Pattern of childhood poisoning in abha city - southwestern saudi arabia.
To describe the pattern of childhood poisoning in the Emergency Room (ER) of the Pediatrics Department in Aseer Central Hospital (ACH), in order to suggest possible causes and preventive measures. This is a retrospective study of cases of childhood poisoning or ingestions attending the pediatric emergency room of Aseer Central Hospital or those admitted to the Pediatric Department of same hospital in Abha, Kingdom of Saudi Arabia, during the period of January 2000 to December 2003. Children aged 12 years and below were included. Review of records was done to collect data on clinical information such as age, sex, type of poison, clinical condition on admission as well as the time, place and date of exposure to the offending agent. In this study, 114 poisoned children aged 12 years and below were studied. It was found that children from 2-4 years were more liable to poisoning (81%, p<0.001). Males were (68%) while females were (32%), with a sex ratio of 2.2:1. Medical drugs offended the most (72%, p<0.001). As regards clinical condition on admission, drowsiness, nausea and vomiting as well as abdominal pain represented (82%) of the cases. Daytime was when 80% of poisoned cases were admitted (p<0.001). The peak months were from June to August (71%, p<0.01). As regard the place of exposure to offending agent, living rooms and bedrooms accounted for 58% of the cases(p<001). The peak age for poisonings in children is before the age of four with significantly high diurnal frequency, significant seasonal variation in favor of summer. Medical drugs were the most common agents of poisoning, and living rooms and bedrooms the places where most poisoning occurred. Good and continuous supervision by parents is essential, especially from the age 1-5 years. There should also be legislation for the use of child resistant containers for home medicines and household agents.


CD24⁺ ovary cancer cells exhibit an invasive mesenchymal phenotype.
We recently reported that the subset of CD24(+) cells in ovarian cancer possesses various cancer stem cell properties. In this study, we further show that this subpopulation of ovarian cancer cells exhibits an epithelial-mesenchymal transition (EMT) phenotype, high invasive capacity, and CXCR4/SDF-1-mediated chemotactic migration. We evaluated CD24 expression in various ovarian cancer cell lines by flow cytometric analysis. CAOV3 and a primary ovarian cancer cell line Clone 4 were sorted into CD24(+) and CD24(-) subpopulations by FACS and Western blot, cell invasion, adhesion, and in vitro chemotaxis assays were performed with these two subpopulations. We also assessed the effects of shRNA depletion of CD24 in CAOV3 and Clone 4 cells by Western blot and cell invasion assays. CD24 expression in ovarian cancer cell lines correlated with aggressive histologic subtypes of epithelial ovarian cancer. The CD24(+) subpopulation was also more invasive than the CD24(-) subpopulation and showed higher CXCR4/SDF-1-mediated chemotactic migration. CD24(+) cells exhibited an EMT phenotype as characterized by loss of E-cadherin expression and gain of vimentin, Twist, and Snail1 expression. In addition, CD24(+) cells stimulated cell attachment to fibronectin through the activation of β1 integrin. Depletion of CD24 expression by CD24 shRNA efficiently suppressed cell invasion and induced downregulation of CXCR4 as well as loss of the EMT phenotype. In conclusion, CD24 expression in ovarian cancer may be related to tumor aggressiveness, in particular cell invasion and chemotactic migration. Therefore, CD24 may be a good candidate for a therapeutic target for ovarian cancer.


Non-equivalent role of inter- and intramolecular hydrogen bonds in the insulin dimer interface.
Apart from its role in insulin receptor (IR) activation, the C terminus of the B-chain of insulin is also responsible for the formation of insulin dimers. The dimerization of insulin plays an important role in the endogenous delivery of the hormone and in the administration of insulin to patients. Here, we investigated insulin analogues with selective N-methylations of peptide bond amides at positions B24, B25, or B26 to delineate their structural and functional contribution to the dimer interface. All N-methylated analogues showed impaired binding affinities to IR, which suggests a direct IR-interacting role for the respective amide hydrogens. The dimerization capabilities of analogues were investigated by isothermal microcalorimetry. Selective N-methylations of B24, B25, or B26 amides resulted in reduced dimerization abilities compared with native insulin (K(d) = 8.8 μM). Interestingly, although the N-methylation in [NMeTyrB26]-insulin or [NMePheB24]-insulin resulted in K(d) values of 142 and 587 μM, respectively, the [NMePheB25]-insulin did not form dimers even at high concentrations. This effect may be attributed to the loss of intramolecular hydrogen bonding between NHB25 and COA19, which connects the B-chain β-strand to the core of the molecule. The release of the B-chain β-strand from this hydrogen bond lock may result in its higher mobility, thereby shifting solution equilibrium toward the monomeric state of the hormone. The study was complemented by analyses of two novel analogue crystal structures. All examined analogues crystallized only in the most stable R(6) form of insulin oligomers (even if the dimer interface was totally disrupted), confirming the role of R(6)-specific intra/intermolecular interactions for hexamer stability.


Sodium vanadate combined with L-ascorbic acid delays disease progression, enhances motor performance, and ameliorates muscle atrophy and weakness in mice with spinal muscular atrophy.
Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation in these organs. Combined treatment beginning at birth and continuing for 1 month conferred protection against neuromuscular damage in mice with milder types of SMA. Further, these mice exhibited enhanced motor performance in adulthood. Therefore, combined treatment could present a feasible treatment option for patients with late-onset SMA.


In vivo and in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene.
Hexachlorobutadiene (HCBD), a renal toxin and carcinogen, is thought to require bioactivation to exert toxicity. The chemically synthesized cysteine conjugate of structurally similar halogenated hydrocarbons, trichloroethylene, chlorotrifluoroethylene, and chlorodifluoroethylene, have been shown to be nephrotoxic. Hence the cysteine conjugate of HCBD, S-pentachlorobuta-1,3-dienyl cysteine (PCBC), was assessed for potential nephrotoxicity. Active acid and base transport in isolated rabbit renal tubules was used to screen nephrotoxicity. A dose-dependent decrease in acid and base transport was observed after incubation with PCBC. At 10(-5) M PCBC transport was similar to that in controls, while at 10(-3) M PCBC completely inhibited active transport. In addition, in vivo exposure of Swiss-Webster male mice caused dose-dependent damage in the pars recta region of the proximal tubules (5-25 mg/kg ip). Genotoxicity in renal tissue was studied by using alkaline elution to detect DNA single-strand breaks and total cross-links. No DNA single-strand breaks were observed in isolated rabbit renal tubules after exposure to 10(-3) to 10(-5) M PCBC. However, at 10(-3) M PCBC there was some evidence of DNA cross-links. Therefore if cysteine conjugates of HCBD are formed in vivo, they could account for the toxicity observed with exposure to HCBD.


Up in the tree--the overlooked richness of bryophytes and lichens in tree crowns.
Assessing diversity is among the major tasks in ecology and conservation science. In ecological and conservation studies, epiphytic cryptogams are usually sampled up to accessible heights in forests. Thus, their diversity, especially of canopy specialists, likely is underestimated. If the proportion of those species differs among forest types, plot-based diversity assessments are biased and may result in misleading conservation recommendations. We sampled bryophytes and lichens in 30 forest plots of 20 m × 20 m in three German regions, considering all substrates, and including epiphytic litter fall. First, the sampling of epiphytic species was restricted to the lower 2 m of trees and shrubs. Then, on one representative tree per plot, we additionally recorded epiphytic species in the crown, using tree climbing techniques. Per tree, on average 54% of lichen and 20% of bryophyte species were overlooked if the crown was not been included. After sampling all substrates per plot, including the bark of all shrubs and trees, still 38% of the lichen and 4% of the bryophyte species were overlooked if the tree crown of the sampled tree was not included. The number of overlooked lichen species varied strongly among regions. Furthermore, the number of overlooked bryophyte and lichen species per plot was higher in European beech than in coniferous stands and increased with increasing diameter at breast height of the sampled tree. Thus, our results indicate a bias of comparative studies which might have led to misleading conservation recommendations of plot-based diversity assessments.


Mechanical regulation of cancer cell apoptosis and autophagy: roles of bone morphogenetic protein receptor, Smad1/5, and p38 MAPK.
Mechanical forces induced by interstitial fluid flow in and surrounding tissues and by blood/lymphatic flow in vessels may modulate cancer cell invasion and metastasis and anticancer drug delivery. Our previous study demonstrated that laminar flow-induced shear stress induces G2/M arrest in tumor cells. However, whether shear stress modulates final cell fate remains unclear. In this study, we investigated the role of flow-induced shear stress in modulating the survival of four human tumor cell lines, i.e., Hep3B hepatocarcinoma cells, MG63 osteosarcoma cells, SCC25 oral squamous carcinoma cells, and A549 carcinomic alveolar basal epithelial cells. Laminar shear stress (LSS) ranging from 0.5 to 12dyn/cm(2) induced death of these four tumor cell lines. In contrast to LSS at 0.5dyn/cm(2), oscillatory shear stress (OSS) at 0.5±4dyn/cm(2) cannot induce cancer cell death. Both LSS and OSS had no effect on human normal hepatocyte, lung epithelial, and endothelial cells. Application of LSS to these four cell lines increased the percentage of cells stained positively for annexin V-FITC, with up-regulations of cleaved caspase-8, -9, and -3, and PARP. In addition, LSS also induced Hep3B cell autophagy, as detected by acidic vesicular organelle formation, LC3B transformation, and p62/SQSTM1 degradation. By transfecting with small interfering RNA, we found that the shear-induced apoptosis and autophagy are mediated by bone morphogenetic protein receptor type (BMPR)-IB, BMPR-specific Smad1 and Smad5, and p38 mitogen-activated protein kinase in Hep3B cells. Our findings provide insights into the molecular mechanisms by which shear stress induces apoptosis and autophagy in tumor cells.


