Quantum versus classical Monte Carlo simulation of low-energy electron transport in condensed amorphous media.
Classical trajectory Monte Carlo (MC) simulations modelling radiation-induced damage on subcellular length scales ignore quantum effects that may be non-negligible as electron energy decreases below 1 keV. This work investigates quantum mechanical (QM) treatments of low-energy electron transport in condensed media, comparing with classical MC. QM calculations involve a simplified model of electron transport in water with a plane wave incident on a cylinder ("droplet") consisting of a cluster of point scatterers (positioned randomly but constrained by a minimum separation, dmin). The system of coupled equations for the electron wavefield incident on each scatterer is solved numerically and results are averaged over many clusters with different point scatterer positions. Average QM cluster cross sections and scattering event densities are compared with analogues computed within the corresponding classical MC model, and relative errors on MC results are calculated. Differences between QM and MC results for both cluster cross section and scattering event density are sensitive to electron energy (wavelength), structure (dmin), and single-scatterer elastic/inelastic cross sections. Relative errors on cluster cross sections generally differ from errors on scattering event densities. The introduction of inelastic scatter generally increases relative errors (compared to calculations with the same single-scatterer elastic cross section) with some exceptions. Accounting for structure (dmin≠0) enhances differences between QM and MC results. The quantum wave nature of electrons is non-negligible for simulations of low-energy electron transport within small-scale biological targets. The development of more realistic models of electron transport in condensed media is motivated for future work.


The human sebocyte culture model provides new insights into development and management of seborrhoea and acne.
Seborrhoea and acne are exclusively human diseases and sebaceous gland differentiation is species specific. Therefore, fundamental research on human sebaceous cell function and control requires human in vitro models. The human sebocyte culture model, introduced in 1989, has been used in several studies to elucidate sebaceous gland activity and its regulation at the cellular level. Cultured human sebocytes have been shown to preserve important sebocytic characteristics, although they undergo an incomplete terminal differentiation in vitro. In vitro synthesis of free fatty acids without bacterial involvement and marked interleukin 1 alpha expression at the mRNA and protein levels with no further induction by lipopolysaccharides lead to the assumption that human sebocytes may initiate acne lesions by an intrinsic mechanism. Androgens affected sebocyte activity in vitro in a manner dependent on the localization of the sebaceous glands. In vitro stimulation of sebocyte proliferation by androgens could be completely abolished by spironolactone. Cultured sebocytes strongly expressed type 1 5 alpha-reductase and metabolized testosterone to androstenedione, 5 alpha-androstanedione, 5 alpha-dihydrotestosterone, androsterone and 5 alpha-androstanediol, whereas the levels of 5 alpha-reductase activity were probably not feedback regulated. 4,7 beta-Dimethyl-4-aza-5 alpha-cholestan-3-one, a type 1 5 alpha-reductase inhibitor, induced an early, marked down-regulation of 5 alpha-reductase activity in human sebocytes in vitro, while hydrofinasteride, a type 2 inhibitor, required 10(3)-fold higher concentrations to induce similar effects. Stimulation of sebocyte proliferation by insulin, thyroid-stimulating hormone and hydrocortisone indicates that the hormonal control of the sebaceous gland could be a complex mechanism. Retinoids inhibited sebocyte proliferation in a dose-dependent manner and down-regulated lipid synthesis and sebocyte differentiation in vitro. Isotretinoin was the most potent compound. On the other hand, vitamin A was found essential for sebocyte activity and differentiation in vitro and could be partially substituted by synthetic retinoids. The inhibitory effect of isotretinoin on sebocyte proliferation was barely affected by the presence of vitamin A. The low persistent isotretinoin levels or, more likely, the considerably elevated tretinoin concentrations detected in human sebocytes after treatment with isotretinoin in vitro may be responsible for the inhibitory effect of this compound on sebocyte activity.


Evaluation of a dipstick enzyme-linked immunosorbent assay for detection of antibodies to dengue virus.
Accurate serological confirmation of dengue (DEN) infection is difficult, because simple reliable assays for the detection of DEN antibodies are not available. To address this problem, a dipstick enzyme-linked immunosorbent assay (ELISA) was evaluated. The dipstick contained dots of serially diluted DEN 2 antigen. To detect immunoglobulin G (IgG), the dipstick was processed through four reaction cuvettes containing test serum, enhancer, enzyme-conjugated anti-human IgG and IgM antibody, and substrate. Total assay time was 45 min. To detect IgM, the serum was passed through a protein G device to remove IgG. The dipstick was then processed as before, except that the incubation times were longer and enzyme-conjugated anti-human IgM was used. The total assay time was 3 h. The dipstick ELISA results were compared with results from microplate ELISA. The IgG dipstick ELISA showed a sensitivity of 95.2% and a specificity of 100% compared to an IgG microplate ELISA with serum samples from 125 individuals living in an area in which DEN is endemic. In tests with 75 serum samples from patients with clinically suspected acute DEN infections, the IgM dipstick ELISA showed a sensitivity of 97.9% and specificity of 100% compared to those of an IgM antibody capture microplate ELISA. These results showed that the dipstick ELISA was a sensitive and specific test for the detection of either DEN IgM or IgG in human serum. The dipstick ELISA was also shown to be useful for detecting seroconversions to DEN IgM or IgG in paired serum samples from 20 patients with virus isolation-confirmed acute DEN infections.


In vitro mechanical fatigue behavior of poly-ɛ-caprolactone macroporous scaffolds for cartilage tissue engineering: Influence of pore filling by a poly(vinyl alcohol) gel.
Polymeric scaffolds used in regenerative therapies are implanted in the damaged tissue and submitted to repeated loading cycles. In the case of articular cartilage engineering, an implanted scaffold is typically subjected to long-term dynamic compression. The evolution of the mechanical properties of the scaffold during bioresorption has been deeply studied in the past, but the possibility of failure due to mechanical fatigue has not been properly addressed. Nevertheless, the macroporous scaffold is susceptible to failure after repeated loading-unloading cycles. In this work fatigue studies of polycaprolactone scaffolds were carried by subjecting the scaffold to repeated compression cycles in conditions simulating the scaffold implanted in the articular cartilage. The behavior of the polycaprolactone sponge with the pores filled with a poly(vinyl alcohol) gel simulating the new formed tissue within the pores was compared with that of the material immersed in water. Results were analyzed with Morrow's criteria for failure and accurate fittings are obtained just up to 200 loading cycles. It is also shown that the presence of poly(vinyl alcohol) increases the elastic modulus of the scaffolds, the effect being more pronounced with increasing the number of freeze/thawing cycles.


The impact of blood component transfusion practices on patient survival after abdominal aortic aneurysm surgery.
The aim of the present study was to investigate the blood transfusion practice in patients operated for abdominal aortic aneurysm (AAA) with special emphasis on massive transfusion in cases with rupture. From a database, 504 patients operated for AAA were stratified into 2 groups; an early transfusion period (1992-1999) and a late transfusion period (2000-2008) to evaluate the changes in transfusion practices over the course of time. Patients operated for nonruptured AAA (n = 330) showed a decreased mortality rate from 4% (early transfusion period) to 1% (late transfusion period) without significant changes in the transfusion practices. In patients operated for ruptured AAA (n = 174) an unexpected low mortality rate was found compared to the 30-day mortality reported in earlier studies. The transfusion practices in ruptured AAA surgery showed a significant increase in platelet use and change of fresh frozen plasma: red blood cell ratio from 0.8 to 0.9 between the early and the late transfusion period. The present database study shows that the operating mortality for AAA surgery has declined during the past decades. The cause of the decline in mortality in patients with ruptured AAA was interpreted as partly due to a modern blood component therapy.


Antecedent moisture and temperature conditions modulate the response of ecosystem respiration to elevated CO2 and warming.
Terrestrial plant and soil respiration, or ecosystem respiration (Reco ), represents a major CO2 flux in the global carbon cycle. However, there is disagreement in how Reco will respond to future global changes, such as elevated atmosphere CO2 and warming. To address this, we synthesized six years (2007-2012) of Reco data from the Prairie Heating And CO2 Enrichment (PHACE) experiment. We applied a semi-mechanistic temperature-response model to simultaneously evaluate the response of Reco to three treatment factors (elevated CO2 , warming, and soil water manipulation) and their interactions with antecedent soil conditions [e.g., past soil water content (SWC) and temperature (SoilT)] and aboveground factors (e.g., vapor pressure deficit, photosynthetically active radiation, vegetation greenness). The model fits the observed Reco well (R2 = 0.77). We applied the model to estimate annual (March-October) Reco , which was stimulated under elevated CO2 in most years, likely due to the indirect effect of elevated CO2 on SWC. When aggregated from 2007 to 2012, total six-year Reco was stimulated by elevated CO2 singly (24%) or in combination with warming (28%). Warming had little effect on annual Reco under ambient CO2 , but stimulated it under elevated CO2 (32% across all years) when precipitation was high (e.g., 44% in 2009, a 'wet' year). Treatment-level differences in Reco can be partly attributed to the effects of antecedent SoilT and vegetation greenness on the apparent temperature sensitivity of Reco and to the effects of antecedent and current SWC and vegetation activity (greenness modulated by VPD) on Reco base rates. Thus, this study indicates that the incorporation of both antecedent environmental conditions and aboveground vegetation activity are critical to predicting Reco at multiple timescales (subdaily to annual) and under a future climate of elevated CO2 and warming.


