Antibiotic prescribing during pediatric ambulatory care visits for asthma.
National guidelines do not recommend antibiotics as an asthma therapy. We sought to examine the frequency of inappropriate antibiotic prescribing during US ambulatory care pediatric asthma visits as well as the patient, provider, and systemic variables associated with such practice. Data from the National Ambulatory Medical Care Surveys and National Hospital Ambulatory Medical Care Survey were examined to assess office and emergency-department asthma visits made by children (aged < 18 years) for frequencies of antibiotic prescription. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to assess the presence of coexisting conditions warranting antibiotics. Multivariable logistic regression models assessed associations with the prescription of antibiotics. From 1998 to 2007, an estimated 60.4 million visits occurred for asthma without another ICD-9 code justifying antibiotic prescription. Antibiotics were prescribed during 16% of these visits, most commonly macrolides (48.8%). In multivariate analysis, controlling for patient age, gender, race, insurance type, region, and controller medication use, systemic corticosteroid prescription (odds ratio [OR]: 2.69 [95% confidence interval (CI): 1.68-4.30]) and treatment during the winter (OR: 1.92 [95% CI: 1.05-3.52]) were associated with an increased likelihood of antibiotic prescription, whereas treatment in an emergency department was associated with decreased likelihood (OR: 0.48 [95% CI: 0.26-0.89]). A second multivariate analysis of only office-based visits demonstrated that asthma education during the visits was associated with reduced antibiotic prescriptions (OR: 0.46 [95% CI: 0.24-0.86]). Antibiotics are prescribed during nearly 1 in 6 US pediatric ambulatory care visits for asthma, ~ 1 million prescriptions annually, when antibiotic need is undocumented. Additional education and interventions are needed to prevent unnecessary antibiotic prescribing for asthma.


Extinctions and introductions in the new zealand avifauna: cause and effect?
New Zealand, like many other islands, has suffered extinctions of native species and successful introductions of exotic species. It has been uncertain whether the introductions caused the extinctions or whether the extinctions permitted the introductions. On New Zealand's Hauraki Gulf islands, which are unusual in their near lack of introduced mammalian predators and complete lack of mammalian browsers, exotic bird species abundant in mainland New Zealand forest and reaching these islands are virtually absent from unmodified forest. Exotic bird species disappeared from Cuvier Island's forest after elimination of mammalian predators and browsers. Hence extinctions of native species were not due to competition from introduced species but to other factors (such as mammalian predators and habitat alteration). Only after decimation of native species and forest alteration by browsing mammals could exotic birds invade forest.


Amygdala activation in maltreated children during pre-attentive emotional processing.
Childhood adversity is associated with significantly increased risk of psychiatric disorder. To date, functional magnetic resonance imaging (fMRI) studies of children have mainly focused on institutionalisation and investigated conscious processing of affect. To investigate neural response to pre-attentively presented affect cues in a community sample of children with documented experiences of maltreatment in the home. A masked dot-probe paradigm involving pre-attentive presentation of angry, happy and neutral facial expressions was employed. Eighteen maltreated children were compared with 23 carefully matched non-maltreated peers. Increased neural response was observed in the right amygdala for pre-attentively presented angry and happy faces in maltreated v. non-maltreated children. Level of amygdala activation was negatively associated with age at onset for several abuse subtypes. Maltreatment is associated with heightened neural response to positive and negative facial affect, even to stimuli outside awareness. This may represent a latent neural risk factor for future psychiatric disorder.


Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101.
Comparison of diverse orthologs is a powerful tool to study the structure and function of channel proteins. We investigated the response of human, killifish, pig, and shark cystic fibrosis transmembrane conductance regulator (CFTR) to specific inhibitors of the channel: CFTR(inh)-172, glibenclamide, and GlyH-101. In three systems, including organ perfusion of the shark rectal gland, primary cultures of shark rectal gland tubules, and expression studies of each ortholog in cRNA microinjected Xenopus laevis oocytes, we observed fundamental differences in the sensitivity to inhibition by these channel blockers. In organ perfusion studies, shark CFTR was insensitive to inhibition by CFTR(inh)-172. This insensitivity was also seen in short-circuit current experiments with cultured rectal gland tubular epithelial cells (maximum inhibition 4 ± 1.3%). In oocyte expression studies, shark CFTR was again insensitive to CFTR(inh)-172 (maximum inhibition 10.3 ± 2.5% at 25 μM), pig CFTR was insensitive to glibenclamide (maximum inhibition 18.4 ± 4.4% at 250 μM), and all orthologs were sensitive to GlyH-101. The amino acid residues considered responsible by previous site-directed mutagenesis for binding of the three inhibitors are conserved in the four CFTR isoforms studied. These experiments demonstrate a profound difference in the sensitivity of different orthologs of CFTR proteins to inhibition by CFTR blockers that cannot be explained by mutagenesis of single amino acids. We believe that the potency of the inhibitors CFTR(inh)-172, glibenclamide, and GlyH-101 on the CFTR chloride channel protein is likely dictated by the local environment and the three-dimensional structure of additional residues that form the vestibules, the chloride pore, and regulatory regions of the channel.


De-escalation of aggressive behaviour in healthcare settings: Concept analysis.
De-escalation is the recommended first-line response to potential violence and aggression in healthcare settings. Related scholarly activity has increased exponentially since the 1980s, but there is scant research about its efficacy and no guidance on what constitutes the gold standard for practice. To clarify the concept of de-escalation of violence and aggression as described within the healthcare literature. Concept analysis guided by Rodgers' evolutionary approach. Multiple nursing and healthcare databases were searched using relevant terms. High quality and/or highly cited, or otherwise relevant published empirical or theoretical English language literature was included. Information about surrogate terms, antecedents, attributes, consequences, and the temporal, environmental, disciplinary, and theoretical contexts of use were extracted and synthesised. Information about the specific attributes of de-escalation were subject to thematic analysis. Proposed theories or models of de-escalation were assessed against quality criteria. N=79 studies were included. Mental health settings were the most commonly reported environment in which de-escalation occurs, and nursing the disciplinary group most commonly discussed. Five theories of de-escalation were proposed; while each was adequate in some respects, all lacked empirical support. Based on our analysis the resulting theoretical definition of de-escalation in healthcare is "a collective term for a range of interwoven staff-delivered components comprising communication, self-regulation, assessment, actions, and safety maintenance which aims to extinguish or reduce patient aggression/agitation irrespective of its cause, and improve staff-patient relationships while eliminating or minimising coercion or restriction". While a number of theoretical models have been proposed, the lack of advances made in developing a robust evidence-base for the efficacy of de-escalation is striking and must, at least in part, be credited to the lack of a clear conceptualisation of the term. This concept analysis provides a framework for researchers to identify the theoretical model that they purport to use, the antecedents that their de-escalation intervention is targeting, its key attributes, and the key negative and positive consequences that are to be avoided or encouraged.


Crowdsourcing RNA structural alignments with an online computer game.
The annotation and classification of ncRNAs is essential to decipher molecular mechanisms of gene regulation in normal and disease states. A database such as Rfam maintains alignments, consensus secondary structures, and corresponding annotations for RNA families. Its primary purpose is the automated, accurate annotation of non-coding RNAs in genomic sequences. However, the alignment of RNAs is computationally challenging, and the data stored in this database are often subject to improvements. Here, we design and evaluate Ribo, a human-computing game that aims to improve the accuracy of RNA alignments already stored in Rfam. We demonstrate the potential of our techniques and discuss the feasibility of large scale collaborative annotation and classification of RNA families.


Failure to engage: A qualitative study of veterans who decline evidence-based psychotherapies for PTSD.
Low engagement in posttraumatic stress disorder (PTSD) psychotherapy is a common problem in the U.S. Department of Veteran Affairs (VA), with up to half of veterans who are referred to an evidence-based psychotherapy failing to engage in that treatment. Prior research has focused on identifying general barriers to mental health treatment rather than barriers specific to evidence-based treatments for PTSD. The purpose of the current study was to identify barriers for veterans who referred specifically for evidence-based psychotherapy (i.e., cognitive processing therapy or prolonged exposure) but who did not attend any sessions of those psychotherapies. Qualitative interviews (N = 24) were used to gain a better understanding of the experiences and attitudes of these veterans. Most veterans reported multiple barriers to treatment engagement (M = 4.2 barriers), suggesting that an accumulation of barriers contributes to poor engagement. Barriers fell into 5 categories: practical, knowledge, emotional, therapy-related, and VA-system-related. The most-endorsed category, mentioned by two thirds of the sample, was VA-system-related barriers, including inefficiencies and delays, negative experiences with VA staff and providers, discomfort with the VA environment, and difficulty navigating the VA system. Veterans' experienced barriers to beginning PE and CPT were diverse but, overall, highlighted the need to transform the VA to a more patient-centered model of care. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Selenium and selenoproteins in viral infection with potential relevance to COVID-19.
Selenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection.