Physical activity and dietary intake among Chinese pregnant women: an observational study.
Physical activity (PA) and dietary intake are important modifiable factors associated with health outcomes. However, Chinese pregnant women's PA and dietary intake are only vaguely understood. The aim of this study was to reveal the characteristics of PA and dietary intake of Chinese women in different trimesters as well as the associations between PA and dietary intake. This is a cross-sectional observational study. PA, dietary intake, and demographics of 1077 Chinese pregnant women were measured. The Chi-square test, Kruskal-Wallis test, multiple logistic regression, and multiple linear regression were used for data analysis. About 57.1% of the participants met the international guideline for PA. Household activity and occupational activity contributed the most to the total PA, while sports/exercise contributed little. The mean energy intake of the participants was 2008 ± 748.0 kcal. Most participants had normal energy intake, but they obtained excessive energy from fat (mean = 41.7 ± 8.7%). PA was not found to be significantly associated with dietary intake. Further, the participants who were unemployed during pregnancy (OR = 0.72, 95% CI: 0.55-0.95; p < 0.05) or had no exercise habits before pregnancy (OR = 0.62, 95% CI: 0.47-0.80; p < 0.01) were less likely to meet the PA guideline. The participants in the third trimester (OR = 1.43, 95% CI: 1.03-1.99; p < 0.05) were more likely to meet the PA guideline compared to those in the first trimester. The older participants (> 30 years) showed higher dietary intake than the younger (< 25 years) participants (p < 0.01). The total PA of Chinese women during pregnancy mostly consists of household and occupational activities, but little sports/exercise. Starting exercise before pregnancy may help women achieve adequate PA during pregnancy. Moreover, these women consumed an excessive amount of fat and their diet intake varies by age.


External quality assessment of AFB smear microscopy performances and its associated factors in selected private health facilities in Addis Ababa, Ethiopia.
Tuberculosis (TB) is still a public health problem in sub Saharan African countries. In resource-limited settings, TB diagnosis relies on sputum smear microscopy, with low and variable sensitivities, especially in paucibacillary pediatric and HIV-associated TB patients. Tuberculosis microscopy centers have several weaknesses like overworking, insufficiently trained personnel, inconsistent reagent supplies, and poorly maintained equipments; thus, there is a critical need for investments in laboratory infrastructure, capacity building, and quality assurance schemes. The performance of TB microscopy centers in the private health facilities in Addis Ababa is not known so far. The main objective of the study was to assess laboratory performance of acid fast bacilli (AFB) smear microscopy and its associated factors in selected private health facilities in Addis Ababa, Ethiopia. A cross-sectional study was conducted in 33 selected private health facilities of Addis Ababa, Ethiopia comprising 7 hospitals, 2 NGO health centers, 23 higher clinics and 1 diagnostic laboratory that provide AFB smear microscopy services. The study was conducted from January to April 2014. A total of 283 stained sputum smears were randomly collected from participant laboratories for blinded rechecking, 320 panel slides were sent to 32 microscopy centers to evaluate their performance on AFB reading, staining and reporting. Checklists were used to assess quality issues of laboratories. Data were captured, cleaned, and analyzed using SPSS version 16.0; χ(2) tests, kappa statistics were used for comparison purpose. P value < 0.05 considered statistically significant. Among the 32 participant laboratories, 2-scored 100%, 15 scored 80-95% & the remaining 15 scored 50-75% for overall proficiency test performance. There were 10 (3.15%) major errors and 121 (37.8%) minor errors. The sensitivity, specificity, PPV and NPV of panel reading by microscopy centers were 89%, 96%, 96%, and 90% respectively. Out of 283 randomly selected slides for blind rechecking, 11 (3.9%) slides interpreted falsely for AFB, with overall agreement of 97.5%, sensitivity of 88.4% and specificity of 99.3%. In terms of slide quality assessment, 71.6% of AFB slides were graded as good for evenness, cleanness, thickness, size, staining and labeling. The performance score for AFB slide evenness was 56.9% (161 slides) and for labeling quality was 90.8% (257 slides); having significant difference in slide quality (p value < 0.05). On-site evaluation indicated problems in terms of infrastructure, standard operating procedure, reagent quality; equipment maintenance, data management and training issues. Most of the health facilities had poor maintenance scheme for microscope (53.5%) and poor inventory management (25.0%) system. Microscopy centers that scored a proficiency of 75.5%; which is below the acceptable minimum score of 80% and an overall error rate of 3.9% for blinded rechecking needs attention. Moreover, there are gaps identified through on site assessment including poor SOP, reagent quality, equipment maintenance, data management & lack of updated training on AFB microscopy techniques, requiring a concerted effort to alleviate the bottle neck problems and strengthening the public private partnership to control TB.


Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland?
The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure. Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites. Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area.


Limiting the impact of light pollution on human health, environment and stellar visibility.
Light pollution is one of the most rapidly increasing types of environmental degradation. Its levels have been growing exponentially over the natural nocturnal lighting levels provided by starlight and moonlight. To limit this pollution several effective practices have been defined: the use of shielding on lighting fixture to prevent direct upward light, particularly at low angles above the horizon; no over lighting, i.e. avoid using higher lighting levels than strictly needed for the task, constraining illumination to the area where it is needed and the time it will be used. Nevertheless, even after the best control of the light distribution is reached and when the proper quantity of light is used, some upward light emission remains, due to reflections from the lit surfaces and atmospheric scatter. The environmental impact of this "residual light pollution", cannot be neglected and should be limited too. Here we propose a new way to limit the effects of this residual light pollution on wildlife, human health and stellar visibility. We performed analysis of the spectra of common types of lamps for external use, including the new LEDs. We evaluated their emissions relative to the spectral response functions of human eye photoreceptors, in the photopic, scotopic and the 'meltopic' melatonin suppressing bands. We found that the amount of pollution is strongly dependent on the spectral characteristics of the lamps, with the more environmentally friendly lamps being low pressure sodium, followed by high pressure sodium. Most polluting are the lamps with a strong blue emission, like Metal Halide and white LEDs. Migration from the now widely used sodium lamps to white lamps (MH and LEDs) would produce an increase of pollution in the scotopic and melatonin suppression bands of more than five times the present levels, supposing the same photopic installed flux. This increase will exacerbate known and possible unknown effects of light pollution on human health, environment and on visual perception of the Universe by humans. We present quantitative criteria to evaluate the lamps based on their spectral emissions and we suggest regulatory limits for future lighting.


Meta-analysis of mNGF therapy for peripheral nerve injury: a systematic review.
To assess the efficacy and safety of mouse nerve growth factor (mNGF) in patients with peripheral nerve injury. Such electronic database as Cochrane Library (Issue 1, 2011), Medline (1950-2011), Embase (1980-2011), National Knowledge Infrastructure (1979-2011) were searched and meanwhile relevant journals such as Chinese Journal of Orthopaedics, Chinese Journal of Microsurgery, Chinese Journal of Neurosurgery, etc were searched as well to collect all randomized controlled trials and quasi-randomi- zed controlled trials of mNGF on patients with peripheral nerve injury. The quality of included studies was assessed according to the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions and the data were extracted by two reviewers independently. Meta-analysis was conducted by RevMan 5.1 software. Forty-one studies involving 3 304 patients with peripheral nerve injury were included. The results of meta-analysis showed that: (1) the total effective rate of peripheral nerve injury treatment in mNGF group was ob- viously higher than that in control group (OR equal to 6.36, 95% CI 4.96-8.15, P less than 0.01); (2) the scores of activities of daily living (ADL) in mNGF group was significantly higher than that in control group (weighted mean difference equal to 1.97, 95% CI 1.33-2.61, P less than 0.01); (3) the incidence of adverse reaction in mNGF group was higher than that in control group, (OR equal to 1.66, 95% CI 1.61-2.38, P equal to 0.006), but the adverse effects were mild, which could be relieved without specific treatment or just given symptomatic treatment, and disappeared at the end of treatment. The mNGF therapy is effective for peripheral nerve injury. It can obviously improve patient's ADL. Though the incidence of adverse reaction in mNGF treatment group is higher than that in control group, this does not influence the treatment outcomes.