Bone marrow transplantation with interleukin-1 plus kit-ligand ex vivo expanded bone marrow accelerates hematopoietic reconstitution in mice without the loss of stem cell lineage and proliferative potential.
Cytokine combinations were tested for their ability to expand murine bone marrow (BM) progenitors in short-term suspension cultures (delta-cultures) with the aim of providing an enriched source of progenitors for BM transplantation (BMT). In a comparison of the efficacy of the combinations interleukin-1 (IL-1) + IL-3, IL-1 + kit-ligand (KL), and IL-1 + IL-6 + KL, BMT with IL-1 + KL expanded progenitors was found to be most effective in accelerating the recovery of peripheral blood leukocytes, platelets, and erythrocytes in lethally irradiated mice. The ex vivo expansion of BM in IL-1 + KL-stimulated delta-cultures also greatly reduced the number of transplanted cells needed to provide radioprotection. All mice survived at least 30 days when receiving 5 x 10(3) delta-cultured d1 5-fluorouracil (5-FU) BM cells (BM cells harvested 1 day after 5-FU administration), whereas complete survival of mice receiving fresh d1 5-FU BM required BMT with a 200-fold greater number of cells. BMT with expanded BM lead to predominantly donor-derived hematopoietic reconstitution for 280 days postprimary BMT and another 71 days after secondary BMT. The expansion of BM did not adversely effect the proliferative capacity and lineage potential of the stem cell compartment.


Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP): a protocol for a phase 2 trial in patients with acute respiratory distress syndrome.
Mechanical ventilation is a life-saving intervention that maintains gas exchange in patients with acute respiratory distress syndrome (ARDS); however, it is associated with high mortality and it may augment, or even initiate, lung injury. An open lung ventilation strategy that combines alveolar recruitment manoeuvres with individually titrated positive end-expiratory pressure (PEEP) and targeting lower tidal volumes, or driving pressures by a permissive approach to hypercapnia, may reduce the lung injury associated with mechanical ventilation. This protocol reports the rationale, study design and analysis plan of the Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP) trial. PHARLAP is a phase 2, international, multicentre, prospective, randomised, controlled, parallel-group clinical trial, which aims to determine if staircase alveolar recruitment and individually titrated PEEP, when combined with permissive hypercapnia and low airway pressures, increases ventilator-free days to Day 28 when compared with conventional mechanical ventilation (Acute Respiratory Distress Syndrome Clinical Network [ARDSNet] strategy) in patients with moderate to severe ARDS. This study will enrol 340 patients. The intervention group will receive daily staircase alveolar recruitment manoeuvres with incremental PEEP to a maximum of 40 cmH2O and peak pressures to a maximum of 55 cmH2O. PEEP will be titrated individually against peripheral oxygen saturation, targeting lower tidal volumes by a permissive approach to hypercapnia. In the control group, patients will receive mechanical ventilation following the ARDSNet-ARMA trial protocol, including PEEP titrated with a PEEP/fraction of inspired oxygen (FiO2) chart. Both groups will receive airway pressures ≤30 cmH2O and tidal volumes of ≤ 6 mL/kg predicted bodyweight or less. The primary outcome is ventilator-free days to Day 28. Secondary outcomes include oxygenation and lung compliance, intensive care unit (ICU) and hospital length of stay, use of rescue therapies for refractory hypoxaemia, rate of barotrauma, mortality (ICU, hospital and at 28, 90 and 180 days), quality of life and a health economic analysis at 6 months. The PHARLAP trial will determine whether the intervention strategy is effective in increasing ventilator-free days in patients with ARDS. If the PHARLAP strategy is proven to improve ventilator-free days, it will provide a strong impetus to conduct an international phase 3 trial to determine the effects of this strategy on mortality. ClinicalTrials.gov identifier NCT01667146.


Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W).
To investigate the efficacy and safety of ixekizumab for up to 52 weeks in two phase 3 studies of patients with active radiographic axial spondyloarthritis (r-axSpA) who were biological disease-modifying antirheumatic drug (bDMARD)-naive (COAST-V) or tumour necrosis factor inhibitor (TNFi)-experienced (COAST-W). Adults with active r-axSpA were randomised 1:1:1:1 (n=341) to 80 mg ixekizumab every 2 (IXE Q2W) or 4 weeks (IXE Q4W), placebo (PBO) or 40 mg adalimumab Q2W (ADA) in COAST-V and 1:1:1 (n=316) to IXE Q2W, IXE Q4W or PBO in COAST-W. At week 16, patients receiving ixekizumab continued their assigned treatment; patients receiving PBO or ADA were rerandomised 1:1 to IXE Q2W or IXE Q4W (PBO/IXE, ADA/IXE) through week 52. In COAST-V, Assessment of SpondyloArthritis international Society 40 (ASAS40) responses rates (intent-to-treat population, non-responder imputation) at weeks 16 and 52 were 48% and 53% (IXE Q4W); 52% and 51% (IXE Q2W); 36% and 51% (ADA/IXE); 19% and 47% (PBO/IXE). Corresponding ASAS40 response rates in COAST-W were 25% and 34% (IXE Q4W); 31% and 31% (IXE Q2W); 14% and 39% (PBO/IXE). Both ixekizumab regimens sustained improvements in disease activity, physical function, objective markers of inflammation, QoL, health status and overall function up to 52 weeks. Safety through 52 weeks of ixekizumab was consistent with safety through 16 weeks. The significant efficacy demonstrated with ixekizumab at week 16 was sustained for up to 52 weeks in bDMARD-naive and TNFi-experienced patients. bDMARD-naive patients initially treated with ADA demonstrated further numerical improvements after switching to ixekizumab. Safety findings were consistent with the known safety profile of ixekizumab. NCT02696785/NCT02696798.


Comparative M-protein analysis of Streptococcus pyogenes from pharyngitis and skin infections in New Zealand: Implications for vaccine development.
Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are responsible for a significant disease burden amongst Māori and Pacific populations in New Zealand (NZ). However, contemporary data are lacking regarding circulating group A Streptococcal (GAS) strains in NZ. Such information is important in guiding vaccine development. GAS isolates from April to June 2015 were recovered from skin and pharyngeal samples from children living in areas of high social deprivation in Auckland, NZ, a significant proportion of which are Māori or Pacific. These children are among the highest risk group for developing ARF. Isolates were compared to concurrently collected pharyngeal isolates from Dunedin, NZ, where both the proportion of Māori and Pacific children and risk of developing ARF is low. Emm typing, emm cluster typing and theoretical coverage of the 30-valent vaccine candidate were undertaken as previously described. A high diversity of emm types and a high proportion of emm-pattern D and cluster D4 isolates were detected amongst both skin and pharyngeal isolates in children at high risk of ARF. Pharyngeal isolates from children at low risk of ARF within the same country were significantly less diverse, less likely to be emm pattern D, and more likely to be theoretically covered by the 30-valent M protein vaccine. The high proportion of emm pattern D GAS strains amongst skin and pharyngeal isolates from children at high risk of ARF raises further questions about the role of skin infection in ARF pathogenesis. Emm types and emm clusters differed considerably between ARF endemic and non-endemic settings, even within the same country. This difference should be taken into account for vaccine development.


Levels of processing in working memory: differential involvement of frontotemporal networks.
How does the brain maintain to-be-remembered information in working memory (WM), particularly when the focus of attention is drawn to processing other information? Cognitive models of WM propose that when items are displaced from focal attention recall involves retrieval from long-term memory (LTM). In this fMRI study, we tried to clarify the role of LTM in performance on a WM task and the type of representation that is used to maintain an item in WM during rehearsal-filled versus distractor-filled delays. Participants made a deep or shallow levels-of-processing (LOP) decision about a single word at encoding and tried to recall the word after a delay filled with either rehearsal of the word or a distracting math task. Recalling one word after 10 sec of distraction demonstrated behavioral and neural indices of retrieval from LTM (i.e., LOP effects and medial-temporal lobe activity). In contrast, recall after rehearsal activated cortical areas that reflected reporting the word from focal attention. In addition, areas that showed an LOP effect at encoding (e.g., left ventrolateral VLPFC and the anterior temporal lobes [ATLs]) were reactivated at recall, especially when recall followed distraction. Moreover, activity in left VLPFC during encoding, left ATL during the delay, and left hippocampus during retrieval predicted recall success after distraction. Whereas shallow LOP and rehearsal-related areas supported active maintenance of one item in focal attention, the behavioral processes and neural substrates that support LTM supported recall of one item after it was displaced from focal attention.


Perfluorooctanesulfonate Mediates Renal Tubular Cell Apoptosis through PPARgamma Inactivation.
Perfluorinated chemicals (PFCs) are ubiquitously distributed in the environments including stainless pan-coating, raincoat, fire extinguisher, and semiconductor products. The PPAR family has been shown to contribute to the toxic effects of PFCs in thymus, immune and excretory systems. Herein, we demonstrated that perfluorooctanesulfonate (PFOS) caused cell apoptosis through increasing ratio of Bcl-xS/xL, cytosolic cytochrome C, and caspase 3 activation in renal tubular cells (RTCs). In addition, PFOS increased transcription of inflammatory cytokines (i.e., TNFα, ICAM1, and MCP1) by NFκB activation. Conversely, PFOS reduced the mRNA levels of antioxidative enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, as a result of reduced PPARγ transactivational activity by using reporter and chromatin immuoprecipitation (ChIP) assays. PFOS reduced the protein interaction between PPARγ and PPARγ coactivator-1 alpha (PGC1α) by PPARγ deacetylation through Sirt1 upregulation, of which the binding of PPARγ and PGC1α to a peroxisome proliferator response element (PPRE) in the promoter regions of these antioxidative enzymes was alleviated in the ChIP assay. Furthermore, Sirt1 also deacetylated p53 and then increased the binding of p53 to Bax, resulting in increased cytosolic cytochrome C. The effect of PPARγ inactivation by PFOS was validated using the PPARγ antagonist GW9662, whereas the adverse effects of PFOS were prevented by PPARγ overexpression and activators, rosiglitozone and L-carnitine, in RTCs. The in vitro finding of protective effect of L-carnitine was substantiated in vivo using Balb/c mice model subjected to PFOS challenge. Altogether, we provide in vivo and in vitro evidence for the protective mechanism of L-carnitine in eliminating PFOS-mediated renal injury, at least partially, through PPARγ activation.