Melanoma in solid organ transplant recipients.
This manuscript outlines estimated risk and clinical course of pretransplant MM, donor-transmitted MM and de novo MM posttransplantation and includes an analysis of risk factors for metastasis, data from clinical studies and current and proposed management. MM in situ and thin melanoma (<1 mm) in the transplant population has similar recurrence and survival estimates to those in the general population. A minimum wait time of 2 years prior to transplantation is suggested for MM with a Breslow depth <1 mm and no clinical evidence of metastasis. More advanced MM may adopt a more aggressive course in transplant recipients. Sentinel lymph node biopsy may be of additional prognostic benefit. Revision of immunosuppression in the management of de novo melanoma in collaboration with the transplant team should be considered. Larger studies utilizing uniform staging criteria or at minimum Breslow depth, are required to assess true risk and outcome of MM in the immunosuppressed transplant population. Emphasis remains on patient education and regular screening to provide early detection of MM.


Identifying standards, meeting expectations: comparing regulatory standards and community health nursing practice standards.
In Canada, standards from regulatory and professional bodies provide a framework for nursing practice. In a research study, the authors compared the national standards of practice developed for community health nurses by the Community Health Nurses Association of Canada (CHNAC) with those in the standards of practice developed by provincial/territorial regulatory bodies. The results of the study revealed that of 210 separate ideas, or categories of ideas, the authors identified in all 13 documents, only 58 appeared in both the regulatory and CHNAC documents; 122 were unique to the regulatory standards; 30 were unique to the CHNAC standards. These results suggest a need for associations and specialty groups, notably national ones, to integrate regulatory standards into their own documents and build upon them to reflect the dimensions of specialty practice.


Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas.
Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both Tp53 and Pten in the mouse mesothelium is sufficient to rapidly drive aggressive MMs. PtenL/L ;Tp53L/L mice injected intraperitoneally or intrapleurally with adenovirus-expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt-mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when Pten and Tp53 are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to Pten loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.


Coercive family process and early-onset conduct problems from age 2 to school entry.
The emergence and persistence of conduct problems (CPs) during early childhood is a robust predictor of behavior problems in school and of future maladaptation. In this study we examined the reciprocal influences between observed coercive interactions between children and caregivers, oppositional and aggressive behavior, and growth in parent report of early childhood (ages 2-5) and school-age CPs (ages 7.5 and 8.5). Participants were drawn from the Early Steps multisite randomized prevention trial that includes an ethnically diverse sample of male and female children and their families (N = 731). A parallel-process growth model combining latent trajectory and cross-lagged approaches revealed the amplifying effect of observed coercive caregiver-child interactions on children's noncompliance, whereas child oppositional and aggressive behaviors did not consistently predict increased coercion. The slope and initial levels of child oppositional and aggressive behaviors and the stability of caregiver-child coercion were predictive of teacher-reported oppositional behavior at school age. Families assigned to the Family Check-Up condition had significantly steeper declines in child oppositional and aggressive behavior and moderate reductions in oppositional behavior in school and in coercion at age 3. Results were not moderated by child gender, race/ethnicity, or assignment to the intervention condition. The implications of these findings are discussed with respect to understanding the early development of CPs and to designing optimal strategies for reducing problem behavior in early childhood with families most in need.


Asthma in Greenwich, UK: impact of the disease and current management practices.
A great deal of the care of patients with asthma takes place in general practices. The aim of the present study was to describe the impact of asthma in the community and to identify current asthma self-management practices. A two-part questionnaire survey was conducted in a random sample (23%; n=24,398) of persons aged 16-50 yrs, registered with one of the 41 general practices in Greenwich, London, UK. The two parts were: a screening questionnaire identifying persons with current asthma (defined as waking with shortness of breath in the last 12 months, attack of asthma in the last 12 months, or currently taking treatment for asthma); and an asthma questionnaire (completed by those with asthma) assessing quality of life, frequency of asthma symptoms, possession and use of self-management tools, and action in the event of an exacerbation of asthma. The crude response rate was 51%, but this may be an underestimate due to errors in the sampling frame. The prevalences of wheeze and asthma in the past 12 months were 26% and 14%, respectively. Among asthma patients: 43% reported symptoms occurring three or more times per week, and 20% were woken by asthma symptoms on three or more nights per week; most had asthma with a mild impact on quality of life; 26% used inhaled steroids on most days in the preceding month; 16% had a peak flow meter at home; and 7% had oral steroids available. Of the 44% of subjects with asthma, who could identify an exacerbation of asthma in the preceding 6 months: 19% had used a peak flow meter during the episode; 19% had changed their treatment without first being told to do so by a doctor; and 50% had sought urgent medical help. Smokers used less appropriate asthma management and subjects whose asthma had a severe impact on quality of life used more treatment and peak flow monitoring. In conclusion, the prevalence of asthma among adults in Greenwich, UK, has increased since a similar survey in 1986. Many people have fairly mild asthma and a smaller number have severe disease. Much remains to be done to promote appropriate strategies for self-management of asthma exacerbations.


Intraspecific variation in symbiont density in an insect-microbe symbiosis.
Many insects host vertically transmitted microbes, which can confer benefits to their hosts but are costly to maintain and regulate. A key feature of these symbioses is variation: for example, symbiont density can vary among host and symbiont genotypes. However, the evolutionary forces maintaining this variation remain unclear. We studied variation in symbiont density using the pea aphid (Acyrthosiphon pisum) and the bacterium Regiella insecticola, a symbiont that can protect its host against fungal pathogens. We found that relative symbiont density varies both between two Regiella phylogenetic clades and among aphid "biotypes." Higher density symbiont infections are correlated with stronger survival costs, but variation in density has little effect on the protection Regiella provides against fungi. Instead, we found that in some aphid genotypes, a dramatic decline in symbiont density precedes the loss of a symbiont infection. Together, our data suggest that the optimal density of a symbiont infection is likely different from the perspective of aphid and microbial fitness. Regiella might prevent loss by maintaining high within-host densities, but hosts do not appear to benefit from higher symbiont numbers and may be advantaged by losing costly symbionts in certain environments. The standing variation in symbiont density observed in natural populations could therefore be maintained by antagonistic coevolutionary interactions between hosts and their symbiotic microbes.


The development of features in object concepts.
According to one productive and influential approach to cognition, categorization, object recognition, and higher level cognitive processes operate on a set of fixed features, which are the output of lower level perceptual processes. In many situations, however, it is the higher level cognitive process being executed that influences the lower level features that are created. Rather than viewing the repertoire of features as being fixed by low-level processes, we present a theory in which people create features to subserve the representation and categorization of objects. Two types of category learning should be distinguished. Fixed space category learning occurs when new categorizations are representable with the available feature set. Flexible space category learning occurs when new categorizations cannot be represented with the features available. Whether fixed or flexible, learning depends on the featural contrasts and similarities between the new category to be represented and the individuals existing concepts. Fixed feature approaches face one of two problems with tasks that call for new features: If the fixed features are fairly high level and directly useful for categorization, then they will not be flexible enough to represent all objects that might be relevant for a new task. If the fixed features are small, subsymbolic fragments (such as pixels), then regularities at the level of the functional features required to accomplish categorizations will not be captured by these primitives. We present evidence of flexible perceptual changes arising from category learning and theoretical arguments for the importance of this flexibility. We describe conditions that promote feature creation and argue against interpreting them in terms of fixed features. Finally, we discuss the implications of functional features for object categorization, conceptual development, chunking, constructive induction, and formal models of dimensionality reduction.


Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery.
Acute kidney injury (AKI) is a frequent complication of cardiac surgery and increases morbidity and mortality. The identification of reliable biomarkers that allow earlier diagnosis of AKI in the postoperative period may increase the success of therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 1219 adults undergoing cardiac surgery to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse patient outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. After multivariable adjustment, the highest quintiles of urine IL-18 and plasma NGAL associated with 6.8-fold and 5-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine and plasma NGAL levels associated with longer length of hospital stay, longer intensive care unit stay, and higher risk for dialysis or death. The clinical prediction model for AKI had an area under the receiver-operating characteristic curve (AUC) of 0.69. Urine IL-18 and plasma NGAL significantly improved the AUC to 0.76 and 0.75, respectively. Urine IL-18 and plasma NGAL significantly improved risk prediction over the clinical models alone as measured by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). In conclusion, urine IL-18, urine NGAL, and plasma NGAL associate with subsequent AKI and poor outcomes among adults undergoing cardiac surgery.