Patient and service user engagement in research: a systematic review and synthesized framework.
There is growing attention towards increasing patient and service user engagement (PSUE) in biomedical and health services research. Existing variations in language and design inhibit reporting and indexing, which are crucial to comparative effectiveness in determining best practices. This paper utilizes a systematic review and environmental scan to derive an evidence-based framework for PSUE. A metanarrative systematic review and environmental scan/manual search using scientific databases and other search engines, along with feedback from a patient advisory group (PAG). English-language studies, commentaries, grey literature and other sources (including systematic and non-systematic reviews) pertaining to patient and public involvement in biomedical and health services research. Study description (e.g. participant demographics, research setting) and design, if applicable; frameworks, conceptualizations or planning schemes for PSUE-related endeavours; and methods for PSUE initiation and gathering patients'/service users' input or contributions. Overall, 202 sources were included and met eligibility criteria; 41 of these presented some framework or conceptualization of PSUE. Sources were synthesized into a two-part framework for PSUE: (i) integral PSUE components include patient and service user initiation, reciprocal relationships, colearning and re-assessment and feedback, (ii) sources describe PSUE at several research stages, within three larger phases: preparatory, execution and translational. Efforts at developing a solid evidence base on PSUE are limited by the non-standard and non-empirical nature of much of the literature. Our proposed two-part framework provides a standard structure and language for reporting and indexing to support comparative effectiveness and optimize PSUE.


Effects of neuromuscular electrical stimulation combined with effortful swallowing on post-stroke oropharyngeal dysphagia: a randomised controlled trial.
Neuromuscular electrical stimulation (NMES) has been used as a therapeutic intervention for dysphagia. However, the therapeutic effects of NMES lack supporting evidence. In recent years, NMES combined with traditional swallowing therapy has been used to improve functional recovery in patients with post-stroke dysphagia. This study aimed to investigate the effects of effortful swallowing combined with neuromuscular electrical stimulation on hyoid bone movement and swallowing function in stroke patients. Fifty stroke patients with mild dysphagia who were able to swallow against the resistance applied by using NMES and cooperate actively in training were included. This study was designed as a 6-week single-blind, randomised, controlled study. In the experimental group, two pairs of electrodes were placed horizontally in the infrahyoid region to depress the hyoid bone. The NMES intensity was increased gradually until the participants felt a grabbing sensation in their neck and performed an effortful swallow during the stimulation. In the placebo group, the same procedure was followed except for the intensity, which was increased gradually until the participants felt an electrical sensation. All participants underwent this intervention for 30 min per session, 5 sessions per week, for 6 weeks. Videofluoroscopic swallowing studies (VFSS) were carried out before and after the intervention and kinematics of the hyoid bone and swallowing function were analysed based on the VFSS. The experimental group revealed a significant increase in anterior and superior hyoid bone movement and the pharyngeal phase of the swallowing function. This intervention can be used as a novel remedial approach in dysphagic stroke patients.


Combining colloidal probe atomic force and reflection interference contrast microscopy to study the compressive mechanics of hyaluronan brushes.
We describe a method that combines colloidal probe atomic force microscopy (AFM) and reflection interference contrast microscopy (RICM) to characterize the mechanical properties of thin and solvated polymer films. When analyzing polymer films, a fundamental problem in colloidal probe AFM experiments is to determine the distance at closest approach between the probe and the substrate on which the film is deposited. By combining AFM and RICM in situ, forces and absolute distances can be measured simultaneously. Using the combined setup, we quantify the compressive mechanics of films of the polysaccharide hyaluronan that is end-grafted to a supported lipid bilayer. The experimental data, and comparison with polymer theory, show that hyaluronan films are well-described as elastic, very soft and highly solvated polymer brushes. The data on these well-defined films should be a useful reference for the investigation of the more complex hyaluronan-rich coats that surround many living cells.


Epistemic virtues and data-driven dreams: On sameness and difference in the epistemic cultures of data science and psychiatry.
Data science and psychiatry have diverse epistemic cultures that come together in data-driven initiatives (e.g., big data, machine learning). The literature on these initiatives seems to either downplay or overemphasize epistemic differences between the fields. In this paper, we study the convergence and divergence of the epistemic cultures of data science and psychiatry. This approach is more likely to capture where and how the cultures differ and gives insights into how practitioners from both fields find ways to work together despite their differences. We introduce the notions of "epistemic virtues" to focus on epistemic differences ethnographically, and "trading zones" to concentrate on how differences are negotiated. This leads us to the following research question: how are epistemic differences negotiated by data science and psychiatry practitioners in a hospital-based data-driven initiative? Our results are based on an ethnographic study in which we observed a Dutch psychiatric hospital department developing prediction models of patient outcomes based on machine learning techniques (September 2017 - February 2018). Many epistemic virtues needed to be negotiated, such as completeness or selectivity in data inclusion. These differences were traded locally and temporarily, stimulated by shared epistemic virtues (such as a systematic approach), boundary objects and socialization processes. Trading became difficult when virtues were too diverse, differences were enlarged by storytelling and parties did not have the time or capacity to learn about the other. In the discussion, we argue that our combined theoretical framework offers a fresh way to study how cooperation between diverse practitioners goes and where it can be improved. We make a call for bringing epistemic differences into the open as this makes a grounded discussion possible about the added value of data-driven initiatives and the role they can play in healthcare.


A database for the provisional identification of species using only genotypes: web-based genome profiling.
For a long time one could not imagine being able to identify species on the basis of genotype only as there were no technological means to do so. But conventional phenotype-based identification requires much effort and a high level of skill, making it almost impossible to analyze a huge number of organisms, as, for example, in microbe-related biological disciplines. Comparative analysis of 16S rRNA has been changing the situation, however. We report here an approach that will allow rapid and accurate phylogenetic comparison of any unknown strain to all known type strains, enabling tentative assignments of strains to species. The approach is based on two main technologies: genome profiling and Internet-based databases. A complete procedure for provisional identification of species using only their genomes is presented, using random polymerase chain reaction, temperature-gradient gel electrophoresis, image processing to generate 'species-identification dots' (spiddos) and data processing. A database website for this purpose was also constructed and operated successfully. The protocol was standardized to make the system reproducible and reliable. The overall methodology thus established has remarkable aspects in that it enables non-experts to obtain an initial species identification without a lot of effort and is self-developing; that is, species can be determined more definitively as the database is used more and accumulates more genome profiles. We have devised a methodology that enables provisional identification of species on the basis of their genotypes only. It is most useful for microbe-related disciplines as they face the most serious difficulties in species identification.


Nonconventional difluoroalkylation of C(sp2)-H bonds through hydroarylation.
An unprecedented Rh-catalyzed C2-difluoroalkylation of indole derivatives with 2,2-difluorovinyl arenesulfonates has been reported. This reaction provides a rare instance of catalytic difluoroalkylation through hydroarylation of gem-difluoroalkenes. The sulfonate group works as a chelating ligand, thus stabilizing the rhodacycle intermediate, leading to the uncommon transformation.


Grazing by large savanna herbivores indirectly alters ant diversity and promotes resource monopolisation.
In savannas, grazing is an important disturbance that modifies the grass layer structure and composition. Habitat structural complexity influences species diversity and assemblage functioning. By using a combination of natural sites and manipulated experiments, we explored how habitat structure (grazing lawns and adjacent bunch grass) affects ant diversity and foraging behaviour, specifically the efficiency of resource acquisition, resource monopolisation and ant body size. We found that in the natural sites there was no difference in the amount of time ants took to locate resources, but in the manipulated experiments, ants were faster at locating resources and were more abundant in the simple treatments than in the more complex treatments. Ant body size was only affected by the manipulated experiments, with smaller ants found in the more complex treatments. In both the grazing lawn and bunch grass habitats there were differences in assemblage patterns of ants discovering resources and those dominating them. Seasonality, which was predicted to affect the speed at which ants discovered resources and the intensity of resource monopolisation, also played a role. We show that ants in winter monopolised more baits and discovered resources at a slower rate, but only at certain times within the experiment. Grazing in conjunction with season thus had a significant effect on ant diversity and foraging behaviour, with dominant ants promoted where habitat complexity was simplified when temperatures were low. Our results indicate that structural complexity plays a major role in determining ant assemblage structure and function in African savannas.


Alternative oxidase dependent respiration leads to an increased mitochondrial content in two long-lived mutants of the aging model Podospora anserina.
The retrograde response constitutes an important signalling pathway from mitochondria to the nucleus which induces several genes to allow compensation of mitochondrial impairments. In the filamentous ascomycete Podospora anserina, an example for such a response is the induction of a nuclear-encoded and iron-dependent alternative oxidase (AOX) occurring when cytochrome-c oxidase (COX) dependent respiration is affected. Several long-lived mutants are known which predominantly or exclusively respire via AOX. Here we show that two AOX-utilising mutants, grisea and PaCox17::ble, are able to compensate partially for lowered OXPHOS efficiency resulting from AOX-dependent respiration by increasing mitochondrial content. At the physiological level this is demonstrated by an elevated oxygen consumption and increased heat production. However, in the two mutants, ATP levels do not reach WT levels. Interestingly, mutant PaCox17::ble is characterized by a highly increased release of the reactive oxygen species (ROS) hydrogen peroxide. Both grisea and PaCox17::ble contain elevated levels of mitochondrial proteins involved in quality control, i. e. LON protease and the molecular chaperone HSP60. Taken together, our work demonstrates that AOX-dependent respiration in two mutants of the ageing model P. anserina is linked to a novel mechanism involved in the retrograde response pathway, mitochondrial biogenesis, which might also play an important role for cellular maintenance in other organisms.


Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.
Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.


Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis.
Vascular endothelial growth factor (VEGF) binding to the kinase domain receptor (KDR/FLK1 or VEGFR-2) mediates vascularization and tumor-induced angiogenesis. Since there is evidence that KDR plays an important role in tumor angiogenesis, we sought to identify peptides able to block the VEGF-KDR interaction. A phage epitope library was screened by affinity for membrane-expressed KDR or for an anti-VEGF neutralizing monoclonal antibody. Both strategies led to the isolation of peptides binding KDR specifically, but those isolated by KDR binding tended to display lower reactivities. Of the synthetic peptides corresponding to selected clones tested to determine their inhibitory activity, ATWLPPR completely abolished VEGF binding to cell-displayed KDR. In vitro, this effect led to the inhibition of the VEGF-mediated proliferation of human vascular endothelial cells, in a dose-dependent and endothelial cell type-specific manner. Moreover, in vivo, ATWLPPR totally abolished VEGF-induced angiogenesis in a rabbit corneal model. Taken together, these data demonstrate that ATWLPPR is an effective antagonist of VEGF binding, and suggest that this peptide may be a potent inhibitor of tumor angiogenesis and metastasis.


Neuropsychological and quality of life outcomes 12 months after unilateral thalamic stimulation for essential tremor.
To evaluate the one year cognitive, mood state, and quality of life (QoL) outcomes of unilateral thalamic deep brain stimulation (DBS) for essential tremor (ET). 40 patients diagnosed with ET completed comprehensive neuropsychological assessments about one month before and three and 12 months after DBS electrode implantation. Data were subjected to multivariate analyses, and significant results were further analysed using univariate techniques. Analyses revealed statistically significant improvements on a cognitive screening measure and in aspects of fine visuomotor and visuoperceptual functions, verbal memory, mood state, and QoL. No group-wise declines in cognition were observed, but more patients showed declines than improvements on language and visual memory tests. Semantic verbal fluency declined significantly in four (10%) of the patients. In these four patients, diminished lexical verbal fluency was present at baseline. Cognitive, mood, and QoL outcomes after one year of DBS for ET are favourable; there were no overall deleterious effects on cognition, and DBS was accompanied by a significant reduction in anxiety and improvements in quality of life. However, preoperative verbal fluency diminution may predispose to further fluency declines after DBS.


A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy.
This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.


Multiple mechanisms promote the retained expression of gene duplicates in the tetraploid frog Xenopus laevis.
Gene duplication provides a window of opportunity for biological variants to persist under the protection of a co-expressed copy with similar or redundant function. Duplication catalyzes innovation (neofunctionalization), subfunction degeneration (subfunctionalization), and genetic buffering (redundancy), and the genetic survival of each paralog is triggered by mechanisms that add, compromise, or do not alter protein function. We tested the applicability of three types of mechanisms for promoting the retained expression of duplicated genes in 290 expressed paralogs of the tetraploid clawed frog, Xenopus laevis. Tests were based on explicit expectations concerning the ka/ks ratio, and the number and location of nonsynonymous substitutions after duplication. Functional constraints on the majority of paralogs are not significantly different from a singleton ortholog. However, we recover strong support that some of them have an asymmetric rate of nonsynonymous substitution: 6% match predictions of the neofunctionalization hypothesis in that (1) each paralog accumulated nonsynonymous substitutions at a significantly different rate and (2) the one that evolves faster has a higher ka/ks ratio than the other paralog and than a singleton ortholog. Fewer paralogs (3%) exhibit a complementary pattern of substitution at the protein level that is predicted by enhancement or degradation of different functional domains, and the remaining 13% have a higher average ka/ks ratio in both paralogs that is consistent with altered functional constraints, diversifying selection, or activity-reducing mutations after duplication. We estimate that these paralogs have been retained since they originated by genome duplication between 21 and 41 million years ago. Multiple mechanisms operate to promote the retained expression of duplicates in the same genome, in genes in the same functional class, over the same period of time following duplication, and sometimes in the same pair of paralogs. None of these paralogs are superfluous; degradation or enhancement of different protein subfunctions and neofunctionalization are plausible hypotheses for the retained expression of some of them. Evolution of most X. laevis paralogs, however, is consistent with retained expression via mechanisms that do not radically alter functional constraints, such as selection to preserve post-duplication stoichiometry or temporal, quantitative, or spatial subfunctionalization.


Memory through metamorphosis in normal and mutant Drosophila.
To establish that a stable, long-lasting form of memory exists in Drosophila, we trained third-instar larvae by electroshocking them in the presence of a specific odor using a Pavlovian conditioning procedure. We show that conditioned odor avoidance produced in larvae still was present in adults 8 d later. Such memory through metamorphosis was specific to the temporal pairing of odor and shock; presentations of odors alone or shock alone did not produce a change. Thus, the memory involved associative processes. We also show that similar training of the single-gene memory mutants dunce and amnesiac did not yield any detectable learning in larvae or memory retention in adults, suggesting that these mutations interfere with long-term memory (LTM) formation even if LTM is induced independently of earlier memory retention processes.


Help to go: T cells transfer CD40L to antigen-presenting B cells.
Most immune cell communication takes place by intercellular transfer of cytokines or the contact-dependent interaction of surface receptors in immunological synapses. In this issue of the European Journal of Immunology, Gardell and Parker (Eur. J. Immunol. 2017, 47, 41-50) point to a new, hybrid mechanism for Th1-cell delivery of help to B cells, based on contact-dependent CD40L transfer. The transfer process and its specificity are both cell contact dependent and antigen dependent. CD40 expression is also required on the B-cell surface to capture the CD40L presented by the Th1 cell. While further studies are needed to confirm the phenomenon in vivo and to test the role of transferred CD40L in other aspects of T-cell help, this study provides an exceptional take-off point and makes excellent use of mouse genetics to work out some possible rules for B cells being able to order help 'to go'.


The global portfolio of new antimalarial medicines under development.
With the elimination of malaria now considered a realistic goal, it would be useful for scientists and policy makers to have an inventory of the arsenal of antimalarials, current and prospective, that could help make this goal a reality. In order to provide an overview of antimalarial projects in recent clinical development, we review here the global portfolio of antimalarial drugs in clinical phases of development complemented by projects in the preclinical and early discovery phases. The portfolio is discussed in terms of the novelty of the new molecules and their potential health impact in terms of addressing the requirements for the control and eventual eradication of malaria.


Role of the carboxy terminus of herpes simplex virus type 1 DNA polymerase in its interaction with UL42.
Several recent reports implicate sequences at or near the C terminus of the catalytic subunit (POL) of herpes simplex virus type 1 (HSV-1) DNA polymerase in its interaction with the accessory protein UL42. We have investigated further the involvement of this region by three different approaches: anti-idiotype antibodies, a competition ELISA and inhibition of the interaction by peptides. Antibodies raised in rabbits to peptides corresponding to regions of POL all reacted in Western blots with POL. Surprisingly, the sera raised against C-terminal peptides (amino acids 1221 to 1235 and 1224 to 1235) also reacted with UL42. The UL42 reactivity was shown to be due to the presence of anti-idiotype antibodies, providing direct evidence for complementarity of the structure of the extreme C terminus of POL to a region of UL42. To measure the contribution of the C terminus of POL to UL42 binding we developed a competition ELISA using POL, a truncated polymerase lacking the carboxyl-terminal 27 amino acids (POLd1) and UL42. UL42 binding to immobilized POL was inhibited approximately four times more effectively by competition, in solution, with POL than with POLd1, indicating that the C-terminal 27 amino acids of POL are responsible for at least 75% of the binding energy. A peptide corresponding to these 27 amino acids (residues 1209 to 1235) inhibited both the POL-UL42 interaction and the stimulation of POL by UL42 and did so more effectively than peptides corresponding to amino acids just away from the C terminus (residues 1195 to 1223 and 1177 to 1195).


Agile, a guiding principle for health care improvement?
The purpose of this paper is to contribute to increased understanding of the concept agile and its potential for hospital managers to optimize design of organizational structures and processes to combine internal efficiency and external effectiveness. An integrative review was conducted using the reSEARCH database. Articles met the following criteria: first, a definition of agility; second, descriptions of enablers of becoming an agile organization; and finally, discussions of agile on multiple organizational levels. In total, 60 articles qualified for the final analysis. Organizational agility rests on the assumption that the environment is uncertain, ranging from frequently changing to highly unpredictable. Proactive, reactive or embracive coping strategies were described as possible ways to handle such uncertain environments. Five organizational capacities were derived as necessary for hospitals to use the strategies optimally: transparent and transient inter-organizational links; market sensitivity and customer focus; management by support for self-organizing employees; organic structures that are elastic and responsive; flexible human and resource capacity for timely delivery. Agile is portrayed as either the "new paradigm" following lean, the needed development on top of a lean base, or as complementary to lean in distinct hybrid strategies. Environmental uncertainty needs to be matched with coping strategies and organizational capacities to design processes responsive to real needs of health care. This implies that lean and agile can be combined to optimize the design of hospitals, to meet different variations in demand and create good patient management. While considerable value has been paid to strategies to improve the internal efficiency within hospitals, this review raise the attention to the value of strategies of external effectiveness.


