was much more effective than a $20 check incentive at increasing response rates to a mailed survey. As physicians become increasingly burdened with surveys, larger incentives may be necessary to engage potential respondents and thus maximize response rates.


Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency.
A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise-induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesised that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long-Chain acyl-CoA Dehydrogenase (VLCAD). Five patients (range 17-45 y; 4 M/1F) patients were included in an investigator-initiated, randomised, blinded, placebo-controlled, 2-way cross-over study. Patients drank either a KE + CHO mix or an isocaloric CHO equivalent and performed 35 minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; approximately 40% VO2 max). The protocol was repeated after a 1-week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo 31 P-MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings. Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD-specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE + CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders. Trial registration: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.


The status of water and sanitation among Pacific Rim nations.
Analysis of relationships among national wealth, access to improved water supply and sanitation facilities, and population health indices suggests that the adequacy of water resources at the national level is a poor predictor of economic development--namely, that low water stress is neither necessary nor sufficient for economic development at the present state of water stress among Pacific Rim nations. Although nations differ dramatically in terms of priority provided to improved water and sanitation, there is some level of wealth (per capita GNP) at which all nations promote the development of essential environmental services. Among the Pacific Rim countries for which there are data, no nation with a per capita GNP > US$18,000 per year has failed to provide near universal access to improved water supply and sanitation. Below US$18,000/person-year, however, there are decided differences in the provision of sanitary services (improved water supply and sanitation) among nations with similar economic success. There is a fairly strong relationship between child mortality/life expectancy and access to improved sanitation, as expected from the experiences of developed nations. Here no attempt is made to produce causal relationships among these data. Failure to meet Millennium Development Goals for the extension of improved sanitation is frequently evident in nations with large rural populations. Under those circumstances, capital intensive water and sanitation facilities are infeasible, and process selection for water/wastewater treatment requires an adaptation to local conditions, the use of appropriate materials, etc., constraints that are mostly absent in the developed world. Exceptions to these general ideas exist in water-stressed parts of developed countries, where water supplies are frequently augmented by water harvesting, water reclamation/reuse, and the desalination of brackish water resources. Each of these processes involves public acceptance of water resources that are at least initially of inferior quality. Despite predictions of looming increases in water stress throughout the world, adaptation and resourcefulness generally allow us to meet water demand while pursuing rational economic development, even in the most water-stressed areas of the Pacific Rim.


Global disparities in the epilepsy treatment gap: a systematic review.
To describe the magnitude and variation of the epilepsy treatment gap worldwide. We conducted a systematic review of the peer-reviewed literature published from 1 January 1987 to 1 September 2007 in all languages using PubMed and EMBASE. The purpose was to identify population-based studies of epilepsy prevalence that reported the epilepsy treatment gap, defined as the proportion of people with epilepsy who require but do not receive treatment. Negative binomial regression models were used to assess trends and associations. The treatment gap was over 75% in low-income countries and over 50% in most lower middle- and upper middle-income countries, while many high-income countries had gaps of less than 10%. However, treatment gaps varied widely both between and within countries. They were significantly higher in rural areas (rate ratio, RR: 2.01; 95% confidence interval, CI: 1.40-2.89) and countries with lower World Bank income classification (RR: 1.55; 95% CI: 1.32-1.82). There was no significant trend in treatment gap over time (RR: 0.92; 95% CI: 0.79-1.07). There is dramatic global disparity in the care for epilepsy between high- and low- income countries, and between rural and urban settings. Our understanding of the factors affecting the treatment gap is limited; future investigations should explore other potential explanations of the gap.


Pulmonary function in a non-pulsatile pulmonary circulation.
The authors suggested that a mammal immediately accommodates well to nonpulsatile flow in the systemic circulation. In the current study, nonpulsatile pulmonary blood flow using a centrifugal pump was established in chronic models to analyze its influence on the pulmonary circulation. A pulsatile right ventricular assist device (RVAD) was implanted to draw blood from both the right atrium and ventricle and send blood to the pulmonary artery in six goats. After 2 weeks, the pulsatile pump was quickly replaced with a centrifugal pump without anesthesia, and a 100% non-pulsatile pulmonary blood flow was obtained. Cardiac output was kept at 80-120 ml/kg/min during the experiments. No changes were observed in hemodynamic parameters, including pulmonary arterial pressure, pulmonary vascular resistance index, and blood gas data, after the immediate depulsation of the pulmonary blood flow. There was also no significant change in the ventral to dorsal tissue blood flow ratio of the lower lobe of the right lung, which was calculated by a colored microsphere method, between pulsatile and non-pulsatile pulmonary blood perfusion. These results suggest that pulmonary function, including blood flow distribution, is not affected by non-pulsatile pulmonary circulation for periods up to 14 days.


Embryonic disc formation following post-hatching bovine embryo development in vitro.
Failures during conceptus elongation are a major cause of pregnancy losses in ungulates, exerting a relevant economic impact on farming. The developmental events occurring during this period are poorly understood, mainly because this process cannot be recapitulated in vitro. Previous studies have established an in vitro post-hatching development (PHD) system that supports bovine embryo development beyond the blastocyst stage, based on agarose gel tunnels and serum- and glucose-enriched medium. Unfortunately, under this system embryonic disc formation is not achieved and embryos show notorious signs of apoptosis and necrosis. The objective of this study has been to develop an in vitro system able to support embryonic disc formation. We first compared post-hatching development inside agarose tunnels or free-floating over an agarose-coated dish in serum- and glucose-enriched medium (PHD medium). Culture inside agarose tunnels shaped embryo morphology by physical constriction, but it restricted embryo growth and did not provide any significant advantage in terms of development of hypoblast and epiblast lineages. In contrast to PHD medium, a chemically defined and enriched medium (N2B27) supported complete hypoblast migration and epiblast survival in vitro, even in the absence of agarose coating. Cells expressing the pluripotency marker SOX2 were observed in ~56% of the embryos and ~25% developed embryonic disc-like structures formed by SOX2+ cells. In summary, here we provide a culture system that supports trophectoderm proliferation, hypoblast migration and epiblast survival after the blastocyst stage.