Health care access among U.S. adults who drink alcohol excessively: missed opportunities for prevention.
Excessive alcohol consumption kills approximately 75,000 people annually in the United States. Although alcohol screening among primary care patients is recommended by the U.S. Preventive Services Task Force, it is rarely performed. It is unclear whether low screening rates are due to limited access to health care, missed screening opportunities during patient visits, or both. Data came from the 2002 Behavioral Risk Factor Surveillance System, a population-based telephone survey of noninstitutionalized U.S. adults. Current health insurance status and a history of a recent medical checkup (within 2 years) were assessed in relation to alcohol consumption status. Excessive drinkers included those who reported binge drinking (consuming five or more drinks on one or more occasions in the past month), heavy drinking (consuming more than 60 drinks in the past month for men or more than 30 for women), or both. The prevalence of excessive drinking among the general population (17%) was only slightly higher than the prevalence among those with current health insurance (15%) or a recent checkup (14%). Among excessive drinkers, 79% had current health insurance and 78% had a recent checkup. Although excessive drinkers were somewhat less likely to have health insurance or a recent checkup compared with nonexcessive drinkers and nondrinkers, these differences were less pronounced after stratifying by age. Excessive drinkers with the lowest rates of health insurance were young, Hispanic, less educated, and unemployed. However, most excessive drinkers who lacked insurance or a checkup were employed. Most excessive drinkers were insured and had a recent medical checkup, suggesting that low screening rates among excessive drinkers are mostly due to missed screening opportunities rather than a lack of screening opportunities. Systems approaches to address these missed opportunities should be aggressively implemented.


Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer.
The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX). The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models. The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status. The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.


Exploration and learning in capuchin monkeys (Sapajus spp.): the role of action-outcome contingencies.
Animals have a strong propensity to explore the environment. Spontaneous exploration has a great biological significance since it allows animals to discover and learn the relation between specific behaviours and their consequences. The role of the contingency between action and outcome for learning has been mainly investigated in instrumental learning settings and much less in free exploration contexts. We tested 16 capuchin monkeys (Sapajus spp.) with a mechatronic platform that allowed complex modules to be manipulated and to produce different outcomes. Experimental subjects could manipulate the modules and discover the contingencies between their own specific actions and the outcomes produced (i.e., the opening and lighting of a box). By contrast, Control subjects could operate on the modules, but the outcomes experienced were those performed by their paired Experimental subjects ("yoked-control" paradigm). In the exploration phase, in which no food reward was present, Experimental subjects spent more time on the board and manipulated the modules more than Yoked subjects. Experimental subjects outperformed Yoked subjects in the following test phase, where success required recalling the effective action so to open the box, now baited with food. These findings demonstrate that the opportunity to experience action-outcome contingencies in the absence of extrinsic rewards promotes capuchins' exploration and facilitates learning processes. Thus, this intrinsically motivated learning represents a powerful mechanism allowing the acquisition of skills and cognitive competence that the individual can later exploit for adaptive purposes.


Consumer underestimation of sodium in fast food restaurant meals: Results from a cross-sectional observational study.
Restaurants are key venues for reducing sodium intake in the U.S. but little is known about consumer perceptions of sodium in restaurant foods. This study quantifies the difference between estimated and actual sodium content of restaurant meals and examines predictors of underestimation in adult and adolescent diners at fast food restaurants. In 2013 and 2014, meal receipts and questionnaires were collected from adults and adolescents dining at six restaurant chains in four New England cities. The sample included 993 adults surveyed during 229 dinnertime visits to 44 restaurants and 794 adolescents surveyed during 298 visits to 49 restaurants after school or at lunchtime. Diners were asked to estimate the amount of sodium (mg) in the meal they had just purchased. Sodium estimates were compared with actual sodium in the meal, calculated by matching all items that the respondent purchased for personal consumption to sodium information on chain restaurant websites. Mean (SD) actual sodium (mg) content of meals was 1292 (970) for adults and 1128 (891) for adolescents. One-quarter of diners (176 (23%) adults, 155 (25%) adolescents) were unable or unwilling to provide estimates of the sodium content of their meals. Of those who provided estimates, 90% of adults and 88% of adolescents underestimated sodium in their meals, with adults underestimating sodium by a mean (SD) of 1013 mg (1,055) and adolescents underestimating by 876 mg (1,021). Respondents underestimated sodium content more for meals with greater sodium content. Education about sodium at point-of-purchase, such as provision of sodium information on restaurant menu boards, may help correct consumer underestimation, particularly for meals of high sodium content.


Utility of Select Plasma MicroRNA for Disease and Cardiovascular Risk Assessment in Patients with Rheumatoid Arthritis.
MicroRNA (miRNA) are small noncoding RNA that posttranscriptionally regulate gene expression and serve as potential mediators and markers of disease. Recently, plasma miR-24-3p and miR-125a-5p concentrations were shown to be elevated in rheumatoid arthritis (RA) and useful for RA diagnosis. We assessed the utility of 7 candidate plasma miRNA, selected for biological relevance, for RA diagnosis and use as markers of disease activity and subclinical atherosclerosis in RA. The cross-sectional study included 168 patients with RA and 91 control subjects of similar age, race, and sex. Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were measured by quantitative PCR. Utility of plasma miRNA concentrations for RA diagnosis was assessed by area under the receiver-operating characteristic curve (AUROC). Associations between plasma miRNA concentrations and RA disease activity and coronary artery calcium score were assessed by Spearman correlations. Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were significantly increased in patients with RA. The highest AUROC for diagnosis of RA (AUROC = 0.725) was found in miR-24-3p, including among rheumatoid factor-negative patients (AUROC = 0.772). Among all patients with RA, the combination of miR-24-3p, miR-26a-5p, and miR-125a-5p improved the model modestly (AUROC = 0.747). One miRNA, miR-155-5p, was weakly inversely associated with swollen joint count (p = 0.024), but no other miRNA were associated with disease activity or coronary artery calcium score. The combination of miR-24-3p, miR-26a-5p, and miR-125a-5p had the strongest diagnostic accuracy for RA. Candidate miRNA had little or no association with RA disease activity or subclinical atherosclerosis.


MultiSite Gateway-Compatible Cell Type-Specific Gene-Inducible System for Plants.
A powerful method to study gene function is expression or overexpression in an inducible, cell type-specific system followed by observation of consequent phenotypic changes and visualization of linked reporters in the target tissue. Multiple inducible gene overexpression systems have been developed for plants, but very few of these combine plant selection markers, control of expression domains, access to multiple promoters and protein fusion reporters, chemical induction, and high-throughput cloning capabilities. Here, we introduce a MultiSite Gateway-compatible inducible system for Arabidopsis (Arabidopsis thaliana) plants that provides the capability to generate such constructs in a single cloning step. The system is based on the tightly controlled, estrogen-inducible XVE system. We demonstrate that the transformants generated with this system exhibit the expected cell type-specific expression, similar to what is observed with constitutively expressed native promoters. With this new system, cloning of inducible constructs is no longer limited to a few special cases but can be used as a standard approach when gene function is studied. In addition, we present a set of entry clones consisting of histochemical and fluorescent reporter variants designed for gene and promoter expression studies.


Activation of the cAMP pathway in Ustilago maydis reduces fungal proliferation and teliospore formation in plant tumors.
In the corn smut fungus Ustilago maydis, mating of two haploid sporidia is a prerequisite for subsequent colonization of the host. Cyclic AMP (cAMP) and pheromone signals have been implicated in this developmental program. The cAMP pathway is also needed for subsequent fungal development in planta, as null mutants in any component of the pathway fail to form tumors. Here we show that moderate activation of the pathway conferred either by mutation in the Galpha subunit or by mutation in the regulatory subunit of the protein kinase A influences tumor morphology. In the resulting tumors, the amount of fungal material is drastically reduced and fungal development is arrested at the stage of sporogenic hyphae. We conclude that tight regulation of the cAMP pathway is crucial for fungal development within the plant but does not interfere with the tumor induction process.


Light reflection models for computer graphics.
During the past 20 years, computer graphic techniques for simulating the reflection of light have progressed so that today images of photorealistic quality can be produced. Early algorithms considered direct lighting only, but global illumination phenomena with indirect lighting, surface interreflections, and shadows can now be modeled with ray tracing, radiosity, and Monte Carlo simulations. This article describes the historical development of computer graphic algorithms for light reflection and pictorially illustrates what will be commonly available in the near future.


Does 'altitude training' increase exercise performance in elite athletes?
What is the topic of this review? The aim is to evaluate the effectiveness of various altitude training strategies as investigated within the last few years. What advances does it highlight? Based on the available literature, the foundation to recommend altitude training to athletes is weak. Athletes may use one of the various altitude training strategies to improve exercise performance. The scientific support for such strategies is, however, not as sound as one would perhaps imagine. The question addressed in this review is whether altitude training should be recommended to elite athletes or not.