Examining the safety of respiratory and intravenous inoculation of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus in a mouse model.
Bdellovibrio spp. and Micavibrio spp. are Gram-negative predators that feed on other Gram-negative bacteria, making predatory bacteria potential alternatives to antibiotics for treating multi-drug resistant infections. While the ability of predatory bacteria to control bacterial infections in vitro is well documented, the in vivo effect of predators on a living host has yet to be extensively examined. In this study, respiratory and intravenous inoculations were used to determine the effects of predatory bacteria in mice. We found no reduction in mouse viability after intranasal or intravenous inoculation of B. bacteriovorus 109J, HD100 or M. aeruginosavorus. Introducing predators into the respiratory tract of mice provoked a modest inflammatory response at 1 hour post-exposure, but was not sustained at 24 hours, as measured by RT-qPCR and ELISA. Intravenous injection caused an increase of IL-6 in the kidney and spleen, TNF in the liver and CXCL-1/KC in the blood at 3 hours post-exposure, returning to baseline levels by 18 hours. Histological analysis of tissues showed no pathological changes due to predatory bacteria. Furthermore, qPCR detected predators were cleared from the host quickly and efficiently. This work addresses some of the safety concerns regarding the potential use of predatory bacteria as a live antibiotic.


Effects of lifestyle intervention in persons at risk for type 2 diabetes mellitus - results from a randomised, controlled trial.
Lifestyle change is probably the most important single action to prevent type 2 diabetes mellitus. The purpose of this study was to assess the effects of a low-intensity individual lifestyle intervention by a physician and compare this to the same physician intervention combined with an interdisciplinary, group-based approach in a real-life setting. The "Finnish Diabetes Risk score" (FINDRISC) was used by GPs to identify individuals at high risk. A randomised, controlled design and an 18 month follow-up was used to assess the effect of individual lifestyle counselling by a physician (individual physician group, (IG)) every six months, with emphasis on diet and exercise, and compare this to the same individual lifestyle counselling combined with a group-based interdisciplinary program (individual and interdisciplinary group, (IIG)) provided over 16 weeks. Primary outcomes were changes in lifestyle indicated by weight reduction ≥ 5%, improvement in exercise capacity as assessed by VO2 max and diet improvements according to the Smart Diet Score (SDS). 213 participants (104 in the IG and 109 in the IIG group, 50% women), with a mean age of 46 and mean body mass index 37, were included (inclusion rate > 91%) of whom 182 returned at follow-up (drop-out rate 15%). There were no significant differences in changes in lifestyle behaviours between the two groups. At baseline 57% (IG) and 53% (IIG) of participants had poor aerobic capacity and after intervention 35% and 33%, respectively, improved their aerobic capacity at least one metabolic equivalent. Unhealthy diets according to SDS were common in both groups at baseline, 61% (IG) and 60% (IIG), but uncommon at follow-up, 17% and 10%, respectively. At least 5% weight loss was achieved by 35% (IG) and 28% (IIG). In the combined IG and IIG group, at least one primary outcome was achieved by 93% while all primary outcomes were achieved by 6%. Most successful was the 78% reduction in the proportion of participants with unhealthy diet (almost 50% absolute reduction). It is possible to achieve important lifestyle changes in persons at risk for type 2 diabetes with modest clinical efforts. Group intervention yields no additional effects. The design of the study, with high inclusion and low dropout rates, should make the results applicable to ordinary clinical settings. ClinicalTrials.gov: NCT00202748.


Exploiting Phenylpropanoid Derivatives to Enhance the Nutraceutical Values of Cereals and Legumes.
Phenylpropanoids are a diverse chemical class with immense health benefits that are biosynthesized from the aromatic amino acid L-phenylalanine. This article reviews the progress for accessing variation in phenylpropanoids in germplasm collections, the genetic and molecular basis of phenylpropanoid biosynthesis, and the development of cultivars dense in seed-phenylpropanoids. Progress is also reviewed on high-throughput assays, factors that influence phenylpropanoids, the site of phenylpropanoids accumulation in seed, Genotype × Environment interactions, and on consumer attitudes for the acceptance of staple foods rich in phenylpropanoids. A paradigm shift was noted in barley, maize, rice, sorghum, soybean, and wheat, wherein cultivars rich in phenylpropanoids are grown in Europe and North and Central America. Studies have highlighted some biological constraints that need to be addressed for development of high-yielding cultivars that are rich in phenylpropanoids. Genomics-assisted breeding is expected to facilitate rapid introgression into improved genetic backgrounds by minimizing linkage drag. More research is needed to systematically characterize germplasm pools for assessing variation to support crop genetic enhancement, and assess consumer attitudes to foods rich in phenylpropanoids.


A cardiovascular extension of the Health Measurement Questionnaire.
To investigate the psychometric properties of a cardiovascular extension of an existing utility-based quality of life questionnaire (Health Measurement Questionnaire). The new instrument has been named the Utility Based Quality of life--Heart questionnaire, or UBQ-H. Explored the test-retest reliability, construct validity, and responsiveness of the UBQ-H. A sample of 322 patients attending cardiac outpatient clinics were recruited from two large metropolitan teaching hospitals. A second sample of 1112 patients taking part in the LIPID trial was also used to investigate the validity and responsiveness of the UBQ-H. Ninety per cent of all UBQ-H questionnaires were returned, and item completion rates were high (median of less than 1% missing or N/A answers). Cronbach's alpha measure of internal consistency for the scales ranged between 0.79-0.91, and each item was also most strongly correlated with its hypothesised domain than alternative domains. The intra-class test-retest reliability of the UBQ-H scales ranged from 0.65 to 0.81 for patients with stable health. Results supported the construct validity of the UBQ-H. The UBQ-H was significantly correlated with other information on quality of life (for example, General Health Questionnaire) as anticipated. The instrument was able to distinguish between contrasted groups of patients (for example, with versus without symptoms of dyspnoea, prior myocardial infarction versus none, etc), and was responsive to changes in health associated with adverse events requiring hospitalisation. The modifications made to the Health Measurement Questionnaire has resulted in an assessment designed for cardiovascular patients that has proved to be both reliable and valid.


Sustained Use of Patient Portal Features and Improvements in Diabetes Physiological Measures.
Personal health records (PHRs) have the potential to improve patient self-management for chronic conditions such as diabetes. However, evidence is mixed as to whether there is an association between PHR use and improved health outcomes. The aim of this study was to evaluate the association between sustained use of specific patient portal features (Web-based prescription refill and secure messaging-SM) and physiological measures important for the management of type 2 diabetes. Using a retrospective cohort design, including Veterans with diabetes registered for the My Health e Vet patient portal who had not yet used the Web-based refill or SM features and who had at least one physiological measure (HbA1c, low-density lipoprotein (LDL) cholesterol, blood pressure) in 2009-2010 (baseline) that was above guideline recommendations (N=111,686), we assessed portal use between 2010 and 2014. We calculated the odds of achieving control of each measure by 2013 to 2014 (follow-up) by years of using each portal feature, adjusting for demographic and clinical characteristics associated with portal use. By 2013 to 2014, 34.13% (38,113/111,686) of the cohort was using Web-based refills, and 15.75% (17,592/111,686) of the cohort was using SM. Users were slightly younger (P<.001), less likely to be eligible for free care based on economic means (P<.001), and more likely to be women (P<.001). In models adjusting for both features, patients with uncontrolled HbA1c at baseline who used SM were significantly more likely than nonusers to achieve glycemic control by follow-up if they used SM for 2 years (odds ratio-OR=1.24, CI: 1.14-1.34) or 3 or more years (OR=1.28, CI: 1.12-1.45). However, there was no significant association between Web-based refill use and glycemic control. Those with uncontrolled blood pressure at baseline who used Web-based refills were significantly more likely than nonusers to achieve control at follow-up with 2 (OR=1.07, CI: 1.01-1.13) or 3 (OR=1.08, CI: 1.02-1.14) more years of Web-based refill use. Both features were significantly associated with improvements in LDL cholesterol levels at follow-up. Although rates of use of the refill function were higher within the population, sustained SM use had a greater impact on HbA1c. Evaluations of patient portals should consider that individual components may have differential effects on health improvements.


Diet and heart disease in the 1980s.
In a climate of increasing concern about the high incidence of coronary heart disease in South Africa, calls are increasingly being made for South Africans to alter their diet. Can this exhortation be justified, and are the right foods being singled out as culprits? If changes in the eating habits of a nation are advocated, the advice must not only be soundly based in terms of likely benefit but must also take account of potential hazards. Critical perusal of the current literature leads to the conclusion that advice promoting a fat-modified, lower-salt diet is sound, safe and likely to be effective, especially as regards the younger segment of the westernized population.


An integrative review of the limited evidence on international travel bans as an emerging infectious disease disaster control measure.
In our increasingly interconnected world, the potential for emerging infectious diseases (EIDs) to spread globally is of paramount concern. Travel bans-herein defined as the complete restriction of travel from at least one geographic region to at least one other international geographic region-are a potential policy solution to control the global spread of disease. The social, economic, and health-related consequences of travel bans, as well as the available evidence on the effectiveness of travel restrictions in preventing the global spread of influenza, have been previously described. However, the effectiveness of travel bans in reducing the spread of noninfluenza EIDs, characterized by different rates and modes of transmission, is less well understood. This study employs an integrative review approach to summarize the minimal evidence on effectiveness of travel bans to decrease the spread of severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS), Ebola virus disease (EVD), and Zika virus disease (ZVD). We describe and qualify the evidence presented in six modeling studies that assess the effectiveness of travel bans in controlling these noninfluenza EID events. We conclude that there is an urgent need for additional research to inform policy decisions on the use of travel bans and other control measures to control noninfluenza EIDs in advance of the next outbreak.