Understanding the factors that influence breast reconstruction decision making in Australian women.
Breast reconstruction is safe and improves quality of life. Despite this, many women do not undergo breast reconstruction and the reasons for this are poorly understood. This study aims to identify the factors that influence a woman's decision whether or not to have breast reconstruction and to better understand their attitudes toward reconstruction. An online survey was distributed to breast cancer patients from Breast Cancer Network Australia. Results were tabulated, described qualitatively and analyzed for significance using a multiple logistic regression model. 501 mastectomy patients completed surveys, of which 62% had undergone breast reconstruction. Factors that positively influenced likelihood of reconstruction included lower age, bilateral mastectomy, access to private hospitals, decreased home/work responsibilities, increased level of home support and early discussion of reconstructive options. Most common reasons for avoiding reconstruction included "I don't feel the need" and "I don't want more surgery". The most commonly sited sources of reconstruction information came from the breast surgeon followed by the plastic surgeon then the breast cancer nurse and the most influential of these was the plastic surgeon. A model using factors easily obtained on clinical history can be used to understand likelihood of reconstruction. This knowledge may help identify barriers to reconstruction, ultimately improving the clinicians' ability to appropriately educate mastectomy patients and ensure effective decision making around breast reconstruction.


Improved synthesis of 2,4,6-trialkylpyridines from 1,5-diketoalkanes: the total synthesis of Anibamine.
Many pyridine syntheses have been developed to date. In this study, we focused on pyridine synthesis with 1,5-diketone derivatives and hydroxylamine. Treatment of simple 1,5-diketoalkanes and hydroxylamine in basic or acidic conditions gave aldol adducts without any pyridine compounds. However, by screening the reaction conditions, we found that acidic conditions produced via the formation of oxime intermediates derived from 1,5-diketoalkanes allowed the formation of the corresponding pyridine derivatives. This is the first example of 2,4,6-trialkylpyridine synthesis from quite simple 1,5-diketoalkanes. In order to demonstrate the utility of the reaction, we demonstrated the synthesis of pyridine derivatives and the total synthesis of a 6-substituted pyridyl-natural product, anibamine. This was achieved by following the above methodology using a reported compound as the starting material to give the product in 12% yield.


The Nairobi Summit and Reproductive Justice: Unmet Needs for People with Infertility.
The Nairobi Summit, held in November 2019 and convened by the United Nations Fund for Population Activities, claims to have represented "all nations and peoples, and all segments" of society during its high-level conference. The overall aim of the summit was to mobilize political will and financial commitments that are urgently needed to "finally and fully" implement the 1994 International Conference on Population and Development (ICPD) Program of Action. Despite the recommendation by ICPD to incorporate infertility care in reproductive health services, the new Nairobi Statement largely neglects the topic of infertility. This is particularly troublesome as infertility is a global health problem affecting between 52.6 and 72.4 million couples worldwide, with a high prevalence in low- and middle-income settings. For many people around the world, infertility constitutes an emotional, social, and financial burden, yet appropriate services directed toward preventing and addressing infertility are often inaccessible, unaffordable, or nonexistent. With the impetus of a wider reproductive justice community, we call for the integration of infertility into global reproductive health research and practice, urging policy makers, practitioners, researchers, activists, and funders worldwide to bring focused attention to addressing challenges posed by a lack of safe, effective, and dignified fertility management among those in need.


Bfsp2 mutation found in mouse 129 strains causes the loss of CP49 and induces vimentin-dependent changes in the lens fibre cell cytoskeleton.
Here we report the first natural mutation in the mouse Bfsp2 gene. Characterisation of mouse Bfsp2 in the 129X1/SvJ revealed a mutation that deleted the acceptor site of exon 2. This results in exon 1 being erroneously spliced to exon 3 causing a frameshift in the reading frame and the introduction of a stop codon at position 2 of exon 3 in the Bfsp2 transcript. RT-PCR studies of lens RNA isolated from 129S1/SvImJ, 129S2/SvPas and 129S4/SvJae strains confirmed the presence of this mutation in these diverse 129 strains and similar mutations were found in both CBA and 101 strains, but not in C3H or C57BL/6J mouse strains. This mutation is predicted to result in a severely truncated protein product called CP49, comprising essentially only exon 1, but polyclonal antibodies to CP49 failed to detect either full length or fragments of CP49 in extracts made from either 129S1/SvImJ or 129S4/SvJae suggesting that these 129 strains lack CP49 protein. Like the knockout of Bfsp2 reported recently, filensin protein levels and its proteolytic processing were altered also in the 129S1/SvImJ and 129S4/SvJae strains compared to C57BL/6J. Electron microscopy of the lens cytoskeleton from 129S2/SvPas revealed similar morphological changes in the cytoskeleton as compared to the CP49 knockout, with beaded and intermediate filaments being apparently replaced by poorly defined filament-like material. Vimentin was a key component of this residual material as shown by immunoelectron microscopy and by the generation of a CP49/vimentin double knockout mouse. This report of a natural mutation in Bfsp2 in the 129 and other mouse strains also has important implications for lens studies that have used the 129X1/SvJ strain in knockout strategies.


Matching identifiers in electronic health records: implications for duplicate records and patient safety.
To quantify the percentage of records with matching identifiers as an indicator for duplicate or potentially duplicate patient records in electronic health records in five different healthcare organisations, describe the patient safety issues that may arise, and present solutions for managing duplicate records or records with matching identifiers. For each institution, we retrieved deidentified counts of records with an exact match of patient first and last names and dates of birth and determined the number of patient records existing for the top 250 most frequently occurring first and last name pairs. We also identified methods for managing duplicate records or records with matching identifiers, reporting the adoption rate of each across institutions. The occurrence of matching first and last name in two or more individuals ranged from 16.49% to 40.66% of records; inclusion of date of birth reduced the rates to range from 0.16% to 15.47%. The number of records existing for the most frequently occurring name at each site ranged from 41 to 2552. Institutions varied widely in the methods they implemented for preventing, detecting and removing duplicate records, and mitigating resulting errors. The percentage of records having matching patient identifiers is high in several organisations, indicating that the rate of duplicate records or records may also be high. Further efforts are necessary to improve management of duplicate records or records with matching identifiers and minimise the risk for patient harm.