Risk of colorectal cancer in men on long-term androgen deprivation therapy for prostate cancer.
Androgen deprivation with gonadotropin-releasing hormone (GnRH) agonists or orchiectomy is a common but controversial treatment for prostate cancer. Uncertainties remain about its use, particularly with increasing recognition of serious side effects. In animal studies, androgens protect against colonic carcinogenesis, suggesting that androgen deprivation may increase the risk of colorectal cancer. We identified 107 859 men in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database who were diagnosed with prostate cancer in 1993 through 2002, with follow-up available through 2004. The primary outcome was development of colorectal cancer, determined from SEER files on second primary cancers. Cox proportional hazards regression was used to assess the influence of androgen deprivation on the outcome, adjusted for patient and prostate cancer characteristics. All statistical tests were two-sided. Men who had orchiectomies had the highest unadjusted incidence rate of colorectal cancer (6.3 per 1000 person-years; 95% confidence interval [CI] = 5.3 to 7.5), followed by men who had GnRH agonist therapy (4.4 per 1000 person-years; 95% CI = 4.0 to 4.9), and men who had no androgen deprivation (3.7 per 1000 person-years; 95% CI = 3.5 to 3.9). After adjustment for patient and prostate cancer characteristics, there was a statistically significant dose-response effect (P(trend) = .010) with an increasing risk of colorectal cancer associated with increasing duration of androgen deprivation. Compared with the absence of these treatments, there was an increased risk of colorectal cancer associated with use of GnRH agonist therapy for 25 months or longer (hazard ratio [HR] = 1.31, 95% CI = 1.12 to 1.53) or with orchiectomy (HR = 1.37, 95% CI = 1.14 to 1.66). Long-term androgen deprivation therapy for prostate cancer is associated with an increased risk of colorectal cancer.


Holding the baby: early mother-infant contact after childbirth and outcomes.
to describe the timing, type and duration of initial infant contact and associated demographic and clinical factors in addition to investigating the impact of early contact on breastfeeding and maternal health and well being after birth. data from a recent population survey of women birthing in Queensland, Australia were used to describe the nature of the first hold and associated demographic characteristics. Initial comparisons, with subsequent adjustment for type of birthing facility and mode of childbirth, were used to assess associations between timing, type and duration of initial contact and outcomes. Further analyses were conducted to investigate a dose-response relationship between duration of first contact and outcomes. women who had an unassisted vaginal birth held their infant sooner, and for longer than women who had an assisted vaginal birth or caesarean and were more satisfied with their early contact. Multivariate models showed a number of demographic and clinical interventions contributing to timing, duration and type of first contact with type of birthing facility (public/private), area of residence, and assisted birth as prominent factors. For women who had a vaginal birth; early, skin-to-skin, and longer duration of initial contact were associated with high rates of breastfeeding initiation and breastfeeding at discharge, but not breastfeeding at 13 weeks. Some aspects of early contact were associated with improved maternal well being. However, these associations were not found for women who had a caesarean birth. With longer durations of first contact, a dose-response effect was found for breastfeeding. results of the study provide a description of current practice in Queensland, Australia and factors impacting on early contact. For vaginal births, findings add to the evidence in support of early skin-to-skin contact for an extended period. It is suggested that all research in this area should consider the effects of early contact separately for women having vaginal and caesarean births. care providers should consider extending the period of early contact in routine care following vaginal birth and explore the way in which women having a caesarean birth might be better supported in benefitting from early contact with their infant.


How Mannheimia haemolytica defeats host defence through a kiss of death mechanism.
Mannheimia haemolytica induced pneumonias are only observed in goats, sheep and cattle. The bacterium produces several virulence factors,whose principal ones are lipopolysaccharide and leukotoxin. The latter is cytotoxic only for ruminant leukocytes, a phenomenon that is correlated with its ability to bind and interact with the ruminant beta2-integrin Lymphocyte Function-associated Antigen 1. This paper globally reviews all the information available on host-pathogen interactions underlying respiratory mannheimiosis (formerly pasteurellosis), from the stable and the Petri dish to the biochemical cascade of events triggered by the leukotoxin inside ruminant leukocytes. One conclusion can be made: the most widespread cattle respiratory disease with the most important impact on beef production worldwide, is probably due to a tiny ruminant-specific focal variation in the CD18- and/or CD11a-expressing genes.


How color, regularity, and good Gestalt determine backward masking.
The strength of visual backward masking depends on the stimulus onset asynchrony (SOA) between target and mask. Recently, it was shown that the conjoint spatial layout of target and mask is as crucial as SOA. Particularly, masking strength depends on whether target and mask group with each other. The same is true in crowding where the global spatial layout of the flankers and target-flanker grouping determine crowding strength. Here, we presented a vernier target followed by different flanker configurations at varying SOAs. Similar to crowding, masking of a red vernier target was strongly reduced for arrays of 10 green compared with 10 red flanking lines. Unlike crowding, single green lines flanking the red vernier showed strong masking. Irregularly arranged flanking lines yielded stronger masking than did regularly arranged lines, again similar to crowding. While cuboid flankers reduced crowding compared with single lines, this was not the case in masking. We propose that, first, masking is reduced when the flankers are part of a larger spatial structure. Second, spatial factors counteract color differences between the target and the flankers. Third, complex Gestalts, such as cuboids, seem to need longer processing times to show ungrouping effects as observed in crowding. Strong parallels between masking and crowding suggest similar underlying mechanism; however, temporal factors in masking additionally modulate performance, acting as an additional grouping cue.


An evolutionarily conserved mechanism of calcium-dependent neurotoxicity in a zebrafish model of fetal alcohol spectrum disorders.
Fetal alcohol spectrum disorders (FASD) are a leading cause of neurodevelopmental disability. Nonhuman animal models offer novel insights into its underlying mechanisms. Although the developing zebrafish has great promise for FASD research, a significant challenge to its wider adoption is the paucity of clear, mechanistic parallels between its ethanol (EtOH) responses and those of nonpiscine, established models. Inconsistencies in the published pharmacodynamics for EtOH-exposed zebrafish, alongside the use of comparatively high EtOH doses, challenge the interpretation of this model's clinical relevance. To address these limitations, we developed a binge, single-exposure model of EtOH exposure in the early zebrafish embryo. Brief (3-hour) EtOH exposure is sufficient to cause significant neural crest losses and craniofacial alterations, with peak vulnerability during neurogenesis and early somitogenesis. These losses are apoptotic, documented using TUNEL assay and secA5-YFP-reporter fish. Apoptosis is dose dependent with an EC50 = 56.2 ± 14.3 mM EtOHint , a clinically relevant value within the range producing apoptosis in chick and mouse neural crest. This apoptosis requires the calcium-dependent activation of CaMKII and recapitulates the well-described EtOH signaling mechanism in avian neural crest. Importantly, we resolve the existing confusion regarding zebrafish EtOH kinetics. We show that steady-state EtOH concentrations within both chorion-intact and dechorionated embryos are maintained at 35.7 ± 2.8% of EtOHext levels across the range from 50 to 300 mM EtOHext , a value consistent with several published reports. Equilibrium is rapid and complete within 5 minutes of EtOH addition. The calcium/CaMKII mechanism of EtOH's neurotoxicity is shared between an amniote (chick) and teleost fish, indicating that this mechanism is evolutionarily conserved. Our data suggest that EtOHext concentrations >2% (v/v) for chorion-intact embryos and 1.5% (v/v) for dechorionated embryos have limited clinical relevance. The strong parallels with established models endorse the zebrafish's relevance for mechanistic studies of EtOH's developmental neurotoxicity.


Intravenous Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Patients With History of Stroke Plus Diabetes Mellitus.
Background and Purpose- Acute ischemic stroke patients with history of prior ischemic stroke plus concomitant diabetes mellitus (DM) were excluded from the ECASS III trial (European Cooperative Acute Stroke Study) because of safety concerns. However, there are few data on use of intravenous tissue-type plasminogen activator and symptomatic intracerebral hemorrhage or outcomes in this population. Methods- Using data from the Get With The Guidelines-Stroke Registry between February 2009 and September 2017 (n=1619 hospitals), we examined characteristics and outcomes among patients with acute ischemic stroke treated with tissue-type plasminogen activator within the 3- to 4.5-hour window who had a history of stroke plus diabetes mellitus (HxS+DM) (n=2129) versus those without either history (n=16 690). Results- Compared with patients without either history, those with both prior stroke and DM treated with tissue-type plasminogen activator after an acute ischemic stroke had a higher prevalence of cardiovascular risk factors in addition to history of stroke, DM, and more severe stroke (National Institutes of Health Stroke Scale: median, 8 [interquartile range, 5-15] versus 7 [4-13]). The unadjusted rates of symptomatic intracerebral hemorrhage and in-hospital mortality were 4.3% (HxS+DM) versus 3.8% (without either history; P=0.31) and 6.2% versus 5.5% ( P=0.20), respectively. These differences were not statistically significant after risk adjustment (symptomatic intracerebral hemorrhage: adjusted odds ratio, 0.79 [95% CI, 0.51-1.21]; P=0.28; in-hospital mortality: odds ratio, 0.77 [95% CI, 0.52-1.14]; P=0.19). Unadjusted rate of functional independence (modified Rankin Scale score, 0-2) at discharge was lower in those with HxS+DM (30.9% HxS+DM versus 44.8% without either history; P≤0.0001), and this difference persisted after adjusting for baseline clinical factors (adjusted odds ratio, 0.76 [95% CI, 0.59-0.99]; P=0.04). Conclusions- Among patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator within the 3- to 4.5-hour window, HxS+DM was not associated with statistically significant increased symptomatic intracerebral hemorrhage or mortality risk.