Childhood Bereavement and Lower Stress Resilience in Late Adolescence.
Although childhood traumatic experiences are recognized as important determinants for adolescent psychiatric health in general, our objective was to explore the specific influence of childhood bereavement on the stress resilience development trajectory. In this national register-based cohort study, we identified 407,639 men born in Sweden between 1973 and 1983, who underwent compulsory military enlistment examinations in late adolescence, including measures of psychological stress resilience. We defined exposure as loss of a first-degree family member in childhood, and estimated relative risk ratios (RRRs) for reduced (moderate or low), compared with high, stress resilience with 95% confidence intervals (CIs) using multinomial logistic regression. Loss of a parent or sibling in childhood conferred a 49% increased risk of subsequent low stress resilience (RRR, 1.49, 95% CI, 1.41-1.57) and an 8% increased risk of moderate stress resilience (RRR, 1.08, 95% CI, 1.03-1.13) in late adolescence. There was also a graded increase in risk with increasing age at loss; teenagers were at higher risk for low resilience (RRR, 1.64, 95% CI, 1.52-1.77) than children aged 7-12 (RRR, 1.47, 95% CI, 1.34-1.61) and ≤6 years (RRR, 1.16 95% CI, 1.02-1.32). The excess risk was observed for all causes of death, including suicide and unexpected deaths as well as deaths due to other illnesses. The associations remained after exclusion of parents with a history of hospitalization for psychiatric diagnoses. The long-term consequences of childhood bereavement may include lower stress resilience in late adolescence.


Research development, current hotspots, and future directions of water research based on MODIS images: a critical review with a bibliometric analysis.
Water is essential for life as it provides drinking water and food for humans and animals. Additionally, the water environment provides habitats for numerous species and plays an important role in hydrological, nutrient, and carbon cycles. Among the existing natural resources on Earth's surface, water is the most extensive as it covers more than 70% of the Earth. To gather a comprehensive understanding of the focus of past, present, and future directions of remote sensing water research, we provide an alternative perspective on water research using moderate resolution imaging spectroradiometer (MODIS) imagery by conducting a comparative quantitative and qualitative analysis of research development, current hotspots, and future directions using a bibliometric analysis. Our study suggests that there has been a rapid growth in the scientific outputs of water research using MODIS imagery over the past 15 years compared to other popular satellites around the world. The analysis indicated that Remote Sensing of Environment was the most active journal, and "remote sensing," "imaging science photographic technology," "environmental sciences ecology," "meteorology atmospheric sciences," and "geology" are the top 5 most popular subject categories. The Chinese Academy of Sciences was the most productive institution with a total of 477 papers, and Hu CM (Chinese) was the most productive author with 76 papers. A keyword analysis indicated that "vegetation index," "evapotranspiration," and "phytoplankton" were the most active research topics throughout the study period. In addition, it is predicted that more attention will be paid to research on climate change and phenology in the future. Based on the keyword analysis and in consideration of current environmental problems, more studies should focus on the following three aspects: (1) develop methods suitable for data assimilation to fully explain climate or phenological phenomena at continental or global scales rather than at local scales; (2) accurately predict the effect of global change and human activities on evapotranspiration and the water cycle; and (3) determine the evolutionary process of the water environment (i.e., water quality, macrophytes, cyanobacteria, etc.), ascertaining its dominant factors and driving mechanisms. By focusing on these three aspects, researchers will be able to provide timely monitoring and evaluation of water quality and its response to global change and human activities.


Anesthetic Management During Atrial Septostomy in a Conjoined Thoraco-Omphalopagus Twin With Tricuspid Atresia and d-Transposition of the Great Arteries Before Separation: A Case Report.
Conjoined twins are uncommon with reported incidences of 1 in 30,000-200,000 births. They represent a heterogeneous population in regard to location of joint body parts and presence/extent of internal organ fusion. Positioning, airway management, possible presence of cross-circulation, and the fact that 2 patients require anesthesia for each procedure present significant challenges to the anesthesiologist. We report the anesthetic care of a conjoined twin set in which one of the patients presented with tricuspid atresia, d-transposition of the great arteries, and both atrial and ventricular septal defect. A balloon atrial septostomy was performed to allow survival after a separation procedure.


A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones.
A high dietary calcium intake is strongly suspected of increasing the risk of kidney stones. However, a high intake of calcium can reduce the urinary excretion of oxalate, which is thought to lower the risk. The concept that a higher dietary calcium intake increases the risk of kidney stones therefore requires examination. We conducted a prospective study of the relation between dietary calcium intake and the risk of symptomatic kidney stones in a cohort of 45,619 men, 40 to 75 years of age, who had no history of kidney stones. Dietary calcium was measured by means of a semiquantitative food-frequency questionnaire in 1986. During four years of follow-up, 505 cases of kidney stones were documented. After adjustment for age, dietary calcium intake was inversely associated with the risk of kidney stones; the relative risk of kidney stones for men in the highest as compared with the lowest quintile group for calcium intake was 0.56 (95 percent confidence interval, 0.43 to 0.73; P for trend, < 0.001). This reduction in risk decreased only slightly (relative risk, 0.66; 95 percent confidence interval, 0.49 to 0.90) after further adjustment for other potential risk factors, including alcohol consumption and dietary intake of animal protein, potassium, and fluid. Intake of animal protein was directly associated with the risk of stone formation (relative risk for men with the highest intake as compared with those with the lowest, 1.33; 95 percent confidence interval, 1.00 to 1.77); potassium intake (relative risk, 0.49; 95 percent confidence interval, 0.35 to 0.68) and fluid intake (relative risk, 0.71; 95 percent confidence interval, 0.52 to 0.97) were inversely related to the risk of kidney stones. A high dietary calcium intake decreases the risk of symptomatic kidney stones.


Increased expression of chemerin in squamous esophageal cancer myofibroblasts and role in recruitment of mesenchymal stromal cells.
Stromal cells such as myofibroblasts influence tumor progression. The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow-derived mesenchymal stromal cells (MSCs) which then colonize tumors. Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs) compared with adjacent tissue myofibroblasts (ATMs). The chemerin receptor, ChemR23, is expressed by MSCs. Conditioned media (CM) from CAMs significantly increased MSC cell migration compared to ATM-CM; the action of CAM-CM was significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor (MIF) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations. In a xenograft model consisting of OE21 esophageal cancer cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression.


Are new workers at elevated risk for work injury? A systematic review.
To identify, appraise and synthesise studies that have examined the degree to which new workers are at an elevated risk of work-related acute injuries and musculoskeletal (MSK) injuries. We searched three relevant electronic databases for studies published between 1995 and early 2018. Fifty-one studies using multivariate analyses met our relevance and quality appraisal criteria. These studies examined two different work outcomes: acute injuries (eg, cuts, burns and falls) and MSK injuries (eg, repetitive strain). In four of six studies looking at acute work injuries, new workers were found to be at an elevated risk of injury (ie, moderate supportive evidence of new worker risk). In another six studies looking at MSK symptoms, injuries or disorders, evidence of an elevated risk among new workers was insufficient or limited. Our review has potential implications for the prevention of work injuries, providing policy-makers and workplace parties with supportive evidence about the importance of prevention efforts focused on new workers, such as developing workplace policies that emphasise hazard exposure reduction, hazard awareness, hazard protection and worker empowerment.


In vitro host range, multiplication and virion forms of recombinant viruses obtained from co-infection in vitro with a vaccinia-vectored influenza vaccine and a naturally occurring cowpox virus isolate.
Poxvirus-vectored vaccines against infectious diseases and cancer are currently under development. We hypothesized that the extensive use of poxvirus-vectored vaccine in future might result in co-infection and recombination between the vaccine virus and naturally occurring poxviruses, resulting in hybrid viruses with unpredictable characteristics. Previously, we confirmed that co-infecting in vitro a Modified vaccinia virus Ankara (MVA) strain engineered to express influenza virus haemagglutinin (HA) and nucleoprotein (NP) genes with a naturally occurring cowpox virus (CPXV-NOH1) resulted in recombinant progeny viruses (H Hansen, MI Okeke, Ø Nilssen, T Traavik, Vaccine 23: 499-506, 2004). In this study we analyzed the biological properties of parental and progeny hybrid viruses. Five CPXV/MVA progeny viruses were isolated based on plaque phenotype and the expression of influenza virus HA protein. Progeny hybrid viruses displayed in vitro cell line tropism of CPXV-NOH1, but not that of MVA. The HA transgene or its expression was lost on serial passage of transgenic viruses and the speed at which HA expression was lost varied with cell lines. The HA transgene in the progeny viruses or its expression was stable in African Green Monkey derived Vero cells but became unstable in rat derived IEC-6 cells. Hybrid viruses lacking the HA transgene have higher levels of virus multiplication in mammalian cell lines and produced more enveloped virions than the transgene positive progenitor virus strain. Analysis of the subcellular localization of the transgenic HA protein showed that neither virus strain nor cell line have effect on the subcellular targets of the HA protein. The influenza virus HA protein was targeted to enveloped virions, plasma membrane, Golgi apparatus and cytoplasmic vesicles. Our results suggest that homologous recombination between poxvirus-vectored vaccine and naturally circulating poxviruses, genetic instability of the transgene, accumulation of non-transgene expressing vectors or hybrid virus progenies, as well as cell line/type specific selection against the transgene are potential complications that may result if poxvirus vectored vaccines are extensively used in animals and man.