A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature.
Alternative pre-mRNA splicing is a highly cell type-specific process essential to generating protein diversity. However, the mechanisms responsible for the establishment and maintenance of heritable cell-specific alternative-splicing programs are poorly understood. Recent observations point to a role of histone modifications in the regulation of alternative splicing. Here we report a new mechanism of chromatin-mediated splicing control involving a long noncoding RNA (lncRNA). We have identified an evolutionarily conserved nuclear antisense lncRNA, generated from within the human FGFR2 locus, that promotes epithelial-specific alternative splicing of FGFR2. The lncRNA acts through recruitment of Polycomb-group proteins and the histone demethylase KDM2a to create a chromatin environment that impairs binding of a repressive chromatin-splicing adaptor complex important for mesenchymal-specific splicing. Our results uncover a new function for lncRNAs in the establishment and maintenance of cell-specific alternative splicing via modulation of chromatin signatures.


A 32 × 32 optical phased array using polysilicon sub-wavelength high-contrast-grating mirrors.
We report on microelectromechanical systems (MEMS)-actuated 32 × 32 optical phased arrays (OPAs) with high fill-factors and microsecond response time. To reduce the mirror weight and temperature-dependent curvature, we use high-contrast-grating (HCG) mirrors comprising a single layer of sub-wavelength polysilicon gratings with 400 nm thickness, 1250 nm pitch, and 570 nm grating bar width. The mirror has a broad reflection band and a peak reflectivity of 99.9% at 1550 nm wavelength. With 20 × 20 μm2 pixels and 2 μm, the OPA has a total aperture of 702 × 702 μm2 and a fill factor of 85%. The OPA is electrostatically controlled by voltage and has a total field of view of ± 2°, an instantaneous field of view (beam width) of 0.14°, and a response time of 3.8 μs. The latter agrees well with the mechanical resonance frequency of the HCG mirror (0.42 MHz).


Successful models of interventional nephrology at academic medical centers.
The foundation of endovascular procedures by nephrologists was laid in the private practice arena. Because of political issues such as training, credentialing, space and equipment expenses, and co-management concerns surrounding the performance of dialysis-access procedures, the majority of these programs provided care in an outpatient vascular access center. On the basis of the improvement of patient care demonstrated by these centers, several nephrology programs at academic medical centers have also embraced this approach. In addition to providing interventional care on an outpatient basis, academic medical centers have taken a step further to expand collaboration with other specialties with similar expertise (such as with interventional radiologists and cardiologists) to enhance patient care and research. The enthusiastic initiative, cooperative, and mutually collaborative efforts used by academic medical centers have resulted in the successful establishment of interventional nephrology programs. This article describes various models of interventional nephrology programs at academic medical centers across the United States.


Genetic heterogeneity of hepatitis C virus cell entry receptors seems to have no influence on selection of virus variants.
No information is available on the possible influence of the genetic heterogeneity of major hepatitis C virus (HCV) cell receptors on selection of virus variants. Anti-D globulin preparations contaminated with the HCV strain AD78 caused hepatitis C infection in more than 3000 women in East Germany in 1978. Analysis of the core to NS2 gene sequences of this strain in several globulin batches revealed the presence of three closely related but distinct virus variants of the same strain. Apparently even distribution of these three virus variants was observed in 91 patients infected with the AD78 strain. None of these patients was infected with more than one virus variant, suggesting a selection mechanism of a particular virus variant in each patient. To verify the hypothesis that heterogeneity of HCV cell receptors might influence the virus variant selection, single-nucleotide polymorphisms (SNPs) in low-density lipoprotein receptor (LDLR), occludin (OCLN), and scavenger receptor B1 (SCARB1) genes in AD patients were analyzed. No evident correlation between receptor polymorphisms and presence of a particular virus variant was noted. SNPs of HCV cell entry receptors have no influence on virus selection in patients infected with an inoculum containing different virus variants.


Improvements in cognitive function following cardiac rehabilitation for older adults with cardiovascular disease.
Cognitive impairment is common in persons with cardiovascular disease (CVD). Cardiac rehabilitation (CR) improves many aspects of CVD linked to cognitive impairment. The current study explored whether CR may improve cognitive function. Potential mechanisms for cognitive changes were also examined through exploratory analyses, including changes in cardiovascular fitness and cerebral blood flow. Fifty-one older adults with CVD underwent neuropsychological assessment at baseline and discharge from a 12-week CR program. Cardiovascular fitness (i.e., metabolic equivalents [METs]) was estimated from a symptom-limited volitional stress test. Transcranial doppler quantified mean cerebral blood flow velocity and pulsatility indexes for the middle cerebral artery and anterior cerebral artery (ACA). Repeated measures ANOVA showed improvements in global cognition, attention-executive-psychomotor function, and memory. Exploratory analyses revealed improvement in METs and changes in ACA flow velocity, but only improvement in METs was related to improved verbal recall. CVD patients exhibited improvements in multiple cognitive domains following a 12-week CR program, suggesting that cognitive impairment is modifiable in this population. Although other studies are needed to elucidate underlying mechanisms, exploratory analyses suggest that cognitive improvements may be better explained by physiological processes other than improved cardiovascular fitness and cerebral blood flow.


Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke.
Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independently associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects. Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg/m(2)) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +/- 13% vs 42% +/-12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01). Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.


The European Tertiary Education Register, the reference dataset on European Higher Education Institutions.
The European Tertiary Education Register (ETER) is the reference dataset on European Higher Education Institutions (HEIs). ETER provides data on nearly 3,500 HEIs in about 40 European countries, including descriptive information, geographical information, students and graduates (with various breakdowns), revenues and expenditures, personnel, and research activities; as of March 2023, data cover the years from 2011-2020. ETER complies with OECD-UNESCO-EUROSTAT standards for educational statistics; most data are collected from National Statistical Authorities (NSAs) or ministries of participating countries and are subject to extensive checks and harmonization. The development of ETER has been funded by the European Commission and is part of the current efforts to establish a European Higher Education Sector Observatory; it is closely connected to the establishment of a broader data infrastructure in the field of science and innovation studies (RISIS). The ETER dataset is widely used in the scholarly literature on higher education and science policy, as well as for policy reports and analyses.