Chronic Supplementation with a Mix of Salvia officinalis and Salvia lavandulaefolia Improves Morris Water Maze Learning in Normal Adult C57Bl/6J Mice.
Background: Two different species of sage, Salvia officinalis and Salvia lavandulaefolia, have demonstrated activities in cognitive function during preclinical and clinical studies related to impaired health situations or single administration. Different memory processes have been described to be significantly and positively impacted. Objective: Our objective is to explore the potential of these Salvia, and their additional activities, in healthy situations, and during prolonged administration, on memory and subsequent mechanisms of action related to putative effects. Design: This mouse study has implicated four investigational arms dedicated to control, Salvia officinalis aqueous extract, Salvia lavandulaefolia-encapsulated essential oil and a mix thereof (Cognivia™) for 2 weeks of administration. Cognitive functions have been assessed throughout Y-maze and Morris water maze models. The impact of supplementation on lipid peroxidation, oxidative stress, neurogenesis, neuronal activity, neurotrophins, neurotrophin receptors, CaM kinase II and glucocorticoid receptors has been assessed via post-interventional tissue collection. Results: All Salvia groups had a significant effect on Y-maze markers on day 1 of administration. Only the mix of two Salvia species demonstrated significant improvements in Morris water maze markers at the end of administration. Considering all biological and histological markers, we did not observe any significant effect of S. officinalis, S. lavandulaefolia and a mix of Salvia supplementation on lipid peroxidation, oxidative stress and neuronal plasticity (neurogenesis, neuronal activity, neurotrophins). Interestingly, CaM kinase II protein expression is significantly increased in animals supplemented with Salvia. Conclusion: The activities of Salvia alone after one intake have been confirmed; however, a particular combination of different types of Salvia have been shown to improve memory and present specific synergistic effects after chronic administration in healthy mice.


Presence of Short Intermolecular Contacts Screens for Kinetic Stability in Packing Polymorphs.
Polymorphism is pervasive in molecular solids. While computational predictions of the molecular polymorphic landscape have improved significantly, identifying which polymorphs are preferentially accessed and experimentally stable remains a challenge. We report a framework that correlates short intermolecular contacts with polymorphic stability. The presence of short contacts between neighboring molecules prevents structural rearrangement and stabilizes the packing arrangement, even when the stabilized polymorph is not enthalpically favored. In the absence of such intermolecular short contacts, the molecules have added degrees of freedom for structural rearrangement, and solid-solid polymorphic transformations occur readily. Starting with a series of core-halogenated naphthalene tetracarboxylic diimides, we establish this framework with the packing polymorphs of more than 20 compounds, ranging from molecular semiconductors to pharmaceutics and biological building blocks. This framework, widely applicable across molecular solids, can help refine computational predictions by identifying the polymorphs that are kinetically stable.


Gas adsorption efficacy of graphene sheets functionalised with carboxyl, hydroxyl and epoxy groups in conjunction with Stone-Thrower-Wales (STW) and inverse Stone-Thrower-Wales (ISTW) defects.
The complete reduction of graphene oxide is difficult to achieve, and hence oxygen-containing functional groups do exist in graphene, along with structural defects. On the other hand, efficient gas sensor materials have been a subject of relentless interest. This instigates the need to explore the gas adsorption on STW and ISTW defective graphene sheets functionalised by -COOH, -OH and C-O-C groups, using density functional theory calculations. Both defects are experimentally feasible as evident through their formation energies. Furthermore mono-functionalisation induces significant buckling of the sheet; in contrast, bi-functionalisation of the sheet restores the planarity of the sheet. We found that the ISTW defective sheet is more reactive than the STW defective sheet to all the functional groups considered, and in particular -COOH is the most adsorptive group to both the defects, while epoxy has consistent adsorptivity towards the defects. Gas molecules such as CO2, H2, N2, CH4 and O2 are physisorbed, whereas HF and H2O are chemisorbed on the functionalised sheets. The sensitivity of the gas molecules towards the functionalised sheets is obtained by ΔEg, which is pronounced for pristine + OH and STW + epoxy and bare ISTW defective sheets. However, the functionalised sheets exhibit improved sensing properties for O2; specifically, mono-epoxy functionalised and bi-carboxylated defective sheets show high sensitivity towards O2. Furthermore, the surface functionalisation enhances the selectivity of the sensor. From the TDOS plot, the functionalised sheet exhibits p-type behaviour. Thus, the results of this study reveal that the functionalised defective sheets can be utilized as O2 sensors.


Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial.
Tumor patients exhibit an increased peripheral demand of fatty acids and protein. Contrarily, tumors utilize glucose as their main source of energy supply. Thus, a diet supplying the cancer patient with sufficient fat and protein for his demands while restricting the carbohydrates (CHO) tumors thrive on, could be a helpful strategy in improving the patients' situation. A ketogenic diet (KD) fulfills these requirements. Therefore, we performed a pilot study to investigate the feasibility of a KD and its influence on the quality of life of patients with advanced metastatic tumors. Sixteen patients with advanced metastatic tumors and no conventional therapeutic options participated in the study. The patients were instructed to follow a KD (less than 70 g CHO per day) with normal groceries and were provided with a supply of food additives to mix a protein/fat shake to simplify the 3-month intervention period. Quality of life [assessed by EORTC QLQ-C30 (version 2)], serum and general health parameters were determined at baseline, after every two weeks of follow-up, or after drop out. The effect of dietary change on metabolism was monitored daily by measuring urinary ketone bodies. One patient did not tolerate the diet and dropped out within 3 days. Among those who tolerated the diet, two patients died early, one stopped after 2 weeks due to personal reasons, one felt unable to stick to the diet after 4 weeks, one stopped after 6 and two stopped after 7 and 8 weeks due to progress of the disease, one had to discontinue after 6 weeks to resume chemotherapy and five completed the 3 month intervention period. These five and the one who resumed chemotherapy after 6 weeks report an improved emotional functioning and less insomnia, while several other parameters of quality of life remained stable or worsened, reflecting their very advanced disease. Except for temporary constipation and fatigue, we found no severe adverse side effects, especially no changes in cholesterol or blood lipids. These pilot data suggest that a KD is suitable for even advanced cancer patients. It has no severe side effects and might improve aspects of quality of life and blood parameters in some patients with advanced metastatic tumors.


Improvement of myocardial ischemic dysfunction with dichloroacetic acid: experimental study by repeated ischemia in dogs.
We investigated metabolic factors related to the recovery of myocardial function during ischemia and after reperfusion using dichloroacetic acid (DCA) in canine models with repeated 10-min regional ischemia and reperfusion. Administration of 100 mg/kg DCA, which activates pyruvate dehydrogenase, improved regional wall motion significantly as compared with the nontreated controls (p < 0.05). The mechanism was studied by determining changes in myocardial levels of pH, glucose, lactate, and nonesterified fatty acids (NEFA). Glucose extraction was increased significantly during ischemia and reperfusion by the pretreatment of DCA (p < 0.01). the calculated contribution of glucose to myocardial oxidative metabolism during ischemia and reperfusion was greater than that of NEFA and lactate in case of DCA treatment. The uptake of [99mTc]pyrophosphate (PYP), which reflects myocardial injury, was also significantly suppressed by DCA (p < 0.01). pH was not affected by an infusion of DCA. These findings suggest that the activation of glucose metabolism by DCA, which is impaired and reduced during ischemia and reperfusion, may be responsible for the improved myocardial function after reperfusion.


Cardiovascular Risk Factors and Ethnicity Are Independent Factors Associated with Lower Urinary Tract Symptoms.
To determine the lower urinary tract symptoms (LUTS) profile and factors affecting its degree of severity including cardiovascular risk profile, age, ethnicity, education level and prostate volume in a multiethnic Asian setting. We conducted a cross-sectional study of 1021 men aged 40-79 years with no clinical evidence of prostate cancer, prostate surgery or 5α-reductase inhibitor treatment of known prostate conditions. The severity of LUTS was assessed using the International Prostate Symptom Score (IPSS). Potential factors associated with LUTS including age, ethnicity, education, history of hypertension, diabetes and hypercholesterolemia, height, weight, and prostate volume were evaluated using univariable and multivariable analyses. There were 506 (50%) men found to have moderate-to-severe LUTS attaining an IPSS above 7. Overall, nocturia (45.5%) was the most frequently reported symptom. Multivariable analysis showed that age, ethnicity, prostate volume and history of hypertension and hypercholesterolemia were independent factors associated with severity of LUTS (p < 0.05). Considering individual lower urinary tract symptoms, we found a strong association of storage symptom with history of hypertension and hypercholesterolemia. Malay men were significantly bothered by post micturition symptom compared to their Chinese and Indian counterparts. Stratified analyses of LUTS demonstrated a mutually exclusive cardiovascular risk factors profile defined by ethnicity. Severity of LUTS varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity and cardiovascular risk factors including hypertension and hypercholesterolemia may also need to be taken into account in managing men with LUTS.


Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and β-catenin interactions.
Dysregulation of canonical Wnt signaling is thought to play a role in colon carcinogenesis. β-Catenin, a key mediator of the pathway, is stabilized upon Wnt activation and accumulates in the nucleus, where it can interact with the transcription factor T cell factor (TCF) to transactivate gene expression. Normal colonic epithelia express a truncated TCF-1 form, called dnTCF-1, that lacks the critical β-catenin-binding domain and behaves as a transcriptional suppressor. How the cell maintains a balance between the two forms of TCF-1 is unclear. Here, we show that ERM-binding phosphoprotein 50 (EBP50) modulates the interaction between β-catenin and TCF-1. We observed EBP50 localization to the nucleus of human colorectal carcinoma cell lines at low cell culture densities and human primary colorectal tumors that manifested a poor clinical outcome. In contrast, EBP50 was primarily membranous in confluent cell lines. Aberrantly located EBP50 stabilized conventional β-catenin/TCF-1 complexes and connected β-catenin to dnTCF-1 to form a ternary molecular complex that enhanced Wnt/β-catenin signaling events, including the transcription of downstream oncogenes such as c-Myc and cyclin D1. Genome-wide analysis of the EBP50 occupancy pattern revealed consensus binding motifs bearing similarity to Wnt-responsive element. Conventional chromatin immunoprecipitation assays confirmed that EBP50 bound to genomic regions highly enriched with TCF/LEF binding motifs. Knockdown of EBP50 in human colorectal carcinoma cell lines compromised cell cycle progression, anchorage-independent growth, and tumorigenesis in nude mice. We therefore suggest that nuclear EBP50 facilitates colon tumorigenesis by modulating the interaction between β-catenin and TCF-1.


Anti-angiogenic and anti-inflammatory properties of kahweol, a coffee diterpene.
Epidemiological studies have shown that unfiltered coffee consumption is associated with a low incidence of cancer. This study aims to identify the effects of kahweol, an antioxidant diterpene contained in unfiltered coffee, on angiogenesis and key inflammatory molecules. The experimental procedures included in vivo angiogenesis assays (both the chicken and quail choriallantoic membrane assay and the angiogenesis assay with fluorescent zebrafish), the ex vivo mouse aortic ring assay and the in vitro analysis of the effects of treatment of human endothelial cells with kahweol in cell growth, cell viability, cell migration and zymographic assays, as well as the tube formation assay on Matrigel. Additionally, two inflammation markers were determined, namely, the expression levels of cyclooxygenase 2 and the levels of secreted monocyte chemoattractant protein-1. We show for the first time that kahweol is an anti-angiogenic compound with inhibitory effects in two in vivo and one ex vivo angiogenesis models, with effects on specific steps of the angiogenic process: endothelial cell proliferation, migration, invasion and tube formation on Matrigel. We also demonstrate the inhibitory effect of kahweol on the endothelial cell potential to remodel extracellular matrix by targeting two key molecules involved in the process, MMP-2 and uPA. Finally, the anti-inflammatory potential of this compound is demonstrated by its inhibition of both COX-2 expression and MCP-1 secretion in endothelial cells. Taken together, our data indicate that, indeed, kahweol behaves as an anti-inflammatory and anti-angiogenic compound with potential use in antitumoral therapies. These data may contribute to the explanation of the reported antitumoral effects of kahweol, including the recent epidemiological meta-analysis showing that drinking coffee could decrease the risk of certain cancers.


Repitools: an R package for the analysis of enrichment-based epigenomic data.
Epigenetics, the study of heritable somatic phenotypic changes not related to DNA sequence, has emerged as a critical component of the landscape of gene regulation. The epigenetic layers, such as DNA methylation, histone modifications and nuclear architecture are now being extensively studied in many cell types and disease settings. Few software tools exist to summarize and interpret these datasets. We have created a toolbox of procedures to interrogate and visualize epigenomic data (both array- and sequencing-based) and make available a software package for the cross-platform R language. The package is freely available under LGPL from the R-Forge web site (http://repitools.r-forge.r-project.org/) firstname.lastname@example.com.


[P4H]+[Al(OTeF5)4]-: protonation of white phosphorus with the Brønsted superacid H[Al(OTeF5)4](solv).
A sustainable transformation of white phosphorus (P4) into chemicals of higher value is one of the key aspects in modern phosphorus research. Even though the chemistry of P4 has been investigated for many decades, its chemical reactivity towards the simplest electrophile, the proton, is still virtually unknown. Based on quantum-chemical predictions, we report for the first time the successful protonation of P4 by the Brønsted acid H[Al(OTeF5)4](solv). Our spectroscopic results are in agreement with acid-mediated activation of P4 under protonation of an edge of the P4-tetrahedron and formation of a three-center two-electron P-H-P bond. These investigations are of fundamental interest as they permit the activation of P4 with the simplest electrophile as a new prototype reaction for this molecule.


Prenatal loud music and noise: differential impact on physiological arousal, hippocampal synaptogenesis and spatial behavior in one day-old chicks.
Prenatal auditory stimulation in chicks with species-specific sound and music at 65 dB facilitates spatial orientation and learning and is associated with significant morphological and biochemical changes in the hippocampus and brainstem auditory nuclei. Increased noradrenaline level due to physiological arousal is suggested as a possible mediator for the observed beneficial effects following patterned and rhythmic sound exposure. However, studies regarding the effects of prenatal high decibel sound (110 dB; music and noise) exposure on the plasma noradrenaline level, synaptic protein expression in the hippocampus and spatial behavior of neonatal chicks remained unexplored. Here, we report that high decibel music stimulation moderately increases plasma noradrenaline level and positively modulates spatial orientation, learning and memory of one day-old chicks. In contrast, noise at the same sound pressure level results in excessive increase of plasma noradrenaline level and impairs the spatial behavior. Further, to assess the changes at the molecular level, we have quantified the expression of functional synapse markers: synaptophysin and PSD-95 in the hippocampus. Compared to the controls, both proteins show significantly increased expressions in the music stimulated group but decrease in expressions in the noise group. We propose that the differential increase of plasma noradrenaline level and altered expression of synaptic proteins in the hippocampus are responsible for the observed behavioral consequences following prenatal 110 dB music and noise stimulation.


Factors influencing suicidal attempt among the agrarian community of central Maharashtra.
Attempted suicides occur 8-20 times more frequently than completed suicides. Attempted suicides are just the tip of the iceberg of the completed suicides, now a universal phenomenon. Several factors such as financial constraints, altercation among family members, and easy availability of pesticides have been attributed as the common factors for attempted suicide among the rural population. On this background, we evaluated all the cases of attempted suicide admitted to our rural medical college during a period of 1 year. Details of sociodemographic profile, mode of attempt, and reason for the attempt were evaluated. All the cases were administered Beck's Depression Inventory. Factors influencing suicidal attempts among farmers and nonfarmers were analyzed using suitable statistical methods. Out of a total of 117 cases of attempted suicide, only 21% of the cases were farmers. Majority of them were males and were married. The main mode of attempt was poisoning. The common psychiatric diagnosis was adjustment disorder followed by depressive disorder. Although the study was conducted in a rural setup from an agrarian background, the majority of the cases were of nonfarmer. The most common mode of suicidal attempt among farmers as well as nonfarmers was pesticide ingestion owing to its easy availability among the agrarian population. Although the most common reason for attempt among the nonfarmer population was interpersonal problems, indebtedness still remains the most common reason for farmers. Attention of policymakers is drawn toward two important aspects: policy on the sale of usual pesticides and policy for the farmers to overcome loss in farming.


Perceived stress scores among Saudi students entering universities: a prospective study during the first year of university life.
In this prospective study we wanted to determine whether perceived stress over time among students in the Preparatory Year of King Saud University (KSU) predisposes them to cardiometabolic abnormalities. A total of 110 apparently healthy Saudi students (35 men and 75 women enrolled during the 2010-2011 academic year) were included. Perceived stress was determined at baseline and 1 year later. Anthropometrics were obtained and morning fasting serum glucose, lipid profile and cortisol were measured at both times. Perceived stress was noted among 48.2% of subjects at baseline and was not significantly different after follow-up, with 45.4% scoring high. In men, the prevalence of perceived stress was 48.6% at baseline (13 out of 35) and 37.1% at follow-up (13 out of 35), while in women it was 48% at baseline and 49.3% at follow-up. Interestingly, significant improvements in the blood pressure and lipid profiles, with the exception of HDL-cholesterol, were observed in both men and women, while fasting glucose also improved in women. Serum cortisol was inversely associated to fasting glucose, and total- and LDL-cholesterol (p-values 0.007, 0.04 and 0.04, respectively). These data are opposite to findings in students entering Western universities, in whom increasing stress and a deteriorating cardiometabolic profile have been repeatedly noted. Perceived stress and morning cortisol levels among students of the Preparatory Year in KSU remained constant for both genders over time, yet an improved cardiometabolic profile was observed, suggesting good adaptation among our pre-college students in their first year of university life.


Assessing the Impact of Airborne Outreach to Build Clinical Capacity in Rural Botswana.
There is a paucity of research demonstrating how best to address inequalities in health and access to specialist care faced by rural disadvantaged populations in high HIV-prevalent settings in Sub Saharan Africa. Delivering equitable and cost-effective specialist clinical services in many parts of Africa is challenging, given human resource shortages, poor transport infrastructure and competing health priorities. In this report we describe how an airborne outreach program to provide HIV services to high HIV burden health facilities in rural Botswana has been an important catalyst for improving specialist service delivery across the spectrum of clinical care. The success of Botswana's airborne program is a consequence of many country-specific determinants as well as external funding support. We argue that lessons learned from the experience in Botswana are normative for other African settings. Specialist medical airborne outreach to rural hospitals can improve access to and quality of care, when part of a multifaceted, multidisciplinary intervention. Furthermore, we demonstrate how an HIV funded program can be a vehicle for enhanced access to essential sub-specialist clinicians in rural Botswana.


