Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec.
Since 2002 an epidemic of Clostridium difficile-associated disease (CDAD) caused by a hypervirulent toxinotype III ribotype 027 strain has spread to many hospitals in Quebec. The strain has also been found in the United States, the United Kingdom and the Netherlands. The effects of this epidemic on mortality and duration of hospital stay remain unknown. We measured these effects among patients admitted to a hospital in Quebec during 2003 and 2004. We compared mortality and total length of hospital stay among inpatients in whom nosocomial CDAD developed and among control subjects without CDAD matched for sex, age, Charlson Comorbidity Index score and length of hospital stay up to the diagnosis of CDAD in the corresponding case. Thirty days after diagnosis 23.0% (37/161) of the patients with CDAD had died, compared with 7.0% (46/656) of the matched control subjects (p < 0.001). Twelve months after diagnosis, mortality was 37.3% (60/161) among patients with CDAD and 20.6% (135/656) among the control subjects (p < 0.001), for a cumulative attributable mortality of 16.7% (95% confidence interval 8.6%-25.2%). Each case of nosocomial CDAD led, on average, to 10.7 additional days in hospital. This study documented a high attributable mortality among elderly patients with CDAD mostly caused by a hypervirulent strain, which represents a dramatic change in the severity of this infection.


Clinical advances in obsessive-compulsive disorder: a position statement by the International College of Obsessive-Compulsive Spectrum Disorders.
In this position statement, developed by The International College of Obsessive-Compulsive Spectrum Disorders, a group of international experts responds to recent developments in the evidence-based management of obsessive-compulsive disorder (OCD). The article presents those selected therapeutic advances judged to be of utmost relevance to the treatment of OCD, based on new and emerging evidence from clinical and translational science. Areas covered include refinement in the methods of clinical assessment, the importance of early intervention based on new staging models and the need to provide sustained well-being involving effective relapse prevention. The relative benefits of psychological, pharmacological and somatic treatments are reviewed and novel treatment strategies for difficult to treat OCD, including neurostimulation, as well as new areas for research such as problematic internet use, novel digital interventions, immunological therapies, pharmacogenetics and novel forms of psychotherapy are discussed.


Effects of age and ischemic times on biochemical evidence of myocardial injury after pediatric cardiac operations.
The vulnerability of pediatric myocardium to ischemia is poorly documented in the clinical setting. Serial measurements of serum concentrations of myoglobin, the MB isoenzyme of creatine kinase, and cardiac troponins T and I and their respective areas under the curve were obtained, with particular reference to age and ischemic time, in 80 children undergoing cardiac operations. Sixteen (the control group) did not require cardiopulmonary bypass and 64 did. In the control group there were increases (p < 0.01) in myoglobin and creatine kinase MB isoenzyme but no increase in cardiac troponin T or I; by contrast, the group treated with cardiopulmonary bypass had significant increases in all four markers but with differing temporal patterns. Younger age (especially < 12 months) was a highly significant explanatory variable only for the release of cardiac troponins T and I, and ischemic time was a significant explanatory variable for the release of creatine kinase MB isoenzyme, cardiac troponins T and I, but not myoglobin. In comparison with previous studies in adults, creatine kinase MB and cardiac troponin T concentrations were three times greater in children than in adults. This study supports the specificity of cardiac troponins T and I as markers of myocardial injury after pediatric cardiac operations and defines the importance of age and ischemic time in determining their release. In comparison with previous data in adults, our results raise the possibility that the pediatric heart may be more vulnerable to the effects of ischemia and reperfusion. Cardiac troponins will permit comparison of new myocardial protective strategies or other potentially therapeutic myocardial interventions.


Reduced repair of the oxidative 8-oxoguanine DNA damage and risk of head and neck cancer.
An increasing number of studies indicate that reduced DNA-repair capacity is associated with increased cancer risk. Using a functional assay for the removal of the oxidative DNA lesion 8-oxoguanine by the DNA-repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), we have previously shown that reduced OGG activity is a risk factor in lung cancer. Here, we report that OGG activity in peripheral blood mononuclear cells from 37 cases with squamous cell carcinoma of the head and neck (SCCHN) was significantly lower than in 93 control subjects, frequency matched for age and gender. Retesting of OGG activity 3 to 4 years after diagnosis and successful treatment of 18 individuals who recovered from the disease showed that OGG activity values were similar to those determined at diagnosis, suggesting that reduced OGG activity in case patients was not caused by the disease. Logistic regression analysis indicated that the adjusted odds ratio (OR) associated with a unit decrease in OGG activity was statistically significantly increased [OR, 2.3; 95% confidence interval (95% CI), 1.5-3.4]. Individuals in the lowest tertile of OGG activity exhibited an increased risk of SCCHN with an OR of 7.0 (95% CI, 2.0-24.5). The combination of smoking and low OGG was associated with a highly increased estimated relative risk for SCCHN. These results suggest that low OGG is associated with the risk of SCCHN, and if confirmed by additional epidemiologic studies, screening of smokers for low OGG activity might be used as a strategy for the prevention of lung cancer and SCCHN.


Lung inflammation caused by inhaled toxicants: a review.
Exposure of the lungs to airborne toxicants from different sources in the environment may lead to acute and chronic pulmonary or even systemic inflammation. Cigarette smoke is the leading cause of chronic obstructive pulmonary disease, although wood smoke in urban areas of underdeveloped countries is now recognized as a leading cause of respiratory disease. Mycotoxins from fungal spores pose an occupational risk for respiratory illness and also present a health hazard to those living in damp buildings. Microscopic airborne particulates of asbestos and silica (from building materials) and those of heavy metals (from paint) are additional sources of indoor air pollution that contributes to respiratory illness and is known to cause respiratory illness in experimental animals. Ricin in aerosolized form is a potential bioweapon that is extremely toxic yet relatively easy to produce. Although the aforementioned agents belong to different classes of toxic chemicals, their pathogenicity is similar. They induce the recruitment and activation of macrophages, activation of mitogen-activated protein kinases, inhibition of protein synthesis, and production of interleukin-1 beta. Targeting either macrophages (using nanoparticles) or the production of interleukin-1 beta (using inhibitors against protein kinases, NOD-like receptor protein-3, or P2X7) may potentially be employed to treat these types of lung inflammation without affecting the natural immune response to bacterial infections.


Reaching consensus on the physiotherapeutic management of patients following upper abdominal surgery: a pragmatic approach to interpret equivocal evidence.
Postoperative pulmonary complications remain the most significant cause of morbidity following open upper abdominal surgery despite advances in perioperative care. However, due to the poor quality primary research uncertainty surrounding the value of prophylactic physiotherapy intervention in the management of patients following abdominal surgery persists. The Delphi process has been proposed as a pragmatic methodology to guide clinical practice when evidence is equivocal. The objective was to develop a clinical management algorithm for the post operative management of abdominal surgery patients. Eleven draft algorithm statements extracted from the extant literature by the primary research team were verified and rated by scientist clinicians (n=5) in an electronic three round Delphi process. Algorithm statements which reached a priori defined consensus-semi-interquartile range (SIQR)<0.5-were collated into the algorithm. The five panelists allocated to the abdominal surgery Delphi panel were from Australia, Canada, Sweden, and South Africa. The 11 draft algorithm statements were edited and 5 additional statements were formulated. The panel reached consensus on the rating of all statements. Four statements were rated essential. An expert Delphi panel interpreted the equivocal evidence for the physiotherapeutic management of patients following upper abdominal surgery. Through a process of consensus a clinical management algorithm was formulated. This algorithm can now be used by clinicians to guide clinical practice in this population.


Strong Impact of Smoking on Multimorbidity and Cardiovascular Risk Among Human Immunodeficiency Virus-Infected Individuals in Comparison With the General Population.
Background. Although acquired immune deficiency syndrome-associated morbidity has diminished due to excellent viral control, multimorbidity may be increasing among human immunodeficiency virus (HIV)-infected persons compared with the general population. Methods. We assessed the prevalence of comorbidities and multimorbidity in participants of the Swiss HIV Cohort Study (SHCS) compared with the population-based CoLaus study and the primary care-based FIRE (Family Medicine ICPC-Research using Electronic Medical Records) records. The incidence of the respective endpoints were assessed among SHCS and CoLaus participants. Poisson regression models were adjusted for age, sex, body mass index, and smoking. Results. Overall, 74 291 participants contributed data to prevalence analyses (3230 HIV-infected; 71 061 controls). In CoLaus, FIRE, and SHCS, multimorbidity was present among 26%, 13%, and 27% of participants. Compared with nonsmoking individuals from CoLaus, the incidence of cardiovascular disease was elevated among smoking individuals but independent of HIV status (HIV-negative smoking: incidence rate ratio [IRR] = 1.7, 95% confidence interval [CI] = 1.2-2.5; HIV-positive smoking: IRR = 1.7, 95% CI = 1.1-2.6; HIV-positive nonsmoking: IRR = 0.79, 95% CI = 0.44-1.4). Compared with nonsmoking HIV-negative persons, multivariable Poisson regression identified associations of HIV infection with hypertension (nonsmoking: IRR = 1.9, 95% CI = 1.5-2.4; smoking: IRR = 2.0, 95% CI = 1.6-2.4), kidney (nonsmoking: IRR = 2.7, 95% CI = 1.9-3.8; smoking: IRR = 2.6, 95% CI = 1.9-3.6), and liver disease (nonsmoking: IRR = 1.8, 95% CI = 1.4-2.4; smoking: IRR = 1.7, 95% CI = 1.4-2.2). No evidence was found for an association of HIV-infection or smoking with diabetes mellitus. Conclusions. Multimorbidity is more prevalent and incident in HIV-positive compared with HIV-negative individuals. Smoking, but not HIV status, has a strong impact on cardiovascular risk and multimorbidity.


Design of a Teleoperated Needle Steering System for MRI-guided Prostate Interventions.
Accurate needle placement plays a key role in success of prostate biopsy and brachytherapy. During percutaneous interventions, the prostate gland rotates and deforms which may cause significant target displacement. In these cases straight needle trajectory is not sufficient for precise targeting. Although needle spinning and fast insertion may be helpful, they do not entirely resolve the issue. We propose robot-assisted bevel-tip needle steering under MRI guidance as a potential solution to compensate for the target displacement. MRI is chosen for its superior soft tissue contrast in prostate imaging. Due to the confined workspace of the MRI scanner and the requirement for the clinician to be present inside the MRI room during the procedure, we designed a MRI-compatible 2-DOF haptic device to command the needle steering slave robot which operates inside the scanner. The needle steering slave robot was designed to be integrated with a previously developed pneumatically actuated transperineal robot for MRI-guided prostate needle placement. We describe design challenges and present the conceptual design of the master and slave robots and the associated controller.


Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust.
The primary aim of this study is to evaluate the gene expression profile of Asian sand dust (ASD)-treated human middle ear epithelial cell (HMEEC) using microarray analysis. The HMEEC was treated with ASD (400 µg/mL) and total RNA was extracted for microarray analysis. Molecular pathways among differentially expressed genes were further analyzed. For selected genes, the changes in gene expression were confirmed by real-time polymerase chain reaction. A total of 1,274 genes were differentially expressed by ASD. Among them, 1,138 genes were 2 folds up-regulated, whereas 136 genes were 2 folds down-regulated. Up-regulated genes were mainly involved in cellular processes, including apoptosis, cell differentiation, and cell proliferation. Down-regulated genes affected cellular processes, including apoptosis, cell cycle, cell differentiation, and cell proliferation. The 10 genes including ADM, CCL5, EDN1, EGR1, FOS, GHRL, JUN, SOCS3, TNF, and TNFSF10 were identified as main modulators in up-regulated genes. A total of 11 genes including CSF3, DKK1, FOSL1, FST, TERT, MMP13, PTHLH, SPRY2, TGFBR2, THBS1, and TIMP1 acted as main components of pathway associated with 2-fold down regulated genes. We identified the differentially expressed genes in ASD-treated HMEEC. Our work indicates that air pollutant like ASD, may play an important role in the pathogenesis of otitis media.


High HIV risk behavior among men who have sex with men in Kigali, Rwanda: making the case for supportive prevention policy.
Rwanda has responded strongly to HIV/AIDS, but prevention among men who have sex with men (MSM) has not yet been addressed due to a strong cultural resistance to homosexuality, and a lack of data showing the public health value of attending to the sexual health needs of this group. We conducted an exploratory study on HIV risk among MSM in Kigali using snowball sampling involving peer leaders. The 99 respondents were demographically, socially, and sexually diverse. Respondents reported relatively high numbers of male and female partners, and considerable HIV risk behaviors including commercial sex with men and women, low condom use during anal and vaginal sex, and high mobility. Many respondents reported verbal and/or physical abuse due to their sexuality. This first study of MSM in Rwanda has brought attention to a previously neglected HIV risk group and their potential driving role in the Rwandan epidemic, demonstrating the need for sensitive and targeted interventions.


Lexical decision with pseudohomophones and reading in the semantic variant of primary progressive aphasia: A double dissociation.
The co-occurrence of semantic impairment and surface dyslexia in the semantic variant of primary progressive aphasia (svPPA) has often been taken as supporting evidence for the central role of semantics in visual word processing. According to connectionist models, semantic access is needed to accurately read irregular words. They also postulate that reliance on semantics is necessary to perform the lexical decision task under certain circumstances (for example, when the stimulus list comprises pseudohomophones). In the present study, we report two svPPA cases: M.F. who presented with surface dyslexia but performed accurately on the lexical decision task with pseudohomophones, and R.L. who showed no surface dyslexia but performed below the normal range on the lexical decision task with pseudohomophones. This double dissociation between reading and lexical decision with pseudohomophones is in line with the dual-route cascaded (DRC) model of reading. According to this model, impairments in visual word processing in svPPA are not necessarily associated with the semantic deficits characterizing this disease. Our findings also call into question the central role given to semantics in visual word processing within the connectionist account.


Molding the flow of light on the nanoscale: from vortex nanogears to phase-operated plasmonic machinery.
Efficient delivery of light into nanoscale volumes by converting free photons into localized charge-density oscillations (surface plasmons) enables technological innovation in various fields from biosensing to photovoltaics and quantum computing. Conventional plasmonic nanostructures are designed as nanoscale analogs of radioantennas and waveguides. Here, we discuss an alternative approach for plasmonic nanocircuit engineering that is based on molding the optical powerflow through 'vortex nanogears' around a landscape of local phase singularities 'pinned' to plasmonic nanostructures. We show that coupling of several vortex nanogears into transmission-like structures results in dramatic optical effects, which can be explained by invoking a hydrodynamic analogy of the 'photon fluid'. The new concept of vortex nanogear transmissions (VNTs) provides new design principles for the development of complex multi-functional phase-operated photonics machinery and, therefore, generates unique opportunities for light generation, harvesting and processing on the nanoscale.


The role of familiarity in correcting inaccurate information.
People frequently continue to use inaccurate information in their reasoning even after a credible retraction has been presented. This phenomenon is often referred to as the continued influence effect of misinformation. The repetition of the original misconception within a retraction could contribute to this phenomenon, as it could inadvertently make the "myth" more familiar-and familiar information is more likely to be accepted as true. From a dual-process perspective, familiarity-based acceptance of myths is most likely to occur in the absence of strategic memory processes. Thus, we examined factors known to affect whether strategic memory processes can be utilized: age, detail, and time. Participants rated their belief in various statements of unclear veracity, and facts were subsequently affirmed and myths were retracted. Participants then rerated their belief either immediately or after a delay. We compared groups of young and older participants, and we manipulated the amount of detail presented in the affirmative or corrective explanations, as well as the retention interval between encoding and a retrieval attempt. We found that (a) older adults over the age of 65 were worse at sustaining their postcorrection belief that myths were inaccurate, (b) a greater level of explanatory detail promoted more sustained belief change, and (c) fact affirmations promoted more sustained belief change in comparison with myth retractions over the course of 1 week (but not over 3 weeks), This supports the notion that familiarity is indeed a driver of continued influence effects. (PsycINFO Database Record


Shifting fungal endophyte communities colonize Bouteloua gracilis: effect of host tissue and geographical distribution.
Communities of root-associated fungi (RAF) commonly have been studied under the auspices of arbuscular mycorrhizal fungi (AMF) or ectomycorrhizal fungi. However many studies now indicate that other groups of endophytic RAF, including dark septate endophytes (DSE) are more abundant in some plants and environments. The common forage grass, Bouteloua gracilis, was used as a model to examine whether RAF also colonize different organs within the same plant and to compare RAF communities from sites across North America, spanning the latitudinal range of B. gracilis (from Canada to Mexico). We compared the RAF communities of organs within individual plants at one site and within plant roots among six sites. With the possible exception of one group related to genus Paraphaeosphaeria there was little evidence that RAF colonized vertically beyond the crowns. Furthermore, although there was some variation in the constitution of rare members of the RAF communities, several taxonomically related groups dominated the RAF community at all sites. These dominant taxa included members in the Pleosporales (related to the DSE, Paraphaeosphaeria spp.), Agaricales (related to Moniliophthora spp., or Campanella spp.) and Hypocreales (related to Fusarium spp.). AMF were notable by their near absence. Similar phylotypes from the dominant groups clustered around adjacent sites so that similarity of the RAF communities was negatively correlated to site inter-distance and the RAF communities appeared to group by country. These results increase the possibility that at least some of these common and widely distributed core members of the RAF community form important, intimate and long lasting relationships with grasses.


Detecting meaning in RSVP at 13 ms per picture.
The visual system is exquisitely adapted to the task of extracting conceptual information from visual input with every new eye fixation, three or four times a second. Here we assess the minimum viewing time needed for visual comprehension, using rapid serial visual presentation (RSVP) of a series of six or 12 pictures presented at between 13 and 80 ms per picture, with no interstimulus interval. Participants were to detect a picture specified by a name (e.g., smiling couple) that was given just before or immediately after the sequence. Detection improved with increasing duration and was better when the name was presented before the sequence, but performance was significantly above chance at all durations, whether the target was named before or only after the sequence. The results are consistent with feedforward models, in which an initial wave of neural activity through the ventral stream is sufficient to allow identification of a complex visual stimulus in a single forward pass. Although we discuss other explanations, the results suggest that neither reentrant processing from higher to lower levels nor advance information about the stimulus is necessary for the conscious detection of rapidly presented, complex visual information.