Forensic analysis of explosives using isotope ratio mass spectrometry (IRMS)--part 2: forensic inter-laboratory trial: bulk carbon and nitrogen stable isotopes in a range of chemical compounds (Australia and New Zealand).
Comparability of data over time and between laboratories is a key issue for consideration in the development of global databases, and more broadly for quality assurance in general. One mechanism that can be utilized for evaluating traceability is an inter-laboratory trial. This paper addresses an inter-laboratory trial conducted across a number of Australian and New Zealand isotope ratio mass spectrometry (IRMS) laboratories. The main objective of this trial was to determine whether IRMS laboratories in these countries would record comparable values for the distributed samples. Four carbon containing and four nitrogen containing compounds were distributed to seven laboratories in Australia and one in New Zealand. The laboratories were requested to analyze the samples using their standard procedures. The data from each laboratory was evaluated collectively using International Standard ISO 13528 (Statistical methods for use in proficiency testing by inter-laboratory comparisons). "Warning signals" were raised against one participant in this trial. "Action signals" requiring corrective action were raised against four participants. These participants reviewed the data and possible sources for the discrepancies. This inter-laboratory trial was successful in providing an initial snapshot of the potential for traceability between the participating laboratories. The statistical methods described in this article could be used as a model for others needing to evaluate stable isotope results derived from multiple laboratories, e.g., inter-laboratory trials/proficiency testing. Ongoing trials will be conducted to improve traceability across the Australian and New Zealand IRMS community.


Practical methods for reducing radioactive contamination incidents in the nuclear cardiology laboratory.
The purpose of this study was to determine the extent and cause of radioactive contamination in our nuclear cardiology laboratory, and to develop possible solutions to minimize future occurrence. We conducted a retrospective review to determine the underlying causes of the 15 minor radioactive contamination events that have occurred in the exercise areas of our laboratory since 1986. Of the 15 documented events, 8 were caused by failure of intravenous apparatus and 7 were due to syringe mishandling. Based on a staff questionnaire, we determined the most prevalent causes of radioactive contamination. Other than problems associated with intravenous setup, the causes were lack of experience by the individual performing the injection, followed closely by radioactive syringe disposal problems, injection technique, and unclear designation of duties during the exercise procedure. Based on these findings, we formulated a 4-part plan: a training program; a closely inspected intravenous apparatus; a mobile radioactive waste container; and a clear designation of duties for personnel to be included in the exercise procedure protocol. We have implemented a sensible and practical plan for reducing radioactive contamination, which is currently being evaluated.


Disease-specific quality indicators, guidelines, and outcome measures in vasculitis.
Measuring quality of care in the anti neutrophil cytoplasm antibody (ANCA) associated vasculitides (AAV) has become more complex, because the introduction of immunosuppressive therapy has resulted in a substantial improvement in survival. Early diagnosis remains a problem, because many patients are seen by non-specialists who may not recognize vasculitis or fail to initiate therapy promptly. A comprehensive assessment to determine the pattern and severity of organ involvement allows a specialist to plan a therapeutic regimen, and to manage co-morbidity effectively. Recent guidelines from the European League Against Rheumatism (EULAR) address the conduct of high-quality clinical trials in vasculitis. Risk factors for poor outcome in vasculitis are probably similar in the different forms of AAV. The risk factors are discussed in the context of failing to achieve remission, relapse, organ failure, and death. Factors indicating a poor prognosis include: the presence of high disease activity at diagnosis (which increases mortality risk even though it is associated with a greater likelihood of response to therapy); the pattern of organ involvement, for example with cardiac features carrying an adverse outcome in Wegener's granulomatosis; significant damage; renal impairment; persistence of ANCA; elderly age at diagnosis; under-use of cyclophosphamide and glucocorticoids in the first 3 months of treatment; persistent nasal carriage of Staphylococcus aureus; and the increased risk of bladder cancer in patients who are given large amounts of cyclophosphamide.


Molecular cloning and expression of flagellar radial spoke and dynein genes of Chlamydomonas.
Several flagellar dynein ATPase and radial spokehead genes have been isolated from a Chlamydomonas genomic expression library in lambda gt11. The library was probed with polyclonal and monoclonal antibodies raised against purified flagellar polypeptides, and recombinant phage giving positive signals were cloned. In vitro translation of mRNAs hybrid-selected by the cloned sequences from whole cell RNA provided confirmation of identity for three of the four clones. Evidence supporting the identification of the fourth, which encodes a dynein heavy chain, was provided by antibody selection; the fusion protein produced by this clone selected heavy chain-specific antibodies from a complex polyclonal antiserum recognizing many dynein determinants. One of the radial spoke sequences isolated here is of particular interest because it encodes the wild-type allele of a locus which was defined previously by temperature-sensitive paralyzed flagella mutation pf-26ts (Huang, B., G. Piperno, Z. Ramanis, and D. J. L. Luck, 1981, J. Cell Biol., 88:80-88). The cloned sequence was used to hybrid-select mRNA from mutant pf-26ts cells, and when translated in vitro, the selected mRNA produced a mutant spokehead polypeptide with an altered electrophoretic mobility. This confirms that the pf-26ts mutation alters the primary structure of a radial spokehead polypeptide. To quantify spokehead and dynein mRNAs during flagellar regeneration, all of the cloned sequences were used as hybridization probes in RNA dot experiments. Levels increased rapidly and coordinately after deflagellation, peaked 3-10-fold above nondeflagellated controls, and then returned to control values within 2 h. This accumulation pattern was similar to that of flagellar alpha-tubulin mRNA.