Inflammatory phenotypes in patients with severe asthma are associated with distinct airway microbiology.
Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly understood. We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and β-diversity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less diverse (P = .022) and more dissimilar (P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these diversity measures (α-diversity: Spearman r = -0.374, P < .001; β-diversity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus, Gemella, and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection.


Refining value-at-risk estimates using a Bayesian Markov-switching GJR-GARCH copula-EVT model.
In this paper, we propose a model for forecasting Value-at-Risk (VaR) using a Bayesian Markov-switching GJR-GARCH(1,1) model with skewed Student's-t innovation, copula functions and extreme value theory. A Bayesian Markov-switching GJR-GARCH(1,1) model that identifies non-constant volatility over time and allows the GARCH parameters to vary over time following a Markov process, is combined with copula functions and EVT to formulate the Bayesian Markov-switching GJR-GARCH(1,1) copula-EVT VaR model, which is then used to forecast the level of risk on financial asset returns. We further propose a new method for threshold selection in EVT analysis, which we term the hybrid method. Empirical and back-testing results show that the proposed VaR models capture VaR reasonably well in periods of calm and in periods of crisis.


Broad-spectrum CC-chemokine blockade by gene transfer inhibits macrophage recruitment and atherosclerotic plaque formation in apolipoprotein E-knockout mice.
The CC-chemokines (CKs) recruit monocytes/macrophages to sites of inflammation; several different CC-CKs play a role in the pathogenesis of atherosclerosis. The vaccinia virus expresses a 35-kDa soluble protein (35K) that binds to and inactivates nearly all of the CC-CKs, providing a potentially useful therapeutic strategy for broad-spectrum CC-CK inhibition in atherosclerosis. A recombinant adenovirus encoding soluble 35K (Ad35K) was generated to investigate the effect of 35K gene transfer on atherosclerosis in Western diet-fed apolipoprotein E-knockout (ApoE KO) mice. ApoE KO mice received tail-vein injections of phosphate-buffered saline, Ad35K, or control adenovirus AdGFP encoding green fluorescence protein. Two weeks after Ad35K gene transfer, atherosclerotic lesion area was significantly reduced in aortic roots by 55% compared with PBS or AdGFP control mice (P<0.05). Furthermore, 35K gene transfer strikingly reduced the macrophage content in aortic root lesions by 85% (P<0.01) and reduced lipid deposition in descending aortas by more than half (P<0.05). By an in vitro chemotaxis assay, plasma and aortic homogenates from 35K gene transfer mice promoted significantly less CC-CK-induced cell migration than did PBS or AdGFP controls. These findings show that a single intravenous injection of a recombinant adenovirus encoding the broad-spectrum CC-CK inhibitor 35K can reduce atherosclerosis by inhibiting CC-CK-induced macrophage recruitment in atherosclerotic ApoE KO mice. These experiments suggest that CC-CKs play an important role in atherogenesis and are a rational target for therapeutic intervention.


A yeast mutant defective at an early stage in import of secretory protein precursors into the endoplasmic reticulum.
We have devised a genetic selection for mutant yeast cells that fail to translocate secretory protein precursors into the lumen of the endoplasmic reticulum (ER). Mutant cells are selected by a procedure that requires a signal peptide-containing cytoplasmic enzyme chimera to remain in contact with the cytosol. This approach has uncovered a new secretory mutant, sec61, that is thermosensitive for growth and that accumulates multiple secretory and vacuolar precursor proteins that have not acquired any detectable posttranslational modifications associated with translocation into the ER. Preproteins that accumulate at the sec61 block sediment with the particulate fraction, but are exposed to the cytosol as judged by sensitivity to proteinase K. Thus, the sec61 mutation defines a gene that is required for an early cytoplasmic or ER membrane-associated step in protein translocation.


The Philippines' antidrug campaign: Spatial and temporal patterns of killings linked to drugs.
As soon as President Rodrigo Duterte assumed office in 2016, the Philippine government launched a nationwide antidrug campaign based on enforcement-led anti-illegal drugs policies primarily implemented by the national police. This was followed by a spate of killings resulting from both acknowledged police operations and by unidentified assailants. This study assembles a victim-level dataset of drug-related killings covered by the media during the Philippine government's antidrug campaign, and presents a spatial and temporal analysis of the killings. The dataset covers information on 5021 people killed from May 10, 2016 to September 29, 2017. Data collected systematically through online search procedures and existing listings of media organizations detailing information about incidences of drug-related police operations and drug-related killings in 'vigilante-style' manner reveal patterns for who were being killed, where, and how. Over half of the killings were due to acknowledged police operations, and the rest were targeted in so-called 'vigilante-style' killings. The first three months after Mr. Duterte was sworn in were the deadliest months. Those who were killed were mostly low-level drug suspects. The analysis of temporal pattern reveals the scale of killings in the country, with rapid escalation starting in July 2016 and lasting throughout the rest of that year. Observable declines occurred during periods when the 'drug war' was suspended and operations were moved to a non-police enforcement unit and rose again when police were brought back into operations. The spatial analysis indicates a large concentration of deaths in the National Capital Region (40%) compared to the rest of the country with wide variations across cities and regions. Overall, the Philippine 'drug war' exhibits similarities with violent wars on drugs waged in other countries such as Thailand, with heavily police-led interventions leading to fatalities in the thousands over a span of under two years. Findings of this study point to important policy adjustments that need to be made, including the role that local governments play in drug policy implementation, the disproportionate negative impacts of enforcement-led policies against drugs on urban and poor areas, the targeting of low-level suspected drug dealers and users, and the importance of proper data monitoring and transparency by the government to inform policy adjustments in the face of high costs to human life. We also discuss the importance of independent monitoring systems when the government reports conflicting information.


Effects of combined alpha- and beta-receptor blockade on peripheral circulation in essential hypertension.
1. Six weeks' treatment with labetalol (600 mg/day) significantly reduced systolic and diastolic blood pressures in 24 patients with essential hypertension. There was a small but not significant decrease in heart rate. 2. After 6 weeks of therapy mean digital arterial blood flow at rest and during reactive hyperaemia had increased by 26%. 3. In nine essential hypertensive patients intravenous administration of 100 mg of labetalol caused prompt and striking reductions of systolic and diastolic blood pressures without significant changes in heart rate. There was a consistent and significant increase in peripheral blood flow by 32% 5 min after administration of the drug. 4. Antagonism of alpha-receptors in addition to beta-receptors might improve peripheral arterial blood flow while achieving antihypertensive control. Thus labetalol, owing to its favourable haemodynamic effects, may have advantages over conventional pure beta-receptor-blocking agents.


Comparison of repeatability and multiple trait threshold models for litter size in sheep using observed and simulated data in Bayesian analyses.
Bayesian analyses were used to estimate genetic parameters on 5580 records of litter size in the first four parities from 1758 Mule ewes. To examine the appropriateness of fitting repeatability (RM) or multiple trait threshold models (MTM) to litter size of different parities, both models were used to estimate genetic parameters on the observed data and were thereafter compared in a simulation study. Posterior means of the heritabilities of litter size in different parities using a MTM ranged from 0.12 to 0.18 and were higher than the heritability based on the RM (0.08). Posterior means of the genetic correlations between litter sizes of different parities were positive and ranged from 0.24 to 0.71. Data sets were simulated based on the same pedigree structure and genetic parameters of the Mule ewe population obtained from both models. The simulation showed that the relative loss in accuracy and increase in mean squared error (MSE) was substantially higher when using the RM, given that the parameters estimated from the observed data using the opposite model are the true parameters. In contrast, Bayesian information criterion (BIC) selected the RM as most appropriate model given the data because of substantial penalty for the higher number of parameters to be estimated in the MTM model. In conclusion, when the relative change in accuracy and MSE is of main interest for estimation of breeding values of litter size of different parities, the MTM is recommended for the given population. When reduction in risk of using the wrong model is the main aim, the BIC suggest that the RM is the most appropriate model.