Further insights into long-term trends in relative survival of vulvar cancer patients: a population-based study.
The main objective of this article was to investigate the trends in relative survival in women diagnosed with invasive squamous cell vulvar cancer in the United States during the periods of 2004 to 2011 and to examine how these trends are associated with the stage of tumor at diagnosis. We identified patients with primary invasive squamous cell vulvar cancer and recorded tumor stage in the Surveillance, Epidemiology, and End Results cancer registry database. Women younger than 40 years were excluded because of small number of patients in this age group. A flexible parametric model was used to estimate 1- and 2-year relative survival ratios and excess mortality rate. In total, 4647 women were identified with invasive squamous cell vulvar cancer and known tumor stage in the data set. One- and two-year relative survival ratios increased over time for women with tumors staged I to III but it decreased for women with tumor staged IV. The excess mortality rate was much larger for stage IV compared to the other stages. Trends in relative survival ratio for invasive vulvar cancer patients have opposite directions depending on the stage of tumor. The mechanism of such behavior is not fully known and yet to be examined in future studies. However, this finding highlights the importance of early detection of preinvasive and early stage disease.


Absent cervical spine pedicle and associated congenital spinal abnormalities - a diagnostic trap in a setting of acute trauma: case report.
Congenital spinal abnormalities can easily be misdiagnosed on plain radiographs. Additional imaging is warranted in doubtful cases, especially in a setting of acute trauma. This patient presented at the emergency unit of our university hospital after a motor vehicle accident and was sent to our radiology department for imaging of the cervical spine. Initial clinical examination and plain radiographs of the cervical spine were performed but not conclusive. Additional CT of the neck helped establish the right diagnosis. CT as a three-dimensional imaging modality with the possibility of multiplanar reconstructions allows for the exact diagnosis and exclusion of acute traumatic lesions of the cervical spine, especially in cases of doubtful plain radiographs and when congenital spinal abnormalities like absent cervical spine pedicle with associated spina bifida may insinuate severe trauma.


Relationship between stroke recurrence, infarct pattern, and vascular distribution in patients with symptomatic intracranial stenosis.
In view of recent literature suggesting that stroke recurrence and risks related to intervention may be related to plaque physiology/instability, our study sought to discern the pattern of stroke and rates of stoke recurrence as they relate to the anatomy and presentation of the underlying stenosis. Retrospective chart as well as CT and MR angiographic imaging review of patients in the institutional stroke database was performed, including identification of patient risk factors, medical therapeutic optimization, compliance, serum cholesterol (low density lipoprotein) levels, blood pressure, physical therapy referrals, follow-up clinical status (using the modified Rankin Scales), and rate of recurrent stroke. 39 patients met the inclusion criteria. We evaluated infarct pattern (embolic, adjacent perforator, or watershed) and vascular distribution. Basilar artery stenosis was most likely to present as a perforator stroke and least likely to recur. Patients discharged with suboptimal medical therapy were twice as likely to have a recurrent stroke. Among patients with optimized medical therapy, no recurrent strokes were seen in patients with an embolic infarct pattern, while a 57% recurrence rate was seen in patients with a watershed infarct pattern. Our results suggest that hemodynamic intracranial vascular stenoses may be less responsive to medical therapy, while stenotic lesions caused by plaque destabilization or in perforator territories may benefit from aggressive medical management with delayed or staged endovascular therapy. Recurrence of stroke may be affected both by vascular territory and by aggressive risk factor control, although the latter remains difficult to evaluate.


Alcohol drinking and brain morphometry in apparently healthy community-dwelling Japanese men.
The clinical implications of alcohol consumption have been extensively examined; however, its effects on brain structures in apparently healthy community-dwellers remain unclear. Therefore, we investigated the relationship between alcohol consumption and brain gray matter volume (GMV) in community-dwelling Japanese men using voxel-based morphometry (VBM). We recruited cognitively intact Japanese men, aged 40-79 years, from a population-based cohort in Shiga, Japan. Brain magnetic resonance imaging was performed, on average, 2 years after demographic and medical information was obtained in 2010-2014. A multivariable linear regression analysis of 639 men was conducted to elucidate the relationship between the amount of alcohol consumed and GMV. VBM statistics were analyzed by threshold-free cluster enhancement with a family-wise error rate of <0.05. The results obtained demonstrated that the amount of alcohol consumed was associated with lower GMV. The VBM analysis showed lower GMV within the parahippocampal, entorhinal, cingulate, insular, temporal, and frontal cortices and cerebellum in very heavy drinkers (≥42 ethanol g/day) than in non-drinkers. Furthermore, alcohol consumption was associated with a higher white matter lesion volume. These results suggest subclinical structural changes similar to alcohol-related neurological diseases.


The Post-Communist Fertility Puzzle.
Fertility has unanimously declined across the entire post-communist region. This study explores the variation in fertility trends over time among these countries and assesses to what degree three explanations are applicable: second demographic transition (SDT), postponement transition (PPT) or reaction to the economic crisis. Moreover, on the basis of SDT and PPT theoretical tenets, as well as descriptive evidence, the economic context is hypothesized to be linked to two processes of fertility decline conversely. The results show that no one theoretical explanation is sufficient to explain the complex fertility declines across the entire post-communist region from 1990 to 2003. In some countries, a great part of the decline in fertility occurred before significant postponement of childbearing began, which indicates that the dramatic decline was due to stopping behavior or postponement of higher order births. Postponement of first births, either through PPT or SDT processes, greatly contributed to fertility decline in a small number of countries. Pooled cross-sectional time-series analyses of age-specific birthrates confirm that these two distinct processes are present and show that the economic crisis explanation has explanatory power for declining birth rates. In contrast, logistic regressions show that the likelihood of postponing childbirth increases with improved economic conditions. These results confirm the importance of taking the economic context into account when discussing explanations for fertility decline. More specifically, the results indicate that the severity and duration of economic crisis, or absence thereof, influenced the extent and manner in which fertility declined.


Clinical Relevance of CYP2D6 Polymorphisms in Patients of an Austrian Medical Practice: A Family Practice-Based Observational Study.
Around 20-30% of all prescribed drugs are estimated to be metabolised by the cytochrome P450 (CYP) 2D6 enzyme. In a medical practice, it is usually not known whether a patient is a poor, intermediate, normal or ultra-rapid metaboliser for CYP2D6-metabolised drugs. This study aims to explore the clinical relevance and the extent of hazardous prescriptions by analysing the metaboliser status of patients already taking such drugs. This is a family practice-based observational study performed in a rural practice for general and family medicine in Lower Austria providing care for approximately 2100 patients annually. In 287 consecutive patients, who had taken or were taking a drug metabolised by CYP2D6 during the last 3 years, the metaboliser status was analysed. The genetic analysis of 287 patients resulted in 51.22% normal metabolisers, 38.68% intermediate metabolisers, 6.27% poor metabolisers and 3.83% ultra-rapid metabolisers. In 50 cases (poor metaboliser, intermediate metaboliser and ultra-rapid metaboliser, i.e. 17.42% of all tested patients taking a CYP2D6-specific drug), an altered gene function was identified, for which clinical guideline annotations, drug label annotations, or clinical annotations are available. Allele and genotype frequencies were in accordance with data from other European studies. In 17.42% of all patients already taking a drug metabolised by CYP2D6, knowledge of the genetically defined metaboliser status would have been of immediate clinical relevance before prescribing the drug. CLINICALTRIALS. NCT03859622.


Relationship between the shape of the central and third tarsal bones and the presence of tarsal osteoarthritis.
Osteoarthritis (OA) of the low motion joints of the tarsus, commonly termed 'bone spavin', is common in horses. Whilst the aetiology of this condition is multifactorial, it has been suggested that dorsal wedging of the central tarsal bone (CTB) and third tarsal bone (TTB) may predispose to the development of this disease. The aim of this study was to investigate the relationship between tarsal bone conformation and osteoarthritis of the proximal intertarsal (PIT), distal intertarsal (DIT) and tarsometatarsal (TMT) joints. It was hypothesised that wedging of the CTB and TTB would be associated with OA in these joints. Multiplanar reconstructions based on computed tomographic (CT) images were used to measure the height of the central and third tarsal bones at their dorsal and plantar aspects in three parasagittal planes in cadaver specimens. A wedging index was calculated as the ratio between the dorsal and plantar measurements. All tarsal bones were graded for OA on CT images. There was a significant moderate negative correlation between the wedging index of the CTB and OA of the DIT (ρ = -0.45, P <0.01), TMT (ρ = -0.49, P <0.01) and PIT joints (ρ = -0.43, P <0.01). Dorsal wedging of the TTB was seen in mild and moderate grades of OA, but severe cases of OA were associated with plantar wedging. Our study suggests that wedging of the small tarsal bones is associated with OA in the associated joints and hence care should be taken in foals to prevent the development of wedging.


Neuroanatomy accounts for age-related changes in risk preferences.
Many decisions involve uncertainty, or 'risk', regarding potential outcomes, and substantial empirical evidence has demonstrated that human aging is associated with diminished tolerance for risky rewards. Grey matter volume in a region of right posterior parietal cortex (rPPC) is predictive of preferences for risky rewards in young adults, with less grey matter volume indicating decreased tolerance for risk. That grey matter loss in parietal regions is a part of healthy aging suggests that diminished rPPC grey matter volume may have a role in modulating risk preferences in older adults. Here we report evidence for this hypothesis and show that age-related declines in rPPC grey matter volume better account for age-related changes in risk preferences than does age per se. These results provide a basis for understanding the neural mechanisms that mediate risky choice and a glimpse into the neurodevelopmental dynamics that impact decision-making in an aging population.


Acceptance and commitment therapy: model, processes and outcomes.
The present article presents and reviews the model of psychopathology and treatment underlying Acceptance and Commitment Therapy (ACT). ACT is unusual in that it is linked to a comprehensive active basic research program on the nature of human language and cognition (Relational Frame Theory), echoing back to an earlier era of behavior therapy in which clinical treatments were consciously based on basic behavioral principles. The evidence from correlational, component, process of change, and outcome comparisons relevant to the model are broadly supportive, but the literature is not mature and many questions have not yet been examined. What evidence is available suggests that ACT works through different processes than active treatment comparisons, including traditional Cognitive-Behavior Therapy (CBT). There are not enough well-controlled studies to conclude that ACT is generally more effective than other active treatments across the range of problems examined, but so far the data are promising.


Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule.
It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play an important role in regulating the reinforcing value of both food and drugs. This experiment examined the effect of disruption of orexinergic mechanisms in the LHA on performance on the progressive ratio schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes. Rats were trained under a progressive ratio schedule using food-pellet reinforcement. They received bilateral injections of conjugated orexin-B-saporin (OxSap) into the LHA or sham lesions. Training continued for a further 40 sessions after surgery. Equations were fitted to the response rate data from each rat, and the parameters of the model were derived for successive blocks of 10 sessions. The OxSap lesion reduced the number of orexin-containing neurones in the LHA by approximately 50% compared with the sham-lesioned group. The parameter expressing the incentive value of the reinforcer was not significantly altered by the lesion. However, the parameter related to the maximum response rate was significantly affected, suggesting that motor capacity was diminished in the OxSap-lesioned group. The results indicate that OxSap lesions of the LHA disrupted food-reinforced responding on the progressive ratio schedule. It is suggested that this disruption was brought about by a change in non-motivational (motor) processes.


Long-term ingestion of high flavanol cocoa provides photoprotection against UV-induced erythema and improves skin condition in women.
Dietary antioxidants contribute to endogenous photoprotection and are important for the maintenance of skin health. In the present study, 2 groups of women consumed either a high flavanol (326 mg/d) or low flavanol (27 mg/d) cocoa powder dissolved in 100 mL water for 12 wk. Epicatechin (61 mg/d) and catechin (20 mg/d) were the major flavanol monomers in the high flavanol drink, whereas the low flavanol drink contained 6.6 mg epicatechin and 1.6 mg catechin as the daily dose. Photoprotection and indicators of skin condition were assayed before and during the intervention. Following exposure of selected skin areas to 1.25 x minimal erythemal dose (MED) of radiation from a solar simulator, UV-induced erythema was significantly decreased in the high flavanol group, by 15 and 25%, after 6 and 12 wk of treatment, respectively, whereas no change occurred in the low flavanol group. The ingestion of high flavanol cocoa led to increases in blood flow of cutaneous and subcutaneous tissues, and to increases in skin density and skin hydration. Skin thickness was elevated from 1.11 +/- 0.11 mm at wk 0 to 1.24 +/- 0.13 mm at wk 12; transepidermal water loss was diminished from 8.7 +/- 3.7 to 6.3 +/- 2.2 g/(h x m2) within the same time frame. Neither of these variables was affected in the low flavanol cocoa group. Evaluation of the skin surface showed a significant decrease of skin roughness and scaling in the high flavanol cocoa group compared with those at wk 12. Dietary flavanols from cocoa contribute to endogenous photoprotection, improve dermal blood circulation, and affect cosmetically relevant skin surface and hydration variables.


Caring for new mothers: diagnosis, management and treatment of nipple dermatitis in breastfeeding mothers.
Breastfeeding is thought to be the most optimal form of infant nutrition. Nursing mothers are generally advised to continue breastfeeding until the infant is two years of age or beyond. Unfortunately, however, a majority of nursing mothers will discontinue breastfeeding much earlier than recommended. The most common reason for early discontinuation of breastfeeding is nipple pain. It is, therefore, essential that dermatologists know how to appropriately diagnose and effectively treat nipple pain associated with nipple dermatitis among nursing mothers. This review article provides a detailed discussion on the clinical features and management of various causes of nipple dermatitis during lactation, including problems with infant latch-on, congenital oral anomalies, plugged lactiferous ducts, atopic dermatitis, irritant contact dermatitis, allergic contact dermatitis, yeast infections, bacterial infections, herpes simplex virus, and Raynaud's phenomenon of the nipple.


Quality of reporting in systematic reviews of adverse events: systematic review.
To examine the quality of reporting of harms in systematic reviews, and to determine the need for a reporting guideline specific for reviews of harms. Systematic review. Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE). Databases were searched for systematic reviews having an adverse event as the main outcome, published from January 2008 to April 2011. Adverse events included an adverse reaction, harms, or complications associated with any healthcare intervention. Articles with a primary aim to investigate the complete safety profile of an intervention were also included. We developed a list of 37 items to measure the quality of reporting on harms in each review; data were collected as dichotomous outcomes ("yes" or "no" for each item). Of 4644 reviews identified, 309 were systematic reviews or meta-analyses primarily assessing harms (13 from CDSR; 296 from DARE). Despite a short time interval, the comparison between the years of 2008 and 2010-11 showed no difference on the quality of reporting over time (P=0.079). Titles in fewer than half the reviews (proportion of reviews 0.46 (95% confidence interval 0.40 to 0.52)) did not mention any harm related terms. Almost one third of DARE reviews (0.26 (0.22 to 0.31)) did not clearly define the adverse events reviewed, nor did they specify the study designs selected for inclusion in their methods section. Almost half of reviews (n=170) did not consider patient risk factors or length of follow-up when reviewing harms of an intervention. Of 67 reviews of complications related to surgery or other procedures, only four (0.05 (0.01 to 0.14)) reported professional qualifications of the individuals involved. The overall, unweighted, proportion of reviews with good reporting was 0.56 (0.55 to 0.57); corresponding proportions were 0.55 (0.53 to 0.57) in 2008, 0.55 (0.54 to 0.57) in 2009, and 0.57 (0.55 to 0.58) in 2010-11. Systematic reviews compound the poor reporting of harms data in primary studies by failing to report on harms or doing so inadequately. Improving reporting of adverse events in systematic reviews is an important step towards a balanced assessment of an intervention.


Near shot-noise limited hyperspectral stimulated Raman scattering spectroscopy using low energy lasers and a fast CMOS array.
We demonstrate near shot-noise limited hyperspectral stimulated Raman scattering (SRS) spectroscopy using oscillator-only excitation conditions. Using a fast CMOS camera synchronized to an acousto-optic modulator and subtracting subsequent frames acquired at up to 1 MHz frame rates, we demonstrate demodulation and recovery of the SRS spectrum. Surprisingly, we observe that the signal-to-noise of SRS spectra is invariant at modulation frequencies down to 2.5 kHz. Our approach allows for a direct comparison of SRS with coherent anti-Stokes Raman scattering (CARS) spectroscopy under identical experimental conditions. Our findings suggest that hyperspectral SRS imaging with shot-noise limited performance at biologically compatible excitation energies is feasible after minor modifications to fast frame-rate CMOS array technology.


Breast cancer stem cells and their role in resistance to endocrine therapy.
Developmentally, tumours can be viewed as aberrant versions of normal tissues. For example, tumours often retain differentiation markers of their tissue of origin. In addition, there is evidence that they contain cancer stem-like cells (CSCs) that drive tumourigenesis. In this review, we summarise current evidence that breast CSCs may partially explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly oestrogen receptor-α-negative (ER-). If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ER and can only respond to treatment by virtue of paracrine signalling from neighbouring, differentiated ER+ tumour cells. Normal breast epithelial stem cells are regulated by the epidermal growth factor receptor and other growth factor receptor signals. The observed increase in growth factor receptor expression in endocrine-resistant breast cancers may reflect a bigger proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ER- and EGR+/HER2+, which would support this view. It is reported that CSCs express mesenchymal genes, which are suppressed by ER expression, further indicating the mutual exclusion between ER+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ER in these cells in diverse breast tumour sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.


Suicide clusters: a review of risk factors and mechanisms.
Suicide clusters, although uncommon, cause great concern in the communities in which they occur. We searched the world literature on suicide clusters and describe the risk factors and proposed psychological mechanisms underlying the spatio-temporal clustering of suicides (point clusters). Potential risk factors include male gender, being an adolescent or young adult, drug or alcohol abuse, and past history of self-harm. However, the majority of studies lack methodological rigor. Many different psychological mechanisms are described, including contagion, imitation, suggestion, learning, and assortative relating, but supporting empirical evidence is generally lacking. More scientifically rigorous studies are needed to improve understanding of suicide clusters.


Spectrum of Lyapunov exponents of non-smooth dynamical systems of integrate-and-fire type.
We discuss how to characterize long-time dynamics of non-smooth dynamical systems, such as integrate-and-fire (I&F) like neuronal network, using Lyapunov exponents and present a stable numerical method for the accurate evaluation of the spectrum of Lyapunov exponents for this large class of dynamics. These dynamics contain (i) jump conditions as in the firing-reset dynamics and (ii) degeneracy such as in the refractory period in which voltage-like variables of the network collapse to a single constant value. Using the networks of linear I&F neurons, exponential I&F neurons, and I&F neurons with adaptive threshold, we illustrate our method and discuss the rich dynamics of these networks.


