Pediatric vascular injuries: acute management and early outcomes.
Although uncommon in children, traumatic vascular injuries have the potential for lifelong disability. We reviewed these injuries, their acute management, and early outcomes at a Level I trauma center. Retrospective review of patients identified through trauma registry was query of all noniatrogenic vascular injuries in a pediatric population during a 13-year period. Demographics, injury type and management, concomitant injuries, and inpatient outcomes were analyzed. From 1995 to 2008, 8,247 children with traumatic injuries were admitted. Of which 116 (1.4%) sustained 138 significant vascular injuries; 111 arterial and 27 venous. Mean age was 12.7 years ± 4.1 years. Penetrating mechanism was more frequent (57.8%; 67 of 116) than blunt (42.2%; 49 of 116). The overall mean injury severity score was 17.3, of which 12.3 ± 11.7 was for penetrating trauma and 24.1 ± 19.3 for blunt trauma. Thirteen of the 36 patients with torso injuries and one with carotid/jugular injury died. The surviving 102 patients sustained 118 vascular injuries (102 arterial and 16 venous). Of this group, 15 (14.6%) had multiple vascular injuries. There were 23 (22.5%) with torso injuries, 72 (70.6%) with extremity injuries, and 7 (6.9%) with cerebrovascular injuries. Primary repair was the most common arterial repair technique for survivors (25.5%, 26 of 102) and was used more frequently in penetrating trauma (35.0%, 21 of 60) than blunt trauma (12.0%, 5 of 42). Limb salvage was 97.4% (113 of 116). Pediatric vascular trauma is uncommon. Penetrating mechanism is more common than blunt. Injuries to the torso carry a high mortality. Limb salvage is almost universal.


Double scattering of light from Biophotonic Nanostructures with short-range order.
We investigate the physical mechanism for color production by isotropic nanostructures with short-range order in bird feather barbs. While the primary peak in optical scattering spectra results from constructive interference of singly-scattered light, many species exhibit secondary peaks with distinct characteristic. Our experimental and numerical studies show that these secondary peaks result from double scattering of light by the correlated structures. Without an analog in periodic or random structures, such a phenomenon is unique for short-range ordered structures, and has been widely used by nature for non-iridescent structural coloration.


A geometric network model of intrinsic grey-matter connectivity of the human brain.
Network science provides a general framework for analysing the large-scale brain networks that naturally arise from modern neuroimaging studies, and a key goal in theoretical neuroscience is to understand the extent to which these neural architectures influence the dynamical processes they sustain. To date, brain network modelling has largely been conducted at the macroscale level (i.e. white-matter tracts), despite growing evidence of the role that local grey matter architecture plays in a variety of brain disorders. Here, we present a new model of intrinsic grey matter connectivity of the human connectome. Importantly, the new model incorporates detailed information on cortical geometry to construct 'shortcuts' through the thickness of the cortex, thus enabling spatially distant brain regions, as measured along the cortical surface, to communicate. Our study indicates that structures based on human brain surface information differ significantly, both in terms of their topological network characteristics and activity propagation properties, when compared against a variety of alternative geometries and generative algorithms. In particular, this might help explain histological patterns of grey matter connectivity, highlighting that observed connection distances may have arisen to maximise information processing ability, and that such gains are consistent with (and enhanced by) the presence of short-cut connections.


Immunological and physiological characteristics of the rapid immune hemolysis of neuraminidase-treated sheep red cells produced by fresh guinea pig serum.
The rapid hemolysis by fresh guinea pig serum known to occur with neuraminidase-treated sheep red cells has been investigated with respect to the immunological and physiological properties of the lytic process. The following observations were made: (a) The susceptibility to hemolysis is directly proportional to the amounts of neuraminic acid enzymatically released from the cell surface. Complement lysis is mediated through binding of an IgM antibody protein to membranes of neuraminidase-treated cells. (b) Hemolysis is relatively temperature-independent above about 28 degrees C but below which a decrease in the hemolysis rate occurs. Arrhenius activation energies above and below the transition temperature were therefore found to be different. (c) Colloid osmotic swelling of neuraminidase-treated high potassium sheep red cells with a chloride ion concentration ratio near unity suspended in high potassium medium could not be prevented by sucrose. Hence, colloid osmotic swelling before lysis must be due to the entrance of sucrose and water since sucrose was the only external solute not at equilibrium. (d) From the rate of swelling and the apparent flux of sucrose under nonsteady state conditions an experimental permeability coefficient (P) for sucrose of 3-10(-8) cm-s-1 was computed. Comparison with a theoretical P of 4-10(-6) cm-s-1 for sucrose freely permeating through a single, hypothetical membrane lesion per cell of 60 A effective diameter indicates a membrane lesion which permits the passage of solutes larger than cations, but clearly constrains the free diffusion of sucrose.


Dynamics of ligand binding to myoglobin.
Myoglobin rebinding of carbon monoxide and dioxygen after photodissociation has been observed in the temperature range between 40 and 350 K. A system was constructed that records the change in optical absorption at 436 nm smoothly and without break between 2 musec and 1 ksec. Four different rebinding processes have been found. Between 40 and 160 K, a single process is observed. It is not exponential in time, but approximately given by N(t) = (1 + t/to)-n, where to and n are temperature-dependent, ligand-concentration independent, parameters. At about 170 K, a second and at 200 K, a third concentration-independent process emerge. At 210 K, a concentration-dependent process sets in. If myoglobin is embedded in a solid, only the first three can be seen, and they are all nonexponential. In a liquid glycerol-water solvent, rebinding is exponential. To interpret the data, a model is proposed in which the ligand molecule, on its way from the solvent to the binding site at the ferrous heme iron, encounters four barriers in succession. The barriers are tentatively identified with known features of myoglobin. By computer-solving the differential equation for the motion of a ligand molecule over four barriers, the rates for all important steps are obtained. The temperature dependences of the rates yield enthalpy, entropy, and free-energy changes at all barriers. The free-energy barriers at 310 K indicate how myoglobin achieves specificity and order. For carbon monoxide, the heights of these barriers increase toward the inside; carbon monoxide consequently is partially rejected at each of the four barriers. Dioxygen, in contrast, sees barriers of about equal height and moves smoothly toward the binding site. The entropy increases over the first two barriers, indicating a rupturing of bonds or displacement of residues, and then smoothly decreases, reaching a minimum at the binding site. The magnitude of the decrease over the innermost barrier implies participation of heme and/or protein. The nonexponential rebinding observed at low temperatures and in solid samples implies that the innermost barrier has a spectrum of activation energies. The shape of the spectrum has been determined; its existence can be explained by assuming the presence of many conformational states for myoglobin. In a liquid at temperatures above about 230 K, relaxation among conformational states occurs and rebinding becomes exponential.


Emergency physicians' attitudes and preferences regarding computed tomography, radiation exposure, and imaging decision support.
Although computerized decision support for imaging is often recommended for optimizing computed tomography (CT) use, no studies have evaluated emergency physicians' (EPs') preferences regarding computerized decision support in the emergency department (ED). In this needs assessment, the authors sought to determine if EPs view overutilization as a problem, if they want decision support, and if so, the kinds of support they prefer. A 42-item, Web-based survey of EPs was developed and used to measure EPs' attitudes, preferences, and knowledge. Key contacts at local EDs sent letters describing the study to their physicians. Exploratory principal components analysis (PCA) was used to determine the underlying factor structure of multi-item scales, Cronbach's alpha was used to measure internal consistency of items on a scale, Spearman correlations were used to describe bivariate associations, and multivariable linear regression analysis was used to identify variables independently associated with physician interest in decision support. Of 235 surveys sent, 155 (66%) EPs responded. Five factors emerged from the PCA. EPs felt that: 1) CT overutilization is a problem in the ED (α = 0.75); 2) a patient's cumulative CT study count affects decisions of whether and what type of imaging study to order only some of the time (α = 0.75); 3) knowledge that a patient has had prior CT imaging for the same indication makes EPs less likely to order a CT (α = 0.42); 4) concerns about malpractice, patient satisfaction, or insistence on CTs affect CT ordering decisions (α = 0.62); and 5) EPs want decision support before ordering CTs (α = 0.85). Performance on knowledge questions was poor, with only 18% to 39% correctly responding to each of the three multiple-choice items about effective radiation doses of chest radiograph and single-pass abdominopelvic CT, as well as estimated increased risk of cancer from a 10-mSv exposure. Although EPs wanted information on patients' cumulative exposures, they feel inadequately familiar with this information to make use of it clinically. If provided with patients' cumulative radiation exposures from CT, 87% of EPs said that they would use this information to discuss imaging options with their patients. In the multiple regression model, which included all variables associated with interest in decision support at p < 0.10 in bivariate tests, items independently associated with EPs' greater interest in all types of decision support proposed included lower total knowledge scores, greater frequency that cumulative CT study count affects EP's decision to order CTs, and greater agreement that overutilization of CT is a problem and that awareness of multiple prior CTs for a given indication affects CT ordering decisions. Emergency physicians view overutilization of CT scans as a problem with potential for improvement in the ED and would like to have more information to discuss risks with their patients. EPs are interested in all types of imaging decision support proposed to help optimize imaging ordering in the ED and to reduce radiation to their patients. Findings reveal several opportunities that could potentially affect CT utilization.


Whole-genome resequencing-based QTL-seq identified candidate genes and molecular markers for fresh seed dormancy in groundnut.
The subspecies fastigiata of cultivated groundnut lost fresh seed dormancy (FSD) during domestication and human-made selection. Groundnut varieties lacking FSD experience precocious seed germination during harvest imposing severe losses. Development of easy-to-use genetic markers enables early-generation selection in different molecular breeding approaches. In this context, one recombinant inbred lines (RIL) population (ICGV 00350 × ICGV 97045) segregating for FSD was used for deploying QTL-seq approach for identification of key genomic regions and candidate genes. Whole-genome sequencing (WGS) data (87.93 Gbp) were generated and analysed for the dormant parent (ICGV 97045) and two DNA pools (dormant and nondormant). After analysis of resequenced data from the pooled samples with dormant parent (reference genome), we calculated delta-SNP index and identified a total of 10,759 genomewide high-confidence SNPs. Two candidate genomic regions spanning 2.4 Mb and 0.74 Mb on the B05 and A09 pseudomolecules, respectively, were identified controlling FSD. Two candidate genes-RING-H2 finger protein and zeaxanthin epoxidase-were identified in these two regions, which significantly express during seed development and control abscisic acid (ABA) accumulation. QTL-seq study presented here laid out development of a marker, GMFSD1, which was validated on a diverse panel and could be used in molecular breeding to improve dormancy in groundnut.


Statins and bone: myth or reality?
In the space of a few weeks, four articles appeared in the The Lancet and JAMA suggesting that using 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) is associated with increased bone mineral density (BMD) and a reduced fracture risk. The stimulus for these case-control studies came from reports that the statins have unexpected effects on bone, increasing bone formation in rodents. These observations offered a new insight into the potential importance of the cholesterol synthesis pathway in bone turnover and future therapeutic opportunities.


The development, reliability, and validity of a clinical rating scale for codependency.
This investigation examined the reliability and validity of a rating scale for codependency in substance abuse treatment. The investigators developed an example-anchored rating scale to operationalize codependency as substance abuse counselors construe it in practice, and recruited 27 counselors for a counterbalanced multiple-treatment experiment. Counselors were randomly assigned to one of four continuing education workshops for rating-scale training, and asked to evaluate codependency in five videotaped cases. Semistructured case interviews were videotaped with a male and a female from five adult populations to vary the gender and codependency of cases: (1) outpatients in treatment for addiction, (2) outpatient spouses, (3) members of Codependents Anonymous, (4) United States Bureau of Land Management smoke jumpers, and (5) college students majoring in business or economics. To control for gender effects, one workshop presented male cases, one workshop presented female cases, and two workshops presented cases of both genders. To control for order effects, the assignment of videotapes to workshops was randomized to counterbalance the order in which counselors viewed them. The findings suggest that the rating scale yields reliable and valid evaluations of codependency without appreciable gender bias.


Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs.
Cartilage-derived matrix (CDM) has emerged as a promising scaffold material for tissue engineering of cartilage and bone due to its native chondroinductive capacity and its ability to support endochondral ossification. Because it consists of native tissue, CDM can undergo cellular remodeling, which can promote integration with host tissue and enables it to be degraded and replaced by neotissue over time. However, enzymatic degradation of decellularized tissues can occur unpredictably and may not allow sufficient time for mechanically competent tissue to form, especially in the harsh inflammatory environment of a diseased joint. The goal of the current study was to engineer cartilage and bone constructs with the ability to inhibit aberrant inflammatory processes caused by the cytokine interleukin-1 (IL-1), through scaffold-mediated delivery of lentiviral particles containing a doxycycline-inducible IL-1 receptor antagonist (IL-1Ra) transgene on anatomically-shaped CDM constructs. Additionally, scaffold-mediated lentiviral gene delivery was used to facilitate spatial organization of simultaneous chondrogenic and osteogenic differentiation via site-specific transduction of a single mesenchymal stem cell (MSC) population to overexpress either chondrogenic, transforming growth factor-beta 3 (TGF-β3), or osteogenic, bone morphogenetic protein-2 (BMP-2), transgenes. Controlled induction of IL-1Ra expression protected CDM hemispheres from inflammation-mediated degradation, and supported robust bone and cartilage tissue formation even in the presence of IL-1. In the absence of inflammatory stimuli, controlled cellular remodeling was exploited as a mechanism for fusing concentric CDM hemispheres overexpressing BMP-2 and TGF-β3 into a single bi-layered osteochondral construct. Our findings demonstrate that site-specific delivery of inducible and tunable transgenes confers spatial and temporal control over both CDM scaffold remodeling and neotissue composition. Furthermore, these constructs provide a microphysiological in vitro joint organoid model with site-specific, tunable, and inducible protein delivery systems for examining the spatiotemporal response to pro-anabolic and/or inflammatory signaling across the osteochondral interface.


Two-dimensional x-ray waveguides and point sources.
We show that resonant coupling of synchrotron beams into suitable nanostructures can be used for the generation of coherent x-ray point sources. A two-dimensionally confining x-ray waveguide structure has been fabricated by e-beam lithography. By shining a parallel undulator beam onto the structure, a discrete set of resonant modes can be excited in the dielectric cavity, depending on the two orthogonal coupling angles between the beam and the waveguide interfaces. The resonant excitation of the modes is evidenced from the characteristic set of coupling angles as well as the observed far-field pattern. The x-ray nanostructure may be used as coherent x-ray point sources with a beam cross section in the nanometer range.


Experiences of registered nurses transitioning from employment in acute care to primary health care-quantitative findings from a mixed-methods study.
To describe the experiences of registered nurses who transition from acute to primary health care (PHC) employment. Internationally the provision of health care in PHC settings is increasing. Nurses are moving from acute care employment to meet the growing demand for a PHC workforce. However, little is known about the transition experiences of these nurses. A sequential mixed-methods study comprising a survey, and semi-structured interviews. This study reports on survey findings relating to the transition experience. Convenience and snowballing techniques were used to recruit 111 registered nurses who had transitioned from Australian acute settings to PHC employment within the last 5 years. An online survey gathered data relating to personal and professional demographics, type of PHC setting and transition experiences. Most respondents (n = 90, 81.1%) reported receiving some orientation, although the length and content varied considerably. Those working in metropolitan locations were more likely to report concerns associated with their orientation, with respondents from rural or remote locations more likely to have access to a preceptor than city/metropolitan respondents. Just under half of respondents found prioritising workload (n = 47; 42.7%) or organisational knowledge (n = 45; 40.9%) difficult or very difficult, and 47.7% (n = 53) felt isolated or unsupported. 49.5% (n = 55) reported being overwhelmed with the new role either sometimes or regularly. Barriers to transitioning successfully included limited employer support to attend professional development activities. Availability of specific support measures may assist in the transition process. Findings from our study should be considered by employers when recruiting nurses new to PHC, and when designing orientation and ongoing education programmes. This study highlights the challenges faced by nurses who transition from acute care into PHC employment. Understanding the barriers and facilitators to successful transitions enhances the process for future recruitment and retention of PHC nurses. This evidence can inform managers, educators and policymakers in developing support programmes for nurses moving into PHC.


Discovery of a new chert-permineralized microbiota in the Proterozoic Buxa Formation of the Ranjit window, Sikkim, northeast India, and its astrobiological implications.
For the foreseeable future, the search for evidence of past life in rocks acquired from other planets will be constrained by the amount of sample available and by the fidelity of preservation of any fossils present. What amount of rock is needed to establish the existence of past life? To address this question, we studied a minute amount of rock collected from cherty dolomites of the Proterozoic Buxa Formation in the metamorphically altered tectonically active northeastern Himalaya. In particular, we investigated 2 small petrographic thin sections-one from each of 2 bedded chert horizons exposed in the Ranjit River stratigraphic section northwest of Rishi, Sikkim, India-that together comprise an area of approximately 5 cm(2) (about the size of a US postage stamp) and have a total rock weight of approximately 0.1 g. Optical microscopy, confocal laser scanning microscopy, and Raman spectroscopy and imagery demonstrate that each of the thin sections contains a rich assemblage of 3-dimensionally permineralized organic-walled microfossils. This study, the first report of Proterozoic microfossils in units of the Ranjit tectonic window, demonstrates that firm evidence of early life can be adduced from even a minuscule amount of fossil-bearing ancient rock.


Human immunodeficiency virus type 1 assembly, budding, and cell-cell spread in T cells take place in tetraspanin-enriched plasma membrane domains.
Human immunodeficiency virus type-1 (HIV-1) egress from infected CD4+ T cells is thought to be via assembly and budding at the plasma membrane and may involve components of the T-cell secretory apparatus, including tetraspanins. However, many studies on HIV-1 assembly have examined the trafficking of viral proteins in isolation, and most have used immortalized epithelial, fibroblastic, or hematopoietic cell lines that may not necessarily reflect natural infection of susceptible T cells. Here we have used immunofluorescence and cryoimmunoelectron microscopy (CEM) to examine protein transport during HIV-1 assembly in productively infected Jurkat CD4+ T cells and primary CD4+ T cells. The HIV-1 envelope glycoprotein (Env) and the core protein (Gag) colocalize strongly with CD63 and CD81 and less strongly with CD9, whereas no colocalization was seen between Env or Gag and the late endosome/lysosomal marker Lamp2. CEM revealed incorporation of CD63 and CD81 but not Lamp2 into virions budding at the plasma membrane, and this was supported by immunoprecipitation studies, confirming that HIV-1 egress in T cells is trafficked via tetraspanin-enriched membrane domains (TEMs) that are distinct from lysosomal compartments. CD63, CD81, and, to a lesser extent, CD9 were recruited to the virological synapse (VS), and antibodies against these tetraspanins reduced VS formation. We propose that HIV-1 promotes virus assembly and cell-cell transfer in T cells by targeting plasma membrane TEMs.


Dissecting new genetic components of salinity tolerance in two-row spring barley at the vegetative and reproductive stages.
Soil salinity imposes an agricultural and economic burden that may be alleviated by identifying the components of salinity tolerance in barley, a major crop and the most salt tolerant cereal. To improve our understanding of these components, we evaluated a diversity panel of 377 two-row spring barley cultivars during both the vegetative, in a controlled environment, and the reproductive stages, in the field. In the controlled environment, a high-throughput phenotyping platform was used to assess the growth-related traits under both control and saline conditions. In the field, the agronomic traits were measured from plots irrigated with either fresh or saline water. Association mapping for the different components of salinity tolerance enabled us to detect previously known associations, such as HvHKT1;5. Using an "interaction model", which took into account the interaction between treatment (control and salt) and genetic markers, we identified several loci associated with yield components related to salinity tolerance. We also observed that the two developmental stages did not share genetic regions associated with the components of salinity tolerance, suggesting that different mechanisms play distinct roles throughout the barley life cycle. Our association analysis revealed that genetically defined regions containing known flowering genes (Vrn-H3, Vrn-H1, and HvNAM-1) were responsive to salt stress. We identified a salt-responsive locus (7H, 128.35 cM) that was associated with grain number per ear, and suggest a gene encoding a vacuolar H+-translocating pyrophosphatase, HVP1, as a candidate. We also found a new QTL on chromosome 3H (139.22 cM), which was significant for ear number per plant, and a locus on chromosome 2H (141.87 cM), previously identified using a nested association mapping population, which associated with a yield component and interacted with salinity stress. Our study is the first to evaluate a barley diversity panel for salinity stress under both controlled and field conditions, allowing us to identify contributions from new components of salinity tolerance which could be used for marker-assisted selection when breeding for marginal and saline regions.