Anticoagulation followed by elective carotid surgery in patients with repetitive transient ischemic attacks and high-grade carotid stenosis.
To evaluate the results of preoperative heparin therapy followed by carotid surgery for patients with repetitive transient ischemic attacks (TIAs) and high-grade carotid stenoses. A 4-year prospective study. Oregon Health Science University Hospital and Portland (Ore) Veterans Affairs Hospital. Twenty-nine consecutive patients with repetitive TIAs referable to 30 high-grade (> or = 70%) ipsilateral carotid stenoses were treated with short-term heparin anticoagulation, followed by cerebral angiography, routine preoperative evaluation, and subsequent carotid reconstruction. Heparin sodium anticoagulation was maintained for a mean of 5 days. Surgical management consisted of 24 standard endarterectomies, five bypasses to the internal carotid artery, and one external carotid endarterectomy. Primary outcome variables included perioperative hemorrhage, thrombocytopenia, stroke, and death. Secondary outcome variables included carotid occlusion and recurrent TIAs with heparin therapy. One symptomatic common carotid occlusion and one asymptomatic internal carotid occlusion occurred during preoperative heparin therapy. Thirteen patients had additional sporadic TIAs while receiving heparin. There were no preoperative cerebral infarcts, thrombocytopenia, or clinical bleeding associated with heparin therapy. There was one postoperative stroke and one death due to myocardial infarction. When necessary, heparin anticoagulation and delayed carotid reconstruction would appear to be an acceptable alternative to emergency carotid surgery in patients with high-grade carotid stenosis and acute repetitive TIAs.


Two-year follow-up of Sanfilippo Disease patients treated with a genistein-rich isoflavone extract: assessment of effects on cognitive functions and general status of patients.
Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by deficiencies in enzymes involved in degradation of glycosaminoglycans. MPS type III (Sanfilippo disease) is clinically characterized mainly by progressive and severe behavioral disturbances and cognitive dysfunction. Recent 1-year experimental treatment of 10 patients with a genistein (4', 5, 7-trihydroxyisoflavone)-rich extract resulted in improvement of tested parameters, including cognitive and behavioral functions. Eight pediatric patients with Sanfilippo disease were enrolled into the study. The modified version of the Brief Assessment Examination was used to assess cognitive functions. Moreover, 18 different parameters concerning changes in conditions of patients were assessed by their parents. During the first year of the treatment, an improvement of cognitive functions in 7 patients and stabilization in 1 patient were assessed, while after the third year (2-year follow-up) further improvement was observed in 2 patients, stabilization in 3 patients and some deterioration in 3 patients. Monitoring of general and behavioral symptoms revealed improvement in all patients after the first year of the treatment, further improvement in 5 patients, and deterioration in 3 patients during the next 2 years. We conclude that the treatment of Sanfilippo patients with a genistein-rich soy isoflavone extract (called gene expression-targeted isoflavone therapy [GET IT]) may be effective in either inhibition (in some patients) or slowing down (in other patients) of behavioral and cognitive problems over a longer period. An increased dose of genistein may improve the efficacy of the treatment.


A Case of Self-treatment Induced Recurrent Fixed Drug Eruptions Associated with the Use of Different Fixed Dose Combinations of Fluoroquinolone-Nitroimidazole.
A young male patient used fixed dose combinations of different fluoroquinolones and nitroimidazoles several times in the last few years for self-treating repeated episodes of diarrhea and loose motion. Each time, he experienced fixed drug eruptions that increased in number and severity on subsequent occasions. Suspecting association between the drug and the rashes, the patient each time discontinued the treatment prematurely, and preferred to switch to a similar formulation next time, but with different molecules of fluoroquinolone (ciprofloxacin or ofloxacin) and nitroimidazole (tinidazole or ornidazole). He could not however avoid the rash. This time the patient presented with multiple, round-to-oval, well-defined, hyperpigmented cutaneous patches of different dimensions, all over the body. He appeared to have run out of options and therefore consulted us seeking advice on how he should treat himself next time he suffered from diarrhea. Causality assessment by Naranjo's algorithm revealed a definite relationship between the cutaneous adverse reaction and the offending drug. He was counselled regarding medication in general and advised, in particular, to avoid the tendency to self-treat any future episode of diarrhea.


Examining the Family Support Role of Older Hispanics, African Americans, and Non-Hispanic Whites and Their Breast Cancer Screening Behaviors.
Disparities in breast cancer mortality rates among older Black and Hispanic women are due in part to low participation in cancer screening. Participation in cancer screening could be affected by an array of factors, including social support. Understanding the complex interplay between social support and breast cancer screening among older female adults, specifically among groups with higher mortality rates, is extremely important for timely and appropriate interventions to increase survival rates. Thus, utilizing the social network theory as the conceptual framework, this study aims to examine effects of social support on receiving a mammogram among a representative sample of older adults, specifically African American and Hispanic populations in the United States. Logistic regression models were conducted using the 2008 and 2012 Health and Retirement Study data. Findings from this study indicate that specific aspects of social support influence breast cancer screening participation among older Hispanic and non-Hispanic White women. However, this was not the case for the older Black women after adjusting for the sociodemographic factors. Given the role that family members play in the care of older adults, it is critical that social workers consider both the possible positive and negative interactions older women may have and how these interactions may affect their cancer screening behaviors. Findings can provide formative data to develop public health and social work interventions to increase positive social support and reduce negative social support by spouses and children to enhance breast cancer screening among older adults.


Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting.
Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors.Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient.Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478-90. ©2016 AACR.


A xenogeneic-free system generating functional human gut organoids from pluripotent stem cells.
Functional intestines are composed of cell types from all 3 primary germ layers and are generated through a highly orchestrated and serial developmental process. Directed differentiation of human pluripotent stem cells (hPSCs) has been shown to yield gut-specific cell types; however, these structures do not reproduce critical functional interactions between cell types of different germ layers. Here, we developed a simple protocol for the generation of mature functional intestinal organoids from hPSCs under xenogeneic-free conditions. The stem cell-derived gut organoids produced here were found to contain distinct types of intestinal cells, including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, that were derived from all 3 germ layers; moreover, they demonstrated intestinal functions, including peptide absorption, and showed innervated bowel movements in response to stimulation with histamine and anticholinergic drugs. Importantly, the gut organoids obtained using this xenogeneic-free system could be stably maintained in culture for prolonged periods and were successfully engrafted in vivo. Our xenogeneic-free approach for generating gut organoids from hPSCs provides a platform for studying human intestinal diseases and for pharmacological testing.


First-principles prediction of new photocatalyst materials with visible-light absorption and improved charge separation: surface modification of rutile TiO₂ with nanoclusters of MgO and Ga₂O₃.
Titanium dioxide is an important and widely studied photocatalytic material, but to achieve photocatalytic activity under visible-light absorption, it needs to have a narrower band gap and reduced charge carrier recombination. First-principles simulations are presented in this paper to show that heterostructures of rutil TiO₂ modified with nanoclusters of MgO and Ga₂O₃ will be new photocatalytically active materials in the UV (MgO-TiO₂) and visible (Ga₂O₃-TiO₂) regions of the solar spectrum. In particular, our investigations of a model of the excited state of the heterostructures demonstrate that upon light excitation electrons and holes can be separated onto the TiO₂ surface and the metal oxide nanocluster, which will reduce charge recombination and improve photocatalytic activity. For MgO-modified TiO₂, no significant band gap change is predicted, but for Ga₂O₃-modified TiO₂ we predict a band gap change of up to 0.6 eV, which is sufficient to induce visible light absorption. Comparisons with unmodified TiO₂ and other TiO₂-based photocatalyst structures are presented.


An immunofluorescent study of the ampicillin rash.
The aetiology of the ampicillin rash is uncertain although numerous theories have been proposed--mainly immunological. One such concerns the presence of anti-epithelial antibodies which have received conflicting reports in the literature. In this study, skin biopsies from three patients with a maculopapular ampicillin-rash were studied by immunofluorescence to investigate the presence of anti-epithelial antibodies. However immunofluorescence for IgG, IgM, IgA and C3 was completely negative so that we were unable to provide any support for this particular hypothesis.