Molecular Engineering of the Autographa californica Nuclear Polyhedrosis Virus Genome: Deletion Mutations Within the Polyhedrin Gene.
We describe a method to introduce site-specific mutations into the genome of Autographa californica nuclear polyhedrosis virus. Specifically, the A. californica nuclear polyhedrosis virus gene for polyhedrin, the major protein that forms viral occlusions in infected cells, was mutagenized by introducing deletions into the cloned DNA fragment containing the gene. The mutagenized polyhedrin gene was transferred to the intact viral DNA by mixing fragment and viral DNAs, cotransfecting Spodoptera frugiperda cells, and screening for viral recombinants that had undergone allelic exchange. Recombinant viruses with mutant polyhedrin genes were obtained by selecting the progeny virus that did not produce viral occlusions in infected cells (occlusion-negative mutants). Analyses of occlusion-negative mutants demonstrated that the polyhedrin gene was not essential for the production of infectious virus and that deletion of certain sequences within the gene did not alter the control, or decrease the level of expression, of polyhedrin. An early viral protein of 25,000 molecular weight was apparently not essential for virus replication in vitro, as the synthesis of this protein was not detected in cells infected with a mutant virus.


Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption.
Previously published Type I (insulin-dependent) diabetes mellitus incidence in 0 to 14-year-old children from 10 countries or areas was compared with the national annual cow milk protein consumption. Countries which were selected for study had appropriate milk protein polymorphism studies, herd breed composition information and low dairy imports from other countries. Total protein consumption did not correlate with diabetes incidence (r = +0.402), but consumption of the beta-casein A1 variant did (r = +0.726). Even more pronounced was the relation between beta-casein (A1+B) consumption and diabetes (r = +0.982). These latter two cow caseins yield a bioactive peptide beta-casomorphin-7 after in vitro digestion with intestinal enzymes whereas the common A2 variant or the corresponding human or goat caseins do not. beta-casomorphin-7 has opioid properties including immunosuppression, which could account for the specificity of the relation between the consumption of some but not all beta-casein variants and diabetes incidence.


Measurement of in vivo spinal cord displacement and strain fields of healthy and myelopathic cervical spinal cord.
Cervical myelopathy (CM) is a common and debilitating form of spinal cord injury caused by chronic compression; however, little is known about the in vivo mechanics of the healthy spinal cord during motion and how these mechanics are altered in CM. The authors sought to measure 3D in vivo spinal cord displacement and strain fields from MR images obtained during physiological motion of healthy individuals and cervical myelopathic patients. Nineteen study participants, 9 healthy controls and 10 CM patients, were enrolled in the study. All study participants had 3T MR images acquired of the cervical spine in neutral, flexed, and extended positions. Displacement and strain fields and corresponding principal strain were obtained from the MR images using image registration. The healthy spinal cord displaces superiorly in flexion and inferiorly in extension. Principal strain is evenly distributed along the spinal cord. The CM spinal cord displaces less than the healthy cord and the magnitude of principal strain is higher, at the midcervical levels. Increased spinal cord compression during cervical myelopathy limits motion of the spinal cord and increases spinal cord strain during physiological motion. Future studies are needed to investigate how treatment, such as surgical intervention, affects spinal cord mechanics.


Regional brain blood flow in man during acute changes in arterial blood gases.
Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso-oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (PaCO2 =∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63±0.26; P<0.05); VA diameter was unaltered in response to changed PaCO2 but yielded a diameter increase of +9% with severe hypoxia. (3) Intra- vs. extra-cerebral measures: MCA and PCA blood velocities yielded smaller reactivities and estimates of flow than VA and ICA flow. The findings respectively indicate: (1) disparate blood flow regulation to the brainstem and cortex; (2) cerebrovascular resistance is not solely modulated at the level of the arteriolar pial vessels; and (3) transcranial Doppler ultrasound may underestimate measurements of CBF during extreme hypoxia and/or hypercapnia.


Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.
Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria. Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated. All CYP2C19/CYP2C9 alleles obeyed Hardy-Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC(0-24)) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C(max) (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071). CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.


Antibodies Targeting Closely Adjacent or Minimally Overlapping Epitopes Can Displace One Another.
Here we describe how real-time label-free biosensors can be used to identify antibodies that compete for closely adjacent or minimally overlapping epitopes on their specific antigen via a mechanism of antibody displacement. By kinetically perturbing one another's binding towards their antigen via the formation of a transient trimolecular complex, antibodies can displace one another in a fully reversible and dose-dependent manner. Displacements can be readily identified when epitope binning assays are performed in a classical sandwich assay format whereby a solution antibody (analyte) is tested for binding to its antigen that is first captured via an immobilized antibody (ligand) because an inverted sandwiching response is observed when an analyte displaces a ligand, signifying the antigen's unusually rapid dissociation from its ligand. In addition to classifying antibodies within a panel in terms of their ability to block or sandwich pair with one another, displacement provides a hybrid mechanism of competition. Using high-throughput epitope binning studies we demonstrate that displacements can be observed on any target, if the antibody panel contains appropriate epitope diversity. Unidirectional displacements occurring between disparate-affinity antibodies can generate apparent asymmetries in a cross-blocking experiment, confounding their interpretation. However, examining competition across a wide enough concentration range will often reveal that these displacements are reversible. Displacement provides a gentle and efficient way of eluting antigen from an otherwise high affinity binding partner which can be leveraged in designing reagents or therapeutic antibodies with unique properties.


Clinical evaluation of autologous platelet-rich fibrin in the treatment of multiple adjacent gingival recession defects: a 12-month study.
Leukocyte- and platelet-rich fibrin (L-PRF) belongs to a new generation of platelet concentrates. There are limited numbers of studies focused on the use of L-PRF in gingival recession defects. This study evaluated the safety and effectiveness of using L-PRF membranes as a substitute for free connective tissue grafts (CTGs) as a treatment method for gingival recession defects. A total of 44 Miller Class I/II gingival recessions that were bilateral, adjacent, and greater than 3 mm in size were selected. Each recession site was randomly assigned to the test group (L-PRF) or the control group (CTG). After 12 months, root coverage was 76.63% and 77.36% in the L-PRF and CTG groups, respectively. It is suggested that L-PRF membrane may be an alternative graft material for treating multiple adjacent recessions greater than 3 mm in size without a requirement for additional surgery.


Identification of antigens presented by MHC for vaccines against tuberculosis.
Mycobacterium tuberculosis (M.tb) is responsible for more deaths globally than any other pathogen. The only available vaccine, bacillus Calmette-Guérin (BCG), has variable efficacy throughout the world. A more effective vaccine is urgently needed. The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. In order to identify mycobacterial antigens bound to MHC, we have immunoprecipitated MHC class-I and class-II complexes from THP-1 macrophages infected with BCG, purified MHC class-I and MHC class-II peptides and analysed them by liquid chromatography tandem mass spectrometry. We have successfully identified 94 mycobacterial peptides presented by MHC-II and 43 presented by MHC-I, from 76 and 41 antigens, respectively. These antigens were found to be highly expressed in infected macrophages. Gene ontology analysis suggests most of these antigens are associated with membranes and involved in lipid biosynthesis and transport. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cell from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying new candidate antigens.


Interferon alfa regulated gene expression in patients initiating interferon treatment for chronic hepatitis C.
Interferon alfa (IFN-alpha) is an approved therapeutic agent for chronic hepatitis C. To directly characterize the effects of IFN-alpha in humans, we used microarrays to profile gene expression in peripheral blood mononuclear cells (PBMCs) from hepatitis C patients treated with IFN-alpha. Seven patients were studied using two strategies: (1) in vivo: PBMCs were collected immediately before the first dose of IFN-alpha, and 3 and 6 hours after the dose; (2) ex vivo: PBMCs that were collected before the first IFN-alpha dose were incubated with IFN-alpha for 3 and 6 hours. The microarray datasets were analyzed with significance analysis of microarrays (SAM) to identify genes regulated by IFN-alpha. We identified 516 named genes up-regulated at least 2-fold, at a false discovery rate (FDR) of less than 1%. In vivo and ex vivo studies generated similar results. No genes were identified as regulated differently between these 2 experimental conditions. The up-regulated genes belonged to a broad range of functional pathways and included multiple genes thought to be involved in the direct antiviral effect of IFN-alpha. Of particular interest, 88 genes directly relating to functions of immune cells were up-regulated, including genes involved in antigen processing and presentation, T-cell activation, lymphocyte trafficking, and effector functions, suggesting that IFN-alpha up-regulates multiple genes involving different aspects of immune responses to enhance immunity against hepatitis C virus. In conclusion, IFN-alpha-inducible genes can be identified in human PBMCs in vivo as well as ex vivo. Signature changes associated with different treatment outcomes may be found among these genes.


Seroprevalence of hemorrhagic septicemia in dairy cows in Assam, India.
Hemorrhagic septicemia (HS) is a highly fatal disease caused by Pasteurella multocida that often cause outbreaks in buffalo and cattle in India, and thus is a major cause of production losses. It is one of the livestock diseases with the highest mortality, and despite available vaccines, outbreaks still occur. To assess the seroprevalence in the state of Assam, Northeast India, 346 serum samples from cows from 224 randomly selected households, from both urban and rural areas of three districts, were tested with a commercial ELISA. In total 88 cows were seropositive (25.4%), and indigenous cattle were significantly more seropositive (33.5%) compared to the crossbred cattle (18.5%) (p = 0.002). Herd prevalence was 35.7%, and more rural farms (47.4%) were positive compared to the urban farms (23.6%) (p < 0.001). No other risk factors were identified in this study. Only one farm had vaccinated against HS, but there were no seropositive animals detected in that herd. This study shows that HS is highly prevalent in Assam. Considering the importance of dairy production in India, and the dependence of the rural Assam population on farming and livestock keeping, more extensive vaccination campaigns would be important.


