Reinforcing Small Wins and Frustrating Near-Misses: Further Investigation Into Scratch Card Gambling.
Scratch card games are incredibly popular in the Canadian marketplace. However, only recently have researchers started to systematically analyze their structural characteristics and how these in turn affect the gambler. We present two studies designed to further understand the underlying physiological and psychological effects that scratch cards have on gamblers. We had gamblers (63 in Experiment 1, 68 in Experiment 2) play custom made scratch cards involving a small win, a regular loss and a near-miss-where they uncovered two out of the three symbols needed to win the top prize. Our predictions were that despite near-misses and losses being objectively equivalent (the gambler wins nothing) gamblers' reactions to these outcomes would differ dramatically. During game play, skin conductance levels and heart rate were recorded, as well as how long gamblers paused between each game. Gamblers' subjective reactions to the different outcomes were then assessed. In both studies, near-misses triggered higher levels of physiological arousal (skin conductance levels and heart rates) than losses. Gamblers paused significantly longer following small wins than other outcomes, and reported high arousal, positive affect and urge to gamble-a constellation of results consistent with their rewarding properties. Importantly near-miss outcomes were rated as highly arousing, negative in emotional tone, and the most frustrating of all three outcome types examined. In Experiment 2, when we measured subjective urge to gamble immediately after each outcome, urge to gamble was significantly higher following near-misses than regular losses. Thus, despite not rewarding the gambler with any monetary gain, these outcomes nevertheless triggered higher arousal and larger urges to gamble than regular losses, a finding that may explain in part, the allure of scratch cards as a gambling activity.


Kinematics of reaching movements in a 2-D virtual environment in adults with and without stroke.
Virtual reality environments are increasingly being used for upper limb rehabilitation in poststroke patients. Our goal was to determine if arm reaching movements made in a 2-D video-capture virtual reality environment are similar to those made in a comparable physical environment. We compared arm and trunk kinematics for reaches made with the right, dominant arm to three targets (14 trials per target) in both environments by 16 adults with right poststroke hemiparesis and by eight healthy age-matched controls. Movement kinematics were recorded with a three-camera optoelectronic system at 100 samples/s. Reaching movements made by both control and stroke subjects were affected by viewing the targets in the video-capture 2-D virtual environment. Movements were slower, shorter, less straight, less accurate and involved smaller ranges of shoulder and elbow joint excursions for target reaches in the virtual environment compared to the physical environment in all subjects. Thus, there was a decrease in the overall movement quality for movements made in the 2-D virtual environment. This suggests that 2-D video-capture virtual reality environments should be used with caution when the goal of the rehabilitation program is to improve the quality of movement patterns of the upper limb.


Research as an impetus to improved treatment.
The relation between psychiatric research and treatment remains a controversial subject. A psychopharmacological research program implemented in a state psychiatric hospital resulted in a significantly improved treatment milieu. Diagnosis, length of stay, amounts and types of medications administered, legal commitment status, seclusion and restraint time, etc, were targeted as variables with which to measure change in the milieu. The variables showed significant changes, ie, improvement during the research period, as compared with a control period. The research discipline created a more rigorous approach to diagnosis and treatment. This, in turn, created an improved treatment milieu in which the research protocols could be implemented more meaningfully.


The potential of whole genome NGS for infectious disease diagnosis.
Non-targeted identification of microbes is now possible directly in biological samples, based on whole-genome-NGS (WG-NGS) techniques that allow deep sequencing of nucleic acids, data mining and sorting out of sequences of pathogens without any a priori hypothesis. WG-NGS was first only used as a research tool due to its cost, complexity and lack of standardization. Recent improvements in sample preparation and bioinformatics pipelines and decrease in cost now allow actionable diagnostics in patients. The potency and limits of WG-NGS and possible future indications are discussed here. WG-NGS will likely soon become a standard procedure in microbiological diagnosis.


Comparative performance of supertree algorithms in large data sets using the soapberry family (Sapindaceae) as a case study.
For the last 2 decades, supertree reconstruction has been an active field of research and has seen the development of a large number of major algorithms. Because of the growing popularity of the supertree methods, it has become necessary to evaluate the performance of these algorithms to determine which are the best options (especially with regard to the supermatrix approach that is widely used). In this study, seven of the most commonly used supertree methods are investigated by using a large empirical data set (in terms of number of taxa and molecular markers) from the worldwide flowering plant family Sapindaceae. Supertree methods were evaluated using several criteria: similarity of the supertrees with the input trees, similarity between the supertrees and the total evidence tree, level of resolution of the supertree and computational time required by the algorithm. Additional analyses were also conducted on a reduced data set to test if the performance levels were affected by the heuristic searches rather than the algorithms themselves. Based on our results, two main groups of supertree methods were identified: on one hand, the matrix representation with parsimony (MRP), MinFlip, and MinCut methods performed well according to our criteria, whereas the average consensus, split fit, and most similar supertree methods showed a poorer performance or at least did not behave the same way as the total evidence tree. Results for the super distance matrix, that is, the most recent approach tested here, were promising with at least one derived method performing as well as MRP, MinFlip, and MinCut. The output of each method was only slightly improved when applied to the reduced data set, suggesting a correct behavior of the heuristic searches and a relatively low sensitivity of the algorithms to data set sizes and missing data. Results also showed that the MRP analyses could reach a high level of quality even when using a simple heuristic search strategy, with the exception of MRP with Purvis coding scheme and reversible parsimony. The future of supertrees lies in the implementation of a standardized heuristic search for all methods and the increase in computing power to handle large data sets. The latter would prove to be particularly useful for promising approaches such as the maximum quartet fit method that yet requires substantial computing power.


Productivity limits and potentials of the principles of conservation agriculture.
One of the primary challenges of our time is to feed a growing and more demanding world population with reduced external inputs and minimal environmental impacts, all under more variable and extreme climate conditions in the future. Conservation agriculture represents a set of three crop management principles that has received strong international support to help address this challenge, with recent conservation agriculture efforts focusing on smallholder farming systems in sub-Saharan Africa and South Asia. However, conservation agriculture is highly debated, with respect to both its effects on crop yields and its applicability in different farming contexts. Here we conduct a global meta-analysis using 5,463 paired yield observations from 610 studies to compare no-till, the original and central concept of conservation agriculture, with conventional tillage practices across 48 crops and 63 countries. Overall, our results show that no-till reduces yields, yet this response is variable and under certain conditions no-till can produce equivalent or greater yields than conventional tillage. Importantly, when no-till is combined with the other two conservation agriculture principles of residue retention and crop rotation, its negative impacts are minimized. Moreover, no-till in combination with the other two principles significantly increases rainfed crop productivity in dry climates, suggesting that it may become an important climate-change adaptation strategy for ever-drier regions of the world. However, any expansion of conservation agriculture should be done with caution in these areas, as implementation of the other two principles is often challenging in resource-poor and vulnerable smallholder farming systems, thereby increasing the likelihood of yield losses rather than gains. Although farming systems are multifunctional, and environmental and socio-economic factors need to be considered, our analysis indicates that the potential contribution of no-till to the sustainable intensification of agriculture is more limited than often assumed.


Genomic-Led Discovery of a Novel Glycopeptide Antibiotic by Nonomuraea coxensis DSM 45129.
Glycopeptide antibiotics (GPAs) are last defense line drugs against multidrug-resistant Gram-positive pathogens. Natural GPAs teicoplanin and vancomycin, as well as semisynthetic oritavancin, telavancin, and dalbavancin, are currently approved for clinical use. Although these antibiotics remain efficient, emergence of novel GPA-resistant pathogens is a question of time. Therefore, it is important to investigate the natural variety of GPAs coming from so-called "rare" actinobacteria. Herein we describe a novel GPA producer-Nonomuraea coxensis DSM 45129. Its de novo sequenced and completely assembled genome harbors a biosynthetic gene cluster (BGC) similar to the dbv BGC of A40926, the natural precursor to dalbavancin. The strain produces a novel GPA, which we propose is an A40926 analogue lacking the carboxyl group on the N-acylglucosamine moiety. This structural difference correlates with the absence of dbv29-coding for an enzyme responsible for the oxidation of the N-acylglucosamine moiety. Introduction of dbv29 into N. coxensis led to A40926 production in this strain. Finally, we successfully applied dbv3 and dbv4 heterologous transcriptional regulators to trigger and improve A50926 production in N. coxensis, making them prospective tools for screening other Nonomuraea spp. for GPA production. Our work highlights genus Nonomuraea as a still untapped source of novel GPAs.


Genetic instability of clathrin-deficient strains of Saccharomyces cerevisiae.
Saccharomyces cerevisiae strains carrying a mutation in the clathrin heavy chain gene (CHC1) are genetically unstable and give rise to heterogeneous populations of cells. Manifestations of the instability include increases in genome copy number as well as compensatory genetic changes that allow better growing clathrin-deficient cells to take over the population. Increases in genome copy number appear to result from changes in ploidy as well as alterations in normal nuclear number. Genetic background influences the frequency at which cells with increased genome content are observed in different Chc- strains. We cannot distinguish whether genetic background affects the rate at which aberrant nuclear division events occur or a growth advantage of cells with increased nuclear and/or genome content. However, survival of chc1-delta cells does not require an increase in genome copy number. The clathrin heavy chain gene was mapped 1-2 cM distal to KEX1 on the left arm of chromosome VII by making use of integrated 2 mu plasmid sequences to destabilize distal chromosome segments and allow ordering of the genes.