Comparison of the risk of psychological and cognitive disorders between persistent and nonpersistent statin users.
Despite their cardiovascular benefits, statin use has been associated with a wide array of actual or perceived psychological and cognitive adverse events. The objective of this study was to compare baseline characteristics and the risk of developing psychological and cognitive disorders between persistent and nonpersistent statin users. We performed a retrospective cohort study (October 1, 2003, to March 1, 2010) of 13,626 statin users in a regional US military health-care system. The persistence of statin use was defined by cumulative pharmacy fill data. Outcomes were the occurrence of psychological diseases during follow-up using prespecified groups based on International Classification of Diseases, Ninth Revision, codes: (1) schizophrenia and psychosis, (2) major depression and bipolar disorders, (3) all psychological diseases, and (4) dementia and cognitive disorders. Statin users who were nonpersistent at 2 years were younger, less likely to be men, and had fewer co-morbidities than persistent users. They were also more likely to be diagnosed with schizophrenia or psychosis (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.20 to 2.10) and cognitive disorders (OR 1.56, 95% CI 1.19 to 2.03) during follow-up compared with persistent users. There was not an association between nonpersistence at 2 years and the development of depression and bipolar disorders (OR 0.99, 95% CI 0.85 to 1.15) or combined psychological diseases (OR 0.97, 95% CI 0.86 to 1.09). Cumulative persistence with statin therapy as a continuous measure was associated with less risk of all outcomes. In conclusion, persistent statin users did not demonstrate an increase in the diagnosis of psychological disorders compared with nonpersistent users. Nonpersistent statin use was associated with a greater likelihood of being diagnosed with psychotic or cognitive disorders.


Culture-independent evaluation of nonenveloped-virus infectivity reduced by free-chlorine disinfection.
The inability of molecular detection methods to distinguish disinfected virions from infectious ones has hampered the assessment of infectivity for enteric viruses caused by disinfection practices. In the present study, the reduction of infectivity of murine norovirus S7-PP3 and mengovirus vMC0, surrogates of human noroviruses and enteroviruses, respectively, caused by free-chlorine treatment was characterized culture independently by detecting carbonyl groups on viral capsid protein. The amount of carbonyls on viral capsid protein was evaluated by the proportion of biotinylated virions trapped by avidin-immobilized gel (percent adsorbed). This culture-independent approach demonstrated that the percent adsorbed was significantly correlated with the logarithm of the infectious titer of tested viruses. Taken together with the results of previous reports, the result obtained in this study indicates that the amount of carbonyls on viral capsid protein of four important families of waterborne pathogenic viruses, Astroviridae, Reoviridae, Caliciviridae, and Picornaviridae, is increased in proportion to the received oxidative stress of free chlorine. There was also a significant correlation between the percent adsorbed and the logarithm of the ratio of genome copy number to PFU, which enables estimation of the infectious titer of a subject virus by measuring values of the total genome copy number and the percent adsorbed. The proposed method is applicable when the validation of a 4-log reduction of viruses, a requirement in U.S. EPA guidelines for virus removal from water, is needed along with clear evidence of the oxidation of virus particles with chlorine-based disinfectants.


Performance analysis of blind timing phase estimators for digital coherent receivers.
The performances of various blind timing phase estimators (TPE) for digital coherent receiver are analyzed. The equivalence among four TPE algorithms is analytically presented, showing that two TPE algorithms applying squaring pre-filters are in fact identical. Three TPE algorithms applicable to Nyquist signals are proposed based on the equivalence analysis. In addition, the impact of receiver bandwidths, spectrum weighting bandwidths and signal timing phases on TPE performance are investigated. The definition of sampling diversity and the analysis of sampling diversity gain for four pulse shapes are presented. The effect of sampling diversity is observed and verified via both simulations and experiments.


What patient factors predict physicians' decision not to treat latent tuberculosis infection in tuberculosis contacts?
The study aimed to determine factors that are associated with physicians' decision to offer treatment for latent tuberculosis infection (LTBI) in contacts of patients with tuberculosis. We performed a nested case-control study in a cohort of contacts of patients with pulmonary tuberculosis who had a tuberculin skin test (TST) ≥ 10 mm. Cases were those who were offered treatment for LTBI. Controls were randomly selected from those who were not offered treatment for LTBI by the reviewing physician. Odds ratios were estimated by multivariate logistic regression. There were 195 cases and 279 controls. The following factors were significantly (positively or negatively) associated with being offered LTBI treatment in the multivariate analysis: female gender (OR 2.9; 95% CI 1.6-5.5), TST conversion (OR 3.9; 2.0-7.9), TST > 20 mm (OR 4.1; 1.8-9.1, for TST of 21-30 mm and OR 7.9; 2.6-23.8, for TST >30 mm), sputum smear positive index case (OR 12.7; 4.5-36.1), being overseas-born and immigration more than 2 years ago (OR 0.1; 0.06-0.3), being a health care worker (OR 0.2; 0.1-0.6), being a non-household contact of the TB index case (OR 0.3; 0.2-0.6) and age >35 years (OR 0.2; 0.1-0.5 for age 35 to 54.9 years and OR 0.04; 0.01-0.2 for age ≥55 years). Previous BCG vaccine and chest x-ray findings were not significantly associated with physicians' decision to offer treatment for LTBI. Most factors that influenced physicians' decisions on treatment for LTBI were based on evidence of an association with risk of developing TB or risk of having an adverse reaction to treatment for LTBI. However, the decreased likelihood of offering treatment for LTBI to people born overseas, men and health care workers, was apparently not based on any evidence of risk. Efforts should be made to ensure that these groups are given access to treatment for LTBI.


Knee adduction moment relates to medial femoral and tibial cartilage morphology in clinical knee osteoarthritis.
The objective was to determine the extent to which the external peak knee adduction moment (KAM) and cumulative knee adductor load explained variation in medial cartilage morphology of the tibia and femur in knee osteoarthritis (OA). Sixty-two adults with clinical knee OA participated (61.5 ± 6.2 years). To determine KAM, inverse dynamics was applied to motion and force data of walking. Cumulative knee adductor load reflected KAM impulse and loading frequency. Loading frequency was captured from an accelerometer. Magnetic resonance imaging scans were acquired with a coronal fat-saturated sequence using a 1.0 T peripheral scanner. Scans were segmented for medial cartilage volume, surface area of the bone-cartilage interface, and thickness. Forward linear regressions assessed the relationship of loading variables with cartilage morphology unadjusted, then adjusted for covariates. In the medial tibia, age and peak KAM explained 20.5% of variance in mean cartilage thickness (p<0.001). Peak KAM alone explained 12.3% of the 5th percentile of medial tibial cartilage thickness (i.e., thinnest cartilage region) (p=0.003). In the medial femur, sex, BMI, age, and peak KAM explained 44% of variance in mean cartilage thickness, with peak KAM contributing 7.9% (p<0.001). 20.7% of variance in the 5th percentile of medial femoral cartilage thickness was explained by BMI and peak KAM (p=0.001). In these models, older age, female sex, greater BMI, and greater peak KAM related with thinner cartilage. Models of KAM impulse produced similar results. In knee OA, KAM peak and impulse, but not loading frequency, were associated with cartilage thickness of the medial tibia and femur.


[The American Malaria Program (1941-1946) and its sequelae for biomedical research after World War II].
After Pearl Harbor 1941 and the Japanese conquest of the Netherlands East Indies the U.S. were confronted with both a war in the malaria-ridden South Pacific and the loss of the sources of quinine. This situation gave birth to a Cooperative Wartime Program with the participation of national scientific and medical organizations, universities, hospitals, industries, and the Armed Forces. It worked as a flexible system of coordinated and cooperative units subsidized by the U.S. Government. In the course of WWII malaria casualties dropped beyond expectation due to an improved usage of quinacrine (Atebrine) which was based on new knowledge in pharmacokinetics. Furthermore, basic knowledge in malariology was improved, and a mass-screening resulted in new antimalarial drugs, such as chloroquine. The experiences of the Malaria Program were used by one of its chief architects, James A. Shannon, to transform the National Institutes of Health (NIH) into the model medical research institution whose budget for extramural programs also allowed for the nationwide post-war boom of medical research.


Examination of hypotheses for the Permo-Triassic boundary extinction by carbon cycle modeling.
The biological extinction that occurred at the Permian-Triassic boundary represents the most extensive loss of species of any known event of the past 550 million years. There have been a wide variety of explanations offered for this extinction. In the present paper, a number of the more popular recent hypotheses are evaluated in terms of predictions that they make, or that they imply, concerning the global carbon cycle. For this purpose, a mass balance model is used that calculates atmospheric CO2 and oceanic delta13C as a function of time. Hypotheses considered include: (i) the release of massive amounts of CO2 from the ocean to the atmosphere resulting in mass poisoning; (ii) the release of large amounts of CO2 from volcanic degassing; (iii) the release of methane stored in methane hydrates; (iv) the decomposition and oxidation of dead organisms to CO2 after sudden mass mortality; and (v) the long-term reorganization of the global carbon cycle. The modeling indicates that measured short-term changes in delta13C at the boundary are best explained by methane release with mass mortality and volcanic degassing contributing in secondary roles. None of the processes result in excessively high levels of atmospheric CO2 if they occurred on time scales of more than about 1,000 years. The idea of poisoning by high levels of atmospheric CO2 depends on the absence of subthermocline calcium carbonate deposition during the latest Permian. The most far-reaching effect was found to be reorganization of the carbon cycle with major sedimentary burial of organic matter shifting from the land to the sea, resulting in less burial overall, decreased atmospheric O2, and higher atmospheric CO2 for the entire Triassic Period.