Clinical outcomes of tuberculum sellae meningiomas focusing on reversibility of postoperative visual function.
Tuberculum sellae meningiomas present a special challenge because of their proximity to major arteries, visual pathways, and the hypothalamus. The aim of this study was to determine the prognostic determinants of clinical and visual outcomes of these tumors, focusing on the functional reversibility of an unserviceable eye after surgery. We retrospectively reviewed 86 patients on the basis of clinical and radiological factors that appeared to affect outcome. The visual acuity and visual fields were analyzed according to the visual impairment score (VIS). Unserviceable visual acuity included no perception of light (NPL), hand movement (HM), and counting fingers (CF). Ophthalmological functioning was tested in the preoperative period, the postoperative short-term period (≤2 weeks after surgery), and the postoperative long-term period (>6 months after surgery). Our own clinical outcome criteria including tumor control, visual improvement, and complications were used for evaluation. Seventy-four of 86 patients (86 %) underwent total removal of the tumor. In three of these cases (3.4 %), recurrence developed. Thirty patients were classified into the "Excellent" group, 21 into the "Good" group, 20 into the "Fair" group, and 15 into the "Poor" group. In multivariate analysis, adhesion to optic nerve was an independent and significant predictor of clinical outcome. Favorable visual outcomes in both short- and long-term postoperative periods were achieved in 80.8 % of cases. Preoperative and short-term visual outcomes were closely related to long-term visual outcome. Six of eight patients with preoperative CF status showed reversibility to a serviceable status after surgery. However, there was no conversion to serviceable status from NPL or HM. For patients with unilateral unserviceable visual function, maintenance of serviceable visual function on the opposite side might be more important. Of the patients with unserviceable visual function, careful surgery might be able to improve the visual function in CF eyes.


The Sickle Cell Disease Ontology: enabling universal sickle cell-based knowledge representation.
Sickle cell disease (SCD) is one of the most common monogenic diseases in humans with multiple phenotypic expressions that can manifest as both acute and chronic complications. Although described more than a century ago, challenges in comprehensive disease management and collaborative research on this disease are compounded by the complex molecular and clinical phenotypes of SCD, environmental and psychosocial factors, limited therapeutic options and ambiguous terminology. This ambiguous terminology has hampered the integration and interoperability of existing SCD knowledge, and SCD research translation. The SCD Ontology (SCDO), which is a community-driven integrative and universal knowledge representation system for SCD, overcomes this issue by providing a controlled vocabulary developed by a group of experts in both SCD and ontology design. SCDO is the first and most comprehensive standardized human- and machine-readable resource that unambiguously represents terminology and concepts about SCD for researchers, patients and clinicians. It is built around the central concept 'hemoglobinopathy', allowing inclusion of non-SCD haemoglobinopathies, such as thalassaemias, which may interfere with or influence SCD phenotypic manifestations. This collaboratively developed ontology constitutes a comprehensive knowledge management system and standardized terminology of various SCD-related factors. The SCDO will promote interoperability of different research datasets, facilitate seamless data sharing and collaborations, including meta-analyses within the SCD community, and support the development and curation of data-basing and clinical informatics in SCD.


A randomized trial of computer-based reminders and audit and feedback to improve HIV screening in a primary care setting.
Despite recommendations for voluntary HIV screening, few medical centres have implemented screening programmes. The objective of the study was to determine whether an intervention with computer-based reminders and feedback would increase screening for HIV in a Department of Veterans Affairs (VA) health-care system. The design of the study was a randomized controlled trial at five primary care clinics at the VA Palo Alto Health Care System. All primary care providers were eligible to participate in the study. The study intervention was computer-based reminders to either assess HIV risk behaviours or to offer HIV testing; feedback on adherence to reminders was provided. The main outcome measure was the difference in HIV testing rates between intervention and control group providers. The control group providers tested 1.0% (n = 67) and 1.4% (n = 106) of patients in the preintervention and intervention period, respectively; intervention providers tested 1.8% (n = 98) and 1.9% (n = 114), respectively (P = 0.75). In our random sample of 753 untested patients, 204 (27%) had documented risk behaviours. Providers were more likely to adhere to reminders to test rather than with reminders to perform risk assessment (11% versus 5%, P < 0.01). Sixty-one percent of providers felt that lack of time prevented risk assessment. In conclusion, in primary care clinics in our setting, HIV testing rates were low. Providers were unaware of the high rates of risky behaviour in their patient population and perceived important barriers to testing. Low-intensity clinical reminders and feedback did not increase rates of screening.


Transcriptional effects of superinfection in HIV chronically infected T cells: studies in dually infected clones.
We had previously shown that chronically infected ACH-2 cells (HIVLAI) could be superinfected with HIVRF, that the frequency of superinfection increased with time, and that the transcription of the superinfecting virus exceeded that of the host HIVLAI provirus. In contrast, ACH-2 cells superinfected with a nef-substituted neomycin-resistant (proNEO) provirus were not detectable by DNA polymerase chain reaction (PCR) until geneticin (G418) was added, suggesting that the ability to propagate progressively in culture may be HIV strain specific. Clonal populations of ACH-2 superinfected with proNEO did not demonstrate preferential transcription of the superinfecting virus. However, clones of ACH-2 superinfected with HIVRF (ACH2/RF) showed a preponderance of HIVRF transcripts similar to that seen in bulk populations. Induction of the superinfecting virus by phorbol ester (PMA) occurred more rapidly than the hose provirus and did not equalize transcriptional activity. PCR-derived long terminal repeat (LTR) fragments and Tat cDNAs from A3.01 cells acutely infected with HIVRF or from ACH-2 cells were sequenced and tested for transactivation. The HIVLAI LTR was two to three times more Tat-responsive than the HIVRF LTR. TatRF was two to three times more transcriptionally active on either LTR than TatLAI. Demethylation with 5-azacytidine did not significantly affect HIV expression from the HIVLAI host provirus of superinfected ACH2/RF cell clones. These data suggest that the mechanism of preferential transcription in HIVRF superinfected ACH2/RF may be attributed to the Tat/TAR axis and the effect of the specific locus of host proviral integration.