Nutrient addition increases grassland sensitivity to droughts.
Grasslands worldwide are expected to experience an increase in extreme events such as drought, along with simultaneous increases in mineral nutrient inputs as a result of human industrial activities. These changes are likely to interact because elevated nutrient inputs may alter plant diversity and increase the sensitivity to droughts. Dividing a system's sensitivity to drought into resistance to change during the drought and rate of recovery after the drought generates insights into different dimensions of the system's resilience in the face of drought. Here, we examine the effects of experimental nutrient fertilization and the resulting diversity loss on the resistance to and recovery from severe regional droughts. We do this at 13 North American sites spanning gradients of aridity, five annual grasslands in California, and eight perennial grasslands in the Great Plains. We measured rate of resistance as the change in annual aboveground biomass (ANPP) per unit change in growing season precipitation as conditions declined from normal to drought. We measured recovery as the change in ANPP during the postdrought period and the return to normal precipitation. Resistance and recovery did not vary across the 400-mm range of mean growing season precipitation spanned by our sites in the Great Plains. However, chronic nutrient fertilization in the Great Plains reduced drought resistance and increased drought recovery. In the California annual grasslands, arid sites had a greater recovery postdrought than mesic sites, and nutrient addition had no consistent effects on resistance or recovery. Across all study sites, we found that predrought species richness in natural grasslands was not consistently associated with rates of resistance to or recovery from the drought, in contrast to earlier findings from experimentally assembled grassland communities. Taken together, these results suggest that human-induced eutrophication may destabilize grassland primary production, but the effects of this may vary across regions and flora, especially between perennial and annual-dominated grasslands.


IgG-neutralized influenza virus undergoes primary, but not secondary uncoating in vivo.
Even when neutralized by saturating amounts of monoclonal IgG directed against the haemagglutinin, influenza virus attaches to cells with kinetics similar to those of infectious virus. It then enters those cells and is uncoated; its RNA becomes localized within the nucleus and its lipid envelope and associated proteins remain in the cytoplasm. In this report we show that despite the apparent normality of these early stages of virus-cell interaction, neutralized virus underwent no detectable primary transcription. In contrast, there was only a slight inhibition of transcription by neutralized virus in vitro which was insufficient to account for the loss in infectivity, despite using mRNA to measure the production of capped oligonucleotides or to prime the elongation step. To test whether the absence of primary transcription in vivo resulted from non-accessibility of the genome rather than an effect on the transcriptase complex itself, we examined the susceptibility to RNase of virion RNA after inoculation of cells with neutralized virus. Data clearly show that, unlike RNA of infectious virus, RNA of neutralized virus did not become sensitive to RNase and we conclude that neutralization of influenza virus by IgG results in failure of virus to undergo a secondary uncoating process which is necessary for the activity of the virion transcriptase complex. Finally we show that by treatment of virions in vitro with detergent it is possible to produce a core structure which is stable and has some of the properties expected of a structure resulting from primary uncoating.


Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons.
Gamma-hydroxybutyrate (GHB) is used for the treatment of narcolepsy, but it is also a drug of abuse. The behavioral pharmacology of GHB is not well defined. The current study was conducted to characterize the behavioral effects of a range of GHB doses in baboons (N=4) and to evaluate whether a GABA-B receptor antagonist and a GHB receptor antagonist would block a behaviorally active dose of GHB. In the first experiment, GHB (32-420 mg/kg) or vehicle was administered via an intragastric catheter. Sixty min after dosing, subjects were presented with a fine-motor task and observed. Food pellets were available under a fixed-ratio schedule of reinforcement 20-h/day. In the second experiment, the GABA-B antagonist CGP36742 (10-56 mg/kg), the putative GHB antagonist NCS-382 (0.1-10 mg/kg), or vehicle were administered alone and then in combination with GHB (320 mg/kg). GHB dose-dependently decreased the number of food pellets earned. Performance in the motor task was also impaired and accompanied by signs of sedation and gastrointestinal discomfort. Pretreatment with CGP36742 antagonized GHB-induced suppression of food-maintained behavior and performance on the fine-motor task. Signs of abdominal discomfort, ataxia, and muscle relaxation produced by GHB were also reduced by pretreatment with CGP36742. In contrast, pretreatment with NCS-382 sometimes restored performance in the fine-motor task and increased food-maintained behavior, but the effect was variable across doses and baboons. Some doses of NCS-382 appeared to exacerbate ataxia and gastrointestinal discomfort produced by GHB in some subjects. These data indicate that while GABA-B receptors play a significant role in mediating the behavioral effects of GHB in baboon, the role of GHB receptors is less clear.


The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo-controlled clinical trials.
Skin dryness and an accelerated fragmentation of the collagen network in the dermis are hallmarks of skin aging. Nutrition is a key factor influencing skin health and consequently its appearance. A wide range of dietary supplements is offered to improve skin health. Collagen peptides are used as a bioactive ingredient in nutricosmetic products and have been shown in preclinical studies to improve skin barrier function, to induce the synthesis of collagen and hyaluronic acid, and to promote fibroblast growth and migration. Our aim was to investigate the effect of oral supplementation with specific collagen peptides on skin hydration and the dermal collagen network in a clinical setting. Two placebo-controlled clinical trials were run to assess the effect of a daily oral supplementation with collagen peptides on skin hydration by corneometry, on collagen density by high-resolution ultrasound and on collagen fragmentation by reflectance confocal microscopy. Human skin explants were used to study extracellular matrix components in the presence of collagen peptides ex vivo. Oral collagen peptide supplementation significantly increased skin hydration after 8 weeks of intake. The collagen density in the dermis significantly increased and the fragmentation of the dermal collagen network significantly decreased already after 4 weeks of supplementation. Both effects persisted after 12 weeks. Ex vivo experiments demonstrated that collagen peptides induce collagen as well as glycosaminoglycan production, offering a mechanistic explanation for the observed clinical effects. The oral supplementation with collagen peptides is efficacious to improve hallmarks of skin aging.


Structure of the Fanconi anaemia monoubiquitin ligase complex.
The Fanconi anaemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks, and responds to replication stress1,2. Genetic inactivation of this pathway by mutation of genes encoding FA complementation group (FANC) proteins impairs development, prevents blood production and promotes cancer1,3. The key molecular step in the FA pathway is the monoubiquitination of a pseudosymmetric heterodimer of FANCD2-FANCI4,5 by the FA core complex-a megadalton multiprotein E3 ubiquitin ligase6,7. Monoubiquitinated FANCD2 then recruits additional protein factors to remove the DNA crosslink or to stabilize the stalled replication fork. A molecular structure of the FA core complex would explain how it acts to maintain genome stability. Here we reconstituted an active, recombinant FA core complex, and used cryo-electron microscopy and mass spectrometry to determine its structure. The FA core complex comprises two central dimers of the FANCB and FA-associated protein of 100 kDa (FAAP100) subunits, flanked by two copies of the RING finger subunit, FANCL. These two heterotrimers act as a scaffold to assemble the remaining five subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a non-functional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The two FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. This structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases. The cryo-electron microscopy structure of the FA core complex provides a foundation for a detailed understanding of its E3 ubiquitin ligase activity and DNA interstrand crosslink repair.


Paucity of genes on the Drosophila X chromosome showing male-biased expression.
Sex chromosomes are primary determinants of sexual dimorphism in many organisms. These chromosomes are thought to arise via the divergence of an ancestral autosome pair and are almost certainly influenced by differing selection in males and females. Exploring how sex chromosomes differ from autosomes is highly amenable to genomic analysis. We examined global gene expression in Drosophila melanogaster and report a dramatic underrepresentation of X-chromosome genes showing high relative expression in males. Using comparative genomics, we find that these same X-chromosome genes are exceptionally poorly conserved in the mosquito Anopheles gambiae. These data indicate that the X chromosome is a disfavored location for genes selectively expressed in males.


Referrals to chiropractors and osteopaths: a survey of general practitioners in rural and regional New South Wales, Australia.
Chiropractic and osteopathy form a significant part of the healthcare setting in rural and regional Australia, with national registration of practitioners, public subsidies for services and high utilisation by the Australian public. However, despite their significant role in rural and regional Australia, there has been little exploration of the interface between chiropractic and osteopathy and conventional primary health care practitioners in this area. The study aim was to examine the referral practices and factors that underlie referral to chiropractors and osteopaths by rural and regional Australian general practitioners (GPs), by drawing on a sample of GPs in rural and regional New South Wales. A 27-item questionnaire was sent to all 1486 GPs currently practising in rural and regional Divisions of General Practice in New South Wales, Australia. A total of 585 GPs responded to the questionnaire, with 49 questionnaires returned as "no longer at this address" (response rate: 40.7%). The majority of GPs (64.1%) referred to a chiropractor or osteopath at least a few times per year while 21.7% stated that they would not refer to a chiropractor or osteopath under any circumstances. Patients asking the GP about CAM (OR=3.59; CI: 1.12, 11.55), GP's use of CAM practitioners as a major source of information (OR=4.39; 95% CI: 2.04, 9.41), lack of other treatment options (OR=2.41; 95% CI: 1.18, 5.12), access to a wide variety of medical specialists (OR=12.5; 95% CI: 2.4, 50.0), GP's belief in the efficacy of chiropractic and osteopathy services (OR=3.39; 95% CI: 2.19, 5.25) and experiencing positive results from patients using these services previously (OR=1.67; CI: 1.02, 2.75) were all independently predictive of increased referral to chiropractic and osteopathy services amongst the rural GPs. There is a significant interface between chiropractic and osteopathy and Australian rural and regional general practice in New South Wales. Although there is generally high support for chiropractic and osteopathy among Australian GPs, this was not absolute and the heterogeneity of responses suggests that there remain tensions between the professions. The significant interface between chiropractic and osteopathy may be due in part to the inclusion of these professions in the publicly subsidised national healthcare delivery scheme. The significant impact of chiropractic and osteopathy and general practice in rural and regional Australian healthcare delivery should serve as an impetus for increased research into chiropractic and osteopathy practice, policy and regulation in these areas.


HIV/AIDS: AIDS Drug Assistance Programs in the era of routine HIV testing.
AIDS [Acquired Immunodeficiency Syndrome] Drug Assistance Programs, operating within the larger Ryan White Program, are state-based, discretionary programs that provide a drug "safety net" for low-income and uninsured individuals infected with human immunodeficiency virus (HIV). Although the AIDS Drug Assistance Programs and the primary care system that provides care for patients with HIV infection are already financially stressed, the Centers for Disease Control and Prevention recently issued guidelines recommending universal HIV testing to help identify the estimated 300,000 individuals in the United States who are unaware that they are infected with HIV. As the number of people living with HIV/AIDS who are coinfected with hepatitis C virus has grown and the cost and complexity of care have increased, the sustainability of the current HIV care system requires a reevaluation in light of the new testing guidelines. We examine the current state of the AIDS Drug Assistance Programs, discuss the implications of the Centers for Disease Control and Prevention guidelines for the already overstretched Ryan White Program, and consider a federally supported national program to ensure high-quality, efficient HIV care for low-income HIV-infected Americans.


Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis.
Although multiple sclerosis (MS) has traditionally been considered to be an inflammatory disease, recent evidence has brought neurodegeneration into the spotlight, suggesting that accumulated damage and loss of axons is critical to disease progression and the associated irreversible disability. Proposed mechanisms of axonal degeneration in MS posit cytosolic and subsequent mitochondrial Ca(2+) overload, accumulation of pathologic reactive oxygen species (ROS), and mitochondrial dysfunction leading to cell death. In this context, the role of the p66 isoform of ShcA protein (p66) may be significant. The ShcA isoform is uniquely targeted to the mitochondrial intermembrane space in response to elevated oxidative stress, and serves as a redox enzyme amplifying ROS generation in a positive feedforward loop that eventually mediates cell death by activation of the mitochondrial permeability transition pore. Consequently, we tested the hypothesis that genetic inactivation of p66 would reduce axonal injury in a murine model of MS, experimental autoimmune encephalomyelitis (EAE). As predicted, the p66-knockout (p66-KO) mice developed typical signs of EAE, but had less severe clinical impairment and paralysis than wild-type (WT) mice. Histologic examination of spinal cords and optic nerves showed significant axonal protection in the p66-KO tissue, despite similar levels of inflammation. Furthermore, cultured p66-KO neurons treated with agents implicated in MS neurodegenerative pathways showed greater viability than WT neurons. These results confirm the critical role of ROS-mediated mitochondrial dysfunction in the axonal loss that accompanies EAE, and identify p66 as a new pharmacologic target for MS neuroprotective therapeutics.


Meta-analysis of genome-wide SNP- and pathway-based associations for facets of neuroticism.
Neuroticism is a heritable personality trait that is comprised of distinct sub-factors, or facets. Sub-factors of neuroticism are linked to different emotional states or psychiatric symptoms and studying the genetic variants associated with these facets may help reveal the biological mechanisms underlying psychiatric disorders. In the present study, a meta-analysis of genome-wide association studies for six facets of neuroticism was performed in 5584 participants from three cohorts. Additionally, a Gene Set Enrichment Analysis was conducted to find biological pathways associated with each facet. Six neuroticism facets (N1: anxiety, N2: angry hostility, N3: depression, N4: self-consciousness, N5: impulsivity and N6: vulnerability) were assessed using the Korean version of the Revised NEO Personality Inventory. In the single-nucleotide polymorphism-based analysis, results showed genome-wide significance for N2 within the MIR548H3 gene (rs1360001, P=4.14 × 10-9). Notable genes with suggestive associations (P<1.0 × 10-6) were ITPR1 for N1, WNT7A for N2, FGF10 and FHIT for N3, DDR1 for N4, VGLL4 for N5 and PTPRD for N6. In the pathway-based analysis, the axon guidance pathway was identified to be associated with multiple facets of neuroticism (N2, N4 and N6). The focal adhesion and extracellular matrix receptor interaction pathways were significantly associated with N2 and N3. Our findings revealed genetic influences and biological pathways that are associated with facets of neuroticism.


Telemedicine Consultation as an Indicator of Local Telemedicine Champions' Contributions, Health Care System Needs or Both: Tales from Two Continents.
Background: Telemedicine systems increase access to care, particularly in remote and developing countries. Nationwide telemedicine programs in Cabo Verde and Albania have been built by the International Virtual e-Hospital Foundation (IVeH) and based on the effective Initiate-Build-Operate-Transfer (IBOT) strategy. The aim of this study was to compare the clinical results between the two programs and examine the relationship between the clinical teleconsultations as an indicator of health care system needs and the contribution of local telemedicine champions. Methods: Data were prospectively collected between 2014 and 2018 from Albania and Cabo Verde. Telemedicine champions were defined as programs, physicians, or hospitals who have contributed at least 100 telemedicine consultations during the study periods. Chi-squared test was utilized to analyze the data. Results: There were 2,442 teleconsultations in Cabo Verde and 2,724 teleconsultations in Albania during the study periods. Using the 100-consultation benchmark as the indicator of telemedicine champion, we identified radiology (n = 1,061), neurotrauma (n = 742), and general neurology or stroke (n = 489) as champion clinical disciplines in Albania. With the same method of 100 consultations, we identified eight champion clinical disciplines in Cabo Verde, including neurology (n = 720), cardiology (n = 313), orthopedics (n = 190), surgery (143), endocrinology (141), otolaryngology (n = 139), urology (n = 139), and dermatology (126). The patient transfer/nontransfer ratio was 0.5 in Cabo Verde and 0.3 in Albania (p < 0.001). Three hospitals in Albania and eight community hospitals/health care centers in Cabo Verde requested the majority of teleconsultations. Two main hospitals in Cabo Verde and Albania responded to the consultations. Conclusion: The successful implementation of a telemedicine program depends on many factors. However, physician champions, who eventually create clinical discipline champions, and represent the hospital champions, are the backbone of the sustainability and progress of any telemedicine program. The number of consultations reflects the lack of local specialty expertise to provide health care service and thus can be used for future planning and investment.


Adaptation of the "ten questions" to screen for autism and other neurodevelopmental disorders in Uganda.
Neurodevelopmental disorders are recognized to be relatively common in developing countries but little data exist for planning effective prevention and intervention strategies. In particular, data on autism spectrum disorders are lacking. For application in Uganda, we developed a 23-question screener (23Q) that includes the Ten Questions screener and additional questions on autism spectrum disorder behaviors. We then conducted household screening of 1169 children, 2-9 years of age, followed by clinical assessment of children who screened positive and a sample of those who screened negative to evaluate the validity of the screener. We found that 320 children (27% of the total) screened positive and 68 children received a clinical diagnosis of one or more moderate to severe neurodevelopmental disorders (autism spectrum disorder; cerebral palsy; epilepsy; cognitive, speech and language, hearing, or vision impairment), including 8 children with autism spectrum disorders. Prevalence and validity of the screener were evaluated under different statistical assumptions. Sensitivity of the 23Q ranged from 0.55 to 0.80 and prevalence for ≥1 neurodevelopmental disorders from 7.7/100 children to 12.8/100 children depending on which assumptions were used. The combination of screening positive on both autism spectrum disorders and Ten Questions items was modestly successful in identifying a subgroup of children at especially high risk of autism spectrum disorders. We recommend that autism spectrum disorders and related behavioral disorders be included in studies of neurodevelopmental disorders in low-resource settings to obtain essential data for planning local and global public health responses.


The making of a physician.
Medicine is a science, and healing, an art. The right mix of a scientist and an artist is essential in a good physician. Clinical detachment is the balance between the scientist and the human. Good physicians are born; however, it is possible to cultivate the qualities. Gaining the patient's confidence is an art; a sense of humor can greatly help. Give a child respect and he becomes your friend. Death is inevitable, but a physician can help make it less agonizing. A good physician is a philosopher, aware of the beauty of life, of his limitations and conscious of the power that controls us.


Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2.
KCC2, a neuronal-specific K-Cl cotransporter, plays a major role in maintaining intracellular Cl(-) concentration in neurons below its electrochemical equilibrium potential, thus favoring robust GABA hyperpolarizing or inhibitory responses. The pharmacology of the K-Cl cotransporter is dominated by loop diuretics such as furosemide and bumetanide, molecules used in clinical medicine because they inhibit the loop of Henle Na-K-2Cl cotransporter with much higher affinity. To identify molecules that affect KCC2 activity, we developed a fluorescence-based assay suitable for high-throughput screening (HTS) and used the assay to screen a library of 234,000 small molecules. We identified a large number of molecules that either decrease or increase the activity of the cotransporter. Here, we report the characterization of a small number of inhibitors, some of which inhibit KCC2 activity in the submicomolar range without substantially affecting NKCC1 activity. Using medicinal chemistry, we synthesized a number of variants, tested their effect on KCC2 function, and provide an analysis of structure/activity relationships. We also used one of the compounds to demonstrate competitive inhibition in regard to external [K(+)] versus noncompetitive inhibition in respect to external [Cl(-)].


Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of collies from the northwestern United States.
To determine the frequency of the MDR1 gene mutation (polymorphism) associated with ivermectin sensitivity in a sample population of Collies in Washington and Idaho. 40 healthy client-owned Collies. A blood sample (8 ml) was collected from each dog and used for RNA extraction. Reverse transcriptase was used to generate MDR1 cDNA. Polymerase chain reaction (PCR) primers were designed to amplify a 1,061-base pair region of the MDR1 gene. The PCR products were sequenced to determine whether the Collies had 0, 1, or 2 mutant alleles. Pedigrees of some dogs were available for analysis to determine relatedness of affected dogs. Of the 40 Collies, 9 (22%) were homozygous for the normal allele (normal), 17 (42%) were heterozygous (carrier), and 14 (35%) were homozygous for the mutant allele (affected). Pedigree analysis revealed that some, but not all, affected dogs were related to each other within the 4 most recent generations. A high percentage of a sample population of Collies in Washington and Idaho are affected or carriers of the mutant MDR1 allele associated with ivermectin sensitivity. A similar frequency of this mutation may be detected in dogs from other geographic areas. Pharmacologic treatment with ivermectin, loperamide, vincristine, and other drugs that are substrates of P-glycoprotein, the MDR1 gene product, may result in neurologic toxicosis in a high percentage of Collies.


Utility of surgeon-performed ultrasound assessment of the lateral neck for metastatic papillary thyroid cancer.
Ultrasound is the recommended staging modality for papillary thyroid cancer. Surgeons proficient in US assessment of the neck and experienced in the management of papillary thyroid cancer (PTC) appear uniquely qualified to assess the lateral cervical lymph nodes for metastatic disease. Of 310 patients treated for PTC between 2000 and 2008, 109 underwent surgeon-performed ultrasound (SUS) of the lateral neck preoperatively. Fine needle aspiration was performed on suspicious lateral lymph nodes. SUS findings were compared with FNA cytology and results of postoperative imaging studies. The sensitivity and negative predictive value of SUS were 88% and 97%, respectively. Four patients were found to have missed metastatic disease within 6 months. No patient underwent a nontherapeutic neck dissection. SUS combined with US-guided FNA of suspicious lymph nodes can accurately stage PTC to reliably direct surgical management.


Revisiting nonclassical HLA II functions in antigen presentation: Peptide editing and its modulation.
The nonclassical major histocompatibility complex of class II molecules (ncMHCII) HLA-DM (DM) and HLA-DO (DO) feature essential functions for the selection of the peptides that are displayed by classical MHCII proteins (MHCII) for CD4+ Th cell surveillance. Thus, although the binding groove of classical MHCII dictates the main features of the peptides displayed, ncMHCII function defines the preferential loading of peptides from specific cellular compartments and the extent to which they are presented. DM acts as a chaperone for classical MHCII molecules facilitating peptide exchange and thereby favoring the binding of peptide-MHCII complexes of high kinetic stability mostly in late endosomal compartments. DO on the other hand binds to DM blocking its peptide-editing function in B cells and thymic epithelial cells, limiting DM activity in these cellular subsets. DM and DO distinct expression patterns therefore define specific antigen presentation profiles that select unique peptide pools for each set of antigen presenting cell. We have come a long way understanding the mechanistic underpinnings of such distinct editing profiles and start to grasp the implications for ncMHCII biological function. DM acts as filter for the selection of immunodominant, pathogen-derived epitopes while DO blocks DM activity under certain physiological conditions to promote tolerance to self. Interestingly, recent findings have shown that the unexplored and neglected ncMHCII genetic diversity modulates retroviral infection in mouse, and affects human ncMHCII function. This review aims at highlighting the importance of ncMHCII function for CD4+ Th cell responses while integrating and evaluating what could be the impact of distinct editing profiles because of natural genetic variations.


A late Middle Pleistocene Denisovan mandible from the Tibetan Plateau.
Denisovans are members of a hominin group who are currently only known directly from fragmentary fossils, the genomes of which have been studied from a single site, Denisova Cave1-3 in Siberia. They are also known indirectly from their genetic legacy through gene flow into several low-altitude East Asian populations4,5 and high-altitude modern Tibetans6. The lack of morphologically informative Denisovan fossils hinders our ability to connect geographically and temporally dispersed fossil hominins from Asia and to understand in a coherent manner their relation to recent Asian populations. This includes understanding the genetic adaptation of humans to the high-altitude Tibetan Plateau7,8, which was inherited from the Denisovans. Here we report a Denisovan mandible, identified by ancient protein analysis9,10, found on the Tibetan Plateau in Baishiya Karst Cave, Xiahe, Gansu, China. We determine the mandible to be at least 160 thousand years old through U-series dating of an adhering carbonate matrix. The Xiahe specimen provides direct evidence of the Denisovans outside the Altai Mountains and its analysis unique insights into Denisovan mandibular and dental morphology. Our results indicate that archaic hominins occupied the Tibetan Plateau in the Middle Pleistocene epoch and successfully adapted to high-altitude hypoxic environments long before the regional arrival of modern Homo sapiens.


Laminin-511: a multi-functional adhesion protein regulating cell migration, tumor invasion and metastasis.
Laminins are major constituents of basement membranes. At least 16 isoforms have now been described, each with distinct spatio-temporal expression patterns and functions. The laminin-511 heterotrimer (α5β1γ1) is one of the more recent isoforms to be identified and a potent adhesive and pro-migratory substrate for a variety of normal and tumor cell lines in vitro. As our understanding of its precise function in normal tissues and in pathologies is rapidly unraveling, current evidence suggests an important regulatory role in cancer. This review describes published data on laminin-511 expression in several malignancies and experimental evidence from both in vitro and in vivo studies supporting its functional role during tumor progression. A particular emphasis is put on more recent studies from our laboratory and that of others indicating that laminin-511 contributes to tumor dissemination and metastasis in advanced breast carcinomas and other tumor types. Collectively, the experimental evidence suggests that high expression of laminin-511 has prognostic significance and that targeting tumor-laminin-511 interactions may have therapeutic potential in advanced cancer patients.


Crossroads of estrogen receptor and NF-kappaB signaling.
Cellular homeostasis in higher organisms is maintained by balancing cell growth, differentiation, and death. Two important systems that transmit extracellular signals into the machinery of the cell nucleus are the signaling pathways that activate nuclear factor kappaB (NF-kappaB) and estrogen receptor (ER). These two transcription factors induce expression of genes that control cell fates, including proliferation and cell death (apoptosis). However, ER has anti-inflammatory effects, whereas activated NF-kappaB initiates and maintains cellular inflammatory responses. Recent investigations elucidated a nonclassical and nongenomic effect of ER: inhibition of NF-kappaB activation and the inflammatory response. In breast cancer, antiestrogen therapy might cause reactivation of NF-kappaB, potentially rerouting a proliferative signal to breast cancer cells and contributing to hormone resistance. Thus, ER ligands that selectively block NF-kappaB activation could provide specific potential therapy for hormone-resistant ER-positive breast cancers.


Reality-Assisted Evolution of Soft Robots through Large-Scale Physical Experimentation: A Review.
We introduce the framework of reality-assisted evolution to summarize a growing trend towards combining model-based and model-free approaches to improve the design of physically embodied soft robots. In silico, data-driven models build, adapt, and improve representations of the target system using real-world experimental data. By simulating huge numbers of virtual robots using these data-driven models, optimization algorithms can illuminate multiple design candidates for transference to the real world. In reality, large-scale physical experimentation facilitates the fabrication, testing, and analysis of multiple candidate designs. Automated assembly and reconfigurable modular systems enable significantly higher numbers of real-world design evaluations than previously possible. Large volumes of ground-truth data gathered via physical experimentation can be returned to the virtual environment to improve data-driven models and guide optimization. Grounding the design process in physical experimentation ensures that the complexity of virtual robot designs does not outpace the model limitations or available fabrication technologies. We outline key developments in the design of physically embodied soft robots in the framework of reality-assisted evolution.


Neutrophil activation monitored by flow cytometry: stimulation by phorbol diester is an all-or-none event.
The population dynamics of single-cell stimulation was analyzed by monitoring autofluorescence by flow cytometry. Stimulation of the respiratory burst in human neutrophils by 12-O-tetradecanoyl phorbol-13-acetate (TPA) caused a decline in highly fluorescent cells (characteristic of resting neutrophils) and a corresponding increase in the number of weakly fluorescent cells (characteristic of activated neutrophils). Increasing concentrations of TPA caused increasing numbers of cells to shift from the highly fluorescent population to the weakly fluorescent population without the appearance of intermediate populations. Thus the neutrophil respiratory burst, a component of neutrophil cytotoxic response, is triggered in an all-or none fashion.


Preparation of an attenuated dengue 4 (341750 Carib) virus vaccine. I. Pre-clinical studies.
Dengue 4 (DEN-4) virus strain 341750 Carib was modified by serial passage in primary canine kidney (PCK) cell cultures. By the 15th PCK passage, this virus was less infectious for monkeys and resulted in a significantly reduced viremia as compared to the parent DEN-4 virus. The 30th PCK passage of DEN-4 341750 Carib was non-infectious for monkeys. A vaccine prepared at the 20th PCK passage in DBS-FRhL-2 cells stimulated the production of both neutralizing and hemagglutination inhibition antibodies in monkeys; these animals were also protected against challenge with the homologous strain as well as a heterologous strain of DEN-4. An ID50 titration in monkeys resulted in a titer of greater than 10(4) plaque-forming units (PFU) for the vaccine virus and 0.5 PFU for the parent virus. Reduced monkey infectivity of this magnitude has been correlated with human attenuation in previous dengue vaccine candidates. The DEN-4 strain 341750 Carib PCK-20/FRhL-4 vaccine has been characterized and sufficiently tested to be considered for safety and immunogenicity trials in humans.