Scalable Fabrication of Photochemically Reduced Graphene-Based Monolithic Micro-Supercapacitors with Superior Energy and Power Densities.
Micro-supercapacitors (MSCs) hold great promise as highly competitive miniaturized power sources satisfying the increased demand of smart integrated electronics. However, single-step scalable fabrication of MSCs with both high energy and power densities is still challenging. Here we demonstrate the scalable fabrication of graphene-based monolithic MSCs with diverse planar geometries and capable of superior integration by photochemical reduction of graphene oxide/TiO2 nanoparticle hybrid films. The resulting MSCs exhibit high volumetric capacitance of 233.0 F cm-3, exceptional flexibility, and remarkable capacity of modular serial and parallel integration in aqueous gel electrolyte. Furthermore, by precisely engineering the interface of electrode with electrolyte, these monolithic MSCs can operate well in a hydrophobic electrolyte of ionic liquid (3.0 V) at a high scan rate of 200 V s-1, two orders of magnitude higher than those of conventional supercapacitors. More notably, the MSCs show landmark volumetric power density of 312 W cm-3 and energy density of 7.7 mWh cm-3, both of which are among the highest values attained for carbon-based MSCs. Therefore, such monolithic MSC devices based on photochemically reduced, compact graphene films possess enormous potential for numerous miniaturized, flexible electronic applications.


Factors Associated with Binge Drinking during the Transition into Adulthood: Exploring Associations Within Two Distinct Young Adult Age Ranges.
Binge drinking among young adults aged 18-21 years has declined over the past decade, but binge drinking rates among people 22-25 years old have remained largely the same. This steady trend in later years represents a departure from the traditional course of maturing out of risky alcohol use, perhaps because young adults are delaying the transition into adulthood. This paper explores the relationship between binge drinking and aspects of the transition into adulthood that could inform interventions targeting these two distinct groups of young adults. We use survey data on 1,081 young adults aged 18-25 living in 10 Indiana counties. Our dataset is unique because it contains both college-attending and non-college attending young adults. We ran weighted logistic regressions to determine the association between college enrollment, living situation, roles common in adulthood, and stressors common during the transition to adulthood (e.g., relationships, economic conditions, job stability) and binge drinking. Our data indicate that different factors are associated with binge drinking based on whether subjects who are in the earlier (18-21 years old) or later (22-25 years old) years of young adulthood. For example, within the 18-21 years old group, college enrollment is associated with higher rates of binge drinking, but it is not associated with increased binge drinking in the older age group. The type of stress related to binge drinking also varies by age group. Our results emphasize the need to disaggregate "young adulthood" into two separate periods when defining target populations and settings for binge drinking interventions.


Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.
Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.


Vertically oriented femoral neck fractures: mechanical analysis of four fixation techniques.
Femoral neck fractures in young individuals are typically high angled shear fractures. These injuries are difficult to stabilize due to a strong varus displacement force across the hip with weight bearing. The purpose of this study was to compare the biomechanical stability of four differing fixation techniques for stabilizing vertical shear femoral neck fractures. Vertical femoral neck fracture stability was assessed using 4 surgical constructs in 32 cadaveric femurs: 7.3 mm cannulated screws placed in a triangular configuration (group 1), a 135-degree dynamic hip screw (group 2), a 95-degree dynamic condylar screw (group 3), and a locking proximal femoral plate (group 4). The 4 groups were matched for mean bone density and each specimen was tested under incremental loading, cyclical loading, and loading to failure. The modes of fixation failure were recorded for each specimen and the mean group stiffness, failure loads, and failure energies were calculated. All 8 specimens failed during incremental loading in group 1. Five of 8 constructs failed with incremental loading, and 3 failed with cyclical testing in group 2. The combined 16 specimens in groups 3 and 4 survived both incremental and cyclical loading. The differences in stiffness, failure loads, and failure energies between the 4 groups were statistically significant (P < 0.001). The strongest construct was the locking plate and the weakest construct was the 7.3-mm cannulated screw configuration. The cannulated screw configuration group failed as the screws backed out of the femoral head and by varus collapse of the osteotomy; the fixed angled devices all failed at the bone-implant interface. The strongest construct for stabilizing a vertical shear femoral neck fracture is the proximal femoral locking plate, followed in descending order by the dynamic condylar screw, the dynamic hip screw, and the 3 cannulated screw configuration.


Reactive desorption electrospray ionization linear ion trap mass spectrometry of latest-generation counterfeit antimalarials via noncovalent complex formation.
Desorption electrospray ionization mass spectrometry (DESI MS) is rapidly becoming accepted as a powerful surface characterization tool for a wide variety of samples in the open air. Besides its well-established high-throughput capabilities, a unique feature of DESI is that chemical reactions between the charged spray microdroplets and surface molecules can be exploited to enhance ionization. Here, we present a rapid screening assay for artesunate antimalarials based on reactive DESI. Artesunate is a vital therapy for Plasmodium falciparum malaria, but artesunate tablets have been counterfeited on a very large scale in SE Asia, and more recently in Africa. For this reason, faster and more sensitive screening tests are urgently needed. The proposed DESI assay is based on the formation of stable noncovalent complexes between linear alkylamines dissolved in the DESI spray solution and artesunate molecules exposed on the tablet surface. We found that, depending on amine type and concentration, a sensitivity gain of up to 170x can be obtained, in comparison to reagent-less DESI. Hexylamine (Hex), dodecylamine (DDA), and octadecylamine (ODA) produced proton-bound noncovalent complexes with gas-phase stabilities, increasing in the order [M + Hex + H]+ < [M + DDA + H]+ < [M + ODA + H]+. Tandem MS experiments revealed that complex formation occurred by hydrogen bonding between the amine nitrogen and the ether-like moieties within the artesunate lactone ring. After the reactive DESI assay was fully characterized, it was applied to a set of recently collected suspicious artesunate tablets purchased in shops and pharmacies in SE Asia. Not only did we find that these samples were counterfeits, but we also detected the presence of several wrong active ingredients. Of particular concern was the positive detection of artesunate traces in the surface of one of the samples, which we quantified with standard chromatographic techniques.


Can Contrast-Enhanced Ultrasound Increase or Predict the Success Rate of Testicular Sperm Aspiration in Patients With Azoospermia?
OBJECTIVE. The objective of our study was to determine whether contrast-enhanced ultrasound (CEUS) perfusion measurements obtained before testicular sperm aspiration (TESA) can improve or predict sperm retrieval (SR) outcomes of TESA in patients with azoospermia. SUBJECTS AND METHODS. Between May 2017 and January 2018, 70 patients with azoospermia (mean age, 29 years; age range, 22-41 years) underwent testes CEUS within 10 days before TESA. Major perfusion areas were visually chosen, and their ranges were recorded. The other areas were defined as minor perfusion. CEUS quantitative features were acquired for both the main perfusion area and whole testis. Testis tissue biopsies were taken for both major and minor perfusion areas by cognitive fusion, and SR outcomes were compared. Associations between testicular volume, quantitative CEUS features, and SR outcomes were analyzed. RESULTS. Twenty-four men were found to have obstructive azoospermia (OA), and the remaining 46 had nonobstructive azoospermia (NOA). All patients with OA had spermatozoa in biopsy. Only one patient with NOA had spermatozoa in the major perfusion area but not the minor perfusion area; the other patients with NOA had the same SR outcomes in both major and minor perfusion areas. In patients with NOA, both wash-in and washout CEUS features were correlated with the success of SR in TESA. CONCLUSION. CEUS-guided TESA with cognitive fusion cannot yield improved SR outcomes of TESA in patients with NOA, possibly because of imprecise correlation between biopsy sites and main perfusion area analyzed by CEUS; however, quantitative CEUS features can be useful predictors of the success of SR.


The principles of medical ethics and medical research.
In this paper I discuss the application of the principles of medical ethics and of medical research to the case of children and others whose consent to treatment and to research is problematic. Public health depends substantially on the possibility of ongoing research into all conditions which affect the health of the people. Constraints on this research are therefore a public health issue. Moreover and more importantly the possibility of predictive testing and indeed of screening for health-relevant conditions is an important public health tool, and limitations on the use of this tool are of great significance to public health medicine. Having considered the particular problems created by research and predictive testing on children for late-onset conditions I go on to discuss research on those whose consent is problematic more generally. I conclude with radical recommendations for the reform of The Declaration of Helsinki and of the International Ethics Guidelines for Biomedical Research Involving Human Subjects, prepared by the Council for International Organizations of Medical Sciences (CIOMS).