Bulgarians vs the other European populations: a mitochondrial DNA perspective.
To define the matrilineal relationships between Bulgarians and other European populations, we have evaluated the mitochondrial DNA (mtDNA) variation in a sample of 855 Bulgarian subjects from the mtDNA perspective. The molecular survey was performed by sequencing ∼750 bp of the control region, which resulted in 557 different haplotypes, and by a subsequent restriction fragment length polymorphism analysis to confirm haplogroup/subhaplogroup affiliation. The classification was carried out according to the most updated criteria as reported by van Oven and Kayser (Hum Mutat 30:386-394, 2009), allowing the identification of 45 mitochondrial clades. The observed pattern of mtDNA variation indicates that the Bulgarian mitochondrial pool is geographically homogeneous across the country, and that is characterized by an overall extremely high frequency of western Eurasian lineages. In the principal component analysis, Bulgarians locate in an intermediate position between Eastern European and Mediterranean populations, which is in agreement with historical events. Thus, while the Mediterranean legacy could be attributed to the Thracians, indigenous people that firstly inhabited the Balkans, the Eastern contribution is likely due to the Proto-Bulgarians originating from the Middle East and to the Slavs migrating from northeast Europe.


Induction of Th2 cytokines and control of collagen-induced arthritis by nondepleting anti-CD4 Abs.
CD4+ T cells play a key role in the development of cell-mediated autoimmune diseases, and their modulation has been used to prevent autoimmune diseases in animal models. The effect of the nondepleting anti-CD4 mAb (KT6) was investigated in collagen-induced arthritis (CIA) in DBA/1 mice and in adoptive transfer of CIA into SCID mice. KT6 (200 microg/dose/mouse) was administered systematically from the day of collagen type II (CII) immunization and continued by alternate-day injection until day 11. Only 20% of KT6-treated mice developed arthritis compared with 100% of the isotype control treated mice (p < 0.001). KT6 treatment in a similar regimen also abrogated the adoptive transfer of CIA into SCID mice. Serum levels of IgG2a anti-CII Abs in KT6-treated DBA/1 mice were significantly reduced (p < 0.001), while IgG1 anti-CII were not significantly changed (p > 0.05). Lymph node cells of mice treated in vivo with KT6 had a reduced production of IFN-gamma but increased IL-4 upon in vitro challenge with CII. Furthermore, KT6 could also reverse the profile of cytokine release of in vivo primed and pathogenic CII-specific T cells. These results demonstrate that in vivo modulation with nondepleting anti-CD4 Abs prevents CIA, likely by altering the functional profile of Th1 T cells to Th2. Furthermore, we demonstrate that this treatment can not only prevent, but more importantly also control pathogenic T cells by switching their cytokine production from a Th1 to a Th2-like profile. Our results thus provide compelling evidence of how treatment with nondepleting anti-CD4 may control an autoimmune process. They also indicate that this approach not only prevents, but also could control ongoing autoimmune diseases.


Human herpesvirus 6.
Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are two closely related yet distinct viruses. These visuses belong to the Roseolovirus genus of the betaherpesvirus subfamily; they are most closely related to human herpesvirus 7 and then to human cytomegalovirus. Over 95% of people older than 2 years of age are seropositive for either or both HHV-6 variants, and current serologic methods are incapable of discriminating infection with one variant from infection with the other. HHV-6A has not been etiologically linked to any human disease, but such an association will probably be found soon. HHV-6B is the etiologic agent of the common childhood illness exanthem subitum (roseola infantum or sixth disease) and related febrile illnesses. These viruses are frequently active and associated with illness in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies. HHV-6 is a commensal inhabitant of brains; various neurologic manifestations, including convulsions and encephalitis, can occur during primary HHV-6 infection or in immunocompromised patients. HHV-6 and distribution in the central nervous system are altered in patients with multiple sclerosis; the significance of this is under investigation.


Type-II myocardial infarction and chronic myocardial injury rates, invasive management, and 4-year mortality among consecutive patients undergoing high-sensitivity troponin T testing in the emergency department.
As assessment of patients with suspected acute coronary syndromes (ACS) in emergency departments (EDs) represents a major workload because high-sensitivity troponin (HsTn) T and I levels are frequently measured, and a minority of patients have final diagnosis of myocardial infarction (MI). We determined the relative frequencies of three patients groups: Type-I MI, Type-II MI (including acute myocardial injury). Among 2738 consecutive patients with suspected ACS presenting to ED at Liverpool Hospital, Australia, between March and June 2014. We studied the use of invasive and pharmacological therapies, and 4-year outcomes. Adjudication of MI was according to the 4th universal definition as follows: (i) Type-I MI; (ii) Type-II MI (including acute myocardial injury), and (iii) chronic myocardial injury. Of 995 patients (36%) [median age 76 years (interquartile range 65-83)] with ≥2 HsTnT measurements and one >14 ng/L, 727 (73%) had chronic myocardial injury, 171 (17%) had Type-II MI, and 97 (9.7%) had Type-I MI; respective late mortality rates to 48 months were 33%, 43%, and 14% (P < 0.001). In-hospital angiography rates were 95% for patients with Type-I MI, [62% had percutaneous coronary intervention (PCI)] 24% (7% PCI) for those with Type-II MI, and 3.4% for chronic myocardial injury. On Cox modelling for mortality relative to Type 1 MI, adjusted hazard ratios were 1.94 [95% confidence intervals (CIs) 1.06-3.57]; P = 0.032 for Type 2 MI, and for chronic myocardial injury 1.14 (95% CIs 0.64-2.02); P = 0.66. Among unselected patients undergoing HsTnT testing in EDs, Type-II MI including acute myocardial injury was more common than Type-I MI. Chronic myocardial injury, which occurred in three of four patients. Whereas patients with Type-II MI had higher late mortality than those with Type-I MI, after multivariable analyses mortality rates were marginally different.


The neuroprotective properties of palmitoylethanolamine against oxidative stress in a neuronal cell line.
N-acylethanolamines (NAEs) are lipids upregulated in response to cell and tissue injury and are involved in cytoprotection. Arachidonylethanolamide (AEA) is a well characterized NAE that is an endogenous ligand at cannabinoid and vanilloid receptors, but it exists in small quantities relative to other NAE types. The abundance of other NAE species, such as palmitoylethanolamine (PEA), together with their largely unknown function and receptors, has prompted us to examine the neuroprotective properties and mechanism of action of PEA. We hypothesized that PEA protects HT22 cells from oxidative stress and activates neuroprotective kinase signaling pathways. Indeed PEA protected HT22 cells from oxidative stress in part by mediating an increase in phosphorylated Akt (pAkt) and ERK1/2 immunoreactivity as well as pAkt nuclear translocation. These changes take place within a time frame consistent with neuroprotection. Furthermore, we determined that changes in pAkt immunoreactivity elicited by PEA were not mediated by activation of cannabinoid receptor type 2 (CB2), thus indicating a novel mechanism of action. These results establish a role for PEA as a neuroprotectant against oxidative stress, which occurs in a variety of neurodegenerative diseases. The results from this study reveal that PEA protects HT22 cells from oxidative stress and alters the localization and expression levels of kinases known to be involved in neuroprotection by a novel mechanism. Overall, these results identify PEA as a neuroprotectant with potential as a possible therapeutic agent in neurodegenerative diseases involving oxidative stress.


Association Between History of Polymerase Chain Reaction-verified COVID-19 Infection and Outcomes of Subsequent ST-Elevation Myocardial Infarction.
While the acute phase of coronavirus disease 2019 (COVID-19) is associated with worsening cardiac outcomes, it is unclear whether it affects the outcome of patients with ST-segment elevation myocardial infarction (STEMI) after the acute phase. In addition, while many studies compared the course of STEMI during the COVID-19 pandemic with the years before the outbreak, we evaluated the course of STEMI during the pandemic according to whether or not patients had history of COVID-19. Patients diagnosed with STEMI during the ongoing COVID-19 pandemic were included in the study. The Ministry of Health database was analyzed retrospectively, and patients with (n = 191) and without (n = 127) a history of polymerase chain reaction (PCR) confirmed COVID-19 infection were divided into groups. Clinical and angiographic characteristics were assessed. The rates of in-hospital major adverse cardiac events (MACE) were higher in those who had a history of PCR-verified COVID-19 infection. Angiographic and procedural findings indicating successful reperfusion were better in patients without a history of COVID-19. A history of COVID-19 infection (odds ratio 1.40, 95% confidence interval 1.25-1.60, P < .01) independently predicted MACE. A history of COVID-19 infection is a predictor of worse outcomes following coronary intervention and in-hospital MACE among patients with STEMI.


An Education in Awareness: Self, Motivation, and Self-Regulated Learning in Contemplative Perspective.
Consistent with the aims of this special issue, we present a systems perspective on self/identity, predicated on William James's classic distinction between I and Me, and use this perspective to explore conceptual relations between self/identity, motivation to learn, and self-regulated learning. We define the I self functionally in terms of the capacity for the conscious shifting and sustaining of awareness. The I is conceived of as that aspect of the self-system that affords the potential for the conscious and willful, rather than the non-conscious and automatic, motivation and regulation of behavior. We introduce contemplative education as a set of pedagogical practices designed to cultivate conscious awareness in an ethical-relational context in which the values of personal growth, learning, moral living, and caring for others are nurtured. We discuss the implications of contemplative education for the cultivation of conscious and willful forms of learning and living among students and educators alike.


Microbiological Response to Periodontal Therapy: A Retrospective Study.
Periodontitis is a multifactorial infection caused by a complex of pathogenic bacterial species that induce the destruction of periodontal structures. The aim of this study is to evaluate the presence and bacterial load of six periodontal pathogens bacteria, measured at initial visit and after osseous surgery in patients affected by chronic periodontitis and treated between 2005 and 2007. This cohort study was carried out on a sample of 38 consecutive patients affected by severe chronic periodontitis, diagnosed at baseline on the basis of probing depths equal to 6.68 ± 1.47 mm. On each subject, a microbiological test was performed before periodontal initial therapy and after osseous surgery (one year later). Five compromised teeth were chosen for each patient (the same teeth, before and after surgery), for a total of 190 teeth. Real-time PCR based analysis computed total bacterial load of the samples and quantified six periodontal pathogens: Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum and Prevotella intermedia. Data collection was made consulting medical charts. Pocket probing depth reduction after surgery was 4.50 ± 1.54 mm (p=0.0001). The mean number of sites with bleeding at baseline was 2.08 ± 1.17 and 0.58 ± 1.00 after surgery (p=0.001). The mean number of sites with suppuration at baseline was 0.26 ± 0.86 and 0 after surgery (p=0.02). Cell count of each pathogen and total cell count were significantly higher at baseline than after surgery. Almost all bacteria presented a mean percentage reduction equal to that of the total count, except for Aa and Pi, which seemed to show a greater resistance. The difference of bacterial load, both before and after surgery, between smokers and non-smokers was not statistically significant (p<0.05). A statistically significant correlation was detected between pocket probing depth variation and bleeding on probing variation before and after the surgery, controlling for age (r=0.6, p=0.001). No significant correlations were observed between pocket probing depth and bacterial loads, except for Pg (r=0.5, p=0.001), Tf (r=0.6, p=0.001) and Td (r=0.4, p=0.02). Reduction of presence and bacterial load of the examined periodontal pathogens bacteria after osseous surgery, along with periodontal pocket reduction, appeared to be essential to achieve and maintain periodontal stability over years.


Celecoxib inhibits interleukin-6/interleukin-6 receptor-induced JAK2/STAT3 phosphorylation in human hepatocellular carcinoma cells.
Growing evidence shows an association between chronic liver inflammation and hepatocellular carcinoma (HCC) development. STAT3, which is associated with inflammation and cellular transformation, is constitutively activated in human HCC tissues but not in normal human liver tissues. Although interleukin-6 (IL-6) is elevated in the serum of patients with HCC, it is not fully understood whether STAT3 constitutive activation is positively correlated with autocrine IL-6 secreted by HCC cells. Here, we reported that in HCC cells, the elevated levels of both IL-6 and IL-6 receptor (IL-6R, gp80), not IL-6 alone, correlated with STAT3 activation. We also explored whether the anticancer effects of celecoxib, an anti-inflammatory drug, may be due to the inhibition of the IL-6/STAT3 pathway in HCC cells. Our results showed that celecoxib decreased STAT3 phosphorylation by reducing Janus-activated kinase (JAK2) phosphorylation and caused apoptosis in HCC cells. Celecoxib could also block exogenous IL-6-induced STAT3 phosphorylation and nuclear translocation. Moreover, we observed more significant inhibition of cell viability when celecoxib was combined with doxorubicin or sorafenib. We conclude that the elevated levels of IL-6/IL-6R may be correlated with STAT3 activation in HCC cells. Celecoxib may be a candidate for HCC therapy through blocking IL-6/STAT3 pathway and can be combined with other anticancer drugs to reduce drug resistance caused by IL-6/STAT3 signals.


Pleistocene glacial refugia across the Appalachian Mountains and coastal plain in the millipede genus Narceus: evidence from population genetic, phylogeographic, and paleoclimatic data.
Species that are widespread throughout historically glaciated and currently non-glaciated areas provide excellent opportunities to investigate the role of Pleistocene climatic change on the distribution of North American biodiversity. Many studies indicate that northern animal populations exhibit low levels of genetic diversity over geographically widespread areas whereas southern populations exhibit relatively high levels. Recently, paleoclimatic data have been combined with niche-based distribution modeling to locate possible refugia during the Last Glacial Maximum. Using phylogeographic, population, and paleoclimatic data, we show that the distribution and mitochondrial data for the millipede genus Narceus are consistent with classical examples of Pleistocene refugia and subsequent post-glacial population expansion seen in other organismal groups. The phylogeographic structure of Narceus reveals a complex evolutionary history with signatures of multiple refugia in southeastern North America followed by two major northern expansions. Evidence for refugial populations were found in the southern Appalachian Mountains and in the coastal plain. The northern expansions appear to have radiated from two separate refugia, one from the Gulf Coastal Plain area and the other from the mid-Atlantic coastal region. Distributional models of Narceus during the Last Glacial Maximum show a dramatic reduction from the current distribution, with suitable ecological zones concentrated along the Gulf and Atlantic coastal plain. We found a strong correlation between these zones of ecological suitability inferred from our paleo-model with levels of genetic diversity derived from phylogenetic and population estimates of genetic structuring. The signature of climatic change, during and after the Pleistocene, on the distribution of the millipede genus Narceus is evident in the genetic data presented. Niche-based historical distribution modeling strengthens the conclusions drawn from the genetic data and proves useful in identifying probable refugia. Such interdisciplinary biogeographic studies provide a comprehensive approach to understanding these processes that generate and maintain biodiversity as well as the framework necessary to explore questions regarding evolutionary diversification of taxa.


A values-based conceptual framework for surgical appropriateness: an illustrative case report.
Appropriateness in surgical decision-making necessitates that surgical treatments are aligned with patients' goals and values for care. To arrive at informed decisions for surgery, patients must have an understanding of post-operative recovery, the impact on quality of life, and expected functional outcomes. This article describes an illustrative case of an older patient who experienced a decline in health, functional status, and quality of life in the months following a major surgical operation that was not clearly aligned with her personal goals and priorities. Palliative care needs that arose during the course of the patient's treatment are identified and described, revealing opportunities for better integration between palliative and postoperative care. A conceptual framework for measuring appropriateness in surgery, which incorporates patients' goals, values and preferences for medical treatments, is proposed.


Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a.
Although pain is a cardinal feature of pancreatitis, its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with activation of protein kinases including trkA, protein kinase C, and protein kinase A. We therefore tested the hypothesis that systemic treatment with a kinase inhibitor, k252a, known to inhibit all of these kinases would alleviate pain in an animal model of pancreatitis. Von Frey filament testing of somatic referral regions was evaluated as a method to measure referred pain in a rat model of acute necrotizing pancreatitis induced by L-arginine. Rats with pancreatitis showed increased sensitivity to abdominal stimulation with Von Frey filament. This referred mechanical sensitivity was associated with an 8-fold increase in levels of phosphorylated trkA in the pancreas and with significant up-regulation of both calcitonin gene-related peptide and preprotachykinin mRNA expression in thoracic dorsal root ganglia and with increased calcitonin gene-related peptide and substance P immunoreactivity in spinal cord segment T10. Treatment with the kinase inhibitor k252a suppressed the phosphorylation of trkA in the pancreas as well as reversed both the behavioral changes and the increase in neuropeptide expression associated with pancreatitis.


Measuring population health: costs of alternative survey approaches in the Nouna Health and Demographic Surveillance System in rural Burkina Faso.
There are more than 40 Health and Demographic Surveillance System (HDSS) sites in 19 different countries. The running costs of HDSS sites are high. The financing of HDSS activities is of major importance, and adding external health surveys to the HDSS is challenging. To investigate the ways of improving data quality and collection efficiency in the Nouna HDSS in Burkina Faso, the stand-alone data collection activities of the HDSS and the Household Morbidity Survey (HMS) were integrated, and the paper-based questionnaires were consolidated into a single tablet-based questionnaire, the Comprehensive Disease Assessment (CDA). The aims of this study are to estimate and compare the implementation costs of the two different survey approaches for measuring population health. All financial costs of stand-alone (HDSS and HMS) and integrated (CDA) surveys were estimated from the perspective of the implementing agency. Fixed and variable costs of survey implementation and key cost drivers were identified. The costs per household visit were calculated for both survey approaches. While fixed costs of survey implementation were similar for the two survey approaches, there were considerable variations in variable costs, resulting in an estimated annual cost saving of about US$45,000 under the integrated survey approach. This was primarily because the costs of data management for the tablet-based CDA survey were considerably lower than for the paper-based stand-alone surveys. The cost per household visit from the integrated survey approach was US$21 compared with US$25 from the stand-alone surveys for collecting the same amount of information from 10,000 HDSS households. The CDA tablet-based survey method appears to be feasible and efficient for collecting health and demographic data in the Nouna HDSS in rural Burkina Faso. The possibility of using the tablet-based data collection platform to improve the quality of population health data requires further exploration.


Topoisomerase levels determine chemotherapy response in vitro and in vivo.
Topoisomerase poisons are chemotherapeutic agents that are used extensively for treating human malignancies. These drugs can be highly effective, yet tumors are frequently refractory to treatment or become resistant upon tumor relapse. Using a pool-based RNAi screening approach and a well characterized mouse model of lymphoma, we explored the genetic basis for heterogeneous responses to topoisomerase poisons in vitro and in vivo. These experiments identified Top2A expression levels as major determinants of response to the topoisomerase 2 poison doxorubicin and showed that suppression of Top2A produces resistance to doxorubicin in vitro and in vivo. Analogously, using a targeted RNAi approach, we demonstrated that suppression of Top1 produces resistance to the topoisomerase 1 poison camptothecin yet hypersensitizes cancer cells to doxorubicin. Importantly, lymphomas relapsing after treatment display spontaneous changes in topoisomerase levels as predicted by in vitro gene knockdown studies. These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic.


Phase-sensitive detection in modulation excitation spectroscopy applied to potential induced electron transfer in cytochrome c oxidase.
Cytochrome c oxidase (CcO) from Rhodobacter sphaeroides was investigated by modulated excitation surface-enhanced infrared-absorption spectroscopy (SEIRAS). Sequential electron transfer (ET) within CcO was initiated by electrochemical excitation. During modulated excitation by periodic potential pulses with frequencies between 20 and 500 Hz, time-resolved infrared spectra were measured by the step-scan technique, with time resolution in the millisecond range. Conformational changes of the protein structure as a result of ET lead to rather complex SEIRA spectra with many overlapping bands embedded in a broad background signal. Phase-sensitive detection (PSD) was used to separate single components within the broad band of overlapping structural bands in the amide I region. PSD is able to extract the periodic response of single components with the same frequency as the excitation from noise or from static background and therefore enhances the signal-to-noise ratio. Moreover, PSD enables validation of the fit model used for the deconvolution of overlapping bands by analyzing phase lags of single components acquired at different stimulation frequencies. Phase lags between the evaluated vibrational components and the modulated excitation increase with increasing excitation frequencies, an inherent prerequisite of this evaluation method.


Is the effect of premature elevated progesterone augmented by human chorionic gonadotropin versus gonadotropin-releasing hormone agonist trigger?
To compare the effect of P on live birth rate between hCG and GnRH agonist (GnRH-a) trigger cycles. Retrospective cohort study. Large private assisted reproductive technology (ART) practice. A total of 3,326 fresh autologous ART cycles. None. Live birth. A total of 647 GnRH-a trigger cycles were compared with 2,679 hCG trigger cycles. Live birth was negatively associated with P in both the hCG trigger (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52-0.76) and the agonist trigger cohorts (OR 0.56, 95% CI 0.45-0.69). Interaction testing evaluating P and trigger medication was not significant, indicating that P had a similar negative effect on live birth rates in both cohorts. Progesterone ≥2 ng/mL occurred more commonly in GnRH-a trigger cycles compared with hCG trigger cycles (5.5% vs. 3.1%) and was negatively associated with live birth in both the hCG trigger (OR 0.28, 95% CI 0.11-0.73) and agonist trigger cohorts (OR 0.35, 95% CI 0.14-0.90). When P ≥2 ng/mL, the live birth rates were poor and similar in the hCG and GnRH-a cohorts (5.9% vs. 14.2%), indicating that P ≥2 ng/mL had a similar negative effect on live birth in both cohorts. Elevated serum P on the day of hCG was negatively associated with live birth rates in both hCG and GnRH-a trigger cycles.


Genetic differentiation among Maruca vitrata F. (Lepidoptera: Crambidae) populations on cultivated cowpea and wild host plants: implications for insect resistance management and biological control strategies.
Maruca vitrata Fabricius (Lepidoptera: Crambidae) is a polyphagous insect pest that feeds on a variety of leguminous plants in the tropics and subtropics. The contribution of host-associated genetic variation on population structure was investigated using analysis of mitochondrial cytochrome oxidase 1 (cox1) sequence and microsatellite marker data from M. vitrata collected from cultivated cowpea (Vigna unguiculata L. Walp.), and alternative host plants Pueraria phaseoloides (Roxb.) Benth. var. javanica (Benth.) Baker, Loncocarpus sericeus (Poir), and Tephrosia candida (Roxb.). Analyses of microsatellite data revealed a significant global FST estimate of 0.05 (P≤0.001). The program STRUCTURE estimated 2 genotypic clusters (co-ancestries) on the four host plants across 3 geographic locations, but little geographic variation was predicted among genotypes from different geographic locations using analysis of molecular variance (AMOVA; among group variation -0.68%) or F-statistics (FSTLoc = -0.01; P = 0.62). These results were corroborated by mitochondrial haplotype data (φSTLoc = 0.05; P = 0.92). In contrast, genotypes obtained from different host plants showed low but significant levels of genetic variation (FSTHost = 0.04; P = 0.01), which accounted for 4.08% of the total genetic variation, but was not congruent with mitochondrial haplotype analyses (φSTHost = 0.06; P = 0.27). Variation among host plants at a location and host plants among locations showed no consistent evidence for M. vitrata population subdivision. These results suggest that host plants do not significantly influence the genetic structure of M. vitrata, and this has implications for biocontrol agent releases as well as insecticide resistance management (IRM) for M. vitrata in West Africa.


α6ß2* and α4ß2* nicotinic receptors both regulate dopamine signaling with increased nigrostriatal damage: relevance to Parkinson's disease.
Nicotinic receptors (nAChRs) are important modulators of dopaminergic transmission in striatum, a region critical to Parkinson's disease. The nAChRs mainly involved are the α6β2* and α4β2* subtypes. Lesion studies show that the α6β2* receptor is decreased to a much greater extent with nigrostriatal damage than the α4β2* subtype raising the question whether this latter nAChR population is more important with increased nigrostriatal damage. To address this, we investigated the effect of varying nigrostriatal damage on α6β2* and α4β2* receptor-modulated dopamine signaling using cyclic voltammetry. This approach offers the advantage that changes in dopamine release can be observed under different neuronal firing conditions. Total single-pulse-evoked dopamine release decreased in direct proportion to declines in the dopamine transporter and dopamine uptake. We next used α-conotoxinMII and mecamylamine to understand the role of the α4β2* and α6β2* subtypes in release. Single-pulse-stimulated α6β2* and α4β2* receptor dopamine release decreased to a similar extent with increasing nigrostriatal damage, indicating that both subtypes contribute to the control of dopaminergic transmission with lesioning. Total burst-stimulated dopamine release also decreased proportionately with nigrostriatal damage. However, the role of the α4β2* and α6β2* nAChRs varied with different degrees of lesioning, suggesting that the two subtypes play a unique function with burst firing, with a somewhat more prominent and possibly more selective role for the α6β2* subtype. These data have important therapeutic implications because they suggest that drugs directed to both α4β2* and α6β2* nAChRs may be useful in the treatment of neurological disorders such as Parkinson's disease.


Effects of doxycycline on gene expression in Wolbachia and Brugia malayi adult female worms in vivo.
Most filarial nematodes contain Wolbachia symbionts. The purpose of this study was to examine the effects of doxycycline on gene expression in Wolbachia and adult female Brugia malayi. Brugia malayi infected gerbils were treated with doxycycline for 6-weeks. This treatment largely cleared Wolbachia and arrested worm reproduction. RNA recovered from treated and control female worms was labeled by random priming and hybridized to the Version 2- filarial microarray to obtain expression profiles. Results showed significant changes in expression for 200 Wolbachia (29% of Wolbachia genes with expression signals in untreated worms) and 546 B. malayi array elements after treatment. These elements correspond to known genes and also to novel genes with unknown biological functions. Most differentially expressed Wolbachia genes were down-regulated after treatment (98.5%). In contrast, doxycycline had a mixed effect on B. malayi gene expression with many more genes being significantly up-regulated after treatment (85% of differentially expressed genes). Genes and processes involved in reproduction (gender-regulated genes, collagen, amino acid metabolism, ribosomal processes, and cytoskeleton) were down-regulated after doxycycline while up-regulated genes and pathways suggest adaptations for survival in response to stress (energy metabolism, electron transport, anti-oxidants, nutrient transport, bacterial signaling pathways, and immune evasion). Doxycycline reduced Wolbachia and significantly decreased bacterial gene expression. Wolbachia ribosomes are believed to be the primary biological target for doxycycline in filarial worms. B. malayi genes essential for reproduction, growth and development were also down-regulated; these changes are consistent with doxycycline effects on embryo development and reproduction. On the other hand, many B. malayi genes involved in energy production, electron-transport, metabolism, anti-oxidants, and others with unknown functions had increased expression signals after doxycycline treatment. These results suggest that female worms are able to compensate in part for the loss of Wolbachia so that they can survive, albeit without reproductive capacity. This study of doxycycline induced changes in gene expression has provided new clues regarding the symbiotic relationship between Wolbachia and B. malayi.


Medication Errors in the Emergency Department: Knowledge, Attitude, Behavior, and Training Needs of Nurses.
The aim was to describe which elements of nurses' knowledge, training needs, behavior, and attitude can prevent Medication errors (Acronym MEs) in the emergency department during all steps of the administration of intravenous (IV) medications. An anonymous questionnaire made up of 43 items has been drafted and delivered to a sample of 103 nurses of a university hospital in Rome. The study has been supported by specific literature review. Majority of the sample (94%) answered that topics related to the preparation and administration of IV medications were covered during the basic course while 63.2% only during the postbasic course. Only 15.6% of nurses judged excellent their level of knowledge about preparation and administration of IV medications while 89.3% considered that it is important to improve their knowledge; 85.6% said that the teaching about the use of IV medications should be increased during the degree course they attended; 30.3% agreed that specific postgraduate courses on the use of IV drugs should be designed. Moreover, only 22% of the sample believed that the coaching of new recruit nurses is critical to prevent errors. The sample showed appropriate knowledge, positive attitudes, and right behavior related to the preparation and administration of IV medications. The skills that nurses must have in pharmacology are still rising, both due to the safety of drug therapy and to the increasing number of drugs available; the result is that nurses have to update their knowledge regularly.


Infant parasite rates and immunoglobulin M seroprevalence as a measure of exposure to Plasmodium falciparum during a randomized controlled trial of insecticide-treated bed nets on the Kenyan coast.
Repeated cross-sectional surveys among infants sleeping under insecticide-treated bed nets (ITBN) and contemporary control infants were used to estimate changes in Plasmodium falciparum exposure due to ITBN use on the Kenyan coast. Presence of P. falciparum parasites or total P. falciparum Immunoglobulin M (IgM) seropositivity were used independently and in combination in a constant risk catalytic conversion model to estimate the force of infection in ITBN and control communities. Such studies during infancy avoid problems of early saturation of prevalence due to high forces of infection and persistence of infection, minimize problems of self-treatment, and can be conducted among large populations covering a wide geographic area. These contrast previous parasitologic studies of ITBN among older children and the traditional entomologic studies of transmission that are logistically demanding. Our investigations demonstrated that parasite prevalence, IgM seropositivity, and the force of transmission were all significantly reduced by 50%. In addition, more infants under ITBN entered their second year of life without previous exposure to P. falciparum than control infants. These effects upon delayed acquisition of effective immunity require careful monitoring during future vector control programs using ITBN.


The initiation of adolescent sexual and contraceptive behavior during changing times.
This paper examines changes in the initiation of adolescent sexual and contraceptive behavior in the United States between 1978 and 1988. Since a number of contextual changes occurred during this time period including a focusing of public attention on adolescent pregnancy along with the widespread publicity surrounding AIDS, we expected that the response to these events not only would change over time, but would also vary across social groups. Using data from Cycles III and IV of the National Survey of Family Growth, we find that the overall population patterns of earlier initiation of sexual intercourse and increased use of condoms at first intercourse are not found in all segments of the population. In general, the effects of race, religion, mother's education, and age changed during this time period. The long-term trend of younger age at first intercourse was halted for Blacks, and reversed for White, fundamentalist Protestants, but continued for all other Whites. Overall, patterns throughout the decade suggest that pressures from parents, religious groups, and others either lead to a later age at first intercourse, or use of contraception, but not both. A notable exception is that increased maternal education leads to both a later age at first intercourse and a higher likelihood of using contraception at first intercourse.


Making monitoring 'work': human-machine interaction and patient safety in anaesthesia.
This study aimed to explore the use of electronic monitoring within the context of anaesthetic practice. We conducted workplace observation of, and interviews with, anaesthetists and other anaesthetic staff in two UK hospitals. Transcripts were analysed inductively for recurrent themes. Whilst formal sources of knowledge in anaesthesia deal with the issue of monitoring in terms of theoretical principles and performance specifications of devices, anaesthetists in practice often 'disbelieve' monitoring information. They call on and integrate other sources of knowledge about the patient, especially from their clinical assessment. The ability to distinguish 'normal' and 'abnormal' findings is vital. Confidence in electronic information varies with experience, as does the degree to which electronic information may be considered 'redundant'. We conclude that electronic monitoring brings new dimensions of understanding but also the potential for new ways of misunderstanding. The tacit knowledge underlying the safe use of monitoring deserves greater acknowledgement in training and practice.


Surgical complications and their implications for surgeons' well-being.
Healthcare professionals can be seriously affected when they are involved in major clinical incidents. The impact of such incidents on staff is of particular relevance to surgery, as the operating room is one of the highest-risk areas for serious complications. This qualitative study aimed to assess the personal and professional impact of surgical complications on surgeons. This single time point study involved semistructured, individual interviews with general and vascular surgeons, consultants and senior registrars from two National Health Service organizations in London, UK. Twenty-seven surgeons participated. Many were seriously affected by major surgical complications. Surgeons' practice was also often affected, not always in the best interest of their patients. The surgeons' reactions depended on the preventability of the complications, their personality and experience, patient outcomes and patients' reactions, as well as colleagues' reactions and the culture of the institution. Discussing complications, deconstructing the incidents and rationalizing were the most commonly quoted coping mechanisms. Institutional support was generally described as inadequate, and the participants often reported the existence of strong institutional blame cultures. Suggestions for supporting surgeons in managing the personal impact of complications included better mentoring, teamwork approaches, blame-free opportunities for the discussion of complications, and structures aimed at the human aspects of complications. Those involved in the management of surgical services need to consider how to improve support for surgeons in the aftermath of major surgical incidents.


The photophysics of fac-[Re(CO)3(dppz)(py)]+ in CH3CN: a comparative picosecond flash photolysis, transient infrared, transient resonance Raman and density functional theoretical study.
The photophysical properties of fac-[Re(CO)3(dppz)(py)]+ (1, where dppz = dipyrido[3,2-a: 2',3'-c]phenazine) in CH3CN have been investigated using a series of complementary techniques including visible and infrared transient absorption and resonance Raman spectroscopy on the picosecond and nanosecond timescales. The results confirm previous reports that the lowest-lying emissive state in 1 is a triplet intra-ligand (3IL) state localised on the dppz ligand and have provided detailed information on the dynamics of 1 upon photoexcitation, including the relative energies of the excited state species encountered and the electronic distribution within these. If the dppz ligand is viewed in terms of phenanthroline (phen) and phenazine (phz) moieties, the emissive state is probably more accurately described as a 3 pi-->pi *(phz) IL state. The picosecond studies have shown that this emissive state is formed, at least in part, within 30 ps of excitation from a precursor, which is possibly a 3 pi-->pi *(phen) IL state. On the nanosecond timescale, TRIR has been employed to elucidate further dynamics and reveal the presence of an energetically close-lying state in equilibrium with the emissive state. This has tentatively been assigned as being 3d pi(Re)-->pi *(phz) metal-to-ligand charge transfer (MLCT) in nature. A summary of the photophysics is proposed in the form of a Jablonski scheme. Time dependent density functional theory (TD-DFT) calculations support the relative ordering and suggested electronic character of the excited state species involved.


Substantive due process after Gonzales v. Carhart.
This Article begins in Part I with a doctrinal evaluation of the status of Washington v. Glucksberg ten years after that decision was handed down. Discussion begins with consideration of the Roberts Court's recent decision in Gonzales v. Carhart and then turns to the subject of Justice Kennedy's views in particular on substantive due process. In Part II, the Article goes on to consider whether the Glucksberg test for substantive due process decision making is correct in light of the original meaning of the Fourteenth Amendment. The Article concludes in Parts II and III that Glucksberg is right to confine substantive due process rights recognition to recognition only of those rights that are deeply rooted in history and tradition.


Imaging assessment of a portable hemodialysis device: detection of possible failure modes and monitoring of functional performance.
The purpose of this study was to investigate the utility and limitations of various imaging modalities in the noninvasive assessment of a novel compact hemodialyzer under development for renal replacement therapy, with specific aim towards monitoring its functional performance. The prototype is a 4×3×6 cm aluminum cartridge housing "blood" and "dialysate" flow paths arranged in parallel. A sheet of semipermeable silicon nanopore membranes forms the blood-dialysate interface, allowing passage of small molecules. Blood flow was simulated using a peristaltic pump to instill iodinated contrast through the blood compartment, while de-ionized water was instilled through the dialysate compartment at a matched rate in the countercurrent direction. Images were acquired under these flow conditions using multi-detector computed tomography (MDCT), fluoroscopy, high-resolution quantitative computed tomography (HR-QCT), and magnetic resonance imaging (MRI). MDCT was used to monitor contrast diffusion efficiency by plotting contrast density as a function of position along the path of flow through the cartridge during steady state infusion at 1 and 20 mL/min. Both linear and exponential regressions were used to model contrast decay along the flow path. Both linear and exponential models of contrast decay appeared to be reasonable approximations, yielding similar results for contrast diffusion during a single pass through the cartridge. There was no measurable difference in contrast diffusion when comparing 1 mL/min and 20 mL/min flow rates. Fluoroscopy allowed a gross qualitative assessment of flow within the device, and revealed flow inhomogeneity within the corner of the cartridge opposite the blood inlet port. MRI and HR-QCT were both severely limited due to the paramagnetic properties and high atomic number of the target material, respectively. During testing, we encountered several causes of device malfunction, including leak formation, trapped gas, and contrast-mediated nanopore clogging. We illustrate the imaging manifestations of each. Despite the inherent challenges in imaging a predominantly metallic device, some modalities show potential in the non-invasive assessment of a novel compact hemodialyzer. The approaches described here could potentially be translated to device evaluation in the implanted setting.


Modification of the electroosmotic flow and separation selectivity of anions in electrochromatography with pseudo-stationary phases of C14-alkyldimethylammoniopropane sulfonate zwitterionic surfactants by addition of salts to the background electrolyte.
The effects of salts (NaCl, NaClO4, MgCl2, CeCl3) added to background electrolyte (BGE) solutions (10 mmol L(-1) sodium phosphate, pH 7.2) on electroosmotic flow (EOF) and the separation selectivity of anions (chloride, bromide, iodide, nitrite, nitrate, chlorate, thiocyanate, iodate, chromate, and molybdate ion) by capillary electrochromatography using the zwitterionic surfactant 3-(N,N-dimethylmyristylammonio)propane sulfonate (C14N3S) as a pseudo-stationary phase were investigated. There are two mechanisms affecting the separations: 1. the cations and anions of the added salts interact with the zwitterionic surfactant to varying degrees, thus changing the overall retention of the analytes; and 2. they change the EOF and the resulting apparent mobilities. It was shown that a BGE containing perchlorate and a low concentration of zwitterionic surfactant (2 mmol L(-1)) gave a stable and reproducible EOF and the concentration of perchlorate could be used to manipulate the separation selectivity for polarizable anions, such as iodide and thiocyanate. These effects are discussed in terms of measured association constants describing the interaction of anions and cations with the zwitterion.


Perceived stress and team performance during a simulated resuscitation.
Barriers to optimal performance of cardiopulmonary resuscitation may partly relate to human factors, such as stress and specific emotions. The aim of this study was to investigate whether mental stress and different perceived emotions have a negative impact on the performance of rescuers. This prospective, observational study was conducted at the Simulator Center of the University Hospital Basel, Switzerland. A total of 120 medical students (70% female) participated in teams of three. They reported levels of perceived stress, feeling overwhelmed, motivation and specific emotions before, during, and after a simulated resuscitation. The association of stress/overload (index of stress and feeling overwhelmed), motivation, and specific emotions with resuscitation performance defined as hands-on time during the first 180 s after cardiac arrest was investigated. During resuscitation, levels of stress/overload, motivation, and negative emotions were significantly higher as compared to the periods before and after resuscitation. In contrast, positive emotions were highest before and after resuscitation and significantly lower during resuscitation. In general, females reported higher stress/overload and negative emotions, whereas males reported more positive emotions. A multivariate linear regression model showed negative associations of stress/overload (regression coefficient -18.12, 95% CI -30.73, -5.51, p = 0.006) and positive associations of motivation (regression coefficient 13.45, 95% CI 0.95, 25.95, p = 0.036) with resuscitation performance. A simulated cardiac arrest caused substantial perceived stress/overload and negative emotions, particularly in female students, which adversely impacted resuscitation performance. Further studies are required to expand our findings to more experienced medical professionals and investigate whether stress coping strategies improve resuscitation performance.


Intradermally-administered influenza virus vaccine is safe and immunogenic in healthy adults 18-64 years of age.
To increase vaccine acceptance, intradermal (ID) influenza vaccine (Fluzone(®) Intradermal, Sanofi Pasteur Inc.) may be an attractive alternative to intramuscular (IM) vaccination due to smaller needle and volume injected. A multicenter, randomized (2:1 ID vs IM vaccines) study, blinded for ID vaccine lots, was conducted among 4292 adults 18-64 years of age enrolled in October 2008. Three lots of investigational trivalent influenza vaccine containing 9μg hemagglutinin (HA) per strain in 0.1mL administered ID with a 30 gauge, 1.5mm long needle were compared to standard dose vaccine (0.5mL containing 15μg HA/strain) given IM. The post-vaccination antibody geometric mean titers (GMT) for the ID vaccine were similar to the IM vaccine (H1N1: 193.2 vs. 178.3, H3N2: 246.7 vs. 230.7, and B: 102.5 vs. 126.9). Non-inferiority was met for the ID vaccine compared to IM vaccine as assessed by antibody GMT ratios (IM/ID) for all three virus strains (H1N1: 0.92, H3N2: 0.94, and B: 1.24). Seroconversion rates were non-inferior for H1N1 and H3N2, but not for B (ID vs. IM: H1N1: 61.2% vs. 60.5%, H3N2: 75.3% vs. 74.8%, and B: 46.2% vs. 54.2%). Seroprotection (HAI titer ≥1:40) rates were similar between groups (ID vs. IM, H1N1: 91.1% vs. 91.7%, H3N2: 90.7% vs. 91.4%, and B: 87.4% vs. 89.3%). Local injection site reactions overall were more common with ID than IM vaccine (ID vs. IM: 89.2% vs. 60.2%), but were usually grade 1 or 2 and transient. The frequencies of local injection site pain and systemic reactions were similar between vaccine groups, except more myalgia with IM vaccine. The ID vaccine elicited immune responses comparable to IM vaccine except for the seroconversion rate to B virus. With the exception of pain, local injection site reactions were more common with the ID vaccine, but well-tolerated and of short duration. ClinicalTrials.gov identifier: NCT00772109.


Aerobic Fitness and Intraindividual Reaction Time Variability in Middle and Old Age.
To examine whether aerobic fitness moderated age differences in within-person reaction time variability (WP RT variability) and given conceptual linkage involving the frontal cortex, whether effects were mediated by executive function. Aerobic fitness (estimated VO2max) and WP RT variability were investigated in 225 healthy, community-dwelling adults aged 50-90 years (M = 63.83) across 4 cognitive domains; psychomotor performance, executive function, visual search, and recognition. Significant Age × Aerobic fitness interactions were found in relation to WP variability in 3 cognitive domains: psychomotor performance (4-choice RT), executive function (Flanker and Stroop arrows), and immediate recognition. Lower aerobic fitness was associated with greater RT variability, and this effect increased with age. Additionally, some of these effects were mediated by executive function. The findings suggest that aerobic fitness moderated the association between age and intraindividual RT variability, and that executive function selectively mediated that association. It is possible that aerobic fitness helps attenuate the neurobiological decline that contributes to cognitive deficits in old age and that WP variability is a measure that may be particularly sensitive to this effect.


On the genome constitution and evolution of intermediate wheatgrass (Thinopyrum intermedium: Poaceae, Triticeae).
The wheat tribe Triticeae (Poaceae) is a diverse group of grasses representing a textbook example of reticulate evolution. Apart from globally important grain crops, there are also wild grasses which are of great practical value. Allohexaploid intermediate wheatgrass, Thinopyrum intermedium (2n = 6x = 42), possesses many desirable agronomic traits that make it an invaluable source of genetic material useful in wheat improvement. Although the identification of its genomic components has been the object of considerable investigation, the complete genomic constitution and its potential variability are still being unravelled. To identify the genomic constitution of this allohexaploid, four accessions of intermediate wheatgrass from its native area were analysed by sequencing of chloroplast trnL-F and partial nuclear GBSSI, and genomic in situ hybridization. The results confirmed the allopolyploid origin of Thinopyrum intermedium and revealed new aspects in its genomic composition. Genomic heterogeneity suggests a more complex origin of the species than would be expected if it originated through allohexaploidy alone. While Pseudoroegneria is the most probable maternal parent of the accessions analysed, nuclear GBSSI sequences suggested the contribution of distinct lineages corresponding to the following present-day genera: Pseudoroegneria, Dasypyrum, Taeniatherum, Aegilops and Thinopyrum. Two subgenomes of the hexaploid have most probably been contributed by Pseudoroegneria and Dasypyrum, but the identity of the third subgenome remains unresolved satisfactorily. Possibly it is of hybridogenous origin, with contributions from Thinopyrum and Aegilops. Surprising diversity of GBSSI copies corresponding to a Dasypyrum-like progenitor indicates either multiple contributions from different sources close to Dasypyrum and maintenance of divergent copies or the presence of divergent paralogs, or a combination of both. Taeniatherum-like GBSSI copies are most probably pseudogenic, and the mode of their acquisition by Th. intermedium remains unclear. Hybridization has played a key role in the evolution of the Triticeae. Transfer of genetic material via extensive interspecific hybridization and/or introgression could have enriched the species' gene pools significantly. We have shown that the genomic heterogeneity of intermediate wheatgrass is higher than has been previously assumed, which is of particular concern to wheat breeders, who frequently use it as a source of desirable traits in wheat improvement.


Preexisting mitral valve prosthesis in patients undergoing left ventricular assist device implantation.
Experience with patients undergoing left ventricular assist device (LVAD) implantation with preexisting mitral valve prostheses is limited. Patients with mechanical heart valves might have an increased risk of thromboembolism; in patients with biologic valves, there might be a risk of structural deterioration of the leaflets. Out of 597 patients supported with a LVAD system between 2000 and 2009, 18 patients had mitral valve surgery prior to implantation. We excluded all patients below 18 years of age, those with postcardiotomy failure, and patients who had had mitral valve reconstruction. Only 1% of the studied patient population (n= 6) had mitral valve replacement. The mitral valve implantation has been performed 7.4 ± 9.4 years prior to LVAD insertion. None of the valves (one biologic, five mechanical) were exchanged or explanted. LVAD implantation was done either with left lateral thoracotomy (n= 5) or with midline resternotomy (n= 1). Temporary right ventricular assist device support was necessary in one case (16.6%); 30-day mortality was 16.6% (n= 1). Median support time was 14 ± 15 months. Two patients received heart transplantation after 6 and 26 months on the device; four patients died on mechanical circulatory support after 1, 2, 5, and 40 months. No valve or pump thrombosis or other clinically relevant thromboembolic events were observed. Only a small number of patients (1%) had a preexisting mitral valve prosthesis prior to LVAD implantation. No severe adverse events were observed when the prosthesis was left in place. Attention should be paid to the anticoagulation regime.


Patterns and predictors of breast cancer chemotherapy use in Kaiser Permanente Northern California, 2004-2007.
Chemotherapy regimens for early stage breast cancer have been tested by randomized clinical trials, and specified by evidence-based practice guidelines. However, little is known about the translation of trial results and guidelines to clinical practice. We extracted individual-level data on chemotherapy administration from the electronic medical records of Kaiser Permanente Northern California (KPNC), a pre-paid integrated healthcare system serving 29 % of the local population. We linked data to the California Cancer Registry, incorporating socio-demographic and tumor factors, and performed multivariable logistic regression analyses on the receipt of specific chemotherapy regimens. We identified 6,004 women diagnosed with Stage I-III breast cancer at KPNC during 2004-2007; 2,669 (44.5 %) received at least one chemotherapy infusion at KPNC within 12 months of diagnosis. Factors associated with receiving chemotherapy included <50 years of age [odds ratio (OR) 2.27, 95 % confidence interval (CI) 1.81-2.86], tumor >2 cm (OR 2.14, 95 % CI 1.75-2.61), involved lymph nodes (OR 11.3, 95 % CI 9.29-13.6), hormone receptor-negative (OR 6.94, 95 % CI 4.89-9.86), Her2/neu-positive (OR 2.71, 95 % CI 2.10-3.51), or high grade (OR 3.53, 95 % CI 2.77-4.49) tumors; comorbidities associated inversely with chemotherapy use [heart disease for anthracyclines (OR 0.24, 95 % CI 0.14-0.41), neuropathy for taxanes (OR 0.45, 95 % CI 0.22-0.89)]. Relative to high-socioeconomic status (SES) non-Hispanic Whites, we observed less anthracycline and taxane use by SES non-Hispanic Whites (OR 0.63, 95 % CI 0.49-0.82) and American Indians (OR 0.23, 95 % CI 0.06-0.93), and more anthracycline use by high-SES Asians/Pacific Islanders (OR 1.72, 95 % CI 1.02-2.90). In this equal-access healthcare system, chemotherapy use followed practice guidelines, but varied by race and socio-demographic factors. These findings may inform efforts to optimize quality in breast cancer care.


Optical integration of a real-valued function by measurement of a Stokes parameter.
We experimentally implement an optical algorithm for integration of a real-valued bivariate function. A user-defined function is encoded in the position-dependent phase of one of the polarization components of an optical beam. The integral of this function is retrieved by measuring a Stokes parameter of the polarization. We analyze the performance of the system as an integration device.


Cloning and chromosomal mapping of the murine norepinephrine transporter.
The norepinephrine (NE) transporter (NET), a target of many clinically prescribed antidepressants, regulates noradrenergic neurotransmission by efficiently clearing NE from synaptic spaces after release. To advance our understanding of NET gene structure, regulation, and potential associations with complex behavioral trait loci, we amplified a mouse norepinephrine transporter (mNET) cDNA from placenta total RNA and utilized mNET probes to isolate and characterize the mNET gene. Inferred translation of the major open reading frame of the mNET cDNA predicts a 617-amino acid protein with 12 putative membrane-spanning regions and 94% identity to human NET. The coding exons of the mNET cDNA were found to be spread across >36 kb of 129/Svj genomic DNA, with exon-intron boundaries bearing consensus gt/ag splice sites. Sequence upstream (202 bp) of the inferred translation initiation site matched the sequence of 5' rapid amplification of cDNA ends products from brain mRNA with no evidence for intervening introns and is preceded by a TATA box and canonical transcriptional regulatory elements that may play a role in mNET expression in vivo. Probes derived from mNET cDNA identified species-specific MspI restriction fragment length variations within the mNET gene that were utilized to position the gene (Slc6a5) to murine chromosome 8, one recombinant distal to D8Mit15. This site is within a recently defined quantitative trait locus defined for ethanol sensitivity in LSXSS recombinant inbred mice, Lore4. The status of Slc6a5 as a candidate gene for alcohol sensitivity is discussed with respect to studies noting ethanol-induced alterations in brain NE receptors, NE receptor-linked adenylate cyclase, and NE transport.


Branched-chain amino acid administration in surgical patients. Effects on amino acid and fuel substrate profiles.
During the first five days following gastric bypass surgery, 15 patients received near isotonic amino acid solutions that varied in their branched-chain amino acid (BCAA) content and amino acid profiles (15.6%, 50%, or 100% BCAA solutions). Plasma valine concentrations were elevated in patients receiving 50% and 100% BCAA solutions. Plasma alanine concentrations were highest in patients receiving 50% BCAA. Plasma free fatty acids and blood lactate concentrations were unchanged by either the operation or BCAA administration. Serum glucose concentration was unaffected by the different amino acid administrations and followed the pattern induced by stress initially and later by starvation. beta-Hydroxybutyrate concentrations increased as starvation proceeded and were highest in patients receiving the 15.6% BCAA solution. Branched-chain amino acid-enriched solutions without additional energy may be administered safely to patients recovering from operative trauma. Plasma amino acid concentrations and fuel substrate profiles appear to follow metabolic patterns determined by the physiologic response to stress and starvation and can be affected by large quantities of BCAAs.


Qualitative study of antibiotic prescription patterns and associated drivers in Sudan, Guinea-Bissau, Central African Republic and Democratic Republic of Congo.
The objective of this study was to address the knowledge gap regarding antibiotic use in Medecins Sans Frontiéres (MSF) projects located in Africa by exploring antibiotic prescription and consumption habits and their drivers at different healthcare levels. This study used an exploratory study design through thematic analysis of semistructured, in-depth interviews, focus group discussions (FGDs) and field observations in order to understand the main drivers influencing current antibiotics prescription habits and consumption habits of patients in different geographical settings. The study took place in MSF centres and towns across four countries: Guinea-Bissau, Central African Republic (CAR), Democratic Republic of Congo (DRC) and Sudan. 384 respondents participated in the study, which includes project staff, prescribers, community members, patients, among other groups. Treatment protocols were physically present in all countries except DRC, but compliance to protocols varied across contexts. A failing health system and barriers to accessing healthcare were perceived as major drivers of overuse and inconsistent prescription practices. Patient demands influenced prescription decisions, and self-medication was commonly reported in the context of failing health systems. Additionally, there was a strong demand for quick cures and communities preferred injections over pills. Patients tended to stop antibiotic treatment once symptoms abated and had major gaps in understanding antibiotic intake instructions and functions. While there were specific findings in each context, the larger trend from these four MSF projects in Africa indicates widespread use of antibiotics based on unclear assumptions, which are often influenced by patient demands. There needs to be a broader focus on the balance between access and excess, especially in such fragile contexts where access to healthcare is a real challenge.


Modeling the relationship between food animal health and human foodborne illness.
To achieve further reductions in foodborne illness levels in humans, effective pre-harvest interventions are needed. The health status of food animals that are destined to enter the human food supply chain may be an important, although often overlooked, factor in predicting the risk of human foodborne infections. The health status of food animals can potentially influence foodborne pathogen levels in three ways. First, diseased animals may shed higher levels of foodborne pathogens. Second, animals that require further handling in the processing plant to remove affected parts may lead to increased microbial contamination and cross-contamination. Finally, certain animal illnesses may lead to a higher probability of mistakes in the processing plant, such as gastrointestinal ruptures, which would lead to increased microbial contamination and cross-contamination. Consequently, interventions that reduce the incidence of food animal illnesses might also help reduce bacterial contamination on meat, thereby reducing human illness. Some of these interventions, however, might also present a risk to human health. For example, the use of antibiotics in food animals can reduce rates of animal illness but can also select for antibiotic-resistant bacteria which can threaten human treatment options. In this study, we present a mathematical model to evaluate human health risks from foodborne pathogens associated with changes in animal illness. The model is designed so that potential human health risks and benefits from interventions such as the continued use of antibiotics in animal agriculture can be evaluated simultaneously. We applied the model to a hypothetical example of Campylobacter from chicken. In general, the model suggests that very minor perturbations in microbial loads on meat products could have relatively large impacts on human health, and consequently, small improvements in food animal health might result in significant reductions in human illness.


Experiences in conducting multiple community-based HIV prevention trials among women in KwaZulu-Natal, South Africa.
South Africa, with its scientific capacity, good infrastructure and high HIV incidence rates, is ideally positioned to conduct large-scale HIV prevention trials. The HIV Prevention Research Unit of the South African Medical Research Council conducted four phase III and one phase IIb trials of women-initiated HIV prevention options in KwaZulu-Natal between 2003 and 2009. A total of 7046 women participated, with HIV prevalence between 25% and 45% and HIV incidence ranging from 4.5-9.1% per year. Unfortunately none of the interventions tested had any impact on reducing the risk of HIV acquisition; however, extremely valuable experience was gained, lessons learned and capacity built, while the communities gained associated benefits. Our experience in conducting these trials ranged from setting up community partnerships to developing clinical research sites and dissemination of trial results. Community engagement included setting up community-based research sites with approval from both political and traditional leaders, and developing community advisory groups to assist with the research process. Community-wide education on HIV/sexually transmitted infection prevention, treatment and care was provided to over 90,000 individuals. Myths and misconceptions were addressed through methods such as anonymous suggestion boxes in clinic waiting areas and intensive education and counselling. Attempts were made to involve male partners to foster support and facilitate recruitment of women. Peer educator programmes were initiated to provide ongoing education and also to facilitate recruitment of women to the trials. Recruitment strategies such as door-to-door recruitment and community group meetings were initiated. Over 90% of women enrolled were retained. Community benefits from the trial included education on HIV prevention, treatment and care and provision of ancillary care (such as Pap smears, reproductive health care and referral for chronic illnesses). Social benefits included training of home-based caregivers and sustainable ongoing HIV prevention education through peer educator programmes. Several challenges were encountered, including manipulation by participants of their eligibility criteria in order to enroll in the trial. Women attempted to co-enroll in multiple trials to benefit from financial reimbursements and individualised care. The trials became ethically challenging when participants refused to take up referrals for care due to stigma, denial of their HIV status and inadequate health infrastructure. Lack of disclosure of HIV status to partners and family members was particularly challenging. Some of the ethical dilemmas put to the test our responsibility as researchers and our obligation to provide health care to research participants. Conducting these five trials in a period of six years provided us with invaluable insights into trial implementation, community participation, recruitment and retention, provision of care and dissemination of trial results. The critical mass of scientists trained as clinical trialists will continue to address the relentless HIV epidemic in our setting and ensure our commitment to finding a biomedical HIV prevention option for women in the future.


The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting.
The occurrence of skeletal muscle atrophy, a devastating complication of a large number of disease states and inactivity/disuse conditions, provides a never ending quest to identify novel targets for its therapy. Proinflammatory cytokines are considered the mediators of muscle wasting in chronic diseases; however, their role in disuse atrophy has just begun to be elucidated. An inflammatory cytokine, tumor necrosis factor (TNF)- like weak inducer of apoptosis (TWEAK), has recently been identified as a potent inducer of skeletal muscle wasting. TWEAK activates various proteolytic pathways and stimulates the degradation of myofibril protein both in vitro and in vivo. Moreover, TWEAK mediates the loss of skeletal muscle mass and function in response to denervation, a model of disuse atrophy. Adult skeletal muscle express very low to minimal levels of TWEAK receptor, Fn14. Specific catabolic conditions such as denervation, immobilization, or unloading rapidly increase the expression of Fn14 in skeletal muscle which in turn stimulates the TWEAK activation of various catabolic pathways leading to muscle atrophy. In this article, we have discussed the emerging roles and the mechanisms of action of TWEAK-Fn14 system in skeletal muscle with particular reference to different models of muscle atrophy and injury and its potential to be used as a therapeutic target for prevention of muscle loss.


The effects of a sick pay reform on absence and on health-related outcomes.
We evaluate the effects of a reduction in sick pay from 100 to 80% of the wage. Unlike previous literature, apart from absence from work, we also consider effects on doctor/hospital visits and subjective health indicators. We also add to the literature by estimating both switch-on and switch-off effects, because the reform was repealed 2 years later. We find a 2-day reduction in the number of days of absence. Quantile regression reveals higher point estimates (both in absolute and relative terms) at higher quantiles, meaning that the reform predominantly reduced long durations of absence. In terms of health, the reform reduced the average number of days spent in hospital by almost half a day, but we cannot find robust evidence for negative effects on health outcomes or perceived liquidity constraints.