Predicting and Experimentally Validating Hot-Spot Residues at Protein-Protein Interfaces.
Protein-protein interactions (PPIs) are vital to all biological processes. These interactions are often dynamic, sometimes transient, typically occur over large topographically shallow protein surfaces, and can exhibit a broad range of affinities. Considerable progress has been made in determining PPI structures. However, given the above properties, understanding the key determinants of their thermodynamic stability remains a challenge in chemical biology. An improved ability to identify and engineer PPIs would advance understanding of biological mechanisms and mutant phenotypes and also provide a firmer foundation for inhibitor design. In silico prediction of PPI hot-spot amino acids using computational alanine scanning (CAS) offers a rapid approach for predicting key residues that drive protein-protein association. This can be applied to all known PPI structures; however there is a trade-off between throughput and accuracy. Here we describe a comparative analysis of multiple CAS methods, which highlights effective approaches to improve the accuracy of predicting hot-spot residues. Alongside this, we introduce a new method, BUDE Alanine Scanning, which can be applied to single structures from crystallography and to structural ensembles from NMR or molecular dynamics data. The comparative analyses facilitate accurate prediction of hot-spots that we validate experimentally with three diverse targets: NOXA-B/MCL-1 (an α-helix-mediated PPI), SIMS/SUMO, and GKAP/SHANK-PDZ (both β-strand-mediated interactions). Finally, the approach is applied to the accurate prediction of hot-spot residues at a topographically novel Affimer/BCL-xL protein-protein interface.


[An index of HIV infection risk in the population].
The paper presents a risk index constructed on the basis of some sexual behaviour-related variables. It is intended for measuring the risk of exposure to HIV infection for the general population. Variables are from a study on Lifestyle and Health conducted on a sample of the population living in the London, Edinburgh, and Glasgow metropolitan area by the Research Unit in Health and Behavioural Change at the Edinburgh University. The construction of the index has been realized through a delphi study which has collected information from a panel of AIDS national experts. Methodological problems in summarising information coming from several variables are discussed. The main task of the study is not to provide a total prediction of HIV infection in the population of Britain, but to assess the component which may stem from sexual behaviours when estimated from self-reports. Major findings are the consistency of the population in the "medium risk" group, that, if a spread of AIDS among the heterosexual population can be hypothesized, gives a rather pessimist scenario. Moreover, a trend analysis (possible because of the continuity in the data collection) shows an increase in this "medium risk" group, although the "high risk" group appears much less consistent (less than two percent) and slowly declining over time.


Assessing the Impact of a Social Marketing Campaign on Program Outcomes for Users of an Internet-Based Testing Service for Sexually Transmitted and Blood-Borne Infections: Observational Study.
While social marketing (SM) campaigns can be effective in increasing testing for sexually transmitted and blood-borne infections (STBBIs), they are seldom rigorously evaluated and often rely on process measures (eg, Web-based ad click-throughs). With Web-based campaigns for internet-based health services, there is a potential to connect campaign process measures to program outcomes, permitting the assessment of venue-specific yield based on health outcomes (eg, click-throughs per test). This study aims to evaluate the impact of an SM campaign by the promotional venue on use and diagnostic test results of the internet-based STBBI testing service GetCheckedOnline.com (GCO). Through GCO, clients create an account using an access code, complete a risk assessment, print a lab form, submit specimens at a lab, and get results online or by phone. From April to August 2015, a campaign promoted GCO to gay, bisexual, and other men who have sex with men in Vancouver, Canada. The campaign highlighted GCO's convenience in 3 types of promotional venues-location advertisements in print or video displayed in gay venues or events, ads on a queer news website, and ads on geosocial websites and apps. Where feasible, individuals were tracked from campaign exposures to account creation and testing using venue-specific GCO access codes. In addition, Web-based ads were linked to alternate versions of the campaign website, which used URLs with embedded access codes to connect ad exposure to account creation. Furthermore, we examined the number of individuals creating GCO accounts, number tested, and cost per account created and test for each venue type. Over 6 months, 177 people created a GCO account because of the campaign, where 22.0% (39/177) of these completed testing; the overall cost was Can $118 per account created and Can $533 per test. Ads on geosocial websites and apps accounted for 46.9% (83/177) of all accounts; ads on the news website had the lowest testing rate and highest cost per test. We observed variation between different geosocial websites and apps with some ads having high click-through rates yet low GCO account creation rates, and vice versa. Developing mechanisms to track individuals from Web-based exposure to SM campaigns to outcomes of internet-based health services permits greater evaluation of the yield and cost-effectiveness of different promotional efforts. Web-based ads with high click-through rates may not have a high conversion to service use, the ultimate outcome of SM campaigns.


Controlled growth of CH3NH3PbI3 nanowires in arrays of open nanofluidic channels.
Spatial positioning of nanocrystal building blocks on a solid surface is a prerequisite for assembling individual nanoparticles into functional devices. Here, we report on the graphoepitaxial liquid-solid growth of nanowires of the photovoltaic compound CH3NH3PbI3 in open nanofluidic channels. The guided growth, visualized in real-time with a simple optical microscope, undergoes through a metastable solvatomorph formation in polar aprotic solvents. The presently discovered crystallization leads to the fabrication of mm(2)-sized surfaces composed of perovskite nanowires having controlled sizes, cross-sectional shapes, aspect ratios and orientation which have not been achieved thus far by other deposition methods. The automation of this general strategy paves the way towards fabrication of wafer-scale perovskite nanowire thin films well-suited for various optoelectronic devices, e.g. solar cells, lasers, light-emitting diodes and photodetectors.


PEAR: PEriodic And fixed Rank separation for fast fMRI.
In functional MRI (fMRI), faster acquisition via undersampling of data can improve the spatial-temporal resolution trade-off and increase statistical robustness through increased degrees-of-freedom. High-quality reconstruction of fMRI data from undersampled measurements requires proper modeling of the data. We present an fMRI reconstruction approach based on modeling the fMRI signal as a sum of periodic and fixed rank components, for improved reconstruction from undersampled measurements. The proposed approach decomposes the fMRI signal into a component which has a fixed rank and a component consisting of a sum of periodic signals which is sparse in the temporal Fourier domain. Data reconstruction is performed by solving a constrained problem that enforces a fixed, moderate rank on one of the components, and a limited number of temporal frequencies on the other. Our approach is coined PEAR - PEriodic And fixed Rank separation for fast fMRI. Experimental results include purely synthetic simulation, a simulation with real timecourses and retrospective undersampling of a real fMRI dataset. Evaluation was performed both quantitatively and visually versus ground truth, comparing PEAR to two additional recent methods for fMRI reconstruction from undersampled measurements. Results demonstrate PEAR's improvement in estimating the timecourses and activation maps versus the methods compared against at acceleration ratios of R = 8,10.66 (for simulated data) and R = 6.66,10 (for real data). This paper presents PEAR, an undersampled fMRI reconstruction approach based on decomposing the fMRI signal to periodic and fixed rank components. PEAR results in reconstruction with higher fidelity than when using a fixed-rank based model or a conventional Low-rank + Sparse algorithm. We have shown that splitting the functional information between the components leads to better modeling of fMRI, over state-of-the-art methods.


Chili Intake Is Inversely Associated with Chronic Kidney Disease among Adults: A Population-Based Study.
We aimed to assess the association between chili consumption and kidney function and chronic kidney disease (CKD). Data from 8429 adults attending the China Health and Nutrition Survey were used. Chili intake was assessed using a 3 day, 24 h food record in combination with household food inventory between 1991 and 2009. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, as measured in 2009. Logistic regression was used to assess the association. Of the 8429 participants, 1008 (12.0%) fit the definition of CKD. The prevalence of CKD was 13.1% in non-consumers of chili and 7.4% among those with chili intake above 50 g/day. After adjusting for demographics, lifestyle factors (i.e., smoking, alcohol drinking, physical activity), dietary patterns, and chronic conditions, the odds ratio (OR) (95% CI) for CKD across chili consumption levels of none, 1-20 g/day, 20.1-50 g/day, ≥50.1 g/day were 1.00 (reference), 0.82 (0.67-1.01), 0.83 (0.65-1.05), and 0.51 (0.35-0.75), respectively (p for trend 0.001). There was no interaction between chili intake with gender, income, urbanization, hypertension, obesity, or diabetes. This longitudinal large population-based study suggests that chili consumption is inversely associated with CKD, independent of lifestyle, hypertension, obesity, and overall dietary patterns.


Family Caregiving for Individuals With Heart Failure: A Scientific Statement From the American Heart Association.
Many individuals living with heart failure (HF) rely on unpaid support from their partners, family members, friends, or neighbors as caregivers to help manage their chronic disease. Given the advancements in treatments and devices for patients with HF, caregiving responsibilities have expanded in recent decades to include more intensive care for increasingly precarious patients with HF-tasks that would previously have been undertaken by healthcare professionals in clinical settings. The specific tasks of caregivers of patients with HF vary widely based on the patient's symptoms and comorbidities, the relationship between patient and caregiver, and the complexity of the treatment regimen. Effects of caregiving on the caregiver and patient range from physical and psychological to financial. Therefore, it is critically important to understand the needs of caregivers to support the increasingly complex medical care they provide to patients living with HF. This scientific statement synthesizes the evidence pertaining to caregiving of adult individuals with HF in order to (1) characterize the HF caregiving role and how it changes with illness trajectory; (2) describe the financial, health, and well-being implications of caregiving in HF; (3) evaluate HF caregiving interventions to support caregiver and patient outcomes; (4) summarize existing policies and resources that support HF caregivers; and (5) identify knowledge gaps and future directions for providers, investigators, health systems, and policymakers.