Standards of evidence: criteria for efficacy, effectiveness and dissemination.
Ever increasing demands for accountability, together with the proliferation of lists of evidence-based prevention programs and policies, led the Society for Prevention Research to charge a committee with establishing standards for identifying effective prevention programs and policies. Recognizing that interventions that are effective and ready for dissemination are a subset of effective programs and policies, and that effective programs and policies are a subset of efficacious interventions, SPR's Standards Committee developed overlapping sets of standards. We designed these Standards to assist practitioners, policy makers, and administrators to determine which interventions are efficacious, which are effective, and which are ready for dissemination. Under these Standards, an efficacious intervention will have been tested in at least two rigorous trials that (1) involved defined samples from defined populations, (2) used psychometrically sound measures and data collection procedures; (3) analyzed their data with rigorous statistical approaches; (4) showed consistent positive effects (without serious iatrogenic effects); and (5) reported at least one significant long-term follow-up. An effective intervention under these Standards will not only meet all standards for efficacious interventions, but also will have (1) manuals, appropriate training, and technical support available to allow third parties to adopt and implement the intervention; (2) been evaluated under real-world conditions in studies that included sound measurement of the level of implementation and engagement of the target audience (in both the intervention and control conditions); (3) indicated the practical importance of intervention outcome effects; and (4) clearly demonstrated to whom intervention findings can be generalized. An intervention recognized as ready for broad dissemination under these Standards will not only meet all standards for efficacious and effective interventions, but will also provide (1) evidence of the ability to "go to scale"; (2) clear cost information; and (3) monitoring and evaluation tools so that adopting agencies can monitor or evaluate how well the intervention works in their settings. Finally, the Standards Committee identified possible standards desirable for current and future areas of prevention science as the field develops. If successful, these Standards will inform efforts in the field to find prevention programs and policies that are of proven efficacy, effectiveness, or readiness for adoption and will guide prevention scientists as they seek to discover, research, and bring to the field new prevention programs and policies.


Quantitative laser speckle flowmetry of the in vivo microcirculation using sidestream dark field microscopy.
We present integrated Laser Speckle Contrast Imaging (LSCI) and Sidestream Dark Field (SDF) flowmetry to provide real-time, non-invasive and quantitative measurements of speckle decorrelation times related to microcirculatory flow. Using a multi exposure acquisition scheme, precise speckle decorrelation times were obtained. Applying SDF-LSCI in vitro and in vivo allows direct comparison between speckle contrast decorrelation and flow velocities, while imaging the phantom and microcirculation architecture. This resulted in a novel analysis approach that distinguishes decorrelation due to flow from other additive decorrelation sources.


Functional and ecological significance of rDNA intergenic spacer variation in a clonal organism under divergent selection for production rate.
It has recently been hypothesized that variation in the intergenic spacer (IGS) of rDNA has considerable developmental, evolutionary and ecological significance through effects on growth rate and body C : N : P stoichiometry resulting from the role of the IGS in production of rRNA. To test these ideas, we assessed changes in size and structure of the repetitive region of the IGS, juvenile growth rate (JGR), RNA and phosphorus (P) contents in clonal lineages of Daphnia pulex derived from a single female and subjected to divergent selection on weight-specific fecundity (WSF). As a result of selection, WSF diverged rapidly, with significant reductions within two generations. Other significant changes accompanying shifts in WSF were that juveniles produced by low-WSF females grew more rapidly and had higher RNA and P contents. An increased predominance of long IGS variants was observed in lineages with elevated JGRs and low WSF. The observed variations in IGS length were related to the number of subrepeat units carrying a promoter sequence in the repetitive region. These results strongly support the hypothesized relationships, indicate a genetic mechanism for the evolution of such associations and demonstrate that Daphnia (and perhaps other parthenogens) possess considerable potential for rapid adaptive change in major life-history traits.


Tuning photoinduced intramolecular electron transfer by electron accepting and donating substituents in oxazolones.
The solvatochromic and spectral properties of oxazolone derivatives in various solvents were reported. Fluorescence spectra clearly showed positive and negative solvatochromism depending on substituents. The solvatochromic plots and quantum chemical computations at DFT-B3LYP/6-31 + G(d,p) level were used to assess dipole moment changes between the ground and the first excited singlet-states. The electron accepting nitro substituent at the para-position increased the π-electron mobility, however, the 3,5-dinitro substituent decreased the π-electron mobility as a result of inverse accumulation of the electronic density as compared with that of its ground state. Experimental and computational studies proved that the photoinduced intramolecular electron transfer (PIET) is responsible for the observed solvatochromic effects. We demonstrate that PIET can be finely tailored by the position of the electron accepting and donating substituents in the phenyl ring of the oxazolone derivatives. We propose that the photoactive CPO derivatives are new molecular class of conjugated push-pull structures using azlactone moiety as the π-conjugated linker and may find applications in photovoltaic cells and light emitting diodes.


Aorto-bronchial and aorto-pulmonary fistulation after thoracic endovascular aortic repair: an analysis from the European Registry of Endovascular Aortic Repair Complications.
To learn upon incidence, underlying mechanisms and effectiveness of treatment strategies in patients with central airway and pulmonary parenchymal aorto-bronchial fistulation after thoracic endovascular aortic repair (TEVAR). Analysis of an international multicentre registry (European Registry of Endovascular Aortic Repair Complications) between 2001 and 2012 with a total caseload of 4680 TEVAR procedures (14 centres). Twenty-six patients with a median age of 70 years (interquartile range: 60-77) (35% female) were identified. The incidence of either central airway (aorto-bronchial) or pulmonary parenchymal (aorto-pulmonary) fistulation (ABPF) in the entire cohort after TEVAR in the study period was 0.56% (central airway 58%, peripheral parenchymal 42%). Atherosclerotic aneurysm formation was the leading indication for TEVAR in 15 patients (58%). The incidence of primary endoleaks after initial TEVAR was n = 10 (38%), of these 80% were either type I or type III endoleaks. Fourteen patients (54%) developed central left bronchial tree lesions, 11 patients (42%) pulmonary parenchymal lesions and 1 patient (4%) developed a tracheal lesion. The recognized mechanism of ABPF was external compression of the bronchial tree in 13 patients (50%), the majority being due to endoleak formation, further ischaemia due to extensive coverage of bronchial feeding arteries in 3 patients (12%). Inflammation and graft erosion accounted for 4 patients (30%) each. Cumulative survival during the entire study period was 39%. Among deaths, 71% were attributed to ABPF. There was no difference in survival in patients having either central airway or pulmonary parenchymal ABPF (33 vs 45%, log-rank P = 0.55). Survival with a radical surgical approach was significantly better when compared with any other treatment strategy in terms of overall survival (63 vs 32% and 63 vs 21% at 1 and 2 years, respectively), as well as in terms of fistula-related survival (63 vs 43% and 63 vs 43% at 1 and 2 years, respectively). ABPF is a rare but highly lethal complication after TEVAR. The leading mechanism behind ABPF seems to be a continuing external compression of either the bronchial tree or left upper lobe parenchyma. In this setting, persisting or newly developing endoleak formation seems to play a crucial role. Prognosis does not differ in patients with central airway or pulmonary parenchymal fistulation. Radical bronchial or pulmonary parenchymal repair in combination with stent graft removal and aortic reconstruction seems to be the most durable treatment strategy.


Simulation model for evaluation of testing strategies for detection of paratuberculosis in midwestern US dairy herds.
We developed a stochastic simulation model to compare the herd sensitivity (HSe) of five testing strategies for detection of Mycobacterium avium subsp. paratuberculosis (Map) in Midwestern US dairies. Testing strategies were ELISA serologic testing by two commercial assays (EA and EB), ELISA testing with follow-up of positive samples with individual fecal culture (EAIFC and EBIFC), individual fecal culture (IFC), pooled fecal culture (PFC), and culture of fecal slurry samples from the environment (ENV). We assumed that these dairies had no prior paratuberculosis-related testing and culling. We used cost-effectiveness (CE) analysis to compare the cost to HSe of testing strategies for different within-herd prevalences. HSe was strongly associated with within-herd prevalence, number of Map organisms shed in feces by infected cows, and number of samples tested. Among evaluated testing methods with 100% herd specificity (HSp), ENV was the most cost-effective method for herds with a low (5%), moderate (16%) or high (35%) Map prevalence. The PFC, IFC, EAIFC and EBIFC were increasingly more costly detection methods. Culture of six environmental samples per herd yielded >or=99% HSe in herds with >or=16% within-herd prevalence, but was not sufficient to achieve 95% HSe in low-prevalence herds (5%). Testing all cows using EAIFC or EBIFC, as is commonly done in paratuberculosis-screening programs, was less likely to achieve a HSe of 95% in low than in high prevalence herds. ELISA alone was a sensitive and low-cost testing method; however, without confirmatory fecal culture, testing 30 cows in non-infected herds yielded HSp of 21% and 91% for EA and EB, respectively.


Genetic interactions between transcription factors cause natural variation in yeast.
Our understanding of the genetic basis of phenotypic diversity is limited by the paucity of examples in which multiple, interacting loci have been identified. We show that natural variation in the efficiency of sporulation, the program in yeast that initiates the sexual phase of the life cycle, between oak tree and vineyard strains is due to allelic variation between four nucleotide changes in three transcription factors: IME1, RME1, and RSF1. Furthermore, we identified that selection has shaped quantitative variation in yeast sporulation between strains. These results illustrate how genetic interactions between transcription factors are a major source of phenotypic diversity within species.


Accommodating intraocular lenses: a review of design concepts, usage and assessment methods.
The correction of presbyopia and restoration of true accommodative function to the ageing eye is the focus of much ongoing research and clinical work. A range of accommodating intraocular lenses (AIOLs) implanted during cataract surgery has been developed and they are designed to change either their position or shape in response to ciliary muscle contraction to generate an increase in dioptric power. Two main design concepts exist. First, axial shift concepts rely on anterior axial movement of one or two optics creating accommodative ability. Second, curvature change designs are designed to provide significant amplitudes of accommodation with little physical displacement. Single-optic devices have been used most widely, although the true accommodative ability provided by forward shift of the optic appears limited and recent findings indicate that alternative factors such as flexing of the optic to alter ocular aberrations may be responsible for the enhanced near vision reported in published studies. Techniques for analysing the performance of AIOLs have not been standardised and clinical studies have reported findings using a wide range of both subjective and objective methods, making it difficult to gauge the success of these implants. There is a need for longitudinal studies using objective methods to assess long-term performance of AIOLs and to determine if true accommodation is restored by the designs available. While dual-optic and curvature change IOLs are designed to provide greater amplitudes of accommodation than is possible with single-optic devices, several of these implants are in the early stages of development and require significant further work before human use is possible. A number of challenges remain and must be addressed before the ultimate goal of restoring youthful levels of accommodation to the presbyopic eye can be achieved.


Evaluation of the effect of chronic antidepressant treatment on neurokinin-1 receptor expression in the rat brain.
Clinically effective antidepressants are thought to exert their therapeutic effects by facilitating central monoamine neurotransmission. However, recent data showing that neurokinin-1 receptor (NK1R) antagonists have antidepressant properties in both animal and clinical studies raise the possibility that classical antidepressants may also influence NK1R expression in the brain. To test this hypothesis, rats were treated with desipramine, paroxetine, venlafaxine, tranylcypromine or vehicle for 14-42 days. NK1R binding sites and mRNA were determined in a wide variety of brain areas using in situ hybridization and quantitative receptor autoradiography. In all areas examined, the abundance of NK1R binding sites was unchanged after 14 days of treatment. None of the treatments altered the number of NK1R binding sites following 42 days treatment with the exception that an increase was found in the locus coeruleus with tranylcypromine. Taken together, we report that repeated treatment with antidepressants of different classes does not cause significant changes in NK1R expression.


The Arts as a Catalyst for Human Prosociality and Cooperation.
We tested the hypothesis that engagement in the arts may act as a catalyst that promotes prosocial cooperation. Using "Understanding Society" data (a nationally representative longitudinal sample of 30,476 people in the UK), we find that beyond major personality traits, demographic variables, wealth, education, and engagement in other social activity (sports), people's greater engagement with the arts predicts greater prosociality (volunteering and charitable giving) over a period of 2 years. The predictive effect of prosociality on subsequent arts engagement is significantly weaker. The evidence is consistent with the hypothesis that the arts provide an important vehicle for facilitating a cohesive and sustainable society. Fostering a society in which engagement in the arts is encouraged and accessible to all may provide an important counter to economic, cultural, and political fracture and division.


Early growth response gene 1 (EGR1) regulates heparanase gene transcription in tumor cells.
Heparanase is an endoglycosidase that degrades heparan sulfate chains of heparan sulfate proteoglycans, a key component of extracellular matrix and basement membranes. Studies using heparanase inhibitors and gene silencing have provided evidence to support an important role for heparanase in tumor metastasis and angiogenesis. The expression of heparanase is normally very tightly controlled, however, it is commonly deregulated in tumor cells, which express elevated heparanase activity that correlates with high levels of heparanase mRNA. We recently identified the transcription factor early growth response gene 1, EGR1, as a key regulator of inducible heparanase transcription in T cells. In this study using chromatin immunoprecipitation, we demonstrate for the first time that EGR1 binds to the heparanase gene promoter in vivo. The important question of the role of EGR1 in regulating heparanase transcription in tumor cells was then assessed. Studies were carried out in four epithelial tumor lines of different tissue origin. Functional dissection of the heparanase promoter identified a 280-bp region that was critical for transcription of the heparanase gene. Transactivation studies using an EGR1 expression vector co-transfected with a reporter construct containing the 280-bp region showed EGR1-activated heparanase promoter activity in a dose-dependent manner in prostate or breast adenocarcinoma and colon carcinoma cell lines. In contrast, overexpression of EGR1 resulted in a dose-dependent repression of promoter activity in melanoma cells. Using site-directed mutagenesis the 280-bp region was found to contain two functional EGR1 sites and electrophoretic mobility shift assays showed binding of EGR1 to both of these sites upon activation of tumor cells. Furthermore, the heparanase promoter region containing the EGR1 sites was also inducible in tumor cells and induction corresponded to HPSE expression levels. These studies show that EGR1 regulates heparanase transcription in tumor cells and importantly, can have a repressive or activating role depending on the tumor type.


CO2 adsorption on different organo-modified SBA-15 silicas: a multidisciplinary study on the effects of basic surface groups.
Hybrid organic-inorganic SBA-15 silicas functionalized with increasing amounts of amino groups were studied in this work aiming to evaluate the effects of their physico-chemical properties on CO2 capture ability. Three different amino-silane species were used: 3-aminopropyltriethoxysilane (APTS), 3-(2-aminoethyl)aminopropyltrimethoxysilane (EAPTS) and 3-[2-(2-aminoethyl)aminoethyl] aminopropyltrimethoxysilane (PAPTS). More specifically, samples were prepared by using two methods, following a post-synthesis grafting procedure and a one-pot preparation method. Experimental and computational techniques were used to study the structural and textural properties of the obtained samples and their surface species in relation to the adopted preparation method. For the most reactive samples, additional hints on the interactions of organosilane species with the silica surface were obtained by a combination of IR and SS-NMR spectroscopy, with particular emphasis on the effects of the silane chain length on the mobility of the organic species. Advanced complementary solid-state NMR techniques provided deeper information on the interactions of organosilane species with the silica surface. Finally, the amount of CO2 adsorbed was estimated by comparing the classical microcalorimetric analysis method with a new type of screening test, the Zero Length Column analysis, which is able to evaluate small amounts of samples in a very short time and the adsorption properties of the adsorbents. The reactivity of the amino-modified silica samples is deeply influenced by both the preparation route and by the type of organosilane used for the functionalization of the materials. In particular, samples prepared by the post-synthesis grafting procedure and containing higher amount of amino groups in the chain are more reactive, following the order PAPTS > EAPTS > APTS.


Logit and fuzzy models in data analysis: estimation of risk in cardiac patients.
The aim of this study was a comparison of risk stratification for death in patients after myocardial infarction (MI) and of risk stratification for malignant arrhythmias in patients with implantable cardioverter-defibrillator (ICD). The individual risk factors and more complex approaches were used, which take into account that a borderline between a risky and non-risky value of each predictor is not clear-cut (fuzzification of a critical value) and that individual risk factors have different weight (area under receiver operating curve - AUC or Sommers' D - Dxy). The risk factors were baroreflex sensitivity, ejection fraction and the number of ventricular premature complexes/hour on Holter monitoring. Those factors were evaluated separately and they were involved into logit model and fuzzy models (Fuzzy, Fuzzy-AUC, and Fuzzy-Dxy). Two groups of patients were examined: a) 308 patients 7-21 days after MI (23 patients died within period of 24 month); b) 53 patients with left ventricular dysfunction examined before implantation of ICD (7 patients with malignant arrhythmia and electric discharge within 11 month after implantation). Our results obtained in MI patients demonstrated that the application of logit and fuzzy models was superior over the risk stratification based on algorithm where the decision making is dependent on one parameter. In patients with implanted defibrillator only logit method yielded statistically significant result, but its reliability was doubtful because all other tests were statistically insignificant. We recommend evaluating the data not only by tests based on logit model but also by tests based on fuzzy models.


Prevalence and Predictors of Depression, Anxiety and Stress Symptoms in Paramedics at Saudi Red Crescent Authority.
Emergency medical professionals often encounter situations when dealing with patients that can affect their mental health. In Saudi Arabia, there is paucity of data regarding the mental health of paramedics involved in prehospital care. To determine the prevalence and predictors of stress, anxiety and depression symptoms among paramedics working at Saudi Red Crescent Authority (SRCA) stations in Riyadh, Saudi Arabia. This cross-sectional, questionnaire study included all paramedics working in the prehospital medical services of 21 SRCA stations in Riyadh (N = 300) between March and June 2017. Sociodemographic data were collected using a self-reporting questionnaire, and the Arabic version of the Depression Anxiety and Stress Scale-21 was used to identify the states of stress, anxiety and depression. Bivariate analysis using chi-square test and multivariate logistic regression analysis were performed to determine the association between sociodemographic factors and mental health. In total, 240 emergency medical professionals responded (response rate = 80%). Of these, 30.5% had stress, 40% had anxiety and 26.7% had depression. All cases of stress were of mild-to-moderate level, while 5.1% of the respondents had severe-to-extremely severe anxiety and 1.3% had severe depression; there were no cases of extremely severe depression. Number of mission calls was identified as a predictor for stress and anxiety; intake of medications for noncommunicable diseases as a predictor for stress and depression; hours of sleep/day for anxiety and depression and use of stimulant beverages other than tea, coffee and energy drinks as predictors for anxiety. This study demonstrates that stress, anxiety and depressive symptoms are relatively common in paramedics working at SRCA stations in Riyadh. The authors suggest that the above-mentioned predictors should be monitored in paramedics and interventions should be made when necessary.


Income, social stratification, class, and private health insurance: a study of the Baltimore metropolitan area.
Most studies of inequalities and access to health care have used income as the sole indicator of social stratification. Despite the significance of social theory in health insurance research, there are no empirical studies comparing the ability of different models of social stratification to predict health insurance coverage. The aim of this study is to provide a comparative analysis using a variety of theory-driven indicators of social stratification and assess the relative strength of the association between these indicators and private health insurance. Data were collected in a 1993 telephone interview of a random digit dialing sample of the white population in the Baltimore Metropolitan Statistical Area. Indicators of social stratification included employment status, full-time work, education, occupation, industry, household income, firm size, and three types of assets: ownership, organizational, and skill/credential. The association between social stratification and private health insurance was strongest for those having higher household incomes, having attained at least a bachelor's degree, and working in a firm with more than 50 employees, followed by being an owner or manager, and by being employed. The addition of education and firm size improved the prediction of the household income model. The authors conclude that studies of inequalities in health insurance coverage can benefit from the inclusion of theory-driven indicators of social stratification such as human capital, labor market segmentation, and control over productive assets.


Whole-genome assembly of Klebsiella pneumoniae coproducing NDM-1 and OXA-232 carbapenemases using single-molecule, real-time sequencing.
The whole-genome sequence of a carbapenem-resistant Klebsiella pneumoniae strain, PittNDM01, which coproduces NDM-1 and OXA-232 carbapenemases, was determined in this study. The use of single-molecule, real-time (SMRT) sequencing provided a closed genome in a single sequencing run. K. pneumoniae PittNDM01 has a single chromosome of 5,348,284 bp and four plasmids: pPKPN1 (283,371 bp), pPKPN2 (103,694 bp), pPKPN3 (70,814 bp), and pPKPN4 (6,141 bp). The contents of the chromosome were similar to that of the K. pneumoniae reference genome strain MGH 78578, with the exception of a large inversion spanning 23.3% of the chromosome. In contrast, three of the four plasmids are unique. The plasmid pPKPN1, an IncHI1B-like plasmid, carries the blaNDM-1, armA, and qnrB1 genes, along with tellurium and mercury resistance operons. blaNDM-1 is carried on a unique structure in which Tn125 is further bracketed by IS26 downstream of a class 1 integron. The IncFIA-like plasmid pPKPN3 also carries an array of resistance elements, including blaCTX-M-15 and a mercury resistance operon. The ColE-type plasmid pPKPN4 carrying blaOXA-232 is identical to a plasmid previously reported from France. SMRT sequencing was useful in resolving the complex bacterial genomic structures in the de novo assemblies.


To diversify or not to diversify, that is the question. Pursuing agricultural development for smallholder farmers in marginal areas of Ghana.
Many smallholder farmers in developing countries grow multiple crop species on their farms, maintaining de facto crop diversity. Rarely do agricultural development strategies consider this crop diversity as an entry point for fostering agricultural innovation. This paper presents a case study, from an agricultural research-for-development project in northern Ghana, which examines the relationship between crop diversity and self-consumption of food crops, and cash income from crops sold by smallholder farmers in the target areas. By testing the presence and direction of these relationships, it is possible to assess whether smallholder farmers may benefit more from a diversification or a specialization agricultural development strategy for improving their livelihoods. Based on a household survey of 637 randomly selected households, we calculated crop diversity as well as its contribution to self-consumption (measured as imputed monetary value) and to cash income for each household. With these data we estimated a system of three simultaneous equations. Results show that households maintained high levels of crop diversity: up to eight crops grown, with an-average of 3.2 per household, and with less than 5% having a null or very low level of crop diversity. The value of crop species used for self-consumption was on average 55% higher than that of crop sales. Regression results show that crop diversity is positively associated with self-consumption of food crops, and cash income from crops sold. This finding suggests that increasing crop diversity opens market opportunities for households, while still contributing to self-consumption. Given these findings, crop diversification seems to be more beneficial to these farmers than specialization. For these diversified farmers, or others in similar contexts, interventions that assess and build on their de facto crop diversity are probably more likely to be successful.


Examination of redirected continuous miner scrubber discharge configurations for exhaust face ventilation systems.
The U.S. National Institute for Occupational Safety and Health (NIOSH) Office of Mine Safety and Health Research (OMSHR) has recently studied several redirected scrubber discharge configurations in its full-scale continuous miner gallery for both dust and gas control when using an exhaust face ventilation system. Dust and gas measurements around the continuous mining machine in the laboratory showed that the conventional scrubber discharge directed outby the face with a 12.2-m (40-ft) exhaust curtain setback appeared to be one of the better configurations for controlling dust and gas. Redirecting all the air toward the face equally up both sides of the machine increased the dust and gas concentrations around the machine. When all of the air was redirected toward the face on the off-curtain side of the machine, gas accumulations tended to be reduced at the face, at the expense of increased dust levels in the return and on the curtain side of the mining machine. A 6.1-m (20-ft) exhaust curtain setback without the scrubber operating resulted in the lowest dust levels around the continuous mining machine, but this configuration resulted in some of the highest levels of dust in the return and gas on the off-curtain side of the mining face. Two field studies showed some similarities to the laboratory findings, with elevated dust levels at the rear corners of the continuous miner when all of the scrubber exhaust was redirected toward the face either up the off-tubing side or equally up both sides of the mining machine.


A quantitative comparison of West Nile virus incidence from 2013 to 2018 in Emilia-Romagna, Italy.
West Nile virus (WNV) transmission was much greater in 2018 than in previous seasons in Europe. Focusing on Emilia-Romagna region (northern Italy), we analyzed detailed entomological and epidemiological data collected in 2013-2018 to quantitatively assess environmental drivers of transmission and explore hypotheses to better understand why the 2018 epidemiological season was substantially different than the previous seasons. In particular, in 2018 WNV was detected at least two weeks before the observed circulation in 2013-2017 and in a larger number of mosquito pools. Transmission resulted in 100 neuroinvasive human cases in the region, more than the total number of cases recorded between 2013 and 2017. We used temperature-driven mathematical models calibrated through a Bayesian approach to simulate mosquito population dynamics and WNV infection rates in the avian population. We then estimated the human transmission risk as the probability, for a person living in the study area, of being bitten by an infectious mosquito in a given week. Finally, we translated such risk into reported WNV human infections. The estimated prevalence of WNV in the mosquito and avian populations were significantly higher in 2018 with respect to 2013-2017 seasons, especially in the eastern part of the region. Furthermore, peak avian prevalence was estimated to have occurred earlier, corresponding to a steeper decline towards the end of summer. The high mosquito prevalence resulted in a much greater predicted risk for human transmission in 2018, which was estimated to be up to eight times higher than previous seasons. We hypothesized, on the basis of our modelling results, that such greater WNV circulation might be partially explained by exceptionally high spring temperatures, which have likely helped to amplify WNV transmission at the beginning of the 2018 season.


Same-day initiation of oral pre-exposure prophylaxis among gay, bisexual, and other cisgender men who have sex with men and transgender women in Brazil, Mexico, and Peru (ImPrEP): a prospective, single-arm, open-label, multicentre implementation study.
Although gay, bisexual, and other cisgender men who have sex with men (MSM) and transgender women have the highest HIV burden in Latin America, pre-exposure prophylaxis (PrEP) implementation is poor. We aimed to assess the feasibility of same-day oral PrEP delivery in Brazil, Mexico, and Peru. Implementation PrEP (ImPrEP) was a prospective, single-arm, open-label, multicentre PrEP implementation study conducted in Brazil (14 sites), Mexico (four sites), and Peru (ten sites). MSM and transgender women were eligible to participate if they were aged 18 years or older, HIV-negative, and reported one or more prespecified criteria. Enrolled participants received same-day initiation of daily oral PrEP (tenofovir disoproxil fumarate [300 mg] coformulated with emtricitabine [200 mg]). Follow-up visits were scheduled at week 4 and quarterly thereafter. We used logistic regression models to identify factors associated with early loss to follow-up (not returning after enrolment), PrEP adherence (medication possession ratio ≥0·6), and long-term PrEP engagement (attending three or more visits within 52 weeks). This study is registered at the Brazilian Registry of Clinical Trials, U1111-1217-6021. From Feb 6, 2018, to June 30, 2021, 9979 participants were screened and 9509 were enrolled (Brazil n=3928, Mexico n=3288, and Peru n=2293). 543 (5·7%) participants were transgender women, 8966 (94·3%) were cisgender men, and 2481 (26·1%) were aged 18-24 years. There were 12 185·25 person-years of follow-up. 795 (8·4%) of 9509 participants had early loss to follow-up, 6477 (68·1%) of 9509 were adherent to PrEP, and 5783 (70·3%) of 8225 had long-term PrEP engagement. Transgender women (adjusted odds ratio 1·60, 95% CI 1·20-2·14), participants aged 18-24 years (1·80, 1·49-2·18), and participants with primary education (2·18, 1·29-3·68) had increased odds of early loss to follow-up. Transgender women (0·56, 0·46-0·70), participants aged 18-24 years (0·52, 0·46-0·58), and those with primary education (0·60, 0·40-0·91) had lower odds of PrEP adherence. Transgender women (0·56, 0·45-0·71), participants aged 18-24 years (0·56, 0·49-0·64), and those with secondary education (0·74, 0·68-0·86) had lower odds of long-term PrEP engagement. HIV incidence was 0·85 per 100 person-years (95% CI 0·70-1·03) and was higher for transgender women, participants from Peru, those aged 18-24 years, Black and mixed-race participants, and participants who were non-adherent to PrEP. Same-day oral PrEP is feasible for MSM and transgender women in Latin America. Social and structural determinants of HIV vulnerability need to be addressed to fully achieve the benefits of PrEP. Unitaid, WHO, and Ministries of Health in Brazil, Mexico, and Peru. For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.


Cerebellar abnormalities typical of methylmercury poisoning in a fledged saltmarsh sparrow, Ammodramus caudacutus.
A fledged, 12-15 day-old saltmarsh sparrow, Ammodramus caudacutus, was collected from an accidental kill on Cinder Island, Long Island, NY, USA. The sparrow was assessed for feather mercury levels and the brain analyzed for cerebellar abnormalities by microscopic examination. In humans, fetal Minamata disease is caused by maternal ingestion of mercury. It is characterized by disrupted and disordered cerebellar neuronal migration in the fetus or infant. Results from this sparrow show cerebellar abnormalities typical of Minamata disease. It is the first known avian or mammalian specimen taken from the wild to show the abnormalities typical of the human fetal syndrome.


Molecular epidemiology of amebiasis.
Entamoeba histolytica, the causative agent of human amebiasis, remains a significant cause of morbidity and mortality in developing countries and is responsible for up to 100,000 deaths worldwide each year. Entamoeba dispar, morphologically indistinguishable from E. histolytica, is more common in humans in many parts of the world. Similarly Entamoeba moshkovskii, which was long considered to be a free-living ameba, is also morphologically identical to E. histolytica and E. dispar, and is highly prevalent in some E. histolytica endemic countries. However, the only species to cause disease in humans is E. histolytica. Most old epidemiological data on E. histolytica are unusable as the techniques employed do not differentiate between the above three Entamoeba species. Molecular tools are now available not only to diagnose these species accurately but also to study intra-species genetic diversity. Recent studies suggest that only a minority of all E. histolytica infections progress to the development of clinical symptoms in the host and there exist population level differences between the E. histolytica strains isolated from the asymptomatic and symptomatic individuals. Nevertheless the underlying factors responsible for variable clinical outcome of infection by E. histolytica remain largely unknown. We anticipate that the recently completed E. histolytica genome sequence and new molecular techniques will rapidly advance our understanding of the epidemiology and pathogenicity of amebiasis.


Dynamics of a two-dimensional vapor bubble confined between superheated or subcooled parallel plates.
The dynamics of a long, two-dimensional vapor bubble confined in the gap between two superheated or subcooled parallel plates is analyzed theoretically. The unsteady expansion and/or contraction of the bubble is driven by mass transfer between the liquid and the vapor. The analysis uses the approach developed by Wilson [J. Fluid Mech. 391, 1 (1999)] for a situation with "large" gaps and "small" superheating or subcooling to consider a situation with small gaps and large superheating or subcooling in which the mass transfer from or to the semicircular nose of the bubble is comparable to that from or to the thin liquid films on the plates. In order to permit a (semi-) analytical treatment the analysis is restricted to low Prandtl number liquids. When both plates are superheated the bubble always expands. In this case there are two possible constant-velocity continuous-film solutions for the expansion of the bubble, namely, an unstable fast mode and a stable slow mode. The evolution of the bubble is calculated numerically for a range of values of the parameters. In particular, these calculations show that eventually the bubble expands either with the constant velocity of the slow mode or exponentially. When both plates are subcooled the bubble always collapses to zero length in a finite time. When one plate is subcooled and the other plate is superheated the situation is rather more complicated. If the magnitude of the subcooling is less than that of the superheating then if the magnitude of the subcooling is greater than a critical value then a variety of complicated behaviors (including the possibility of an unexpected "waiting time" behavior in which the bubble remains almost stationary for a finite period of time) can occur before the bubble eventually collapses to a finite length in an infinite time, whereas if it is less than this critical value then the bubble always expands and eventually does so exponentially. If the magnitude of the subcooling is greater than that of the superheating then the bubble always collapses to zero length in a finite time.


Deficiency of functional mannose-binding lectin is not associated with infections in patients with systemic lupus erythematosus.
Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented in the 103 SLE patients (mean age 41 +/- 13 years, mean disease duration 7 +/- 4 years). The percentage of SLE patients with severe MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients frequently suffer from infections, but deficiency of functional MBL does not confer additional risk.


P450-dependent and nonenzymatic human liver microsomal defluorination of fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A), a sevoflurane degradation product.
The volatile anesthetic sevoflurane is degraded by strong bases in the carbon dioxide absorbent in clinical anesthesia machines to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE, also called "Compound A"). FDVE is nephrotoxic in rats, where it is extensively biotransformed. Patients undergoing sevoflurane anesthesia have been exposed to low inhaled concentrations of FDVE. Although sevoflurane renal toxicity under conditions of FDVE formation has not been reported, there is still considerable concern about FDVE metabolism in humans and the potential for FDVE nephrotoxicity. Sevoflurane undergoes P450-catalyzed liver microsomal defluorination. We tested the hypothesis that FDVE also undergoes human liver microsomal defluorination. Defluorination occurred both in the absence and presence of NADPH; rates of total and NADPH-dependent fluoride formation were 1.6 +/- 0.1 and 1 +/- 0.1 nmol.min-1.mg-1 protein (mean +/- SD), respectively, in four human livers. Enzymatic defluorination was linear with respect to time, protein concentration, and was saturable with respect to substrate concentration. NADPH-dependent, but not NADPH-independent, FDVE defluorination was partially inhibited by coumarin, orphenadrine, diethyldithlocarbamate, and 4-methypyrazole. Microsomes containing cDNA-expressed human P4502E1 exhibited substantial catalytic activity toward FDVE defluorination. Microsomal FDVE defluorination was significantly diminished in the presence of the parent anesthetic, sevoflurane, from 1.3 to 0.6 nmol.min-1.mg-1. These results show that FDVE undergoes both P450-catalyzed and nonenzymatic defluorination by human liver microsomes. P4502E1 is implicated in the enzymatic defluorination. Nonenzymatic defluorination may result from FDVE addition to protein thiols. Enzymatic and/or nonenzymatic defluorination may be etiologic factors in FDVE nephrotoxicity in rats. In contrast, P450-dependent FDVE defluorination may be of less clinical consequence in humans, because it is inhibited by the parent anesthetic, sevoflurane.


Visual short-term memory impairments in presymptomatic familial Alzheimer's disease: A longitudinal observational study.
Visual short-term memory (VSTM) deficits including VSTM binding have been associated with Alzheimer's disease (AD) from preclinical to dementia stages, cross-sectionally. Yet, longitudinal investigations are lacking. The objective of this study was to evaluate VSTM function longitudinally and in relation to expected symptom onset in a cohort of familial Alzheimer's disease. Ninety-nine individuals (23 presymptomatic; 9 symptomatic and 67 controls) were included in an extension cross-sectional study and a sub-sample of 48 (23 presymptomatic carriers, 6 symptomatic and 19 controls), attending two to five visits with a median interval of 1.3 years, included in the longitudinal study. Participants completed the "What was where?" relational binding task (which measures memory for object identification, localisation and object-location binding under different conditions of memory load and delay), neuropsychology assessments and genetic testing. Compared to controls, presymptomatic carriers within 8.5 years of estimated symptom onset showed a faster rate of decline in localisation performance in long-delay conditions (4s) and in traditional neuropsychology measures of verbal episodic memory. This study represents the first longitudinal VSTM investigation and shows that changes in memory resolution may be sensitive to tracking cognitive decline in preclinical AD at least as early as changes in the more traditional verbal episodic memory tasks.


Intelligent whole-blood imaging flow cytometry for simple, rapid, and cost-effective drug-susceptibility testing of leukemia.
Drug susceptibility (also called chemosensitivity) is an important criterion for developing a therapeutic strategy for various cancer types such as breast cancer and leukemia. Recently, functional assays such as high-content screening together with genomic analysis have been shown to be effective for predicting drug susceptibility, but their clinical applicability is poor since they are time-consuming (several days long), labor-intensive, and costly. Here we present a highly simple, rapid, and cost-effective liquid biopsy for ex vivo drug-susceptibility testing of leukemia. The method is based on an extreme-throughput (>1 million cells per second), label-free, whole-blood imaging flow cytometer with a deep convolutional autoencoder, enabling image-based identification of the drug susceptibility of every single white blood cell in whole blood within 24 hours by simply flowing a drug-treated whole blood sample as little as 500 μL into the imaging flow cytometer without labeling. Our results show that the method accurately evaluates the drug susceptibility of white blood cells from untreated patients with acute lymphoblastic leukemia. Our method holds promise for affordable precision medicine.


Magnesium, calcium, potassium, and sodium intakes and risk of stroke in male smokers.
A high intake of magnesium, calcium, and potassium and a low intake of sodium have been hypothesized to reduce the risk of stroke. However, prospective data relating intake of these minerals to risk of stroke are inconsistent. We examined the relationship of dietary magnesium, calcium, potassium, and sodium intake with risk of stroke in a cohort of 26 556 Finnish male smokers, aged 50 to 69 years, who were free from stroke at baseline. Dietary intake was assessed at baseline using a detailed and validated food frequency questionnaire. During a mean follow-up of 13.6 years (1985-2004), 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were identified in the national registries. After adjustment for age and cardiovascular risk factors, a high magnesium intake was associated with a statistically significant lower risk of cerebral infarction but not with intracerebral or subarachnoid hemorrhages. The multivariate relative risk of cerebral infarction was 0.85 (95% confidence interval, 0.76-0.97; P for trend = .004) for men in the highest quintile of magnesium intake compared with those in the lowest quintile. The inverse association between magnesium intake and cerebral infarction was stronger in men younger than 60 years (relative risk, 0.76; 95% confidence interval, 0.64-0.89; P for interaction = .02). Calcium, potassium, and sodium intake was not significantly associated with risk of any subtype of stroke (P for trend > .05). These findings in male smokers suggest that a high magnesium intake may play a role in the primary prevention of cerebral infarction.


Neurologic continuum of care: Evidence-based model of a post-hospital system of care.
There is increasing need for a well-organized continuum of post-hospital rehabilitative care to reduce long term disability resulting from acquired brain injury. This study examined the effectiveness of four levels of post-hospital care (active neurorehabilitation, neurobehavioral intensive, day treatment, and supported living) and the functional variables most important to their success. Participants were 1276 adults with acquired brain injury who were being treated in one of the four program levels. A Repeated Measures MANOVA was used to evaluate change from admission to discharge on the Mayo Portland Adaptability Inventory-4 T-scores. Regression analyses were used to identify predictors of outcome. Statistical improvement on the MPAI-4 was observed at each program level. Self-care and Initiation were the strongest predictors of outcome. The results support the effectiveness of a continuum of care for acquired brain injury individuals beyond hospitalization and acute in-hospital rehabilitation. It is particularly noteworthy that reduction in disability was achieved for all levels of programming even with participants whose onset to admission exceeded 7 years post-injury.


The Genetic Basis of Metabolic Disease.
Recent developments in genetics and genomics are providing a detailed and systematic characterization of the genetic underpinnings of common metabolic diseases and traits, highlighting the inherent complexity within systems for homeostatic control and the many ways in which that control can fail. The genetic architecture underlying these common metabolic phenotypes is complex, with each trait influenced by hundreds of loci spanning a range of allele frequencies and effect sizes. Here, we review the growing appreciation of this complexity and how this has fostered the implementation of genome-scale approaches that deliver robust mechanistic inference and unveil new strategies for translational exploitation.


Towards evidence-based policies to strengthen acute stroke care in low-middle-income countries.
Stroke is a major public health issue in many low- and middle-income countries (LMICs). Despite the emergence of new effective interventions for acute stroke care, uptake remains slow and largely inaccessible to patients in LMICs, where health systems response has been inadequate. In this paper, we propose a policy framework to optimise access to acute stroke care in LMICs. We draw on evidence from relevant primary studies, such as availability of evidence-based acute stroke care interventions, barriers to uptake of interventions for stroke care and insights on stroke mortality and morbidity burden in LMICs. Insights from review of secondary studies, principally systematic reviews on evidence-based acute stroke care; and the accounts and experiences of some regional experts on stroke and other NCDs have been taken into consideration. In LMICs, there is limited availability and access to emergency medical transport services, brain imaging services and best practice interventions for acute stroke care. Availability of specialist acute stroke workforce and low awareness of early stroke signs and symptoms are also major challenges impeding the delivery of quality stroke care services. As a result, stroke care in LMICs is patchy, fragmented and often results in poor patient outcomes. Reconfiguration of LMIC health systems is thus required to optimise access to quality acute stroke care. We therefore propose a ten-point framework to be adapted to country-specific health system capacity, needs and resources: Emergency medical transport and treatment services, scaling-up interventions and services for acute stroke care, clinical guidelines for acute stroke treatment and management, access to brain imaging services, human resource capacity development strategies, centralisation of stroke services, tele-stroke care, public awareness campaigns on early stroke symptoms, establish stroke registers and financing of stroke care in LMICs. While we recognise the challenges of implementing the recommendations in low resource settings, this list can provide a platform as well serve as the starting point for advocacy and prioritisation of interventions depending on context.


On Configuration Trajectory Formation in Spatiotemporal Profile for Reproducing Human Hand Reaching Movement.
Most functional reaching activities in daily living generally require a hand to reach the functional position in appropriate orientation with invariant spatiotemporal profile. Effectively reproducing such spatiotemporal feature of hand configuration trajectory in real time is essential to understand the human motor control and plan human-like motion on anthropomorphic robotic arm. However, there are no novel computational models in literature toward reproducing hand configuration-to-configuration movement in spatiotemporal profile. In response to the problem, this paper presents a computational framework for hand configuration trajectory formation based on hierarchical principle of human motor control. The composite potential field is constructed on special Euclidean Group to induce time-varying configuration toward target. The dynamic behavior of hand is described by a second-order kinematic model to produce the external representation of high-level motor control. The multivariate regression relation between intrinsic and extrinsic coordinates of arm, is statistically analyzed for determining the arm orientation in real time, which produces the external representation of low-level motor control. The proposed method is demonstrated in an anthropomorphic arm by performing several highly curved self-reaching movements. The generated configuration trajectories are compared with actual human movement in spatiotemporal profile to validate the proposed method.


Partially etched chirped fiber Bragg grating (pECFBG) for joint temperature, thermal profile, and refractive index detection.
In this work, a partially etched chirped fiber Bragg grating (pECFBG) is introduced, as a compact sensor for multi-parametric measurement of temperature, thermal gradients over the active length, and refractive index. The sensor is fabricated by wet-etching a portion of a 14-mm linearly chirped FBG with linear chirp profile. The resulting device has two active areas: the unetched part of the grating (2 mm) can be used either as a uniform temperature sensor, or to detect thermal gradients experienced through the grating length by means of a spectral reconstruction technique; the etched part (12 mm), besides having a similar thermal sensitivity, is exposed to refractive index sensing through the introduction of a sensitivity to external refractive index. Overall, the pECFBG structure behaves as a compact sensor with multi-parameter capability, that can both measure temperature and refractive index on the same grating, but also spatially resolve temperature detection through the grating section. The results have been validated through both a model and experimental setup, showing that the mutual correlation algorithm applied to different spectral parts of the grating is able to discriminate between uniform and gradient-shaped temperature profiles, and refractive index changes.


Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).
Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial. URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.


Self-Other Mergence in the Frontal Cortex during Cooperation and Competition.
To survive, humans must estimate their own ability and the abilities of others. We found that, although people estimated their abilities on the basis of their own performance in a rational manner, their estimates of themselves were partly merged with the performance of others. Reciprocally, their ability estimates for others also reflected their own, as well as the others', performance. Self-other mergence operated in a context-dependent manner: interacting with high or low performers, respectively, enhanced and diminished own ability estimates in cooperative contexts, but the opposite occurred in competitive contexts. Self-other mergence not only influenced subjective evaluations, it also affected how people subsequently objectively adjusted their performance. Perigenual anterior cingulate cortex tracked one's own performance. Dorsomedial frontal area 9 tracked others' performances, but also integrated contextual and self-related information. Self-other mergence increased with the strength of self and other representations in area 9, suggesting it carries interdependent representations of self and other.


Prefrontal cortex and schizophrenia. A quantitative magnetic resonance imaging study.
To measure prefrontal cortical volume in a group of schizophrenic subjects who presented with mainly positive symptoms and who were previously shown to have volume reductions in left temporal lobe structures. Fourteen men with chronic schizophrenia and 15 male control subjects were matched for age, IQ, handedness, and parental socioeconomic status. Magnetic resonance images were obtained by means of a 1.5-T magnet, and contiguous 1.5-mm slices of the entire brain were obtained. No significant differences were found between schizophrenic and control subjects in mean values for prefrontal white or gray matter on either the right or the left side. However, within the schizophrenic group, there was evidence of a relationship between the volumes of left prefrontal gray matter and left temporal lobe structures that was not present in the control group. At least in this group of schizophrenic subjects with mainly positive symptoms, temporal lobe abnormalities can exist in conjunction with no gross volumetric abnormalities of the prefrontal cortex.


The effect of rehearsal rate and memory load on verbal working memory.
While many neuroimaging studies have investigated verbal working memory (WM) by manipulating memory load, the subvocal rehearsal rate at these various memory loads has generally been left uncontrolled. Therefore, the goal of this study was to investigate how mnemonic load and the rate of subvocal rehearsal modulate patterns of activity in the core neural circuits underlying verbal working memory. Using fMRI in healthy subjects, we orthogonally manipulated subvocal rehearsal rate and memory load in a verbal WM task with long 45-s delay periods. We found that middle frontal gyrus (MFG) and superior parietal lobule (SPL) exhibited memory load effects primarily early in the delay period and did not exhibit rehearsal rate effects. In contrast, we found that inferior frontal gyrus (IFG), premotor cortex (PM) and Sylvian-parietal-temporal region (area Spt) exhibited approximately linear memory load and rehearsal rate effects, with rehearsal rate effects lasting through the entire delay period. These results indicate that IFG, PM and area Spt comprise the core articulatory rehearsal areas involved in verbal WM, while MFG and SPL are recruited in a general supervisory role once a memory load threshold in the core rehearsal network has been exceeded.


Sleep-disordered breathing is associated with brain vascular reactivity in spinal cord injury.
To determine the population-level odds of individuals with spinal cord injury (SCI) experiencing fatigue and sleep apnea, to elucidate relationships with level and severity of injury, and to examine associations with abnormal cerebrovascular responsiveness. We used population-level data, meta-analyses, and primary physiologic assessments to provide a large-scale integrated assessment of sleep-related complications after SCI. Population-level and meta-analyses included more than 60,000 able-bodied individuals and more than 1,800 individuals with SCI. Physiologic assessments were completed on a homogenous sample of individuals with cervical SCI and matched controls. We examined the prevalence of (1) self-reported chronic fatigue, (2) clinically identified sleep apnea, and 3) cerebrovascular responsiveness to changing CO2. Logistic regression revealed a 7-fold elevated odds of chronic fatigue after SCI (odds ratio [OR] 7.9, 95% confidence interval [CI] 3.5-16.2), and that fatigue and trouble sleeping are correlated with the level and severity of injury. We further show that those with SCI experience elevated risk of clinically defined sleep-disordered breathing in more than 600 individuals with SCI (pooled OR 3.1, 95% CI 1.3-7.5). We confirmed that individuals with SCI experience a high rate of clinically defined sleep apnea using primary polysomnography assessments. We then provide evidence using syndromic analysis that sleep-disordered breathing is a factor strongly associated with impaired cerebrovascular responsiveness to CO2 in patients with SCI. Individuals with SCI have an increased prevalence of sleep-disordered breathing, which may partially underpin their increased risk of stroke. There is thus a need to integrate sleep-related breathing examinations into routine care for individuals with SCI.


The intestinal parasite Pomphorhynchus laevis (Acanthocephala) from barbel as a bioindicator for metal pollution in the Danube River near Budapest, Hungary.
Concentrations of As, Al, Ag, Ba, Bi, Cd, Co, Cr, Cu, Fe, Ga, Mg, Mn, Ni, Pb, Sb, Sn, Sr, Tl, V and Zn were analyzed by inductively coupled mass spectrometry (ICP-MS) in the intestinal helminth Pomphorhynchus laevis and its host Barbus barbus. The fish were caught in the Danube river downstream of the city of Budapest (Hungary). Ten out of twenty one elements analyzed were found at higher concentrations in the acanthocephalan than in different tissues (muscle, intestine, liver and kidney) of barbel. Considering the fish tissues, most of the elements were present at highest concentrations in liver, followed by kidney, intestine and muscle. Spearman correlation analyses indicate that there is competition for metals between the parasites and the host. The negative relationships between parasite number and metal levels in organs of the barbel support this hypothesis. The bioconcentration factors for Ag, As, Ba, Bi, Cu, Ga, Mn, Pb, Sr, Tl, and Zn showed that the parasites concentrated metals to a higher degree than the fish tissues. They accumulated the metals As, Cd, Cu, Fe, Ni, Pb, Sr and Zn even better than established bioindicators such as the mussel Dreissena polymorpha as revealed by data from the literature. The results presented here emphasize that acanthocephalans of fish are very useful as sentinels for metal pollution in aquatic ecosystems. Ratio of metal concentrations in the parasites and the host tissues provide additional information. Not including acanthocephalans in accumulation bioindication studies with fishes (as still customarily done) may lead to false results.


Revealing the transcriptomic complexity of switchgrass by PacBio long-read sequencing.
Switchgrass (Panicum virgatum L.) is an important bioenergy crop widely used for lignocellulosic research. While extensive transcriptomic analyses have been conducted on this species using short read-based sequencing techniques, very little has been reliably derived regarding alternatively spliced (AS) transcripts. We present an analysis of transcriptomes of six switchgrass tissue types pooled together, sequenced using Pacific Biosciences (PacBio) single-molecular long-read technology. Our analysis identified 105,419 unique transcripts covering 43,570 known genes and 8795 previously unknown genes. 45,168 are novel transcripts of known genes. A total of 60,096 AS transcripts are identified, 45,628 being novel. We have also predicted 1549 transcripts of genes involved in cell wall construction and remodeling, 639 being novel transcripts of known cell wall genes. Most of the predicted transcripts are validated against Illumina-based short reads. Specifically, 96% of the splice junction sites in all the unique transcripts are validated by at least five Illumina reads. Comparisons between genes derived from our identified transcripts and the current genome annotation revealed that among the gene set predicted by both analyses, 16,640 have different exon-intron structures. Overall, substantial amount of new information is derived from the PacBio RNA data regarding both the transcriptome and the genome of switchgrass.


Upper normal values of blood pressure response to exercise in Olympic athletes.
Exercise test is widespread performed in athletes to assess cardiovascular adaptations during effort; however, scarce information exists relative to the behavior of blood pressure during exercise in athletes. We sought to define the normal values and upper limits of blood pressure response to exercise in a large population of elite, healthy athletes. A total of 1,876 healthy, normotensive elite athletes (aged 25 ± 6 years, 64% male) underwent a comprehensive clinical evaluation including maximal bicycle exercise test. At maximum exercise, the systolic blood pressure increased significantly (Δ = +69 ± 18 mm Hg; P< .001), whereas diastolic blood pressure showed minimal change (Δ = +1 ± 7 mm Hg; P= .001). The upper reference values were 220 mm Hg in male and 200 mm Hg in female athletes for systolic blood pressure, and 85 mm Hg in male and 80 mm Hg in female for diastolic blood pressure. A subgroup of 142 athletes (7.5%) showed high blood pressure response to exercise, that is, increase in systolic and/or diastolic blood pressure above the 95th percentile. Multivariate logistic regression analysis showed that endurance and mixed sport disciplines, body mass index, and baseline systolic blood pressure were the strongest determinants for high blood pressure response to exercise. The gender-specific reference values for systolic and diastolic blood pressure at maximum exercise in athletes were defined. A small subset (7.5%) of athletes showed higher blood pressure response, in the absence of target organ disease or metabolic abnormalities, and associated with superior physical performance and larger cardiac remodeling.


MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development.


Arsenic exposure and mortality: a case-referent study from a Swedish copper smelter.
An increased mortality from lung cancer, cardiovascular disease, haematolymphatic malignancy and cirrhosis of the liver has been reported among smelter workers and others exposed to arsenic. This study uses the case-referent (case-control) technique and is concerned with workers in a copper smelter in a complex work environment, characterised by the presence of trivalent arsenic in combination with sulphur dioxide and copper, and also with other agents. Lung cancer mortality was found to be increased about five-fold and cardiovascular disease about two-fold, showing a dose-response relationship to arsenic exposure. Mortality from malignant blood disease (leukaemia and myeloma) and cirrhosis of the liver was also slightly increased. This mortality pattern among the smelter workers is consistent with earlier reports. An increased mortality from cardiovascular disease in this type of industry is of particular interest as it has been reported only once before.


Close encounters with eddies: oceanographic features increase growth of larval reef fishes during their journey to the reef.
Like most benthic marine organisms, coral reef fishes produce larvae that traverse open ocean waters before settling and metamorphosing into juveniles. Where larvae are transported and how they survive is a central question in marine and fisheries ecology. While there is increasing success in modelling potential larval trajectories, our knowledge of the physical and biological processes contributing to larval survivorship during dispersal remains relatively poor. Mesoscale eddies (MEs) are ubiquitous throughout the world's oceans and their propagation is often accompanied by upwelling and increased productivity. Enhanced production suggests that eddies may serve as important habitat for the larval stages of marine organisms, yet there is a lack of empirical data on the growth rates of larvae associated with these eddies. During three cruises in the Straits of Florida, we sampled larval fishes inside and outside five cyclonic MEs. Otolith microstructure analysis revealed that four of five species of reef fish examined had consistently faster growth inside these eddies. Because increased larval growth often leads to higher survivorship, larvae that encounter MEs during transit are more likely to contribute to reef populations. Successful dispersal in oligotrophic waters may rely on larval encounter with such oceanographic features.


Femtosecond infrared intrastromal ablation and backscattering-mode adaptive-optics multiphoton microscopy in chicken corneas.
The performance of femtosecond (fs) laser intrastromal ablation was evaluated with backscattering-mode adaptive-optics multiphoton microscopy in ex vivo chicken corneas. The pulse energy of the fs source used for ablation was set to generate two different ablation patterns within the corneal stroma at a certain depth. Intrastromal patterns were imaged with a custom adaptive-optics multiphoton microscope to determine the accuracy of the procedure and verify the outcomes. This study demonstrates the potential of using fs pulses as surgical and monitoring techniques to systematically investigate intratissue ablation. Further refinement of the experimental system by combining both functions into a single fs laser system would be the basis to establish new techniques capable of monitoring corneal surgery without labeling in real-time. Since the backscattering configuration has also been optimized, future in vivo implementations would also be of interest in clinical environments involving corneal ablation procedures.


A comparison of average wages with age-specific wages for assessing indirect productivity losses: analytic simplicity versus analytic precision.
Numerous approaches are used to estimate indirect productivity losses using various wage estimates applied to poor health in working aged adults. Considering the different wage estimation approaches observed in the published literature, we sought to assess variation in productivity loss estimates when using average wages compared with age-specific wages. Published estimates for average and age-specific wages for combined male/female wages were obtained from the UK Office of National Statistics. A polynomial interpolation was used to convert 5-year age-banded wage data into annual age-specific wages estimates. To compare indirect cost estimates, average wages and age-specific wages were used to project productivity losses at various stages of life based on the human capital approach. Discount rates of 0, 3, and 6 % were applied to projected age-specific and average wage losses. Using average wages was found to overestimate lifetime wages in conditions afflicting those aged 1-27 and 57-67, while underestimating lifetime wages in those aged 27-57. The difference was most significant for children where average wage overestimated wages by 15 % and for 40-year-olds where it underestimated wages by 14 %. Large differences in projecting productivity losses exist when using the average wage applied over a lifetime. Specifically, use of average wages overestimates productivity losses between 8 and 15 % for childhood illnesses. Furthermore, during prime working years, use of average wages will underestimate productivity losses by 14 %. We suggest that to achieve more precise estimates of productivity losses, age-specific wages should become the standard analytic approach.