Bimodal concentration-response of nicotine involves the nicotinic acetylcholine receptor, transient receptor potential vanilloid type 1, and transient receptor potential ankyrin 1 channels in mouse trachea and sensory neurons.
High concentrations of nicotine, as in the saliva of oral tobacco consumers or in smoking cessation aids, have been shown to sensitize/activate recombinant transient receptor potential vanilloid type 1 (rTRPV1) and mouse TRPA1 (mTRPA1) channels. By measuring stimulated calcitonin gene-related peptide (CGRP) release from the isolated mouse trachea, we established a bimodal concentration-response relationship with a threshold below 10 µM (-)-nicotine, a maximum at 100 µM, an apparent nadir between 0.5 and 10 mM, and a renewed increase at 20 mM. The first peak was unchanged in TRPV1/A1 double-null mutants as compared with wild-types and was abolished by specific nicotinic acetylcholine receptor (nAChR) inhibitors and by camphor, discovered to act as nicotinic antagonist. The nicotine response at 20 mM was strongly pHe-dependent, - five times greater at pH 9.0 than 7.4, indicating that intracellular permeation of the (uncharged) alkaloid was required to reach the TRPV1/A1 binding sites. The response was strongly reduced in both null mutants, and more so in double-null mutants. Upon measuring calcium transients in nodose/jugular and dorsal root ganglion neurons in response to 100 µM nicotine, 48% of the vagal (but only 14% of the somatic) sensory neurons were activated, the latter very weakly. However, nicotine 20 mM at pH 9.0 repeatedly activated almost every single cultured neuron, partly by releasing intracellular calcium and independent of TRPV1/A1 and nAChRs. In conclusion, in mouse tracheal sensory nerves nAChRs are 200-fold more sensitive to nicotine than TRPV1/A1; they are widely coexpressed with the capsaicin receptor among vagal sensory neurons and twice as abundant as TRPA1. Nicotine is the major stimulant in tobacco, and its sensory impact through nAChRs should not be disregarded.


Conditional likelihood methods for haplotype-based association analysis using matched case-control data.
Genetic epidemiologists routinely assess disease susceptibility in relation to haplotypes, that is, combinations of alleles on a single chromosome. We study statistical methods for inferring haplotype-related disease risk using single nucleotide polymorphism (SNP) genotype data from matched case-control studies, where controls are individually matched to cases on some selected factors. Assuming a logistic regression model for haplotype-disease association, we propose two conditional likelihood approaches that address the issue that haplotypes cannot be inferred with certainty from SNP genotype data (phase ambiguity). One approach is based on the likelihood of disease status conditioned on the total number of cases, genotypes, and other covariates within each matching stratum, and the other is based on the joint likelihood of disease status and genotypes conditioned only on the total number of cases and other covariates. The joint-likelihood approach is generally more efficient, particularly for assessing haplotype-environment interactions. Simulation studies demonstrated that the first approach was more robust to model assumptions on the diplotype distribution conditioned on environmental risk variables and matching factors in the control population. We applied the two methods to analyze a matched case-control study of prostate cancer.


HIV-1 Nefs Are Cargo-Sensitive AP-1 Trimerization Switches in Tetherin Downregulation.
The HIV accessory protein Nef counteracts immune defenses by subverting coated vesicle pathways. The 3.7 Å cryo-EM structure of a closed trimer of the clathrin adaptor AP-1, the small GTPase Arf1, HIV-1 Nef, and the cytosolic tail of the restriction factor tetherin suggested a mechanism for inactivating tetherin by Golgi retention. The 4.3 Å structure of a mutant Nef-induced dimer of AP-1 showed how the closed trimer is regulated by the dileucine loop of Nef. HDX-MS and mutational analysis were used to show how cargo dynamics leads to alternative Arf1 trimerization, directing Nef targets to be either retained at the trans-Golgi or sorted to lysosomes. Phosphorylation of the NL4-3 M-Nef was shown to regulate AP-1 trimerization, explaining how O-Nefs lacking this phosphosite counteract tetherin but most M-Nefs do not. These observations show how the higher-order organization of a vesicular coat can be allosterically modulated to direct cargoes to distinct fates.


The need for independent research on the health effects of glyphosate-based herbicides.
Glyphosate, formulated as Roundup, is the world's most widely used herbicide. Glyphosate is used extensively on genetically modified (GM) food crops designed to tolerate the herbicide, and global use is increasing rapidly. Two recent reviews of glyphosate's health hazards report conflicting results. An independent review by the International Agency for Research on Cancer (IARC) found that glyphosate is a "probable human carcinogen". A review by the European Food Safety Agency (EFSA) found no evidence of carcinogenic hazard. These differing findings have produced regulatory uncertainty. Reflecting this regulatory uncertainty, the European Commission on November 27 2017, extended authorization for glyphosate for another 5 years, while the European Parliament opposed this decision and issued a call that pesticide approvals be based on peer-reviewed studies by independent scientists rather than on the current system that relies on proprietary industry studies. The Ramazzini Institute has initiated a pilot study of glyphosate's health hazards that will be followed by an integrated experimental research project. This evaluation will be independent of industry support and entirely sponsored by worldwide crowdfunding. The aim of the Ramazzini Institute project is to explore comprehensively the effects of exposures to glyphosate-based herbicides at current real-world levels on several toxicological endpoints, including carcinogenicity, long-term toxicity, neurotoxicity, endocrine disrupting effects, prenatal developmental toxicity, the microbiome and multi-generational effects.


Bereavement interventions to support informal caregivers in the intensive care unit: a systematic review.
Informal caregivers of critically ill patients in intensive care unit (ICUs) experience negative psychological sequelae that worsen after death. We synthesized outcomes reported from ICU bereavement interventions intended to improve informal caregivers' ability to cope with grief. MEDLINE, EMBASE, CINAHL and PsycINFO from inception to October 2020. Randomized controlled trials (RCTs) of bereavement interventions to support informal caregivers of adult patients who died in ICU. Two reviewers independently extracted data in duplicate. Narrative synthesis was conducted. Bereavement interventions were categorized according to the UK National Institute for Health and Clinical Excellence three-tiered model of bereavement support according to the level of need: (1) Universal information provided to all those bereaved; (2) Selected or targeted non-specialist support provided to those who are at-risk of developing complex needs; and/or (3) Professional specialist interventions provided to those with a high level of complex needs. Outcome measures were synthesized according to core outcomes established for evaluating bereavement support for adults who have lost other adults to illness. Three studies of ICU bereavement interventions from 31 ICUs across 26 hospitals were included. One trial examining the effect of family presence at brain death assessment integrated all three categories of support but did not report significant improvement in emotional or psychological distress. Two other trials assessed a condolence letter intervention, which did not decrease grief symptoms and may have increased symptoms of depression and post-traumatic stress disorder, and a storytelling intervention that found no significant improvements in anxiety, depression, post-traumatic stress, or complicated grief. Four of nine core bereavement outcomes were not assessed anytime in follow-up. Currently available trial evidence is sparse and does not support the use of bereavement interventions for informal caregivers of critically ill patients who die in the ICU.


The Radiation-Transmission-Reception (RTR) model of propagation: Implications for the effectiveness of network interventions.
Propagating phenomena in networks have received significant amount of attention within various domains, ranging from contagion in epidemiology, to diffusion of innovations and social influence on behavior and communication. Often these studies attempt to model propagation processes in networks to create interventions that steer propagation dynamics towards desired or away from undesired outcomes. Traditionally, studies have used relatively simple models of the propagation mechanism. In most propagation models this mechanism is described as a monolithic process and a single parameter for the infection rate. Such a description of the propagation mechanism is a severe simplification of mechanisms described in various theoretical exchange theories and phenomena found in real world settings, and largely fails to capture the nuances present in such descriptions. Recent work has suggested that such a simplification may not be sufficient to explain observed propagation dynamics, as nuances of the mechanism of propagation can have a severe impact on its dynamics. This suggests a better understanding of the role of the propagation mechanism is desired. In this paper we put forward a novel framework and model for propagation, the RTR framework. This framework, based on communication theory, decomposes the propagation mechanism into three sub-processes; Radiation, Transmission and Reception (RTR). We show that the RTR framework provides a more detailed way for specifying and conceptually thinking about the process of propagation, aligns better with existing real world interventions, and allows for gaining new insights into effective intervention strategies. By decomposing the propagation mechanism, we show that the specifications of this mechanism can have significant impact on the effectiveness of network interventions. We show that for the same composite single-parameter specification, different decompositions in Radiation, Transmission and Reception yield very different effectiveness estimates for the same network intervention, from 30% less effective to 70% more effective. We find that the appropriate choice for intervention depends strongly on the decomposition of the propagation mechanism. Our findings highlight that a correct decomposition of the mechanism is a prerequisite for developing effective network intervention strategies, and that the use of monolithic models, which oversimplify the mechanism, can be problematic of supporting decisions related to network interventions. In contrast, by allowing more detailed specification of the propagation mechanism and enabling this mechanism to be linked to existing interventions, the RTR framework provides a valuable tool for those designing interventions and implementing interventions strategies.


Multiple cancer type classification by small RNA expression profiles with plasma samples from multiple facilities.
Liquid biopsy is expected to be a promising cancer screening method because of its low invasiveness and the possibility of detecting multiple types in a single test. In the last decade, many studies on cancer detection using small RNAs in blood have been reported. To put small RNA tests into practical use as a multiple cancer type screening test, it is necessary to develop a method that can be applied to multiple facilities. We collected samples of eight cancer types and healthy controls from 20 facilities to evaluate the performance of cancer type classification. A total of 2,475 cancer samples and 496 healthy control samples were collected using a standardized protocol. After obtaining a small RNA expression profile, we constructed a classification model and evaluated its performance. First, we investigated the classification performance using samples from five single facilities. Each model showed areas under the receiver curve (AUC) ranging from 0.67 to 0.89. Second, we performed principal component analysis (PCA) to examine the characteristics of the facilities. The degree of hemolysis and the data acquisition period affected the expression profiles. Finally, we constructed the classification model by reducing the influence of these factors, and its performance had an AUC of 0.76. The results reveal that small RNA can be used for the classification of cancer types in samples from a single facility. However, interfacility biases will affect the classification of samples from multiple facilities. These findings will provide important insights to improve the performance of multiple cancer type classifications using small RNA expression profiles acquired from multiple facilities.


A Two-Domain Self-Report Measure of Periodontal Disease Has Good Accuracy for Periodontitis Screening in Dental School Outpatients.
The assessment of periodontitis and treatment needs is primarily based on clinical and radiographic examinations. Albeit effective in predicting treatment needs, these examinations are costly, time-consuming, and impractical for assessing population-level needs. The purpose of the present study is to evaluate a two-domain self-report questionnaire for rapid periodontitis screening. Six hundred white adult individuals, dentate or partially dentate and seeking dental therapy at a university clinic, underwent oral examination utilizing the full-mouth Community Periodontal Index of Treatment Needs (CPITN). To assess predictive value of self-reported periodontal measures (SRPMs) for periodontitis screening, four questions were formulated. Two questions aimed to assess "dentist-diagnosed periodontal disease" and two inquired about "self-assessed periodontitis." Multiple logistic regression models were used to construct receiver-operating characteristic curves, and predictor selection was performed via a forward stepwise selection process. Five hundred thirty-five volunteers with a mean age of 50.1 years elected to respond to SRPMs via telephone interview. After oral examination, 17.8% of participants were assessed as having CPITN = 4, representing compromised periodontal status. Sensitivity and specificity for correctly classifying compromised periodontal status ranged from 5.3% to 72.6%, and 87.8% to 99.5% for individual SRPMs. Sensitivity and specificity were increased when combining a measure of self-assessed periodontal disease and a measure of dentist-diagnosed disease as predictors. Addition of age and sex maximized sensitivity/specificity at 82.1%/82.2%. Diabetic status, smoking, and body mass index did not enhance the prediction. A two-domain self-report measure combining two self-report items with age and sex has good sensitivity and specificity for periodontitis screening in a white, university-based population. The proposed self-report measure can be valuable for periodontitis screening in resource-limited settings where gold standard clinical examination may not be pragmatic. Further validation studies are required to assess whether findings from this study are context-specific.


Paracetamol with and without codeine in acute pain: a quantitative systematic review.
In order to assess the analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in postoperative pain, we conducted a systematic review of randomised controlled trials. We found 31 trials of paracetamol against placebo with 2515 patients, 19 trials of paracetamol plus codeine against placebo with 1204 patients and 13 trials of paracetamol plus codeine against the same dose of paracetamol with 874 patients. Pain relief information was extracted, and converted into dichotomous information (number of patients with at least 50% pain relief). Wide variations in responses to placebo (0-72%) and active drug (3-89%) were observed. In postoperative pain states paracetamol 1000 mg alone against placebo had an number-needed-to-treat (NNT) of 3.6 (3.0-4.4) and paracetamol 600/650 mg alone an NNT of 5.0 (4.1-6.9). Paracetamol 600/650 mg plus codeine 60 mg against placebo had a better NNT of 3.1 (2.6-3.8), with no overlap of 95% confidence intervals with paracetamol 600/650 mg alone. In direct comparisons of paracetamol plus codeine with paracetamol alone the additional analgesic effect of 60 mg of codeine added to paracetamol was 12 extra patients in every 100 achieving at least 50% pain relief. In indirect comparisons of each with placebo it was 14 extra patients per 100. This was an NNT for adding codeine 60 mg of 9.1 (5.8-24). The results confirm that paracetamol is an effective analgesic, and that codeine 60 mg added to paracetamol produces worthwhile additional pain relief even in single oral doses.


Care, Autonomy, and Gender in Nursing Practice: A Historical Study of Nurses' Experiences.
Care is the essence of the nursing role and is closely related to the concept of professional autonomy. Autonomy is implicated in power relations between doctors and nurses and between men and women. These relationships are closely linked to care practices and the inequality of nursing and medicine. The aim of this study was to analyze nursing discourse regarding the concept of care and its relationship to the concept of autonomy and gender. This is a historical study based on oral interviews that took place between November 2008 and February 2011. We interviewed 19 nursing professionals who currently worked at the Hospital of the Holy Spirit (near Barcelona) or had worked there between 1961 and 2010. Semistructured interviews were recorded, transcribed, and analyzed. We highlight four main themes: "a real nurse"; "more technology, less care"; "the fragility of autonomy"; and "the invisibility of nursing work." These themes show the contradictions in the nursing profession that are based on the concept of care. However, in daily practice, the concept of care varies. Time pressure distances the nursing practice from its theoretical context. Changes in the concept of care are related to transformations in the health system and nursing work. Changes related to the autonomy of nursing are related to changes in the concept of care. In practice, care has a biomedical orientation. Care has become technologized and bureaucratized, which reduces the time that is spent with the patient. In a context in which medical authority predominates, nursing's struggle for autonomy is based on the recognition of the value of care. When care becomes invisible, the autonomy of nursing as a profession is threatened. This conclusion allows reflections about shifts in the concept of care and how they affect clinical practice and the autonomy of the nursing profession.


Interventions to improve exercise behaviour in sedentary people living with and beyond cancer: a systematic review.
To systematically review the effects of interventions to improve exercise behaviour in sedentary people living with and beyond cancer. Only randomised controlled trials (RCTs) that compared an exercise intervention to a usual care comparison in sedentary people with a homogeneous primary cancer diagnosis, over the age of 18 years were eligible. The following electronic databases were searched: Cochrane Central Register of Controlled Trials MEDLINE; EMBASE; AMED; CINAHL; PsycINFO; SportDiscus; PEDro from inception to August 2012. Fourteen trials were included in this review, involving a total of 648 participants. Just six trials incorporated prescriptions that would meet current recommendations for aerobic exercise. However, none of the trials included in this review reported intervention adherence of 75% or more for a set prescription that would meet current aerobic exercise guidelines. Despite uncertainty around adherence in many of the included trials, the interventions caused improvements in aerobic exercise tolerance at 8-12 weeks (SMD=0.73, 95% CI=0.51-0.95) in intervention participants compared with controls. At 6 months, aerobic exercise tolerance is also improved (SMD=0.70, 95% CI=0.45-0.94), although four of the five trials had a high risk of bias; hence, caution is warranted in its interpretation. Expecting the majority of sedentary survivors to achieve the current exercise guidelines is likely to be unrealistic. As with all well-designed exercise programmes, prescriptions should be designed around individual capabilities and frequency, duration and intensity or sets, repetitions, intensity of resistance training should be generated on this basis.


Functional and selective targeting of adenovirus to high-affinity Fcgamma receptor I-positive cells by using a bispecific hybrid adapter.
Adenovirus (Ad) efficiently delivers its DNA genome into a variety of cells and tissues, provided that these cells express appropriate receptors, including the coxsackie-adenovirus receptor (CAR), which binds to the terminal knob domain of the viral capsid protein fiber. To render CAR-negative cells susceptible to Ad infection, we have produced a bispecific hybrid adapter protein consisting of the amino-terminal extracellular domain of the human CAR protein (CARex) and the Fc region of the human immunoglobulin G1 protein, comprising the hinge and the CH2 and CH3 regions. CARex-Fc was purified from COS7 cell supernatants and mixed with Ad particles, thus blocking Ad infection of CAR-positive but Fc receptor-negative cells. The functionality of the CARex domain was further confirmed by successful immunization of mice with CARex-Fc followed by selection of a monoclonal anti-human CAR antibody (E1-1), which blocked Ad infection of CAR-positive cells. When mixed with Ad expressing eGFP, CARex-Fc mediated an up to 250-fold increase of transgene expression in CAR-negative human monocytic cell lines expressing the high-affinity Fcgamma receptor I (CD64) but not in cells expressing the low-affinity Fcgamma receptor II (CD32) or III (CD16). These results open new perspectives for Ad-mediated cancer cell vaccination, including the treatment of acute myeloid leukemia.