Interferometric alignment using parabolic and off-axis conical zone plates.
The use of zone plates in optical alignment and displacement measurement is discussed. A simple theory of positioning using two coherent wavefronts is proposed. A few examples, already described in the literature as well as new ones, are presented as an illustration of the theory. The application of the specific case of the offaxis cylindrical zone plate (so-called parabolic zone plate) and off-axis conical zone plate for sensing the motion along a straight line parallel and inclined to the hologram plane is established. There are also adduced results of simple experiments supporting the analysis.


Dispersion of the HIV-1 Epidemic in Men Who Have Sex with Men in the Netherlands: A Combined Mathematical Model and Phylogenetic Analysis.
The HIV-1 subtype B epidemic amongst men who have sex with men (MSM) is resurgent in many countries despite the widespread use of effective combination antiretroviral therapy (cART). In this combined mathematical and phylogenetic study of observational data, we aimed to find out the extent to which the resurgent epidemic is the result of newly introduced strains or of growth of already circulating strains. As of November 2011, the ATHENA observational HIV cohort of all patients in care in the Netherlands since 1996 included HIV-1 subtype B polymerase sequences from 5,852 patients. Patients who were diagnosed between 1981 and 1995 were included in the cohort if they were still alive in 1996. The ten most similar sequences to each ATHENA sequence were selected from the Los Alamos HIV Sequence Database, and a phylogenetic tree was created of a total of 8,320 sequences. Large transmission clusters that included ≥10 ATHENA sequences were selected, with a local support value ≥ 0.9 and median pairwise patristic distance below the fifth percentile of distances in the whole tree. Time-varying reproduction numbers of the large MSM-majority clusters were estimated through mathematical modeling. We identified 106 large transmission clusters, including 3,061 (52%) ATHENA and 652 Los Alamos sequences. Half of the HIV sequences from MSM registered in the cohort in the Netherlands (2,128 of 4,288) were included in 91 large MSM-majority clusters. Strikingly, at least 54 (59%) of these 91 MSM-majority clusters were already circulating before 1996, when cART was introduced, and have persisted to the present. Overall, 1,226 (35%) of the 3,460 diagnoses among MSM since 1996 were found in these 54 long-standing clusters. The reproduction numbers of all large MSM-majority clusters were around the epidemic threshold value of one over the whole study period. A tendency towards higher numbers was visible in recent years, especially in the more recently introduced clusters. The mean age of MSM at diagnosis increased by 0.45 years/year within clusters, but new clusters appeared with lower mean age. Major strengths of this study are the high proportion of HIV-positive MSM with a sequence in this study and the combined application of phylogenetic and modeling approaches. Main limitations are the assumption that the sampled population is representative of the overall HIV-positive population and the assumption that the diagnosis interval distribution is similar between clusters. The resurgent HIV epidemic amongst MSM in the Netherlands is driven by several large, persistent, self-sustaining, and, in many cases, growing sub-epidemics shifting towards new generations of MSM. Many of the sub-epidemics have been present since the early epidemic, to which new sub-epidemics are being added.


They produce the sperm, but whose is it?: The 11 Biology of Spermatozoa Meeting September 5-9, 2011-Derbyshire UK.
Sperm biology pervades numerous research areas from clinical research to evolutionary biology and animal conservation. Integrating these fields for a better understanding of each is one of the main goals of the Biology of Spermatozoa meeting, a conference held biennially outside of Sheffield in the United Kingdom. This September, at the 11th meeting, scientists from around the globe presented their ongoing research on numerous aspects of reproductive biology, from assisted reproduction in humans and animal conservation through stem cell research and proteomics to sophisticated evolutionary adaptations of ejaculates and female reproductive traits in order to bias paternity toward one or the other male in situations of female promiscuity. Throughout the conference, ethical controversies with reproductive applications (e.g., sperm banking) found their place just as much as novel clinical technologies (e.g., sperm quality assays) or major advances in understanding the mechanisms underlying fundamental processes of postcopulatory sexual selection (e.g., using transgenic animals that produce fluorescently labeled sperm). Across a wide range of different taxa, this meeting has presented a fascinating synthesis of current research and emerging directions in the study of sperm biology.


Regional vascular capacitance in rabbit one-kidney, one clip hypertension.
One-kidney Goldblatt hypertensive rabbits (New Zealand White) were studied after durations of renal artery clipping that varied from 6 to 17 days. Measurements included arterial pressure (ABP), iliac venous pressure (IVP), left atrial pressure (LAP), cardiac output (CO) (by thermodilution), blood volume (BV), cardiopulmonary volume (CPV), and hindleg thermodilution volume (HLV). These were determined at steady-state as well as during acute blood volume expansion. In sham-clipped animals, ABP was 74 +/- 1 mm Hg. This increased to 92 +/- 3 mm Hg by 6 to 9 days post-clipping, to 96 +/- 3 mm Hg by 10 to 13 days, to 89 +/- 4 mm Hg by 14 to 17 days. CO remained near 150 ml/min . kg until Day 13 and fell to 127 +/- 8 ml/min . kg at 14 to 17 days because of a fall in heart rate. Blood volume and stroke volume did not change significantly from 62 +/- 1 ml/kg and 0.60 +/- 0.04 ml/kg, respectively. The development of hypertension was due entirely to changes in peripheral resistance. CPV was 8.5 ml/kg initially and increased significantly as hypertension developed. HLV did not change significantly from about 10 ml/kg. During acute blood volume expansion, hypertensive animals showed smaller transient increases in CO than did sham-clipped normotensives, but the associated blood pressure rise was greater. This reduced vasodilator capacity was accompanied by reduced distensibility of the cardiopulmonary bed. In sham-clipped animals, the cardiopulmonary pressure/volume slope was between 0.05 and 0.07 mm Hg per ml/kg. This increased to 0.44 mm Hg per ml/kg by 14--17 days of clipping. The corresponding value for the hindleg region did not change significantly from 0.2 mm Hg per ml/kg. Cardiac output and stroke volume were directly correlated with cardiopulmonary volume. The slope of this correlation decreased significantly during hypertension. The data suggest that decreased cardiopulmonary compliance in hypertension minimizes transient changes in cardiac output. This is especially important for arterial blood pressure control in view of the impaired vasodilator capacity of the hypertensive circulation.


Global Problem of Hospital Detention Practices.
Although an official definition by the World Health Organization (WHO) or any other authority is currently lacking, hospital detention practices (HDP) can be described as: "refusing release of either living patients after medical discharge is clinically indicated or refusing release of bodies of deceased patients if families are unable to pay their hospital bills." Reports of HDP are very scarce and lack consistent terminology. Consequently, the problem's scale is unknown. This study aimed to find evidence of HDP worldwide, explore characteristics of HDP reports, and compare countries with or without reports. PubMed and Google were examined for relevant English, Spanish, and French publications up to January 2019. Of 195 countries, HDP reports were found in 46 countries (24%) in Africa, Asia, South-America, Europe, and North-America. Most reports were published by journalists in newspapers. In most countries reports concern living adults and children who are imprisoned in public hospitals. A majority (52%) of reports were of individuals detained for at least a month. Almost all countries, with or without HDP reports, have signed the Universal Declaration of Human Rights. Countries with reported HDP have larger population size (P<.001), worse Corruption Perception Index score (P=.025), higher out-of-pocket expenditure (P=.024), lower Universal Health Coverage Index score (P=.015), and worse Press Freedom Index score (P=.012). We conclude that HDP are more widespread than currently acknowledged. Urgent intervention by stakeholders is required to stop HDP.


An Integrated Downstream Process Development Strategy along QbD Principles.
The development, optimization, and analysis of downstream processes are challenged by a high number of potentially critical process parameters that need to be investigated using lab-scale experiments. These process parameters are spread across multiple unit operations and potentially show interactions across unit operations. In this contribution, we present a novel strategy for bioprocess development that considers the risk of parameter interactions across unit operations for efficient experimental design. A novel risk assessment tool (interaction matrix) is introduced to the Quality by Design (QbD) workflow. Using this tool, the risk of interaction across unit operations is rated. Subsequently, a design of experiments (DoE) across unit operations is conducted that has the power to reveal multivariate interdependencies. The power of the presented strategy is demonstrated for protein isolation steps of an inclusion body process, focusing on the quality attribute inclusion body purity. The concentration of Triton X-100 in the course of inclusion body (IB) purification was shown to interact with the g-number of the subsequent centrifugation step. The presented strategy targets a holistic view on the process and allows handling of a high number of experimental parameters across unit operations using minimal experimental effort. It is generically applicable for process development along QbD principles.


A role for the subthalamic nucleus in response inhibition during conflict.
The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15-35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials--in which response times were elongated due to the Stroop effect--a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved.