Revisiting the curvature-mediated interactions between proteins in biological membranes.
Proteins embedded in soft biological membranes experience a long-range force mediated by elastic curvature deformations. The classical linearized Helfrich-Canham Hamiltonian based derivations reveal the nature of the force between a pair of proteins to be repulsive in the zero-temperature limit and the interaction potential is inversely proportional to the fourth power of the distance separating the inclusions. Such a result is the starting point to understand many-body interactions between proteins in biological membranes and the study of their clustering or, more broadly, self-organization. A key observation regarding this widely quoted result is that any two (mechanically rigid) proteins will experience an identical force. In other words, there is no specificity in the currently employed continuum models that purport to explain protein interactions. In this work we argue that each protein has a unique mechanical signature based on its interaction with the surrounding lipid bilayer membrane and cannot be treated as a non-specific rigid object. We modify the classical Helfrich-Canham theory of curvature elasticity to incorporate protein-membrane specificity, discuss the estimation of the new model parameters via atomistic simulations and re-evaluate the curvature-mediated force between proteins. We find that the incorporation of protein-specificity can reduce the interaction force by several orders of magnitude. Our result may provide at least one plausible reason behind why in some computational and experimental studies, a net attractive force between proteins is in evidence.


Synthesis and CO2/CH4 separation performance of Bio-MOF-1 membranes.
Herein we present the preparation of continuous and reproducible Bio-MOF-1 membranes supported on porous stainless steel tubes. These membranes displayed high CO(2) permeances for equimolar mixtures of CO(2) and CH(4). The observed CO(2)/CH(4) selectivities above one indicate that the separation is promoted by competitive adsorption.


Biomarkers in early-stage colorectal cancer: ready for prime time?
During the last two decades, hundreds of reports have detailed putative prognostic and predictive biomarkers for colorectal cancer (CRC). However, the majority of these studies have been small and retrospective, reporting results that are highly likely to represent false positives. Consequently, their relevance to clinical practice requires definition. Review of published literature on CRC biomarkers, focusing on early-stage disease. Although most putative biomarkers have failed to be validated in subsequent studies, level I evidence now indicates that tumour microsatellite instability can be used to identify a cohort of patients with stage IIA disease at low risk of relapse who can be spared adjuvant chemotherapy. Emerging data suggest that gene expression arrays may have a role in selecting patients with stage IIA disease and mismatch repair-proficient tumours for chemotherapy following tumour resection. Despite the profusion of biomarker literature, only mismatch repair status can be recommended as routine in current clinical practice. High-quality, adequately powered studies are essential to accurately define the utility of existing and putative biomarkers, and to support their rational application in the clinic.


STK11 and KEAP1 mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic value among Hispanics (STRIKE registry-CLICaP).
Mutations in STK11 (STK11Mut) and, frequently co-occurring, KEAP1 mutations (KEAP1Mut) are associated with poor survival in metastatic Non-small Cell Lung Cancer (mNSCLC) patients treated with immunotherapy. However, there are limited data regarding the prognostic or predictive significance of these genomic alterations among Hispanics. This retrospective study analyzed a cohort of Hispanic patients (N = 103) diagnosed with mNSCLC from the US and seven Latin American countries (LATAM) treated with immune checkpoint inhibitors (ICI) alone or in combination as first-line (Cohort A). All cases were treated in routine care between January 2016 and December 2021. The main objectives were to determine the association of mutations in STK11 or KEAP1 in these patients' tumors with overall (OS) and progression-free survival (PFS), presence of KRAS mutations, tumor mutational burden (TMB), and other relevant clinical variables. To compare outcomes with a STK11Wt/KEAP1Wt population, historical data from a cohort of Hispanic patients (N = 101) treated with first-line ICI was used, matching both groups by country of origin, gender, and Programed Death-ligand 1 (PD-L1) expression level (Cohort B). Most tumors had mutations only in STK11 or KEAP1 (45.6%) without KRAS co-mutation or any other genomic alteration. Besides, 35%, 8.7%, 6.8%, and 3.9% were KRASMut + STK11Mut, KRASMut + STK11Mut + KEAP1Mut, STK11Mut + KEAP1Mut, and KRASMut + KEAP1Mut, respectively. Based on KRAS status, STK11 alterations were associated with significantly lower PD-L1 expression among those with KRASWt (p = 0.023), whereas KEAP1 mutations were predominantly associated with lower PD-L1 expression among KRASMut cases (p = 0.047). Tumors with KRASMut + KEAP1Mut had significantly higher median TMB when compared to other tumors (p = 0.040). For Cohort A, median PFS was 4.9 months (95%CI 4.3-5.4), slightly longer in those with KEAP1mut 6.1 months versus STK11Mut 4.7 months (p = 0.38). In the same cohort, PD-L1 expression and TMB did not influence PFS. OS was significantly longer among patients with tumors with PD-L1 ≥ 50% (30.9 months), and different from those with PD-L1 1-49% (22.0 months), and PD-L1 < 1% (12.0 months) (p = 0.0001). When we compared the cohorts A and B, OS was significantly shorter for patients carrying STK1 [STK11Mut 14.2 months versus STK11Wt 27.0 months (p = 0.0001)] or KEAP1 [KEAP1Mut 12.0 months versus KEAP1Wt 24.4 months (p = 0.005)] mutations. PD-L1 expression significantly affected OS independently of the presence of mutations in STK11, KEAP1, or KRAS. TMB-H favored better OS. This is the first large Hispanic cohort to study the impact of STK11 and KEAP1 mutations in NSCLC patient treated with ICI. Our data suggest that mutations in the above-mentioned genes are associated with PD-L1 expression levels and poor OS.


Hypothesis: butyrate is not an HDAC inhibitor, but a product inhibitor of deacetylation.
The short-chain fatty acid butyrate is classically referred to as an inhibitor of histone deacetylases (HDACi), however evidence from direct assays is both sparse and contradictory. This paper assesses the strength of the historical evidence, potential gaps, inadequacies and simplifications in the butyrate-as-HDACi hypothesis. An alternate model to explain the action of butyrate is proposed wherein butyrate acts as a product inhibitor of deacetylation. The model makes testable predictions which may enable future determination of the mode of action of this and other SCFAs.


Drinking water and cancer.
Any and all chemicals generated by human activity can and will find their way into water supplies. The types and quantities of carcinogens present in drinking water at the point of consumption will differ depending on whether they result from contamination of the source water, arise as a consequence of treatment processes, or enter as the water is conveyed to the user. Source-water contaminants of concern include arsenic, asbestos, radon, agricultural chemicals, and hazardous waste. Of these, the strongest evidence for a cancer risk involves arsenic, which is linked to cancers of the liver, lung, bladder, and kidney. The use of chlorine for water treatment to reduce the risk of infectious disease may account for a substantial portion of the cancer risk associated with drinking water. The by-products of chlorination are associated with increased risk of bladder and rectal cancer, possibly accounting for 5000 cases of bladder cancer and 8000 cases of rectal cancer per year in the United States. Fluoridation of water has received great scrutiny but appears to pose little or no cancer risk. Further research is needed to identify and quantify risks posed by contaminants from drinking-water distribution pipes, linings, joints, and fixtures and by biologically active micropollutants, such as microbial agents. We need more cost-effective methods for monitoring drinking-water quality and further research on interventions to minimize cancer risks from drinking water.


Three-dimensional-printed gas dynamic virtual nozzles for x-ray laser sample delivery.
Reliable sample delivery is essential to biological imaging using X-ray Free Electron Lasers (XFELs). Continuous injection using the Gas Dynamic Virtual Nozzle (GDVN) has proven valuable, particularly for time-resolved studies. However, many important aspects of GDVN functionality have yet to be thoroughly understood and/or refined due to fabrication limitations. We report the application of 2-photon polymerization as a form of high-resolution 3D printing to fabricate high-fidelity GDVNs with submicron resolution. This technique allows rapid prototyping of a wide range of different types of nozzles from standard CAD drawings and optimization of crucial dimensions for optimal performance. Three nozzles were tested with pure water to determine general nozzle performance and reproducibility, with nearly reproducible off-axis jetting being the result. X-ray tomography and index matching were successfully used to evaluate the interior nozzle structures and identify the cause of off-axis jetting. Subsequent refinements to fabrication resulted in straight jetting. A performance test of printed nozzles at an XFEL provided high quality femtosecond diffraction patterns.


Efficacy of different strategies to treat anemia in children: a randomized clinical trial.
Anemia continues to be a major public health problem among children in many regions of the world, and it is still not clear which strategy to treat it is most effective. To evaluate the efficacy and children's acceptance of several recognized strategies to treat anemia. Non-breastfed children (n = 577), 6 to 43 mo of age, were screened for the trial; 267 were anemic (hemoglobin < 11.7 g/dL), and 266 of those were randomized into 1 of 5 treatments to received daily either: an iron supplement (IS), an iron+folic acid supplement (IFS), a multiple micronutrient supplement (MMS), a micronutrient-fortified complementary food as porridge powder (FCF), or zinc+iron+ascorbic acid fortified water (FW). The iron content of each daily dose was 20, 12.5, 10, 10 and 6.7 mg respectively. Hemoglobin (Hb), ferritin, total iron, weight and height were measured at baseline and after 4 months of treatment. Morbidity, treatment acceptability and adherence were recorded during the intervention. All treatments significantly increased Hb and total iron concentration; ferritin did not change significantly. Groups MMS, IS and IFS increased Hb (g/dL) [1.50 (95%CI: 1.17, 1.83), 1.48 [(1.18, 1.78) and 1.57 (1.26, 1.88), respectively] and total iron ((μg/dL) [0.15 (0.01, 0.29), 0.19 (0.06, 0.31) and 0.12(-0.01, 0.25), respectively] significantly more than FCF [0.92 (0.64, 1.20)] but not to FW group [0.14 (0.04, 0.24)]. The prevalence of anemia was reduced to a greater extent in the MMS and IFS groups (72% and 69%, respectively) than in the FCF group (45%) (p < 0.05). There were no significant differences in anthropometry or in the number of episodes of diarrhea and respiratory infections among treatment groups. The supplements MMS and IS were less acceptable to children, than IFS, FCF and FW. The three supplements IS, ISF and MMS increased Hb more than the FCF; the supplements that contained micronutrients (IFS and MMS) were more effective for reducing the prevalence of anemia. In general, fortified foods were better accepted by the study participants than supplements. CLINICALTRIAL.GOV IDENTIFIER: NCT00822380.


Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate.
Flavanols from chocolate appear to increase nitric oxide bioavailability, protect vascular endothelium, and decrease cardiovascular disease (CVD) risk factors. We sought to test the effect of flavanol-rich dark chocolate (FRDC) on endothelial function, insulin sensitivity, beta-cell function, and blood pressure (BP) in hypertensive patients with impaired glucose tolerance (IGT). After a run-in phase, 19 hypertensives with IGT (11 males, 8 females; 44.8 +/- 8.0 y) were randomized to receive isocalorically either FRDC or flavanol-free white chocolate (FFWC) at 100 g/d for 15 d. After a wash-out period, patients were switched to the other treatment. Clinical and 24-h ambulatory BP was determined by sphygmometry and oscillometry, respectively, flow-mediated dilation (FMD), oral glucose tolerance test, serum cholesterol and C-reactive protein, and plasma homocysteine were evaluated after each treatment phase. FRDC but not FFWC ingestion decreased insulin resistance (homeostasis model assessment of insulin resistance; P < 0.0001) and increased insulin sensitivity (quantitative insulin sensitivity check index, insulin sensitivity index (ISI), ISI(0); P < 0.05) and beta-cell function (corrected insulin response CIR(120); P = 0.035). Systolic (S) and diastolic (D) BP decreased (P < 0.0001) after FRDC (SBP, -3.82 +/- 2.40 mm Hg; DBP, -3.92 +/- 1.98 mm Hg; 24-h SBP, -4.52 +/- 3.94 mm Hg; 24-h DBP, -4.17 +/- 3.29 mm Hg) but not after FFWC. Further, FRDC increased FMD (P < 0.0001) and decreased total cholesterol (-6.5%; P < 0.0001), and LDL cholesterol (-7.5%; P < 0.0001). Changes in insulin sensitivity (Delta ISI - Delta FMD: r = 0.510, P = 0.001; Delta QUICKI - Delta FMD: r = 0.502, P = 0.001) and beta-cell function (Delta CIR(120) - Delta FMD: r = 0.400, P = 0.012) were directly correlated with increases in FMD and inversely correlated with decreases in BP (Delta ISI - Delta 24-h SBP: r = -0.368, P = 0.022; Delta ISI - Delta 24-h DBP r = -0.384, P = 0.017). Thus, FRDC ameliorated insulin sensitivity and beta-cell function, decreased BP, and increased FMD in IGT hypertensive patients. These findings suggest flavanol-rich, low-energy cocoa food products may have a positive impact on CVD risk factors.


Characterization of the regulatory function of the ICP22 protein of equine herpesvirus type 1.
The IR4 gene (inverted repeat gene 4) of equine herpesvirus type 1 (EHV-), the homolog of the herpes simplex virus type 1 ICP22 gene, is differentially expressed as a 1.4-kb early transcript and a 1.7-kb late transcript that encode a series of proteins that migrate between 42 to 47 kDa, localize to the nucleus of EHV-1-infected cells, and become packaged within EHV-1 virions (V. R. Holden, G. B. Caughman, Y. Zhao, R. N. Harty, and D. J. O'Callaghan, J. Virol. 68, 4329-4340, 1994). To assess the role of the IR4 protein in EHV-1 gene regulation, an IR4 expression vector was cotransfected with EHV-1 chimeric promoter-CAT reporter constructs and EHV-1 effector plasmids to determine the effects of the IR4 protein on the expression of immediate-early (IE), early, and late promoters. These studies revealed that the IR4 protein: (i) minimally trans-activates EHV-1 promoters, (ii) acts synergistically with the UL3 (ICP27) gene product to trans-activate the IE promoter, (iii) does not interfere with the trans-repression of the IE promoter by the IE protein, (iv) enhances transactivation of early promoters by the IE protein, (v) enhances the transactivation of both early and late promoters by the IE and UL3 proteins, and (vi) interacts synergistically with the IE protein to trans-activate the heterologous HSV-1 ICP4 promoter. These data suggest that the IR4 gene product plays a significant role in EHV-1 gene regulation.


Unemployment, public-sector health-care spending and breast cancer mortality in the European Union: 1990-2009.
The global economic crisis has been associated with increased unemployment, reduced health-care spending and adverse health outcomes. Insights into the impact of economic variations on cancer mortality, however, remain limited. We used multivariate regression analysis to assess how changes in unemployment and public-sector expenditure on health care (PSEH) varied with female breast cancer mortality in the 27 European Union member states from 1990 to 2009. We then determined how the association with unemployment was modified by PSEH. Country-specific differences in infrastructure and demographic structure were controlled for, and 1-, 3-, 5- and 10-year lag analyses were conducted. Several robustness checks were also implemented. Unemployment was associated with an increase in breast cancer mortality [P < 0.0001, coefficient (R) = 0.1829, 95% confidence interval (CI) 0.0978-0.2680]. Lag analysis showed a continued increase in breast cancer mortality at 1, 3, 5 and 10 years after unemployment rises (P < 0.05). Controlling for PSEH removed this association (P = 0.063, R = 0.080, 95% CI -0.004 to 0.163). PSEH increases were associated with significant decreases in breast cancer mortality (P < 0.0001, R = -1.28, 95% CI -1.67 to -0.877). The association between unemployment and breast cancer mortality remained in all robustness checks. Rises in unemployment are associated with significant short- and long-term increases in breast cancer mortality, while increases in PSEH are associated with reductions in breast cancer mortality. Initiatives that bolster employment and maintain total health-care expenditure may help minimize increases in breast cancer mortality during economic crises.


An alternative physiological role for the EmhABC efflux pump in Pseudomonas fluorescens cLP6a.
Efflux pumps belonging to the resistance-nodulation-division (RND) superfamily in bacteria are involved in antibiotic resistance and solvent tolerance but have an unknown physiological role. EmhABC, a RND-type efflux pump in Pseudomonas fluorescens strain cLP6a, extrudes hydrophobic antibiotics, dyes and polycyclic aromatic hydrocarbons including phenanthrene. The effects of physico-chemical factors such as temperature or antibiotics on the activity and expression of EmhABC were determined in order to deduce its physiological role(s) in strain cLP6a in comparison to the emhB disruptant strain, cLP6a-1. Efflux assays conducted with (14)C-phenanthrene showed that EmhABC activity is affected by incubation temperature. Increased phenanthrene efflux was measured in cLP6a cells grown at 10°C and decreased efflux was observed at 35°C compared with cells grown at the optimum temperature of 28°C. Membrane fatty acids in cLP6a cells were substantially altered by changes in growth temperature and in the presence of tetracycline. Changed membrane fatty acids and increased membrane permeability were associated with ~30-fold increased expression of emhABC in cLP6a cells grown at 35°C, and with increased extracellular free fatty acids. Growth of P. fluorescens cLP6a at supra-optimal temperature was enhanced by the presence of EmhABC compared to strain cLP6a-1. Combined, these observations suggest that the EmhABC efflux pump may be involved in the management of membrane stress effects such as those due to unfavourable incubation temperatures. Efflux of fatty acids replaced as a result of membrane damage or phospholipid turnover may be the primary physiological role of the EmhABC efflux pump in P. fluorescens cLP6a.


Who Should We Target? The Impact of Individual and Family Characteristics on the Expressed Need for Community-Based Treatment Support in HIV Patients in South Africa.
Reviews of impact evaluations of community-based health workers and peer support groups highlight the considerable variability in the effectiveness of such support in improving antiretroviral treatment (ART) outcomes. Evidence indicates that community-based support interventions targeting patients known to be at risk will probably display better results than generic interventions aimed at the entire population of people living with HIV. It is however difficult to identify these at-risk populations, rendering knowledge on the characteristics of patients groups who are in need of community-based support a clear research priority. The current study aims to address the knowledge gap by exploring the predictors of the willingness to (1) receive the support from a community-based health worker or (2) to participate in a support group in public sector ART programme of the Free State Province of South Africa. Based on the Individual-Family-Community framework for HIV research, the study employs a comprehensive approach by not only testing classical individual-level but also family-level predictors of the willingness to receive community-based support. In addition to individual-level predictors-such as age, health status and coping styles-our analysis demonstrated the importance of family characteristics. The results indicated that discrepancies in the family's changeability level were an important predictor of the demand for community-based support services. Conversely, the findings indicated that patients living in a family more flexible than deemed ideal are more likely to require the support of a community health worker. The current study expands theory by indicating the need to acknowledge all social ecological levels in the study of chronic HIV care. The detection of both individual level and family level determinants of the expressed need for community-based support can inform health policy to devise strategies to target scarce resources to those vulnerable patients who report the greatest need for this support. In this way, the study results are a first step in an attempt to move away from generic, broad based community-based interventions towards community support that is tailored to the patient needs at both the individual and family level.


Integrated information theory of consciousness: an updated account.
This article presents an updated account of integrated information theory of consciousness (IIT) and some of its implications. IIT stems from thought experiments that lead to phenomenological axioms and ontological postulates. The information axiom asserts that every experience is one out of many, i.e. specific - it is what it is by differing in its particular way from a large repertoire of alternatives. The integration axiom asserts that each experience is one, i.e. unified - it cannot be reduced to independent components. The exclusion axiom asserts that every experience is definite - it is limited to particular things and not others and flows at a particular speed and resolution. IIT formalizes these intuitions with three postulates. The information postulate states that only "differences that make a difference" from the intrinsic perspective of a system matter: a mechanism generates cause-effect information if its present state has specific past causes and specific future effects within a system. The integration postulate states that only information that is irreducible matters: mechanisms generate integrated information only to the extent that the information they generate cannot be partitioned into that generated within independent components. The exclusion postulate states that only maxima of integrated information matter: a mechanism specifies only one maximally irreducible set of past causes and future effects - a concept. A complex is a set of elements specifying a maximally irreducible constellation of concepts, where the maximum is evaluated at the optimal spatio-temporal scale. Its concepts specify a maximally integrated conceptual information structure or quale, which is identical with an experience. Finally, changes in information integration upon exposure to the environment reflect a system's ability to match the causal structure of the world. After introducing an updated definition of information integration and related quantities, the article presents some theoretical considerations about the relationship between information and causation and about the relational structure of concepts within a quale. It also explores the relationship between the temporal grain size of information integration and the dynamic of metastable states in the corticothalamic complex. Finally, it summarizes how IIT accounts for empirical findings about the neural substrate of consciousness, and how various aspects of phenomenology may in principle be addressed in terms of the geometry of information integration.