Harry M. Vars Research Award. Glutamine enhances immunoregulation of tumor growth.
It is known that tumor progression is associated with a depletion in host glutamine (Gln) stores and a depression of natural killer (NK) cell activity. After demonstrating an in vitro dependence of NK cell activity on Gln and glutathione concentration, this study evaluated the effects of oral Gln on Gln and glutathione metabolism, NK cell activity, and tumor growth in the tumor-bearing rat. Two days before tumor implantation, rats (n = 32) were randomized to receive Gln (1 g/kg/d) or an isonitrogenous amount of glycine by gavage and pair-fed food. On day 21 after tumor implantation, rats were killed, and tumors were measured and processed for glutaminase activity, glutathione content, and tumor morphometrics. Splenic lymphocytes were assayed for NK cell activity via a chromium (51Cr) release assay using YAC (NK-cell-sensitive mouse tumor cell line) target cells. Blood Gln and glutathione were measured. A second set of rats (n = 16) were treated similarly except that ketamine was given twice weekly to suppress NK cell activity. During the 3-week study period, tumor growth was decreased by 40% in the Gln group. This decrease in growth was associated with a 30% increase in NK cell activity. Administration of ketamine to rats completely reversed the higher NK cell activity and decreased the tumor growth seen in the Gln-treated group. These data indicate that oral Gln supplementation, through support of host Gln stores and glutathione production, may decrease tumor growth by enhancing NK cell activity.


Racial disparities in the use of cardiac revascularization: does local hospital capacity matter?
To assess the extent to which the observed racial disparities in cardiac revascularization use can be explained by the variation across counties where patients live, and how the within-county racial disparities is associated with the local hospital capacity. Administrative data from Pennsylvania Health Care Cost Containment Council (PHC4) between 1995 and 2006. The study sample included 207,570 Medicare patients admitted to hospital for acute myocardial infarction (AMI). We identified the use of coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) procedures within three months after the patient's initial admission for AMI. Multi-level hierarchical models were used to determine the extent to which racial disparities in procedure use were attributable to the variation in local hospital capacity. Blacks were less likely than whites to receive CABG (9.1% vs. 5.8%; p<0.001) and PCI (15.7% vs. 14.2%; p<0.001). The state-level racial disparity in use rate decreases for CABG, and increases for PCI, with the county adjustment. Higher number of revascularization hospitals per 1,000 AMI patients was associated with smaller within-county racial differences in CABG and PCI rates. Meanwhile, very low capacity of catheterization suites and AMI hospitals contributed to significantly wider racial gap in PCI rate. County variation in cardiac revascularization use rates helps explain the observed racial disparities. While smaller hospital capacity is associated with lower procedure rates for both racial groups, the impact is found to be larger on blacks. Therefore, consequences of fewer medical resources may be particularly pronounced for blacks, compared with whites.


Attitudes to evolution among Christians, Muslims and the Non-Religious in Britain: Differential effects of religious and educational factors.
According to poll results and media reports, Britain has a significant and growing number of creationists. However, little scholarly research has been carried out to explore this phenomenon. We present results from a national survey of 6020 individuals to give a comprehensive picture of contemporary public attitudes to evolution in Britain. Furthermore, we explore the effects of religion and education on attitudes to evolution. Unique to this study, we analyse the effects of attending a religiously affiliated school ('faith school') on acceptance of evolutionary theory. We examine these effects in the general population, and additionally, across different Christian, Muslim and Non-Religious subpopulations. Results give strong evidence that the number of creationists has been overstated previously. We find the effect of education is complex and varies between different religious groups, but that faith school attendance is associated with more acceptance of evolution for people belonging to groups that tend to reject it.


Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease.
Venous thromboembolic events (VTEs) in children are usually associated with underlying clinical conditions. The added contribution of prothrombotic conditions to the occurrence of VTEs in children is not clear. This study reports the prevalence of prothrombotic conditions in 171 consecutive children with VTE followed in the Hospital for Sick Children Thrombosis Outpatient Clinic. The median age of the children at the time of VTE was 2.3 months (range 1 day to 16.5 years). An underlying medical condition and a central venous line (CVL) were present in 156 (91%) and 132 (77%) of 171 children, respectively. A positive family history was present in 8% of children. The prevalence of factor V Leiden was 4.7%, prothrombin G20210A polymorphism was 2.3%, protein S deficiency was 1.2%, protein C deficiency was 0.6% and increased plasma lipoprotein (a) concentration (>30 mg dL-1) was 7.5% (tested in 107 children). The overall frequency of inherited prothrombotic coagulation proteins was 13% (95% confidence interval 7 to 19%) and the frequency was not significantly different between neonates and older children with VTE. Inherited prothrombotic coagulation proteins were not associated with gender, CVL-related VTE, a positive family history of thrombosis or spontaneous VTE in neonates. Increased frequency of inherited prothrombotic coagulation proteins was, however, found in older children with spontaneous VTE (60%) compared with older children with VTEs secondary to an underlying medical condition (10%) (P = 0.02). In conclusion, this study indicates that inherited prothrombotic coagulation proteins do not contribute significantly to the pathogenesis of VTEs in neonates and children, in whom the most significant etiological factors are the presence of a CVL and/or other medical conditions.


Hiding negative trials by pooling them: a secondary analysis of pooled-trials publication bias in FDA-registered antidepressant trials.
Previous studies on reporting bias generally examined whether trials were published in stand-alone publications. In this study, we investigated whether pooled-trials publications constitute a specific form of reporting bias. We assessed whether negative trials were more likely to be exclusively published in pooled-trials publications than positive trials and examined the research questions, individual trial results, and conclusions presented in these articles. Data from a cohort of 105 randomized controlled trials of 16 antidepressants were extracted from earlier publications and the corresponding Food and Drug Administration (FDA) reviews. A systematic literature search was conducted to identify pooled-trials publications. We found 107 pooled-trials publications that reported results of 23 (72%) of 32 trials not published in stand-alone publications. Only two (3.8%) of 54 positive trials were published exclusively in pooled-trials publications, compared with 21 (41.1%) of 51 negative trials (p < 0.001). Thirteen (12%) of 107 publications had as primary aim to present data on the trial's primary research question (drug efficacy compared with placebo). Only four of these publications, reporting on five (22%) trials, presented individual efficacy data for the primary research question. Additionally, only five (5%) of 107 pooled-trials publications had a negative conclusion. Compared with positive trials, negative trials of antidepressants for depression were much more likely to be reported exclusively in pooled-trials publications. Pooled-trials publications flood the evidence base with often-redundant articles that, instead of addressing the original primary research question, present (positive) results on secondary questions. Therefore, pooled-trials publications distort the apparent risk-benefit profile of antidepressants.


Electrophoretic transport and dynamic deformation of bio-vesicles.
Study of the deformation dynamics of cells and other sub-micron vesicles, such as virus and neurotransmitter vesicles are necessary to understand their functional properties. This mechanical characterization can be done by submerging the vesicle in a fluid medium and deforming it with a controlled electric field, which is known as electrodeformation. Electrodeformation of biological and artificial lipid vesicles is directly influenced by the vesicle and surrounding media properties and geometric factors. The problem is compounded when the vesicle is naturally charged, which creates electrophoretic forcing on the vesicle membrane. We studied the electrodeformation and transport of charged vesicles immersed in a fluid media under the influence of a DC electric field. The electric field and fluid-solid interactions are modeled using a hybrid immersed interface-immersed boundary technique. Model results are verified with experimental observations for electric field driven translocation of a virus through a nanopore sensor. Our modeling results show interesting changes in deformation behavior with changing electrical properties of the vesicle and the surrounding media. Vesicle movement due to electrophoresis can also be characterized by the change in local conductivity, which can serve as a potential sensing mechanism for electrodeformation experiments in solid-state nanopore setups.


Bcl-XL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line.
Bcl-2 and Bcl-XL are anti-apoptotic paralogues that inhibit apoptosis elicited by a wide variety of stimuli, and play critical roles in cancer development and resistance to treatment. Many clinical studies have indicated that expression of these anti-apoptotic proteins in tumours is associated with poor prognosis. It has therefore been assumed that in cells the essential difference between Bcl-2 and Bcl-XL involves regulation of expression and that they are otherwise functionally similar. To examine this issue, we have compared the function of the proteins and of mutants of Bcl-2 and Bcl-XL specifically targeted to different subcellular sites. We generated clones of the human breast cancer line MCF-7 stably expressing known amounts of Bcl-2, or Bcl-XL as determined by quantitative immunoblotting. Clones expressing equivalent amounts of wild-type and mutants of Bcl-2 and Bcl-XL with subcellular localization restricted to the cytoplasm, endoplasmic reticulum or outer mitochondrial membrane were studied in both MCF-7 and Rat-1 fibroblasts. In MCF-7 cells we measured the functional activities of these proteins in preventing apoptosis induced by four different agents (doxorubicin, ceramide, thapsigargin, TNF-alpha). Etoposide and low serum were used to compare the effect of Bcl-2, Bcl-XL and mutants located at the endoplasmic reticulum on induction of apoptosis in fibroblasts. We noted both qualitative and quantitative differences in the functional activity of these two anti-apoptotic proteins in cells: Bcl-2 localized to the endoplasmic reticulum inhibits apoptosis induced by ceramide and thapsigargin but not by doxorubicin or TNFalpha, while Bcl-XL at the endoplasmic reticulum is active against all four drugs. In fibroblasts Bcl-2 localized to the ER did not prevent cell death due to etoposide whereas Bcl-XL in the same location did. Finally in MCF-7 cells, Bcl-XL is approximately ten times more active than Bcl-2 in repressing apoptosis induced by doxorubicin. This difference can be manifest as a large difference in clonal survival. When examined in the same cellular context, Bcl-2 and Bcl-XL differ substantially in the potency with which they inhibit apoptosis, mediated in part by differences in the inhibition of specific subcellular pathways.