Random field-union intersection tests for EEG/MEG imaging.
Electrophysiological (EEG/MEG) imaging challenges statistics by providing two views of the same spatiotemporal data: topographic and tomographic. Until now, statistical tests for these two situations have developed separately. This work introduces statistical tests for assessing simultaneously the significance of spatiotemporal event-related potential/event-related field (ERP/ERF) components and that of their sources. The test for detecting a component at a given time instant is provided by a Hotelling's T(2) statistic. This statistic is constructed in such a manner to be invariant to any choice of reference and is based upon a generalized version of the average reference transform of the data. As a consequence, the proposed test is a generalization of the well-known Global Field Power statistic. Consideration of tests at all time instants leads to a multiple comparison problem addressed by the use of Random Field Theory (RFT). The Union-Intersection (UI) principle is the basis for testing hypotheses about the topographic and tomographic distributions of such ERP/ERF components. The performance of the method is illustrated with actual EEG recordings obtained from a visual experiment of pattern reversal stimuli.


Strategies addressing barriers to clinical trial enrollment of underrepresented populations: a systematic review.
Underrepresentation of racial and ethnic minorities in clinical trials remains a reality while they have disproportionately higher rates of health disparities. The purpose of this study was to identify successful community-engaged interventions that included health care providers as a key strategy in addressing barriers to clinical trial enrollment of underrepresented patients. A systematic review of the literature on interventions addressing enrollment barriers to clinical trials for racial and ethnic minorities was performed in Ovid MEDLINE, EBSCO Megafile, and EBSCO CINAHL. The systematic review identified 360 studies, and 20 were selected using the inclusion criteria. An iterative process extracted information from the eligible studies. The 20 selected studies were analyzed and then grouped by first author, nature of the clinical research initiative, priority populations, key strategies, and study outcomes. Nine of the studies addressed cancer clinical trials and 11 related to chronic medical conditions, including diabetes, hypertension management, and chronic kidney disease. The key strategies employed were categorized according to their presumed impact on barriers incurred at distinct steps in study recruitment: clinical trial awareness, opportunity to participate, and acceptance of enrollment. The strategies were further categorized by whether they would address barriers associated with minority perceptions of the research process and barriers related to how studies were designed and implemented. Multiple and flexible strategies targeting providers and participants at provider sites and within communities might be needed to enroll underrepresented populations into clinical trials.


Histologic and clinical evaluation for maxillary sinus augmentation using macroporous biphasic calcium phosphate in human.
This study evaluated both the clinical and histological aspects of bone formation in maxillary sinus augmentation using MBCP as the bone-grafting material. MBCP was used as a primary bone substitute for maxillary sinus augmentation. Fifty-two patients were selected after a medical and dental examination, and were divided into the following three groups: those augmented with MBCP only; MBCP combined with irradiated cancellous bone; and MBCP combined with intraoral autogenous bone. After a healing period (average 6.78 months after surgery), bone cores were harvested for a histological evaluation and the implant fixtures were installed. These bone cores were evaluated via light microscope and implants were followed up for at least six months after loading. Four to ten months after surgery, new vital bone surrounding the MBCP particles was observed in 18 bone biopsies. Two out of the 130 implants installed were explanted due to a failure of osseointegration before the prosthetic procedure. All the remaining implants were functioning for 6 to 27 months (average 12.96 months). The cumulative survival rate of the implants was 98.46%. These results show that MBCP can be used as a grafting material for sinus floor augmentation, whether combined with other bone graft materials or not, and lead to a predictable prognosis for dental implants in the posterior maxillary area where there is insufficient vertical height for fixture installation.


Static and dynamic properties of 1,1'-bi-2-naphthol and its conjugated acids and bases.
Several convergent techniques were used to characterize 1,1'-bi-2-naphthol (BINOL) and some of its properties. Its acidity in the gas-phase, from neutral species to monoanion, was measured by mass spectrometry. The conformation and structure of BINOL in the gas phase was determined by microwave rotational spectroscopy. NMR experiments in fluorosulfonic acid established that BINOL was monoprotonated on one of the hydroxyl oxygen atoms. The enantiomerization barriers reported in the literature for BINOL under neutral, basic, and acid conditions were analyzed with regard to the species involved. Finally, DFT calculations allowed all of these results to be gathered in a coherent picture of the BINOL structure.


Endocrine and behavioural factors affecting water balance in sheep subjected to isolation stress.
The effect of stress on drinking, water balance and endocrine profile was studied using ten castrated rams. Individual sheep were exposed to 30-h periods of total isolation (psychological stress) or physical separation from their social group (control). Plasma was analysed for haematocrit, osmolality, electrolyte levels and concentrations of cortisol and arginine vasopressin. Isolation stress significantly reduced water intake, increased haematocrit and plasma concentration of cortisol, but did not alter osmolality or vasopressin concentration. The physiological effects of this self-imposed water restriction contrast with those obtained by depriving the sheep of water for 24 h under conditions that were not stressful, i.e. by keeping them grouped together. These results suggest that cortisol may act to defend plasma volume in sheep exposed to acute stress. The results also indicate that vasopressin probably should not be considered to be a 'stress hormone' in the sheep.


Non-white noise in fMRI: does modelling have an impact?
The sources of non-white noise in Blood Oxygenation Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) are many. Familiar sources include low-frequency drift due to hardware imperfections, oscillatory noise due to respiration and cardiac pulsation and residual movement artefacts not accounted for by rigid body registration. These contributions give rise to temporal autocorrelation in the residuals of the fMRI signal and invalidate the statistical analysis as the errors are no longer independent. The low-frequency drift is often removed by high-pass filtering, and other effects are typically modelled as an autoregressive (AR) process. In this paper, we propose an alternative approach: Nuisance Variable Regression (NVR). By inclusion of confounding effects in a general linear model (GLM), we first confirm that the spatial distribution of the various fMRI noise sources is similar to what has already been described in the literature. Subsequently, we demonstrate, using diagnostic statistics, that removal of these contributions reduces first and higher order autocorrelation as well as non-normality in the residuals, thereby improving the validity of the drawn inferences. In addition, we also compare the performance of the NVR method to the whitening approach implemented in SPM2.


Learning disabilities: Developmental dyscalculia.
Developmental dyscalculia (DD) is a developmental learning disability that manifests as a persistent difficulty in comprehending even the most basic numeric and arithmetic concepts, despite normal intelligence and schooling opportunities. Given the predominant use of numbers in modern society, this condition can pose major challenges in the sufferer's everyday life, both in personal and professional development. Since, to date, we still lack a universally recognized and psychometrically driven definition of DD, its diagnosis has been applied to a wide variety of cognitive profiles. In this chapter, we review the behavioral and neural characterization of DD as well as the different neurocognitive and etiologic accounts of this neurodevelopmental disorder. We underline the multicomponential nature of this heterogeneous disability: different aspects of mathematical competence can be affected by both the suboptimal recruitment of general cognitive functions supporting mathematical cognition (such as attention, memory, and cognitive control) and specific deficits in mastering numeric concepts and operations. Accordingly, both intervention paradigms focused on core numeric abilities and more comprehensive protocols targeting multiple neurocognitive systems have provided evidence for effective positive outcomes.


Bone material properties in actively bone-forming trabeculae in postmenopausal women with osteoporosis after three years of treatment with once-yearly Zoledronic acid.
Zoledronic acid (ZOL), a third-generation aminobisphosphonate, showed pronounced antifracture efficacy in a phase III clinical trial [Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT)] when administered yearly (5-mg infusions of ZOL), producing significant reductions in morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively, over a 3-year period. The purpose of this study was to analyze the biopsies obtained during the HORIZON clinical trial (152 patients, 82 ZOL and 70 placebo) by means of Raman microspectroscopy (a vibrational spectroscopic technique capable of analyzing undecalcified bone tissue with a spatial resolution of approximately 0.6 µm) to determine the effect of ZOL therapy on bone material properties (in particular mineral/matrix ratio, lamellar organization, carbonate and proteoglycan (based on spectral identification of glycosaminoglycan) content, and mineral maturity/crystallinity) at similar tissue age (based on the presence of tetracycline double labels). The results indicated that while ZOL administration increased the mineral/matrix ratio compared with placebo, it also resulted in mineral crystallites with a quality profile (based on carbonate content and maturity/crystallinity characteristics) of younger (with respect to tissue age) bone. Since the comparisons between ZOL- and placebo-treated patients were performed at similar tissue age at actively forming bone surfaces, these results suggest that ZOL may be exerting an effect on bone matrix formation in addition to its well-established antiresorptive effect, thereby contributing to its antifracture efficacy.


The effect of dietary supplementation with blueberry, alpha-tocopherol or astaxanthin on oxidative stability of Arctic char (Salvelinus alpinus) semen.
The objective was to determine the oxidative stability of Arctic char (Salvelinus alpinus) semen following dietary supplementation with lowbush blueberry (Vaccinium angustifolium) product, alpha-tocopherol, alpha-tocopherol+blueberry product, or alpha-tocopherol+astaxanthin. Sperm lipid peroxidation was initiated by challenging with ferrous sulphate/ascorbic acid (Fe(++)/Asc) at level of 0.04/0.2 mmol/L. Addition of blueberry, alpha-tocopherol, or both to char diets inhibited semen lipid peroxidation by: (a) decreasing the rate of sperm lipid peroxidation, an effect which was more pronounced with alpha-tocopherol treatments; and (b) increasing the antioxidant potential of seminal plasma, based on the lipid peroxidation process of sperm and an in vitro chicken brain tissue model. Dietary supplementation with astaxanthin and alpha-tocopherol had the same effect as the supplementation with alpha-tocopherol alone on inhibiting the lipid peroxidation process of sperm and chicken brain. Catalase-like activity increased significantly in sperm of fish fed alpha-tocopherol, blueberry, or both. There was a negative correlation (r= -0.397, P < 0.05) between catalase-like activity in sperm cells and the rate of sperm lipid peroxidation. Seminal plasma alpha-tocopherol levels increased significantly in fish supplemented with alpha-tocopherol alone or in combination with blueberry or astaxanthin. There were negative correlations between seminal plasma alpha-tocopherol levels and lipid peroxidation rates of sperm cells (r= -0.625, P < 0.01) and brain tissue (r= -0.606, P < 0.01). In conclusion, dietary supplementation of blueberry product or alpha-tocopherol inhibited lipid peroxidation in Arctic char semen. Further experiments are needed to test the effect of dietary blueberry and antioxidants on Arctic char semen quality during liquid and cryopreserved storage.


The intention of future mammography screening among Korean women.
The purpose of this study was to understand factors that influence future mammography intention and to differentiate significant factors influencing future mammography intention between those who have past mammography experience and those who do not. A cross-sectional study design was used to analyze characteristics and factors that influence the intention to have a mammogram among middle-aged Korean women. A total of 310 women, aged 30 and older, participated in the study. The study results indicated that a combination of the Health Belief Model and the Theory of Reasoned Action was effective in predicting mammography intention of Korean women. It found that knowledge, perceived benefits, self-efficacy, and the subjective norm were significant factors affecting mammography intention in women who have past mammography experience. For women who have never had a mammogram, age, knowledge, perceived benefits, and self-efficacy provided a significant contribution to predicting mammography intention. Thirty-three to 43% of the variability in mammography intention can be explained by the combined influence of these independent variables. The findings from this study can be used to guide the design and implementation of tailored health education and promotion programs for Korean women according to their mammography experience, so as to increase mammography screening.


Comparative Evaluation of Bond Strength and Microleakage of Standard and Expired Composite at Resin-Dentin Interface: An in vitro Study.
Evaluation of bond strength and microleakage caused by polymerization shrinkage provides a screening mechanism and an indication of the potential for the clinical success of composite restorations. The aim of this study was to determine the effect on shear bond strength and microleakage of standard and expired composites. Selected specimens were etched using 37% phosphoric acid for 15 seconds and were randomly divided into four groups. Group I: Standard composite and bonding agent; group II: Expired composite and bonding agents; group III: Standard composite and expired bonding agent; and group IV: Expired composite and standard bonding agent. Specimens were further subdivided into two subgroups. In subgroup A, specimens were sheared with a universal testing machine, and the results were calculated in MPa; in subgroup B, specimens was sectioned longitudinally and analyzed for leakage (dye penetration) using a stereomicroscope. The results of the present study showed that acceptable values for bond strength and microleakage were obtained even if one of the components of the dental resin composite is expired. In Indian scenario, the expired composite material may provide some assistance in compromised clinical situations. It can be used as an interim restoration and compensate for the high material cost. Talreja N, Singla S, Shashikiran ND. Comparative Evaluation of Bond Strength and Microleakage of Standard and Expired Composite at Resin-Dentin Interface: An in vitro Study. Int J Clin Pediatr Dent 2017;10(1):1-4.


Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.


Renal transplantation in the UK and Republic of Ireland.
RENAL TRANSPLANT OUTCOME: Analysis of 5-year transplant survival in the UK showed a number of significant factors influencing outcome of adult cadaveric renal transplantation. Data from 5,963 first grafts and 1,078 regrafts carried out between 1990-1997 showed year of graft, recipient age and diabetes, donor age, kidney exchange between centres and HLA matching to influence 5-year outcome. The most important prognostic factor was donor age: the risk of transplant failure within 5 years for grafts using kidneys from donors aged 60 years and over was double that of grafts using donors aged 18-34 years. Unlike the effect of donor age, the influence of HLA matching would appear to be diminishing with time. In contrast to transplants in the 1980's, the difference in 5-year transplant survival between 000 mismatched and favourably matched (100, 010 or 110 mismatched) transplants is no longer significant. An analysis of posttransplant survival for first grafts in different epochs (0-3 months, 3 months to 3 years and beyond 3 years) showed that one factor affected short-term outcome (exchange of kidneys between centres), whereas others affected outcome throughout the epochs (most notably donor age, recipient age and recipient diabetes). RECIPIENT AND DONOR AGE MATCHING: The mean recipient age in the UK and Republic of Ireland increased by 5 years between 1981-1990 but has remained at approximately 45 years since then. The mean donor age increased by 7 years to 42.5 years (s.e. 0.5) between 1981-1991 and since then has increased at a slower rate to 43.4 years (s.e. 0.5) in 1998. The mean donor-recipient age difference for more than 15,000 transplants carried out between 1990-1998 has decreased, primarily due to increasing donor age over this time. However, the introduction of a new Kidney Allocation Scheme in the UK in July 1998, part of which is aimed at minimising age differences, has increased the likelihood that recipients aged over 60 years will be allocated grafts from donors closer to their own age than previously. The new UK Kidney Allocation Scheme also gave children increased access to well-matched adult organs leading to an increased mean age difference for this group between July-December 1998. DONOR AND RECIPIENT HLA MATCHING: Modifications to the Kidney Allocation Scheme introduced in January 1997 with the aim of increasing the number of well-matched transplants has led to a rise in 000 mismatched grafts from 5% to 7% and favourably matched (100/010/110 mismatches) from 29% to 36% between 1990-1992 and 1996-1998. Over this same time the proportion of 2 DR-mismatched grafts has decreased from 10% to 4%. The revised Kidney Allocation Scheme implemented in July 1998 gave a further increase in priority to 000 mismatches, increasing the proportion of these transplants to 12% for the last half of 1998, a level which has been maintained since then.


Visual Specializations in Five Sympatric Species of Stingrays from the Family Dasyatidae.
The eyes of five ray species (Taeniura lymma, Neotrygon kuhlii, Pastinachus atrus, Himantura uarnak and Urogymnus asperrimus) from the same taxonomic family (Dasyatidae) and the same geographic region (Ningaloo Reef, Western Australia) were studied to identify differences in retinal specializations that may reflect niche specialization. The topographic distributions of photoreceptors (rods and all cones) and ganglion cells were assessed and used to identify localized peaks in cell densities that indicate specializations for acute vision. These data were also used to calculate summation ratios of photoreceptors to ganglion cells in each species and estimate the anatomical spatial resolving power of the eye. Subtle differences in the distribution of retinal neurons appear to be related to the ecology of these closely related species of stingrays. The main specialization in the retinal cell density distribution is the dorsal streak that allows these animals to scan the substrate for potential prey. The blue-spotted fantail ray, T. lymma, showed the highest peak density of rods (86,700 rods mm(-2)) suggesting a specialization for scotopic vision. The highest peak density of cones (9,970 cones mm(-2)) was found in H. uarnak, and the highest peak density of ganglion cells (4,500 cells mm(-2)) was found in P. atrus. The proportion of rods to cones in the dorsal streak was higher in the two smaller species (12.5-14:1 in T. lymma and N. kuhlii) than the larger stingrays (6-8:1 in P. atrus, H. uarnak and U. asperrimus). Visual specializations in different sympatric species are subtle but may reflect specializations to specific ecological niches.


[Salvage surgery after unsuccessful radiotherapy of cancer of the larynx].
The problem of the surgical management of irradiation failures in laryngeal carcinoma is taken into consideration. A series of 60 consecutive laryngectomies performed at the E.N.T. Department of the Regional Hospital of Varese from 1982-1987 is presented. All patients had previously undergone curative radiotherapy for squamous cell carcinoma of the larynx with subsequent local recurrence. The postoperative course is examined in relation to the observed 11 cases of complications (18.3%) taking them into consideration individually. A statistical analysis is also presented for the incidence of complications in relation to the most significant parameters. No significant difference was found in regard to timer elapsed since termination of radiotherapy (more or less than 6 months), irradiation field extension (limited to the larynx or extended to the neck nodes), type of surgical salvage (including neck dissection or not) and pre-operative hemoglobin and blood proteins values. In those patients who had previously undergone irradiation, total laryngectomy is quite a safe procedure in terms of potential local-regional complications. The choice of primary radiotherapy should not be influenced by the fear of such complications arising if salvage surgery is required after local recurrence.


The release of phosphorus to porewater and surface water from river riparian sediments.
Sediments can be both a source and a sink of dissolved phosphorus (P) in surface water and shallow groundwater. Using laboratory mesocosms, we studied the influence of flooding with deionized water and simulated river water on P release to solution using sediment columns taken from a riparian wetland. The mesocosm incubation results showed that rather than retaining nutrients, sediments in the riparian zone may be a significant source of P. Concentrations of dissolved P in porewater reached more than 3 mg L(-1) and in surface water over 0.8 mg L(-1) within a month of sediment inundation. The reductive dissolution of P-bearing iron (Fe) oxides was the likely mechanism responsible for P release. Dissolved P to Fe molar ratios in anaerobic samples were approximately 0.45 when columns were flooded with water that simulated the chemistry of the adjacent river. This suggests there was insufficient Fe in the anaerobic samples to precipitate all P if the solutions were oxygenated or transported to an aerobic environment. If the anaerobic wetland solutions were delivered to oxygenated rivers and streams adjacent to the riparian zone, the equilibrium concentration of P in these systems could rise. The timing of P release was inversely related to the nitrate (NO3-) concentration in floodwater. This indicates that in riparian zones receiving low nitrate loads, or where NO3- loads are being progressively reduced, the risk of dissolved P release may increase. These findings present particular challenges for restoration and management in riparian areas.


A pilot study of a group mindfulness-based cognitive-behavioral intervention for smartphone addiction among university students.
Mindfulness-based intervention (MBI) has been applied in behavioral addiction studies in recent years. However, few empirical studies using MBI have been conducted for smartphone addiction, which is prevalent among Chinese university students. The aim of this study was to investigate the effectiveness of a group mindfulness-based cognitive-behavioral intervention (GMCI) on smartphone addiction in a sample of Chinese university students. Students with smartphone addiction were divided into a control group (n = 29) and an intervention group (n = 41). The students in the intervention group received an 8-week GMCI. Smartphone addiction was evaluated using scores from the Mobile Phone Internet Addiction Scale (MPIAS) and self-reported smartphone use time, which were measured at the baseline (1st week, T1), post-intervention (8th week, T2), the first follow-up (14th week, T3), and the second follow-up (20th week, T4). Twenty-seven students in each group completed the intervention and the follow-up. Smartphone use time and MPIAS scores significantly decreased from T1 to T3 in the intervention group. Compared with the control group, the intervention group had significantly less smartphone use time at T2, T3, and T4 and significantly lower MPIAS scores at T3. This pilot study demonstrated that the GMCI could significantly alleviate smartphone addiction among university students.


Coadaptive brain-machine interface via reinforcement learning.
This paper introduces and demonstrates a novel brain-machine interface (BMI) architecture based on the concepts of reinforcement learning (RL), coadaptation, and shaping. RL allows the BMI control algorithm to learn to complete tasks from interactions with the environment, rather than an explicit training signal. Coadaption enables continuous, synergistic adaptation between the BMI control algorithm and BMI user working in changing environments. Shaping is designed to reduce the learning curve for BMI users attempting to control a prosthetic. Here, we present the theory and in vivo experimental paradigm to illustrate how this BMI learns to complete a reaching task using a prosthetic arm in a 3-D workspace based on the user's neuronal activity. This semisupervised learning framework does not require user movements. We quantify BMI performance in closed-loop brain control over six to ten days for three rats as a function of increasing task difficulty. All three subjects coadapted with their BMI control algorithms to control the prosthetic significantly above chance at each level of difficulty.


The histone demethylase UTX enables RB-dependent cell fate control.
Trimethylation of histone H3 on Lys 27 (H3K27me3) is key for cell fate regulation. The H3K27me3 demethylase UTX functions in development and tumor suppression with undefined mechanisms. Here, genome-wide chromatin occupancy analysis of UTX and associated histone modifications reveals distinct classes of UTX target genes, including genes encoding Retinoblastoma (RB)-binding proteins. UTX removes H3K27me3 and maintains expression of several RB-binding proteins, enabling cell cycle arrest. Genetic interactions in mammalian cells and Caenorhabditis elegans show that UTX regulates cell fates via RB-dependent pathways. Thus, UTX defines an evolutionarily conserved mechanism to enable coordinate transcription of a RB network in cell fate control.


Assessment of brain activities in immersive environments.
The primary goal of this study was to establish an objective baseline for subjects who participated in a study in an immersed environment created for the virtual reality therapy (VRT) situation. Since the effects of VRT on the subjects treated for neurosis have traditionally been measured by subjective measurements, there is a need to include objective measures. This will improve and validate the effectiveness of VRT. Fifteen college students participated in this study. Specifically, the researchers measured the activity of the subjects' brainwaves in response to the VRT using EEG technology. The preliminary data indicated that, in most cases, subjects had a decline in brain wave activity between what is deemed a normal / baseline brain activity and the brainwave activity recorded when they were when they were connected to the virtual reality equipment and under influence of an immersive scene. In rare instances, there were some subjects that showed extreme increases in brain activities. In addition, the data indicated that, in most cases, subjects are more relaxed while under the immersive influence with respect to brain activities than those that are not.


Double-clad fiber with a tapered end for confocal endomicroscopy.
We present a double-clad fiber coupler (DCFC) for use in confocal endomicroscopy to reduce speckle contrast, increase signal collection while preserving optical sectioning. The DCFC is made by incorporating a double-clad tapered fiber (DCTF) to a fused-tapered DCFC for achromatic transmission (from 1265 nm to 1325 nm) of > 95% illumination light trough the single mode (SM) core and collection of > 40% diffuse light through inner cladding modes. Its potential for confocal endomicroscopy is demonstrated in a spectrally-encoded imaging setup which shows a 3 times reduction in speckle contrast as well as 5.5 × increase in signal collection compared to imaging with a SM fiber.


Investigating the human binocular visual system using multi-modal magnetic resonance imaging.
Having two forward-facing eyes with slightly different viewpoints enables animals, including humans, to discriminate fine differences in depth (disparities), which can facilitate interaction with the world. The binocular visual system starts in the primary visual cortex because that is where information from the eyes is integrated for the first time. Magnetic resonance imaging (MRI) is an ideal tool to non-invasively investigate this system since it can provide a range of detailed measures about structure, function, neurochemistry and connectivity of the human brain. Since binocular disparity is used for both action and object recognition, the binocular visual system is a valuable model system in neuroscience for understanding how basic sensory cues are transformed into behaviourally relevant signals. In this review, we consider how MRI has contributed to the understanding of binocular vision and depth perception in the human brain. Firstly, MRI provides the ability to image the entire brain simultaneously to compare the contribution of specific visual areas to depth perception. A large body of work using functional MRI has led to an understanding of the extensive networks of brain areas involved in depth perception, but also the fine-scale macro-organisation for binocular processing within individual visual areas. Secondly, MRI can uncover mechanistic information underlying binocular combination with the use of MR spectroscopy. This method can quantify neurotransmitters including GABA and glutamate within restricted regions of the brain, and evaluate the role of these inhibitory and excitatory neurochemicals in binocular vision. Thirdly, it is possible to measure the nature and microstructure of pathways underlying depth perception using diffusion MRI. Understanding these pathways provides insight into the importance of the connections between areas implicated in depth perception. Finally, MRI can help to understand changes in the visual system resulting from amblyopia, a neural condition where binocular vision does not develop correctly in childhood.


Evaluation of the radiopacity of esthetic root canal posts.
The radiopacity of esthetic root canal posts may impair the assessment of their fit to the root canal when using radiographic images. This study determined in vitro the radiographic density of esthetic root canal posts using digital images. Thirty-six roots of human maxillary canines were assigned to six groups (N=6 per group): Reforpost (RP); Aestheti-Plus (AP); Reforpost MIX (RPM); D.T. Light Post (LP); Reforpost Radiopaque (RPR); and White Post DC (WP). Standardized digital images of the posts were obtained in different conditions: outside the root canal, inside the canal before and after cementation using luting material, and with a tissue simulator. Analysis of variance was used to compare the radiopacity mean values among the posts outside the root canal and among the posts under the other conditions, and the "t" unpaired test to compare the radiopacity between the posts and the dentin, and between the posts and the root canal space. There was no statistically significant difference in radiopacity between RP and RPM, and LP and WP. AP posts showed radiopacity values significantly lower than those for dentin. No statistically significant difference was found between posts (RP and AP) and the root canal space. A statistically significant difference was observed between the luted and non-luted posts; additionally, luted posts with and without tissue simulator showed no significant differences. Most of the cement-luted posts analyzed in this study were distinguishable from the density of adjacent dentin surfaces, allowing radiographic confirmation of the fit of the post in the canal. The success of using esthetic root canal posts depends mainly on the fit of the post within the canal.[1] The radiopacity of a post allows for radiographic imaging to be used to determine the fit, an important factor in a clinical perspective.


Aplastic anemia treated by allogeneic bone marrow transplantation: a report on 49 new cases from Seattle.
Forty-nine patients with severe aplastic anemia, 33 due to unknown cause, 11 drug or chemical related, 2 associated with hepatitis, 1 with paroxysmal nocturnal hemoglobinuria, and 2 possibly associated with Fanconi syndrome did not show recovery after 0.5-96 (median 2) mo of conventional therapy. Twenty-two were infected and 21 were refractory to random platelet transfusions at the time of admission. All were given marrow grafts from HLA-identical siblings. Forty-five were conditioned for grafting by cyclophosphamide (CY), 50 mg/kg on each of 4 successive days, and four by 1000 rad total body irradiation. All were given intermittent methotrexate therapy within the first 100 days of grafting to modify graft-versus-host disease (GVHD). Three patients died from infection too early to evaluate (days 1-8). Forty-six had marrow engraftment. Of these, 20 are surviving with good peripheral blood counts between 186 and 999 days, and 18 have returned to normal activities. Chronic GCHD is a problem in five. Twelve patients died of infection following rejection of the marrow graft. Twelve patients died with bacterial or fungal infections or interstitial pneumonia and active GVHD or soon following resolution of GVHD. Two patients died with marrow engraftment and no GVHD, one with an interstitial, and the other with a bacterial pneumonia. Thirty-six patients who had received random donor blood transfusions were randomly assigned to receive either CY or procarbazine-antithymocyte globulin-CY as conditioning regimens to test whether the incidence of graft rejection could be decreased. There was no difference in the incidence of graft rejection between the two regimens. In 13 patients with rejection, second transplants were attempted either with the original marrow donor (9 patients) or another HLA-identical sibling (4 patients). Three of these transplants were not evaluable, seven were unsuccessful and three were successful with only one of the three surviving for more than 468 days. In conclusion, the long-term survival of 41% of the patients in the present study is similar to that achieved in our first 24 patients, and confirms the importance of marrow transplantation for the treatment of severe aplastic anemia. Marrow graft rejection, GVHD, and infections continue to be the major causes of failure.


Generation of squeezed light with a monolithic optical parametric oscillator: simultaneous achievement of phase matching and cavity resonance by temperature control.
We generate squeezed state of light at 860 nm with a monolithic optical parametric oscillator. The optical parametric oscillator consists of a periodically poled KTiOPO(4) crystal, both ends of which are spherically polished and mirror-coated. We achieve both phase matching and cavity resonance by controlling only the temperature of the crystal. We observe up to -8.0±0.2 dB of squeezing with the bandwidth of 142 MHz. Our technique makes it possible to drive many monolithic cavities simultaneously by a single laser. Hence our monolithic optical parametric oscillator is quite suitable to continuous-variable quantum information experiments where we need a large number of highly squeezed light beams.


Recruiting Hard-to-Reach Populations for Survey Research: Using Facebook and Instagram Advertisements and In-Person Intercept in LGBT Bars and Nightclubs to Recruit LGBT Young Adults.
Tobacco public education campaigns focus increasingly on hard-to-reach populations at higher risk for smoking, prompting campaign creators and evaluators to develop strategies to reach hard-to-reach populations in virtual and physical spaces where they spend time. The aim of this study was to describe two novel recruitment strategies (in-person intercept interviews in lesbian, gay, bisexual, and transgender [LGBT] social venues and targeted social media ads) and compares characteristics of participants recruited via these strategies for the US Food and Drug Administration's This Free Life campaign evaluation targeting LGBT young adults who smoke cigarettes occasionally. We recruited LGBT adults aged 18-24 years in the United States via Facebook and Instagram ads (N=1709, mean age 20.94, SD 1.94) or intercept in LGBT social venues (N=2348, mean age 21.98, SD 1.69) for the baseline evaluation survey. Covariates related to recruitment strategy were age; race or ethnicity; LGBT identity; education; pride event attendance; and alcohol, cigarette, and social media use. Lesbian or gay women (adjusted odds ratio, AOR 1.88, 95% CI 1.54-2.29, P<.001), bisexual men and women (AOR 1.46, 95% CI 1.17-1.82, P=.001), gender minorities (AOR 1.68, 95% CI 1.26-2.25, P<.001), and other sexual minorities (AOR 2.48, 95% CI 1.62-3.80, P<.001) were more likely than gay men to be recruited via social media (than intercept). Hispanic (AOR 0.73, 95% CI 0.61-0.89, P=.001) and other or multiracial, non-Hispanic participants (AOR 0.70, 95% CI 0.54-0.90, P=.006) were less likely than white, non-Hispanic participants to be recruited via social media. As age increased, odds of recruitment via social media decreased (AOR 0.76, 95% CI 0.72-0.80, P<.001). Participants with some college education (AOR 1.27, 95% CI 1.03-1.56, P=.03) were more likely than those with a college degree to be recruited via social media. Participants reporting past 30-day alcohol use were less likely to be recruited via social media (AOR 0.33, 95% CI 0.24-0.44, P<.001). Participants who reported past-year pride event attendance were more likely to be recruited via social media (AOR 1.31, 95% CI 1.06-1.64, P=.02), as well as those who used Facebook at least once daily (AOR 1.43, 95% CI 1.14-1.80, P=.002). Participants who reported using Instagram at least once daily were less likely to be recruited via social media (AOR 0.73, 95% CI 0.62-0.86, P<.001). Social media recruitment was faster (incidence rate ratio, IRR=3.31, 95% CI 3.11-3.52, P<.001) and less expensive (2.2% of combined social media and intercept recruitment cost) but had greater data quality issues-a larger percentage of social media respondents were lost because of duplicate and low-quality responses (374/4446, 8.41%) compared with intercept respondents lost to interviewer misrepresentation (15/4446, 0.34%; P<.001). Social media combined with intercept provided access to important LGBT subpopulations (eg, gender and other sexual minorities) and a more diverse sample. Social media methods have more data quality issues but are faster and less expensive than intercept. Recruiting hard-to-reach populations via audience-tailored strategies enabled recruitment of one of the largest LGBT young adult samples, suggesting these methods' promise for accessing hard-to-reach populations.


A new technique for radiographic measurement of acetabular cup orientation.
Accurate radiographic measurement of acetabular cup orientation is required in order to assess susceptibility to impingement, dislocation, and edge loading wear. In this study, the accuracy and precision of a new radiographic cup orientation measurement system were assessed and compared to those of two commercially available systems. Two types of resurfacing hip prostheses and an uncemented prosthesis were assessed. Radiographic images of each prosthesis were created with the cup set at different, known angles of version and inclination in a measurement jig. The new system was the most accurate and precise and could repeatedly measure version and inclination to within a fraction of a degree. In addition it has a facility to distinguish cup retroversion from anteversion on anteroposterior radiographs.


Prediction of massive blood transfusion in cardiac surgery.
In cardiac surgery with cardiopulmonary bypass (CPB), excessive blood loss requiring the transfusion of multiple red blood cell (RBC) units is a common complication that is associated with significant morbidity and mortality. The objective of this study was to develop a prediction rule for massive blood transfusion (MBT) that could be used to optimize the management of, and research on, at-risk patients. Data were collected prospectively over the period from 2000 to 2005, on patients who underwent surgery with CPB at one hospital. Patients who received > or = five units of RBC within one day of surgery were classified as MBT. Logistic regression was used to appropriately select and weigh perioperative variables in the prediction rule, which was developed on the initial 60% of the sample and validated on the remaining 40%. Of the 10,667 patients included, 925 (8.7%) had MBT. The clinical prediction rule included 12 variables (listed in order of predictive value: CPB duration, preoperative hemoglobin concentration, body surface area, nadir CPB hematocrit, previous sternotomy, preoperative shock, preoperative platelet count, urgency of surgery, age, surgeon, deep hypothermic circulatory arrest, and type of procedure) and was highly discriminative (c-index = 0.88). In the validation set, those classified as low-, moderate-, and high-risk by a simple risk score derived from the prediction rule had a 5%, 27%, and 58% chance of MBT, respectively. A clinical prediction rule was developed that accurately identified patients at low-risk or high-risk for MBT. Studies are needed to determine the external generalizability and clinical utility of the prediction rule.


Harnessing biomechanics to develop cartilage regeneration strategies.
As this review was prepared specifically for the American Society of Mechanical Engineers H.R. Lissner Medal, it primarily discusses work toward cartilage regeneration performed in Dr. Kyriacos A. Athanasiou's laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of chondrogenic cells. The challenging problem of enhanced integration of engineered cartilage with native cartilage is approached with both familiar and novel methods, such as lysyl oxidase (LOX). These diverse tissue engineering strategies all aim to build upon thorough biomechanical characterizations to produce functional neotissue that ultimately will help combat the pressing problem of cartilage degeneration. As our prior research is reviewed, we look to establish new pathways to comprehensively and effectively address the complex problems of musculoskeletal cartilage regeneration.


High-birefringence fiber loop mirror sensor using a WDM fused fiber coupler.
An intensity-based highly birefringent (Hi-Bi) fiber loop mirror (FLM) sensor is proposed which uses a wavelength-division multiplexing (WDM) fiber coupler. The effect of integrating the WDM coupler in a FLM configuration is first studied. A section of Hi-Bi (bow-tie) fiber of length 0.26 m is then placed in the fiber loop, making the spectral response of the device simultaneously dependent on the Hi-Bi fiber section and WDM coupler characteristics. When strain is applied to the sensing head, the spectral signal is modulated in amplitude, in contrast with the conventional Hi-Bi FLM sensors in which there are wavelength shifts. The sensor was characterized in strain and a sensitivity of (-2.2±0.4)×10(-3) με(-1) for a range of 300 με was attained. The self-referenced character of the sensor is noted.


End-systolic measures of regional ventricular performance.
Dimension change measures of regional ventricular function, such as absolute or percent wall thickening (delta T or % delta T) or segmental shortening (delta L or % delta L), are highly load dependent. In 16 anesthetized mongrel dogs we assessed use of the end-systolic pressure-thickness and end-systolic pressure-length relationships (ESPTR, ESPLR) as more load-independent measures of regional function. We found that the ESPTR and ESPLR could be measured without detectable baroreceptor-mediated reflex changes in cardiac contractile state. Systemic administration of dobutamine shifted the ESPTR to the right and the ESPLR to the left of control, mainly due to a change in the slope (Ees) of the relationships. Both delta T, % delta T and delta L, % delta L failed to detect the positive inotropic effect of dobutamine because of an associated reduction in preload. With systemic administration of propranolol, ESPTR, ESPLR, delta T, % delta T, and delta L, % delta L detected the negative inotropic effect. Thus systemic propranolol shifted the ESPTR to the left and the ESPLR to the right of control, mainly due to a change in Ees. Regional administration of dobutamine shifted the ESPTR and the ESPLR in the direction of positive contractility in the region receiving the drug, whereas simple dimension change measures of regional function failed to detect the inotropic effect because preload fell and the timing of regional end-systole was altered. With regional propranolol both the ESPTR, ESPLR and simple dimension change measures detected the negative inotropic effect. Thus the ESPTR, ESPLR is a reliable measure of regional ventricular function and may be better than simple dimension change measures of regional function, particularly when loading conditions or the timing of regional systole is altered by an intervention.