The use of the sterically demanding IPr* and related ligands in catalysis.
This account highlights the synthesis and applications of one of the very bulky NHC ligands, IPr* (1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazo-2-ylidene). This ligand and some of its derivatives have been found very effective in several catalytic applications and have enabled the isolation of highly reactive organometallic complexes. More specifically, applications of this ligand in Pd and Ni chemistry have permitted challenging transformations under mild reaction conditions and low catalyst loadings. We report the successes as well as the limitations encountered using transition-metal systems bearing this ligand-type. This report will hopefully serve as a guide to synthetic chemists, providing insights as to when the very sterically demanding IPr* ligand (and its congeners) and in a broader context, very bulky NHC ligands, should be used.


Psychometric properties of the Liebowitz Social Anxiety Scale.
The present study provides data on the reliability, validity and treatment sensitivity of the Liebowitz Social Anxiety Scale (LSAS), one of the most commonly used clinician-administered scales for the assessment of social phobia. Three hundred and eighty-two patients from several studies of the treatment of social phobia were evaluated. An independent assessor administered the LSAS to each patient prior to the initiation of treatment. Patients also completed other measures of social anxiety and avoidance, although the specific measures varied across samples. The LSAS and its subscales were normally distributed and demonstrated excellent internal consistency. The convergent validity of the LSAS was demonstrated via significant correlations with other commonly-used measures of social anxiety and avoidance. These correlations also tended to be larger than correlations with measures of depression, especially after treatment. However, the pattern of correlations of LSAS subscales with one another and with the other measures suggest that the fear subscales and the avoidance subscales may not be sufficiently distinct in clinical samples. The LSAS was also demonstrated to be sensitive to the effects of pharmacological treatments of social phobia over time and in comparison to double-blind pill placebo. The LSAS appears to be a reliable, valid and treatment sensitive measure of social phobia. Further study of the LSAS, both in samples with severe social phobia and in community samples, is needed.


False memories in highly superior autobiographical memory individuals.
The recent identification of highly superior autobiographical memory (HSAM) raised the possibility that there may be individuals who are immune to memory distortions. We measured HSAM participants' and age- and sex-matched controls' susceptibility to false memories using several research paradigms. HSAM participants and controls were both susceptible to false recognition of nonpresented critical lure words in an associative word-list task. In a misinformation task, HSAM participants showed higher overall false memory compared with that of controls for details in a photographic slideshow. HSAM participants were equally as likely as controls to mistakenly report they had seen nonexistent footage of a plane crash. Finding false memories in a superior-memory group suggests that malleable reconstructive mechanisms may be fundamental to episodic remembering. Paradoxically, HSAM individuals may retrieve abundant and accurate autobiographical memories using fallible reconstructive processes.


Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2.
The hepatitis C virus (HCV) glycoprotein E2 is the major target of neutralizing antibodies and is therefore highly relevant for vaccine design. Its structure features a central immunoglobulin (Ig)-like β-sandwich that contributes to the binding site for the cellular receptor CD81. We show that a synthetic peptide corresponding to a β-strand of this Ig-like domain forms an α-helix in complex with the anti-E2 antibody DAO5, demonstrating an inside-out flip of hydrophobic residues and a secondary structure change in the composite CD81 binding site. A detailed interaction analysis of DAO5 and cross-competing neutralizing antibodies with soluble E2 revealed that the Ig-like domain is trapped by different antibodies in at least two distinct conformations. DAO5 specifically captures retrovirus particles bearing HCV glycoproteins (HCVpp) and infectious cell culture-derived HCV particles (HCVcc). Infection of cells by DAO5-captured HCVpp can be blocked by a cross-competing neutralizing antibody, indicating that a single virus particle simultaneously displays E2 molecules in more than one conformation on its surface. Such conformational plasticity of the HCV E2 receptor binding site has important implications for immunogen design.IMPORTANCE Recent advances in the treatment of hepatitis C virus (HCV) infection with direct-acting antiviral drugs have enabled the control of this major human pathogen. However, due to their high costs and limited accessibility in combination with the lack of awareness of the mostly asymptomatic infection, there is an unchanged urgent need for an effective vaccine. The viral glycoprotein E2 contains regions that are crucial for virus entry into the host cell, and antibodies that bind to these regions can neutralize infection. One of the major targets of neutralizing antibodies is the central immunoglobulin (Ig)-like domain within E2. We show here that this Ig-like domain is conformationally flexible at the surface of infectious HCV particles and pseudoparticles. Our study provides novel insights into the interactions of HCV E2 with the humoral immune system that should aid future vaccine development.


Effect of preoperative combined treatment with alendronate and calcitriol on fixation of hydroxyapatite-coated implants in ovariectomized rats.
Osteoporosis is a potential risk factor affecting implant stability following total joint arthroplasty. Bisphosphonates are potent inhibitors of osteoblastic bone resorption, and vitamin D is an important hormone involved in the regulation of calcium metabolism. We investigated the benefit of preoperative treatment with alendronate, vitamin D (calcitriol), or a combination of these substances on fixation of hydroxyapatite-coated implants in an ovariectomized rat model of osteoporosis. Of sixty-four female rats in the study, fifty-six underwent ovariectomy and eight, a sham operation. A hydroxyapatite-coated femoral implant and an uncoated implant were implanted in all rats seven months after the ovariectomy or the sham operation. Of the fifty-six rats that underwent ovariectomy, eight served as the control group. The remaining forty-eight were treated with alendronate, calcitriol, or a combination of these agents either starting eight weeks before implantation of the rod or starting immediately after implantation. The treatment was continued until four weeks after the implantation. Four weeks after the implantation, the total and cancellous bone mineral density at the proximal part of the tibia and the shear strength of the bone-implant interface were measured in all rats. Although total bone mineral density increased in all of the alendronate-treated groups, compared with that in the ovariectomized control group, cancellous bone mineral density increased only in the group pretreated with both alendronate and calcitriol. The implant stability in the ovariectomized control rats was significantly decreased compared with that in the sham-operation rats. While treatment with alendronate only or calcitriol only did not improve the stability of the implants, treatment with a combination of alendronate and calcitriol, starting preoperatively, significantly improved the stability of the hydroxyapatite-coated implants. Treatment with a combination of alendronate and calcitriol, starting preoperatively, can improve cancellous bone mineral density and the stability of hydroxyapatite-coated implants in an osteoporotic rat.


A sun-pumped cw one-watt laser.
1 W of w laser output has been obtained at room temperature from a sun-pumped, neodymium-doped YAG crystal. The water-cooled laser rod was pumped with a modified Cassegrain sun-tracking telescope consisting of a 61-cm diam paraboloidal primary mirror collector, a water-cooled hyperbolic-cylindric secondary mirror and a hemicircular cylindric tertiary mirror. The cylindrical image volume was coincident with 24 mm of the 3-mm by 30-mm YAG rod. The spike-free output was obtained for hours at a time with a late October sun at a 42 degrees North latitude. Using the same primary mirror and near-unity numerical aperture refractors, approximately 1.25 W were obtained in 7 msec pulses from an uncooled, sun-pumped, neodymium-doped, glass rod. Further refinements in the telescope and the laser crystal, and a space environment, should allow 1 W of laser output to be generated by using a 30-cm diam collector.


Numerical simulation of undular jumps on graveled bed using volume of fluid method.
Undular hydraulic jumps are characterized by a smooth rise of the free surface, followed by a train of stationary waves. These jumps sometimes occur in natural waterways and rivers. Numerical difficulties are especially distinct when the flow condition is close to the critical value because of the high sensitivity of the near-critical flow field to flow and channel conditions. Furthermore, the free surface has a wavy shape, which may indicate the occurrence of several transitions from supercritical to subcritical states and vice versa (i.e., undular hydraulic jumps). In this study, a flow model is used to predict an undular hydraulic jump in a rectangular open channel. The model is based on the general two-dimensional, Reynolds-averaged, Navier-Stokes flow equations. The resulting set of partial differential equations is solved using the FLOW-3D solver. The results are compared with the experimental data to validate the model. The comparative analysis shows that the proposed model yields good results. Several types of undular hydraulic jumps occurring in different situations are then simulated to prove the potential application of the model.


Wound drainage following groin dissection for malignant disease in adults.
Groin dissection is commonly performed for the treatment of a variety of cancers, including melanoma, and squamous cell carcinoma of the skin, penis or vulva. It is uncertain whether insertion of a drain reduces complication rates, and, if used, the optimum time for drain removal after surgery is also unknown. To assess the current level of evidence to determine whether placement of a drain is beneficial after groin dissection in terms of reducing seroma, haematoma, wound dehiscence and wound infection rates, and to determine the optimal type and duration of drainage following groin dissection if it is shown to be beneficial. In September 2014 we searched the following electronic databases using a pre-designed search strategy: the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library). In November 2013 we searched Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We did not restrict the search and study selection with respect to language, date of publication or study setting. We considered all randomised controlled trials (RCTs) comparing wound drainage with no wound drainage in individuals undergoing groin dissection, where the most superior node excised was Cloquet's node (the most superior inguinal lymph node). No limits were applied to language of publication or trial location. Two review authors independently determined the eligibility of each trial. Two review authors, working independently, screened studies identified from the search; there were no disagreements. We did not identify any RCTs that met the inclusion criteria for the review. There is a need for high quality RCTs to guide clinical practice in this under-researched area.


N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot Study.
There is increasing evidence that redox dysregulation, which can lead to oxidative stress and eventually to impairment of oligodendrocytes and parvalbumin interneurons, may underlie brain connectivity alterations in schizophrenia. Accordingly, we previously reported that levels of brain antioxidant glutathione in the medial prefrontal cortex were positively correlated with increased functional connectivity along the cingulum bundle in healthy controls but not in early psychosis patients. In a recent randomized controlled trial, we observed that 6-month supplementation with a glutathione precursor, N-acetyl-cysteine, increased brain glutathione levels and improved symptomatic expression and processing speed. We investigated the effect of N-acetyl-cysteine supplementation on the functional connectivity between regions of the cingulate cortex, which have been linked to positive symptoms and processing speed decline. In this pilot study, we compared structural connectivity and resting-state functional connectivity between early psychosis patients treated with 6-month N-acetyl-cysteine (n = 9) or placebo (n = 11) supplementation with sex- and age-matched healthy control subjects (n = 74). We observed that 6-month N-acetyl-cysteine supplementation increases functional connectivity along the cingulum and more precisely between the caudal anterior part and the isthmus of the cingulate cortex. These functional changes can be partially explained by an increase of centrality of these regions in the functional brain network. N-acetyl-cysteine supplementation has a positive effect on functional connectivity within the cingulate cortex in early psychosis patients. To our knowledge, this is the first study suggesting that increased brain glutathione levels via N-acetyl-cysteine supplementation may improve brain functional connectivity.


Elevated Concentrations of Serum Immunoglobulin Free Light Chains in Systemic Lupus Erythematosus Patients in Relation to Disease Activity, Inflammatory Status, B Cell Activity and Epstein-Barr Virus Antibodies.
In this study, we examined the concentration of serum immunoglobulin free light chains (FLCs) in systemic lupus erythematosus (SLE) patients and investigated its association with various disease parameters in order to evaluate the role of FLCs as a potential biomarker in SLE. Furthermore, FLCs' association with Epstein-Barr virus (EBV) antibodies was examined. Using a nephelometric assay, κFLC and λFLC concentrations were quantified in sera from 45 SLE patients and 40 healthy controls. SLE patients with renal insufficiency were excluded in order to preclude high concentrations of serum FLCs due to decreased clearance. Serum FLC concentrations were significantly elevated in SLE patients compared to healthy controls (p<0.0001) also after adjusting for Ig levels (p<0.0001). The concentration of serum FLCs correlated with a global disease activity (SLE disease activity index (SLEDAI)) score of the SLE patients (r = 0.399, p = 0.007). Furthermore, concentrations of FLCs correlated with titers of dsDNA antibodies (r = 0.383, p = 0.009), and FLC levels and SLEDAI scores correlated in the anti-dsDNA-positive SLE patients, but not in anti-dsDNA-negative SLE patients. Total immunoglobulin (IgG and IgA) concentrations correlated with FLC concentrations and elevated FLC levels were additionally shown to associate with the inflammatory marker C-reactive protein and also with complement consumption determined by low C4 in SLE patients. Collectively, results indicated that elevated serum FLCs reflects increased B cell activity in relation to inflammation. SLE patients had an increased seropositivity of EBV-directed antibodies that did not associate with elevated FLC concentrations. An explanation for this could be that serum FLC concentrations reflect the current EBV activity (reactivation) whereas EBV-directed antibodies reflect the extent of previous infection/reactivations. SLE patients have elevated concentrations of serum FLCs that correlate with global disease activity scores and especially serologic markers for active disease. These findings are suggestive of circulating FLCs having potential as a new supplementary serologic biomarker in SLE.


Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy (LANCE).
Observational studies have supported the practice of offering minimally invasive interval debulking surgery after neoadjuvant chemotherapy for well-selected patients with advanced epithelial ovarian cancer. However, there are no prospective randomized data comparing the oncologic efficacy of minimally invasive and open interval debulking surgery in epithelial ovarian cancer. The primary objective of this study is to examine whether minimally invasive surgery is non-inferior to laparotomy in terms of disease-free survival in women with advanced stage epithelial ovarian cancer that responded to three or four cycles of neoadjuvant chemotherapy. We hypothesize that in patients who had a complete or partial response to neoadjuvant chemotherapy, minimally invasive interval debulking surgery is not inferior to laparotomy. The Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy (LANCE) trial is an international, prospective, randomized, multicenter, non-inferiority phase III trial to compare minimally invasive surgery vs laparotomy in women with advanced stage high-grade epithelial ovarian cancer that had a complete or partial response to three or four cycles of neoadjuvant chemotherapy and normalization of CA-125. The first 100 participants will be enrolled into a pilot lead-in to determine feasibility. The study will be considered feasible and will continue to Phase III under the following conditions: the accrual rate reaches at least 80% of the target rate after all pilot sites are open; the crossover rate in the minimally invasive group is less than 25%; and the difference of complete gross resection between the minimally invasive and open group is less than 20%. If the study is determined to be feasible, all remaining participants will be enrolled into the Phase III stage. Patients with stage IIIC or IV high-grade epithelial ovarian, primary peritoneal or fallopian tube carcinoma who had a complete or partial response to three or four cycles of neoadjuvant chemotherapy based on imaging and normalization of CA-125 will be enrolled. Patients with evidence of tumor not amenable to minimally invasive resection on pre-operative imaging will be excluded. The primary endpoint is non-inferiority of disease-free survival in minimally invasive vs laparotomic interval debulking surgery. To demonstrate non-inferiority with a margin of 33% in the hazard ratio (HR=1.33), 549 patients will be randomized.


The evolution of virulence and host specialization in malaria parasites of primates.
Parasite virulence, i.e. the damage done to the host, may be a by-product of the parasite's effort to maximize its fitness. Accordingly, several life-history trade-offs may explain interspecific differences in virulence, but such constraints remain little tested in an evolutionary context. In this phylogenetic study of primate malarias, I investigated the relationship between virulence and other parasite life-history traits. I used peak parasitaemia as a proxy for virulence, because it reflected parasite reproductive success and parasite-induced mortality. Peak parasitaemia was higher in specialist than in generalist species, even when confounding life-history traits were controlled. While there was a significant phylogenetic relationship between the number of competitors per host and host specialization, peak parasitaemia was unrelated to within-host competition. Therefore, the key evolutionary factor that favours virulence is host specialization, and the evolutionary success of virulent parasites, such as Plasmodium falciparum, may be better understood when the trade-off in virulence between different hosts is considered. Such phylogenetic results may help us design better protection programmes against malaria.


The potential use of autopsy for continuous quality improvement in hospice and palliative care.
In 2006, the Centers for Medicare & Medicaid Services (CMS) contracted with The Carolinas Center for Medical Excellence (CCME), the Quality Improvement Organization (QIO) for North and South Carolina, to develop an instrument package and procedures for hospice and palliative care programs to assess and monitor the quality of the care that they provide. As part of our work, we investigated the potential uses of autopsy for continuous quality improvement purposes. Our objective is to understand (1) the potential benefits and uses of autopsy for various constituents, (2) the reasons for the decline in the use of autopsy despite these potential benefits, (3) the practical aspects of autopsy in the hospice setting, and (4) current hospice practices in regard to autopsy. To achieve these goals, we reviewed the existing literature and interviewed stakeholders, including hospice and palliative care providers, professional organizations and advocacy groups, quality improvement and measurement experts, and pathologists. Important barriers limit the use of autopsy to understand and improve quality of care in hospice, including costs, unintended consequences, and the limited ability to systematically use autopsy information to improve care. Some themes were more predominant among providers, whereas others emerged primarily from interviews with nonproviders. On the basis of existing research and stakeholder interviews, autopsy is currently not a feasible mechanism to improve quality of care in hospice. If financial and attitudinal barriers are reduced, a systematic sampling of deaths for autopsy may provide evidence for the value of this information source.


Nrf2 Is a Key Regulator on Puerarin Preventing Cardiac Fibrosis and Upregulating Metabolic Enzymes UGT1A1 in Rats.
Puerarin is an isoflavone isolated from Radix puerariae. Emerging evidence shown that puerarin possesses therapeutic benefits that aid in the prevention of cardiovascular diseases. In this study, we evaluated the effects of puerarin on oxidative stress and cardiac fibrosis induced by abdominal aortic banding (AB) and angiotensin II (AngII). We also investigated the mechanisms underlying this phenomenon. The results of histopathological analysis, as well as measurements of collagen expression and cardiac fibroblast proliferation indicated that puerarin administration significantly inhibited cardiac fibrosis induced by AB and AngII. These effects of puerarin may reflect activation of Nrf2/ROS pathway. This hypothesis is supported by observed decreases of reactive oxygen species (ROS), decreases Keap 1, increases Nrf2 expression and nuclear translocation, and decreases of collagen expressions in cardiac fibroblasts treated with a combination of puerarin and AngII. Inhibition of Nrf2 with specific Nrf2 siRNA or Nrf2 inhibitor brusatol attenuated anti-fibrotic and anti-oxidant effects of puerarin. The metabolic effects of puerarin were mediated by Nrf2 through upregulation of UDP-glucuronosyltransferase (UGT) 1A1. The Nrf2 agonist tBHQ upregulated protein expression of UGT1A1 over time in cardiac fibroblasts. Treatment with Nrf2 siRNA or brusatol dramatically decreased UGT1A1 expression in puerarin-treated fibroblasts. The results of chromatin immunoprecipitation-qPCR further confirmed that puerarin significantly increased binding of Nrf2 to the promoter region of Ugt1a1. Western blot analysis showed that puerarin significantly inhibited AngII-induced phosphorylation of p38-MAPK. A specific inhibitor of p38-MAPK, SB203580, decreased collagen expression, and ROS generation induced by AngII in cardiac fibroblast. Together, these results suggest that puerarin prevents cardiac fibrosis via activation of Nrf2 and inactivation of p38-MAPK. Nrf2 is the key regulator of anti-fibrotic effects and upregulates metabolic enzymes UGT1A1. Autoregulatory circuits between puerarin and Nrf2-regulated UGT1A1 attenuates side effects associated with treatment, but it does not weaken puerarin's pharmacological effects.


Coronary artery bypass graft surgery: clinical decision making and cost-effectiveness analysis.
Decision-analytic techniques were used to evaluate the choice between an aortocoronary bypass operation and medical management in a set of hypothetical patients with coronary artery disease. The decision framework incorporates variables believed to have an important bearing on the choice of treatment. Probability estimates were obtained from two cardiologists and one cardiac surgeon. Patient preferences for the trade-off between years of survival and the quality of life as reflected by the severity of angina pectoris were made explicit by assigning utility values to alternative health outcomes. The results are expressed in terms of quality-adjusted years of life expectancy. Decision analysis favored operation for 13 of the 14 hypothetical patients, including patients with one- and two-vessel disease. The one patient for whom medical treatment was preferred had mild angina pectoris, severe left ventricular dysfunction, and a poor prognosis regardless of therapeutic modality. The results are sensitive to changes in the probability of long-term survival, but not to changes in operative mortality rates. In five patients, the physicians' clinical judgments favored medical treatment, whereas their decision-analysis-derived estimates of survival favored operation. Possible explanations for these discrepancies are discussed. A simplified cost-effectiveness analysis for patients in whom surgery was the optimal treatment indicated costs ranging from $1,500 to $250,000 per year of life gained and from $1,500 to $32,000 per quality-adjusted year of life gained.


A comparison of survivourship and function (grazing and behaviour) of three gastropod species used as clean-up crew for the marine aquarium trade.
Several million gastropods are collected each year for the marine ornamental trade to graze on algae detrimental to aquarium species, however, little is known about popular species' suitability to perform this clean-up crew role. Three commonly traded gastropods, Turbo bruneus, Tectus fenestratus, and Tegula eiseni were assessed on their performance. Their survival was quantified as was their movement, and positioning with respect to water level and growth rates were calculated from the start and end weights. Nitrocellulose-coated slides were impregnated with an algal extract and the amount of grazing by each species was also compared. After 53 days final mortality levels of species were significantly different with all T. bruneus individuals surviving, whilst all T. fenestratus individuals apart from two and 35% of the T. eiseni had died by the end of the experiment. T. bruneus grazed significantly more than individuals of T. eiseni, and T. fenestratus. Both T. bruneus and T. eiseni were heavier after one month with T. bruneus gaining significantly more weight than T. eiseni. Greater percentages of algae were grazed by T. bruneus of increasing weight, although this relationship was not found for T. eiseni and T. fenestratus. All three species were generally active and remained within the water for the vast majority of time, although a small, but significant amount of time was spent out of the water for T. eiseni. T. fenestratus were significantly less active than T. bruneus, although the mean activity of T. eiseni was not significantly different from either species. T. bruneus out performs the other two species as a cleaning organism especially in the context of fluctuating water quality, thus highlighting the varying suitability of organisms for this task. Preference in the ornamental trade should be given to T. bruneus over the other topshells, but accurate species identification is critical.


Evaluation of clinical and laboratory markers of cardiometabolic risk in overweight and obese children and adolescents.
This study analyzed the frequency of cardiometabolic risk markers and metabolic syndrome occurrence in overweight and obese children and adolescents. The participants included 161 overweight (n=65) and obese (n=96) individuals aged between 5 and 19 years. Clinical markers were assessed (body mass index, body fat percentage, waist circumference, acanthosis, systolic and diastolic blood pressures, laboratory parameters [glucose, insulin, cholesterol (total and fractions) and triglyceride levels and homeostasis model assessment of insulin resistance (HOMA-IR) index] and leptin and adiponectin levels). The frequency of changes, odds ratios and correlations among markers were determined. Metabolic syndrome was assessed according to International Diabetes Federation criteria. A high frequency of acanthosis (51.6%); increased waist circumference (45.4%), systolic blood pressure / diastolic blood pressure (8.1% / 9.3%), glucose (10%), insulin (36.9%) and HOMA-IR (44.3%) values; and reduced high-density lipoprotein levels (47.2%) were observed. Leptin levels were increased in 95% of obese and in 66% of overweight subjects. Adiponectin was decreased in 29.5% of obese and in 34% of overweight subjects. An odd ratio analysis revealed a greater probability of increased waist circumference (9.0), systolic blood pressure (4.1), triglyceride (2.3) and insulin (2.9) levels and HOMA-IR (3.0) in the obese group than in the overweight group. The clinical and laboratory parameters and leptin levels exhibited significant correlations, whereas adiponectin was negatively correlated with systolic blood pressure. The occurrence rate of metabolic syndrome was 13.6%. The high frequency of changes in clinical, laboratory and adipokine markers indicates the need for early interventions aimed at preventing cardiometabolic complications in adulthood.


Transoral robotic total laryngectomy: report of 3 cases.
Because of the significant toxicity of chemoradiation regimens, there has been a resurgence of interest in the primary surgical management of head and neck cancer and, in particular, the use of minimally invasive surgery. One such technique is transoral robotic surgery (TORS). We aim to discuss the potential role of TORS in patients requiring total laryngectomy (TL). Three patients underwent TORS-assisted narrow-field TL. Relative data on preoperative, intraoperative, and postoperative management were collated including postoperative complications. We present 3 cases of transoral robotic surgery (TORS)-assisted TL in patients requiring narrow field laryngectomy without requirement for neck dissection. In reviewing these cases we provide a discussion of pertinent preoperative and intraoperative considerations that can assist in facilitating successful completion of the procedure. In particular, appropriate assessment at the pinsertlinePOLA_Del_Blank_PgPOLA_Shift_FramePORT_rem_fpg_underremovelinetabminilanning endoscopy in addition to a methodical surgical approach are vital to the successful use of the robot in TORS-assisted TL.


Using High Frequency Transcranial Random Noise Stimulation to Modulate Face Memory Performance in Younger and Older Adults: Lessons Learnt From Mixed Findings.
High-frequency transcranial random noise stimulation (tRNS) has been shown to improve a range of cognitive and perceptual abilities. Here we sought to examine the effects of a single session of tRNS targeted at the ventrolateral prefrontal cortices (VLPFC) on face memory in younger and older adults. To do so, we conducted three experiments. In Experiment 1, we found that younger adults receiving active tRNS outperformed those receiving sham stimulation (i.e., using a between-participant factor for stimulation condition; Experiment 1). This effect was not observed for object memory (car memory) in younger adults (Experiment 2), indicating that the effect is not a general memory effect. In Experiment 3, we sought to replicate the effects of Experiment 1 using a different design (within-participant factor of stimulation - active or sham tRNS to the same individual) and to extend the study by including older adult participants. In contrast to Experiment 1, we found that active tRNS relative to sham tRNS reduced face memory performance in both younger and older adults. We also found that the degree of decline in performance in the active tRNS relative to sham tRNS condition was predicted by baseline ability, with higher performing participants showing the largest decreases in performance. Overall, the results indicate that tRNS to the VLPFC modulates face memory, but that there may be performance and protocol specific moderators of this effect. We discuss these findings in the context of the broader literature showing the importance of individual variation in the outcome of non-invasive brain stimulation intervention approaches. We conclude that while tRNS may have potential as an intervention approach, generalizing from single experiment studies to wide application is risky and caution should be adopted in interpreting findings.


A prospective evaluation of cardiovascular magnetic resonance measures of dyssynchrony in the prediction of response to cardiac resynchronization therapy.
Many patients with electrical dyssynchrony who undergo cardiac resynchronization therapy (CRT) do not obtain substantial benefit. Assessing mechanical dyssynchrony may improve patient selection. Results from studies using echocardiographic imaging to measure dyssynchrony have ultimately proved disappointing. We sought to evaluate cardiac motion in patients with heart failure and electrical dyssynchrony using cardiovascular magnetic resonance (CMR). We developed a framework for comparing measures of myocardial mechanics and evaluated how well they predicted response to CRT. CMR was performed at 1.5 Tesla prior to CRT. Steady-state free precession (SSFP) cine images and complementary modulation of magnetization (CSPAMM) tagged cine images were acquired. Images were processed using a novel framework to extract regional ventricular volume-change, thickening and deformation fields (strain). A systolic dyssynchrony index (SDI) for all parameters within a 16-segment model of the ventricle was computed with high SDI denoting more dyssynchrony. Once identified, the optimal measure was applied to a second patient population to determine its utility as a predictor of CRT response compared to current accepted predictors (QRS duration, LBBB morphology and scar burden). Forty-four patients were recruited in the first phase (91% male, 63.3 ± 14.1 years; 80% NYHA class III) with mean QRSd 154 ± 24 ms. Twenty-one out of 44 (48%) patients showed reverse remodelling (RR) with a decrease in end systolic volume (ESV) ≥ 15% at 6 months. Volume-change SDI was the strongest predictor of RR (PR 5.67; 95% CI 1.95-16.5; P = 0.003). SDI derived from myocardial strain was least predictive. Volume-change SDI was applied as a predictor of RR to a second population of 50 patients (70% male, mean age 68.6 ± 12.2 years, 76% NYHA class III) with mean QRSd 146 ± 21 ms. When compared to QRSd, LBBB morphology and scar burden, volume-change SDI was the only statistically significant predictor of RR in this group. A systolic dyssynchrony index derived from volume-change is a highly reproducible measurement that can be derived from routinely acquired SSFP cine images and predicts RR following CRT whilst an SDI of regional strain does not.


Serological evaluation of Mycobacterium ulcerans antigens identified by comparative genomics.
A specific and sensitive serodiagnostic test for Mycobacterium ulcerans infection would greatly assist the diagnosis of Buruli ulcer and would also facilitate seroepidemiological surveys. By comparative genomics, we identified 45 potential M. ulcerans specific proteins, of which we were able to express and purify 33 in E. coli. Sera from 30 confirmed Buruli ulcer patients, 24 healthy controls from the same endemic region and 30 healthy controls from a non-endemic region in Benin were screened for antibody responses to these specific proteins by ELISA. Serum IgG responses of Buruli ulcer patients were highly variable, however, seven proteins (MUP045, MUP057, MUL_0513, Hsp65, and the polyketide synthase domains ER, AT propionate, and KR A) showed a significant difference between patient and non-endemic control antibody responses. However, when sera from the healthy control subjects living in the same Buruli ulcer endemic area as the patients were examined, none of the proteins were able to discriminate between these two groups. Nevertheless, six of the seven proteins showed an ability to distinguish people living in an endemic area from those in a non-endemic area with an average sensitivity of 69% and specificity of 88%, suggesting exposure to M. ulcerans. Further validation of these six proteins is now underway to assess their suitability for use in Buruli ulcer seroepidemiological studies. Such studies are urgently needed to assist efforts to uncover environmental reservoirs and understand transmission pathways of the M. ulcerans.


A scoping review of African swine fever virus spread between domestic and free-living pigs.
Since 2007, African swine fever virus (ASFV) has spread to countries in Europe, Asia and Oceania and has caused devastating impacts on pigs and the pork industry. Transmission can be direct or indirect, and epidemiologic scenarios have been described in which spread occurs between free-living and domestic pigs. The purpose of this scoping review was to identify primary research in which authors made statements to support ASFV transmission between free-living and domestic pigs and assess the circumstances in which transmission events occurred. A search was conducted in five bibliographic databases and the grey literature. Two reviewers (from a team of ten) independently screened each record and charted data (demographics of the pig populations, their husbandry [domestic pigs] and habitat [free-living pigs], the spatial and temporal distribution of ASF, the occurrence or burden of ASF in the populations, and whether ticks were present in the geographic range of the pig populations). Data synthesis included statistics and a narrative summary. From 1,349 records screened, data were charted from 46 individual studies published from 1985 to 2020. Outbreak investigations revealed that whilst poor biosecurity of domestic pig operations was often reported, direct contact resulting in transmission between free-living and domestic pigs was rarely reported. Studies in which quantitative associations were made generally found that spread within populations was more important than spread between populations, although this was not always the case, particularly when domestic pigs were free-ranging. We conclude that there is limited evidence that transmission of ASFV between free-living and domestic pigs is an important feature of ASF epidemiology, especially in the current ASF epidemic in Europe and the Russian Federation. If ASFV elimination cannot be achieved in free-living pigs, compartmentalization of domestic pig populations from free-living populations via biosecurity strategies could be used to support trade of domestic pigs.


The reaction of cobaloximes with hydrogen: products and thermodynamics.
A cobalt hydride has been proposed as an intermediate in many reactions of the Co(dmgBF2)2L2 system, but its observation has proven difficult. We have observed the UV-vis spectra of Co(dmgBF2)2L2 (1) in CH3CN under hydrogen pressures of up to 70 atm. A Co(I) compound (6a) with an exchangeable proton is eventually formed. We have determined the bond dissociation free energy and pK(a) of the new O-H bond in 6a to be 50.5 kcal/mol and 13.4, respectively, in CH3CN, matching previous reports.


Mixed adjuvant formulations reveal a new combination that elicit antibody response comparable to Freund's adjuvants.
Adjuvant formulations capable of inducing high titer and high affinity antibody responses would provide a major advance in the development of vaccines to viral infections such as HIV-1. Although oil-in-water emulsions, such as Freund's adjuvant (FCA/FIA), are known to be potent, their toxicity and reactogenicity make them unacceptable for human use. Here, we explored different adjuvants and compared their ability to elicit antibody responses to FCA/FIA. Recombinant soluble trimeric HIV-1 gp140 antigen was formulated in different adjuvants, including FCA/FIA, Carbopol-971P, Carbopol-974P and the licensed adjuvant MF59, or combinations of MF59 and Carbopol. The antigen-adjuvant formulation was administered in a prime-boost regimen into rabbits, and elicitation of antigen binding and neutralizing antibodies (nAbs) was evaluated. When used individually, only FCA/FIA elicited significantly higher titer of nAbs than the control group (gp140 in PBS (p<0.05)). Sequential prime-boost immunizations with different adjuvants did not offer improvements over the use of FCA/FIA or MF59. Remarkably however, the concurrent use of the combination of Carbopol-971P and MF59 induced potent adjuvant activity with significantly higher titer nAbs than FCA/FIA (p<0.05). This combination was not associated with any obvious local or systemic adverse effects. Antibody competition indicated that the majority of the neutralizing activities were directed to the CD4 binding site (CD4bs). Increased antibody titers to the gp41 membrane proximal external region (MPER) and gp120 V3 were detected when the more potent adjuvants were used. These data reveal that the combination of Carbopol-971P and MF59 is unusually potent for eliciting nAbs to a variety of HIV-1 nAb epitopes.


Conservation of structure and function of DNA replication protein A in the trypanosomatid Crithidia fasciculata.
Human replication protein A (RP-A) is a three-subunit protein that is required for simian virus 40 (SV40) replication in vitro. The trypanosome homologue of RP-A has been purified from Crithidia fasciculata. It is a 1:1:1 complex of three polypeptides of 51, 28, and 14 kDa, binds single-stranded DNA via the large subunit, and is localized within the nucleus. C. fasciculata RP-A substitutes for human RP-A in the large tumor antigen-dependent unwinding of the SV40 origin of replication and stimulates both DNA synthesis and DNA priming by human DNA polymerase alpha/primase, but it does not support efficient SV40 DNA replication in vitro. This extraordinary conservation of structure and function between human and trypanosome RP-A suggests that the mechanism of DNA replication, at both the initiation and the elongation level, is conserved in organisms that diverged from the main eukaryotic lineage very early in evolution.


Alleviation of commercial collagen sponge- and membrane-induced apoptosis and dysfunction in cultured osteoblasts by an amino acid derivative.
The objectives of this in vitro study were to determine whether the commercial collagen material used in bone augmentation procedures induces oxidative stress-mediated adverse effects on the viability and function of osteoblasts and to determine whether N-acetyl cysteine (NAC), an antioxidant amino acid derivative, can alleviate these effects. Commercial collagen sponge (Collaplug) and membrane (BioGide) were treated with NAC. Rat calvaria-derived osteoblasts were directly seeded on these materials with or without NAC pretreatment. Cytotoxic evaluation was performed by flowcytometric cell viability assay, confocal laser microscopic analysis of attached cell morphology and reactive oxygen species (ROS) localization, and alkaline phosphatase staining. Cell viability was less than 40% on both collagen sponge and membrane 24 hours after seeding and increased to 50% with NAC pretreatment. Cell death was characterized by apoptosis. Colonization of attached cells was sparse on the untreated sponge and membrane on day 1, and the cells were round, small, and filled with intense and closely packed intracellular ROS. In contrast, NAC-pretreated material had dense cell colonies consisting of well-spread osteoblasts and fully developing cytoskeleton and cellular processes with little ROS generation. On day 7 of culture, NAC-pretreated collagen sponge and membrane yielded an expanded alkaline phosphatase-positive area occupying 60% and 80% of the surface area, respectively, whereas the untreated collagen materials had limited alkaline phosphatase activity (7% or less). Commercial collagen sponge and membrane induced considerable cell death, impaired initial function, and generated extraordinary intracellular ROS in attached osteoblasts, whereas NAC pretreatment substantially ameliorated these effects. The potential benefits of NAC's detoxifying capacity on bone regeneration using collagen matrix materials in an animal model should be confirmed with further study.


Loss of cutaneous TSLP-dependent immune responses skews the balance of inflammation from tumor protective to tumor promoting.
Inflammation can promote or inhibit cancer progression. In this study we have addressed the role of the proinflammatory cytokine thymic stromal lymphopoietin (TSLP) during skin carcinogenesis. Using conditional loss- and gain-of-function mouse models for Notch and Wnt signaling, respectively, we demonstrate that TSLP-mediated inflammation protects against cutaneous carcinogenesis by acting directly on CD4 and CD8 T cells. Genetic ablation of TSLP receptor (TSLPR) perturbs T-cell-mediated protection and results in the accumulation of CD11b(+)Gr1(+) myeloid cells. These promote tumor growth by secreting Wnt ligands and augmenting β-catenin signaling in the neighboring epithelium. Epithelial specific ablation of β-catenin prevents both carcinogenesis and the accumulation of CD11b(+)Gr1(+) myeloid cells, suggesting tumor cells initiate a feed-forward loop that induces protumorigenic inflammation.


Genetic and phenotypic parameters for dietary selection of mountain big sagebrush (Artemisia tridentata Nutt. ssp. vaseyana.
The heritability of diet selection for mountain big sagebrush (Artemisia tridentata Nutt. ssp. vaseyana [Rydb] Beetle) by grazing sheep was estimated from fecal samples collected from 549 Rambouillet ewes. Fecal samples were collected in September and October during 1996 and 1997 from free-grazing ewes on intermountain sagebrush-bunchgrass rangelands at the U.S. Sheep Experiment Station in Idaho. The total number of fecal samples was 1,949. Fecal samples were evaluated for composition of big sagebrush by near-infrared spectroscopy. Percentage of sagebrush in the diet was less in September than in October (21.6 vs 31.7%, respectively). Single-trait and bivariate derivative-free REML analyses were performed to genetically compare percentage of sagebrush in the diet in September and October. Heritability estimates were similar between September and October measurements (0.25 and 0.28, respectively). The genetic correlation between September and October percentages of sagebrush in the diet was high (0.91), implying that there is strong genetic similarity between September and October measurements and that an annual measurement may be sufficient for selection. These results contribute to a greater understanding of dietary preferences in freely grazing sheep, and suggest opportunities to improve production efficiency and forage management through selection for dietary preferences.


Midterm outcomes in supravalvular aortic stenosis demonstrate the superiority of multisinus aortoplasty.
Surgical techniques for repair of supravalvular aortic stenosis (SVAS) include McGoon's one-patch, Doty's two-patch, and Brom's three-patch method. In this review we evaluated mid-term clinical outcomes of these techniques at our institution. Our cardiac surgery database identified patients with SVAS repair from 1990 to 2008. Follow-up records, reintervention and reoperation data, and most recent echocardiograms were obtained. From 1990 to 2008, 20 patients (70% male) underwent surgery for SVAS. Mean age was 3.6 +/- 5.6 years. In chronological sequence, 8 patients had single-patch aortoplasty, 4 had the Doty procedure, and 8 received Brom's symmetric three-patch aortoplasty. Of the Brom patients, 6 had Williams syndrome. Aortic cross-clamp times were 40.1 +/- 13.6 minutes (one-patch), 60.3 +/- 38.8 minutes (Doty), and 104 +/- 20.5 minutes (Brom). Perioperative mortality was 5.0% (1 patient in one-patch group). Mean postoperative length of stay was 10 +/- 10.6 days. Follow-up data were available for all survivors (mean follow-up, 6.3 +/- 6.0 years; range, 6 months to 16 years). There were no late deaths. Follow-up echocardiograms revealed a peak Doppler gradient across the aortic outflow tract of 33 +/- 18.0 mm Hg (one-patch), 10 +/- 1 mm Hg (Doty), and 18 +/- 12 mm Hg (Brom). All patients in the Doty and Brom groups had less than moderate aortic insufficiency. Reoperations were required in 5 of 8 one-patch patients (62%) for residual aortic stenosis (n = 3), aortic insufficiency (n = 1), and subvalvar stenosis (n = 1). No Doty or Brom patient has required aortic reoperations, which was nearly statistically associated with freedom from reoperation (p = 0.06). Subvalvar stenosis was the only risk factor associated with reoperation (p = 0.0028). Despite a longer cross-clamp time, SVAS repair by Doty or Brom aortoplasty restores normal hemodynamics and reduces the need for reoperation when compared with the classic one-patch technique. Our current preference for SVAS repair is the Brom three-patch symmetric aortoplasty.


Diabetic hyperglycemia: link to impaired glucose transport in pancreatic beta cells.
Glucose uptake into pancreatic beta cells by means of the glucose transporter GLUT-2, which has a high Michaelis constant, is essential for the normal insulin secretory response to hyperglycemia. In both autoimmune and nonautoimmune diabetes, this glucose transport is reduced as a consequence of down-regulation of the normal beta-cell transporter. In autoimmune diabetes, circulating immunoglobulins can further impair this glucose transport by inhibiting functionally intact transporters. Insights into mechanisms of the unresponsiveness of beta cells to hyperglycemia may improve the management and prevention of diabetes.


Folic acid supplementation and colorectal cancer risk: a meta-analysis.
This meta-analysis aims to determine the effect of folic acid supplementation on colorectal cancer risk. A structured search of the MEDLINE, EMBASE, Cochrane and CINAHL databases was undertaken in July 2008. All published full text English language articles were searched that included a randomized or pseudo-randomized comparison of subjects who received folate vs subjects who did not in relation to their risk of adenoma or advanced adenomatous lesions, including colorectal cancer. A weighted treatment effect (using fixed effects) was calculated across trials. Overall, the risk of an adenomatous lesion was not increased (odds ratio 1.09, 95% confidence interval 0.93-1.28) among patients who received folate supplementation for up to 3 years; however, for those who received folate for over 3 years, the risk of an adenomatous lesion was increased (odds ratio 1.35, 95% confidence interval 1.06-1.70). The risk associated with treatment was the highest for the occurrence of an advanced lesion (odds ratio 1.50, 95% confidence interval 1.06-2.10). There was no significant statistical heterogeneity in the analyses. At the 3-year colonoscopic follow up, folate supplementation had no effect on adenoma recurrence overall. While colonic surveillance beyond 3 years revealed an increased risk of colorectal adenoma, especially advanced adenoma, among those participants randomized to the folate group. This meta-analysis challenges the results from epidemiological studies that folate status is inversely related to the risk of developing colorectal cancer.


The effect of sedation during upper gastrointestinal endoscopy.
We aimed to study whether sedation reduces discomfort during endoscopy and a comparison of longer-acting diazepam with shorter-acting midazolam. A prospective, randomized, single-blinded study was conducted at the Department of Medicine at Government Medical College and Hospital, Chandigarh, and was completed over a period of 6 months. The patients were randomized to receive either placebo or sedation with midazolam or diazepam before endoscopy. The endoscopist and the observer recording patient's/physician's responses were blinded to the drugs administered. Two hundred and fifty two consecutive patients undergoing diagnostic or therapeutic upper gastrointestinal endoscopy were recruited. The patient's discomfort and the physician's comfort during the procedure were recorded on a visual analogue scale rated from 1-10 with-in 10 minutes of the procedure by an independent observer. The Patient's discomfort ratings were further divided into 3 groups, comfortable (score, 1-3), satisfactory (score, 4-7) and uncomfortable (a score of >7). Similarly the physician's ease of performing the procedure was also recorded on the same scale. This was again divided into 3 groups: easy (score, 1-3), satisfactory (score, 4-7) and difficult (a score of >7). Out of the total of 252 patients, 82 patients received no sedation (group I), 85 received diazepam (group II) and 85 received midazolam (group III). There was no statistical difference in the discomfort experienced by the patients during endoscopy when sedation was used (P=0.0754). Out of 252 patients, 49 underwent endoscopic procedures. Nineteen patients were included in group I, 18 in group II and 12 in group III. Only 10 (20%) patients undergoing endoscopic procedures complained of significant discomfort, but there was no difference in the ones undergoing interventions with or without sedation (P=0.854). The physicians were more comfortable in performing endoscopic procedure in sedated patients, however, the difference between patients in group II and group III was not statistically significant (P=0.0461). Both diazepam and midazolam fared equally well in increasing physician's comfort (P=0.617). There was no difference in the patient's discomfort with regard to the sedative used (midazolam or diazepam). Although endoscopy was easy or satisfactory in the majority of patients in the unsedated as well as the sedated groups, more often the endoscopist found it difficult to do endoscopy on the unsedated patients.


Progress of recyclable magnetic particles for biomedical applications.
Recyclable magnetic particles constitute a class of particles that can be manipulated by external magnetic fields and reused multiple times. These particles consist of a magnetic part and a functional part and have been widely used in the biomedical field, such as in enzyme immobilization, biochemical separation, nucleic acid detection and antibacterial agents, owing to their advantages of convenient operation, high efficiency, mild separation, and easy recycling. In this review, we investigate the research status of recyclable magnetic particles, and discuss their preparation methods, types and recycling methods in detail. According to their structure, existing recyclable magnetic particles are divided into three main types: core-shell structure particles, matrix-dispersed structure particles and hollow structure particles. Each type of recyclable magnetic particle requires a treatment procedure for reuse, which includes direct reuse, washing treatment, chemical treatment and high-temperature calcination. To date, most recycling methods for magnetic particles belong to washing and chemical treatment, and few studies focus on novel magnetic recycling methods, owing to the lack of systemic summary and theoretical studies. We also point out the limitations of preparation and treatment methods, and predict the development direction of recyclable magnetic particles. We predict that recyclable magnetic particles will occupy an important position in the field of sustainable development and environmental protection, and considerable perspectives will be presented for the development of recyclable magnetic particles.


Discontinuous gas-exchange in centipedes and its convergent evolution in tracheated arthropods.
We have examined the gas-exchange characteristics of five southern African centipede species from three orders. Two scolopendromorph species exhibit discontinuous gas-exchange cycles (DGCs) identical to those recorded for several insect and chelicerate species. Another scolopendromorph and a lithobiomorph species exhibit weak periodic patterns, and a scutigermorph species shows continuous gas exchange. A crucial component for DGCs in tracheated arthropods is the presence of occludible spiracles. However, on the basis of studies of temperate centipedes, most recent invertebrate biology texts hold the view that centipedes, as a group, cannot close their spiracles. Using flow-through normoxic and normoxic-anoxic-normoxic respirometry and electron microscopy, we conclusively demonstrate that at least one of the scolopendromorph species, Cormocephalus morsitans L., can close its spiracles fully, thus accounting for its DGCs. Homologies in spiracular structure and DGCs suggest that several other tracheated arthropod taxa probably have this ability too and that DGCs have evolved convergently at least four times in the Arthropoda. Spiracular closure and discontinuous gas-exchange cycles are probably more widespread in arthropods than has previously been suspected.


Influence of alveolar hypoxia on pulmonary vasomotor responses to almitrine in the dog.
Almitrine bismesylate (5-10 micrograms/kg) was given as an intravenous bolus to anaesthetized, paralysed dogs with closed-chest (n = 5) and with open-chest (n = 7) in whom the retrocardiac lobe was separately ventilated. Pulmonary, lobar and systemic haemodynamics were measured under hypoxic, normoxic and hyperoxic conditions. Total pulmonary blood flow was measured by thermodilution and lobar flow by electromagnetic flow meter. In the closed-chest preparations, almitrine caused an increase in pulmonary vascular resistance (PVR) at all levels of inspired oxygen, the increments being 82% (30% O2), 91% (air) and 9% (13% O2). The control PVR varied inversely with arterial PO2 but there was no significant interaction between the almitrine and hypoxia induced vasoconstriction with multiple linear regression analysis. In the open-chest preparations, PVR and lobar vascular resistance (LVR) increased after almitrine by 48% and 41% respectively when both lung and lobe inspired 30% O2. When the lobe was switched to 12.5% O2 or nitrogen (lung inspiring 30%) PVR again increased (+52%) after almitrine but LVR decreased in five of seven lobes (lobar flow increasing despite constant cardiac output), the overall change being -4%. Analysis of covariance showed that the lobar response to almitrine was significantly different under hypoxic conditions compared with hyperoxic (P less than 0.05). With ventilation maintained constant, there was no significant change in arterial PO2 after almitrine in any experimental condition. In conclusion, almitrine is generally a pulmonary vasoconstrictor but can dilate vessels when they are constricted by local hypoxia. Almitrine does not enhance local hypoxic vasoconstriction in the dog.


Secretion of old versus new exportable protein in rat parotid slics. Control by neurotransmitters.
The possibility that old and new secretory granules do not mix and that older exportable protein can be secreted preferentially was tested on parotid gland in vitro. Slices from fasted animals were pulse labeled for 3 min with L-[3H]leucine. Subcellular fractionstion showed that after 1 90-min chase period, the formation of new labeled secretory granules was mostly completed. The ratio of label in secretory granules to label in microsomes increased 250-fold during the period 5--90 min postpulse. After the 90-min chase, a submaximal rate of secretion was initiated by adding a low concentration of isoproterenol to the slices. Preferential secretion of old unlabeled exportable protein was evident from the finding that the percent of total amylase secreted was 3.5-fold greater than the percent of labeled protein secreted. Preferential secretion of old unlabeled exportable amylase was undiminished even when the chase period before addition of isoproterenol was extended to 240 min. Such long chase incubations were still meaningful due to the fact that the spontaneous rat of amylase release and radioactive protein release from the slices was negligibly low. A high isoproterenol concentration added to the slices after a 90-min chase produced the following results. An initial phase of preferential secretion of old unlabeled protein was soon replaced by secretion of a random mixture of new and old exportable protein. Electron micrographs indicated that high rates of secretion involved sequential fusion of secretory granules so that the lumen extended deep into the cell where the new labeled granules were presumably located. At low rates of secretion, the lumen showed no such deep extensions. Experiments were also conducted on slices from glands which had been largely depleted of old granules by prior injection of isoproterenol into the animals. Secretion of labeled protein from such slices stopped with the export of 80% of the labeled protein. This finding indicates that about 20% of the radioactive protein is cellular nonexportable protein and that the slices are capable of exporting the entire amount of secretory protein which was symthesized in vitrol. In addition to the beta-adrenergic receptor which mediates protein secretion, the parotid acinar cell also possesses an alpha-adrenergic and a cholinergic receptor both of which cause K+ release, vacuole formation, and water secretion. Activation of either of the latter two receptors in conjunction with the beta-adrenergic receptor increased randomization of the protein secreted. It is concluded that in the rat parotid acinar cell there is little spontaneous mixing between old granules near the luminal cell membrane and new granules coming up behind from the Golgi complex. The neurotransmitters which induce secretion produce the observed randomization.


Spatial segmentation and the black middle class.
Ethnographic studies of the black middle class focus attention on the ways in which residential environments condition the experiences of different segments of the black class structure. This study places these arguments in a larger demographic context by providing a national analysis of neighborhood inequality and spatial inequality of different racial and ethnic groups in urban America. The findings show that there has been no change over time in the degree to which majority-black neighborhoods are surrounded by spatial disadvantage. Predominantly black neighborhoods, regardless of socioeconomic composition, continue to be spatially linked with areas of severe disadvantage. However, there has been substantial change in the degree to which middle- and upper-income African-American households have separated themselves from highly disadvantaged neighborhoods. These changes are driven primarily by the growing segment of middle- and upper-income African-Americans living in neighborhoods in which they are not the majority group, both in central cities and in suburbs.


Semantic preview benefit in eye movements during reading: A parafoveal fast-priming study.
Eye movements in reading are sensitive to foveal and parafoveal word features. Whereas the influence of orthographic or phonological parafoveal information on gaze control is undisputed, there has been no reliable evidence for early parafoveal extraction of semantic information in alphabetic script. Using a novel combination of the gaze-contingent fast-priming and boundary paradigms, we demonstrate semantic preview benefit when a semantically related parafoveal word was available during the initial 125 ms of a fixation on the pretarget word (Experiments 1 and 2). When the target location was made more salient, significant parafoveal semantic priming occurred only at 80 ms (Experiment 3). Finally, with short primes only (20, 40, 60 ms), effects were not significant but were numerically in the expected direction for 40 and 60 ms (Experiment 4). In all experiments, fixation durations on the target word increased with prime durations under all conditions. The evidence for extraction of semantic information from the parafoveal word favors an explanation in terms of parallel word processing in reading.


Mortality among people who inject drugs: a systematic review and meta-analysis.
To systematically review cohort studies of mortality among people who inject drugs, examine mortality rates and causes of death in this group, and identify participant- and study-level variables associated with a higher risk of death. Tailored search strings were used to search EMBASE, Medline and PsycINFO. The grey literature was identified through online grey literature databases. Experts were consulted to obtain additional studies and data. Random effects meta-analyses were performed to estimate pooled crude mortality rates (CMRs) and standardized mortality ratios (SMRs). Sixty-seven cohorts of people who inject drugs were identified, 14 of them from low- and middle-income countries. The pooled CMR was 2.35 deaths per 100 person-years (95% confidence interval, CI: 2.12-2.58). SMRs were reported for 32 cohorts; the pooled SMR was 14.68 (95% CI: 13.01-16.35). Comparison of CMRs and the calculation of CMR ratios revealed mortality to be higher in low- and middle-income country cohorts, males and people who injected drugs that were positive for human immunodeficiency virus (HIV). It was also higher during off-treatment periods. Drug overdose and acquired immunodeficiency syndrome (AIDS) were the primary causes of death across cohorts. Compared with the general population, people who inject drugs have an elevated risk of death, although mortality rates vary across different settings. Any comprehensive approach to improving health outcomes in this group must include efforts to reduce HIV infection as well as other causes of death, particularly drug overdose.


Clinical, Hormonal, and Metabolic Parameters in Women with Subclinical Hypothyroidism and Polycystic Ovary Syndrome: A Cross-Sectional Study.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive age women, yet its clinical presentation shares similarities with several other endocrine disorders such as thyroid disease. Hence, the objective of this study was to further evaluate this association by investigating the clinical, hormonal, and metabolic parameters between subclinical hypothyroidism (SCH) and PCOS. This is a cross-sectional study conducted in a tertiary care clinic at Cleveland, Ohio, USA. A total of 137 women diagnosed with PCOS by Rotterdam criteria were examined. SCH was defined as thyroid-stimulating hormone >2.5 mIU/L in the absence of symptoms of overt hypothyroidism. The mean age, body mass index (BMI), fasting plasma glucose (FPG), glucose tolerance test, hemoglobin A1c, fasting insulin, a 2 hours insulin level after 75 g glucose load, cholesterol, LDL, HDL, and homeostatic model assessment (HOMA) were compared between women with and without SCH. Logistic regression was used to adjust for age and BMI. Among 137 women with PCOS, 21.9% had SCH. Comparison groups were similar in both age and BMI and there was no difference in the mean values of all endocrine and metabolic parameters tested. However, abnormal FPG levels (OR 3.01; CI: 1.12-8.07. p = 0.03) and abnormal HOMA (OR 3.7; CI: 1.14-12.00. p = 0.03) were more likely in women who had SCH than in women without SCH independent of age and BMI. Women with PCOS and SCH are more likely to have impaired FPG values and impaired insulin sensitivity even after adjusting for age and BMI. Hence, close monitoring of PCOS patients for SCH may be beneficial.


Facial action recognition for facial expression analysis from static face images.
Automatic recognition of facial gestures (i.e., facial muscle activity) is rapidly becoming an area of intense interest in the research field of machine vision. In this paper, we present an automated system that we developed to recognize facial gestures in static, frontal- and/or profile-view color face images. A multidetector approach to facial feature localization is utilized to spatially sample the profile contour and the contours of the facial components such as the eyes and the mouth. From the extracted contours of the facial features, we extract ten profile-contour fiducial points and 19 fiducial points of the contours of the facial components. Based on these, 32 individual facial muscle actions (AUs) occurring alone or in combination are recognized using rule-based reasoning. With each scored AU, the utilized algorithm associates a factor denoting the certainty with which the pertinent AU has been scored. A recognition rate of 86% is achieved.


Post-traumatic stress, depression, and community integration a long time after whiplash injury.
Psychological factors such as post-traumatic stress and depression may play an important role in the recovery after whiplash injuries. Difficulties in psychosocial functioning with limitations in everyday life may dominate for some time after the injury. Our study therefore investigates the relationships between pain, post-traumatic stress, depression, and community integration. A set of questionnaires was answered by 191 persons (88 men, 103 women) five years after a whiplash injury to assess pain intensity (visual analogue scale, VAS), whiplash-related symptoms, post-traumatic stress (impact of event scale, IES), depression (Beck depression inventory, BDI-II), community integration (community integration questionnaire, CIQ), life satisfaction (LiSat-11). One or more depressive symptoms were reported by 74% of persons; 22% reported scores that were classified as mild to severe depression. The presence of at least one post-traumatic symptom was reported by 70% of persons, and 38% reported mild to severe stress. Total scores of community integration for women were statistically significantly higher than for men. The total VAS score was correlated positively to the IES (r=0.456, P<0.456), the BDI (r=0.646, P<0.001), and negatively to the CIQ (r=-0.300, P<0.001). These results highlight the view that a significant proportion of people experience both pain and psychological difficulties for a long time after a whiplash injury. These findings should be taken into consideration in the management of subjects with chronic whiplash symptoms and may support a multi-professional rehabilitation model that integrates physical, psychological, and psychosocial factors.


Emergence of carbapenem-resistant Acinetobacter baumannii in hospitals in Pakistan.
The emergence of pan-resistance in bacterial pathogens poses a threat to human health. Carbapenem-resistant Acinetobacter baumannii has emerged as a serious challenge, causing nosocomial infection and community-acquired outbreaks in hospitals globally, including in Pakistan. We collected 90 Acinetobacter isolates from patients with secondary or nosocomial infections from different hospitals in Pakistan and screened for carbapenem-resistant strains. Of the 90 isolates, 59 were resistant to carbapenems. Among oxacillinase -encoding genes, blaOXA-51-like was common in all isolates, including in combination with blaOXA-23-like in 14 isolates; however, blaOXA-24-like and blaOXA-58-like were completely absent. Among metallo-β-lactamase-encoding genes, only blaNDM-1 was found in one isolate, while the other three genes, blaIMP, blaVIM and blaSIM, were completely absent. None of the isolates was found to harbour the blaCTX-M gene. The isolates were also tested for susceptibilities to a panel of different antibiotics belonging to several classes. Of all the drugs tested, tigecycline was the most effective with 80 % sensitivity amongst isolates, followed by colistin with 50 % sensitivity. Three categories of resistance were found in these isolates: extreme drug resistance in 26, pan-drug resistance in 19 and multidrug resistance in 87 isolates. The isolates exhibited a high resistance to cephalosporins, trimethoprim-sulfamethoxazole and β-lactam antibiotics, followed by tetracycline and β-lactam/β-lactam inhibitor combination, fluoroquinolone and aminoglycosides. The results show a prominent level of antibiotic-resistance phenotypes in A. baumannii and strongly suggest the need for full-scale national surveillance of carbapenem-resistant A. baumannii with particular emphasis on the newly identified NDM-1 (New Delhi metallo-β-lactamase-1).