Acquired immunity to malaria.
Naturally acquired immunity to falciparum malaria protects millions of people routinely exposed to Plasmodium falciparum infection from severe disease and death. There is no clear concept about how this protection works. There is no general agreement about the rate of onset of acquired immunity or what constitutes the key determinants of protection; much less is there a consensus regarding the mechanism(s) of protection. This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria with the help of evolving insights provided by biotechnology and places these insights in the context of historical, clinical, and epidemiological observations. We advocate that naturally acquired immunity should be appreciated as being virtually 100% effective against severe disease and death among heavily exposed adults. Even the immunity that occurs in exposed infants may exceed 90% effectiveness. The induction of an adult-like immune status among high-risk infants in sub-Saharan Africa would greatly diminish disease and death caused by P. falciparum. The mechanism of naturally acquired immunity that occurs among adults living in areas of hyper- to holoendemicity should be understood with a view toward duplicating such protection in infants and young children in areas of endemicity.


The GalNAc-type O-Glycoproteome of CHO cells characterized by the SimpleCell strategy.
The Chinese hamster ovary cell (CHO) is the major host cell factory for recombinant production of biological therapeutics primarily because of its "human-like" glycosylation features. CHO is used for production of several O-glycoprotein therapeutics including erythropoietin, coagulation factors, and chimeric receptor IgG1-Fc-fusion proteins, however, some O-glycoproteins are not produced efficiently in CHO. We have previously shown that the capacity for O-glycosylation of proteins can be one limiting parameter for production of active proteins in CHO. Although the capacity of CHO for biosynthesis of glycan structures (glycostructures) on glycoproteins are well established, our knowledge of the capacity of CHO cells for attaching GalNAc-type O-glycans to proteins (glycosites) is minimal. This type of O-glycosylation is one of the most abundant forms of glycosylation, and it is differentially regulated in cells by expression of a subset of homologous polypeptide GalNAc-transferases. Here, we have genetically engineered CHO cells to produce homogeneous truncated O-glycans, so-called SimpleCells, which enabled lectin enrichment of O-glycoproteins and characterization of the O-glycoproteome. We identified 738 O-glycoproteins (1548 O-glycosites) in cell lysates and secretomes providing the first comprehensive insight into the O-glycosylation capacity of CHO (http://glycomics.ku.dk/o-glycoproteome_db/).


Incorporating regulatory guideline values in analysis of epidemiology data.
Fundamental to regulatory guidelines is to identify chemicals that are implicated with adverse human health effects and inform public health risk assessors about "acceptable ranges" of such environmental exposures (e.g., from consumer products and pesticides). The process is made more difficult when accounting for complex human exposures to multiple environmental chemicals. Herein we propose a new class of nonlinear statistical models for human data that incorporate and evaluate regulatory guideline values into analyses of health effects of exposure to chemical mixtures using so-called 'desirability functions' (DFs). The DFs are incorporated into nonlinear regression models to allow for the simultaneous estimation of points of departure for risk assessment of combinations of individual substances that are parts of chemical mixtures detected in humans. These are, in contrast to published so-called biomonitoring equivalent (BE) values and human biomonitoring (HBM) values that link regulatory guideline values from in vivo studies of single chemicals to internal concentrations monitored in humans. We illustrate the strategy through the analysis of prenatal concentrations of mixtures of 11 chemicals with suspected endocrine disrupting properties and two health effects: birth weight and language delay at 2.5 years. The strategy allows for the creation of a Mixture Desirability Function i.e., MDF, which is a uni-dimensional construct of the set of single chemical DFs; thus, it focuses the resulting inference to a single dimension for a more powerful one degree-of-freedom test of significance. Based on the application of this new method we conclude that the guideline values need to be lower than those for single chemicals when the chemicals are observed in combination to achieve a similar level of protection as was aimed for the individual chemicals. The proposed modeling may thus suggest data-driven uncertainty factors for single chemical risk assessment that takes environmental mixtures into account.


Blocked 3×2 cross-validated t-test for comparing supervised classification learning algorithms.
In the research of machine learning algorithms for classification tasks, the comparison of the performances of algorithms is extremely important, and a statistical test of significance for generalization error is often used to perform it in the machine learning literature. In view of the randomness of partitions in cross-validation, a new blocked 3×2 cross-validation is proposed to estimate generalization error in this letter. We then conduct an analysis of variance of the blocked 3×2 cross-validated estimator. A relatively conservative variance estimator that considers the correlation between any two two-fold cross-validations, and was previously neglected in 5×2 cross-validated t and F-tests is put forward. A corresponding test using this variance estimator is presented to compare the performances of algorithms. Simulated results show that the performance of our test is comparable with that of 5×2 cross-validated tests but with less computation complexity.


ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice.
Pregnancy is associated with substantial physiological changes of the heart, and disruptions in these processes can lead to peripartum cardiomyopathy (PPCM). The molecular processes that cause physiological and pathological changes in the heart during pregnancy are not well characterized. Here, we show that mTORc1 was activated in pregnancy to facilitate cardiac enlargement that was reversed after delivery in mice. mTORc1 activation in pregnancy was negatively regulated by the mRNA-destabilizing protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocyte hypertrophy during pregnancy, and mice with cardiac-specific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved postpartum cardiac function. Collectively, these data provide what we believe to be a novel pathway for the regulation of mTORc1 through mRNA stabilization of a P53 ubiquitin ligase. This pathway was critical for normal cardiac growth during pregnancy, and its reduction led to PPCM-like adverse remodeling in mice.


Taming a silyldiium cation and its reactivity towards sodium phosphaethynolate.
A dicationic bis(NHC)-stabilised silyldiium complex, [bis(NHC)-SiPh2]2+ (72+) (bis(NHC) = [CH2(NC3H2NDipp)2], Dipp = 2,6-iPr2C6H3), was synthesised for the first time. It reacts with sodium phosphaethynolate (NaOCP) as a source of monoanionic phosphorus to give the P-insertion product [bis(NHC)-PSiPh2]+ (8+). The latter comprises a seven-membered heterocycle containing a Si-P moiety which can easily be desilylated when exposed to dichlorophosphanes as exemplified by the synthesis of the diphosphanide cations [bis(NHC)-PPCy]+ (9+) and [bis(NHC)-PPPh]+ (10+).


Islet cell dysfunction in progression to diabetes mellitus.
The epidemic of type 2 diabetes mellitus is increasing in most nations. This illness is a major cause of cardiovascular disease, stroke, blindness, renal failure, and amputations. Because available interventions have failed to show durability, new modes of therapy need to be directed at the underlying causes of abnormal glucose metabolism. The development of such modes of therapy will require an improved understanding of how the beta-cell mass compensates for changes in insulin resistance and why beta cells lose the capacity to secrete insulin. In addition, new therapeutic modalities need to address alpha-cell dysregulation, because the inability to suppress glucagon production results in ongoing elevated levels of hepatic glucose.


Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.
Dietary supplements that contain ephedra alkaloids (sometimes called ma huang) are widely promoted and used in the United States as a means of losing weight and increasing energy. In the light of recently reported adverse events related to use of these products, the Food and Drug Administration (FDA) has proposed limits on the dose and duration of use of such supplements. The FDA requested an independent review of reports of adverse events related to the use of supplements that contained ephedra alkaloids to assess causation and to estimate the level of risk the use of these supplements poses to consumers. We reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra alkaloids that were submitted to the FDA between June 1, 1997, and March 31, 1999. A standardized rating system for assessing causation was applied to each adverse event. Thirty-one percent of cases were considered to be definitely or probably related to the use of supplements containing ephedra alkaloids, and 31 percent were deemed to be possibly related. Among the adverse events that were deemed definitely, probably, or possibly related to the use of supplements containing ephedra alkaloids, 47 percent involved cardiovascular symptoms and 18 percent involved the central nervous system. Hypertension was the single most frequent adverse effect (17 reports), followed by palpitations, tachycardia, or both (13); stroke (10); and seizures (7). Ten events resulted in death, and 13 events produced permanent disability, representing 26 percent of the definite, probable, and possible cases. The use of dietary supplements that contain ephedra alkaloids may pose a health risk to some persons. These findings indicate the need for a better understanding of individual susceptibility to the adverse effects of such dietary supplements.


Space-time adaptation for patch-based image sequence restoration.
We present a novel space-time patch-based method for image sequence restoration. We propose an adaptive statistical estimation framework based on the local analysis of the bias-variance trade-off. At each pixel, the space-time neighborhood is adapted to improve the performance of the proposed patch-based estimator. The proposed method is unsupervised and requires no motion estimation. Nevertheless, it can also be combined with motion estimation to cope with very large displacements due to camera motion. Experiments show that this method is able to drastically improve the quality of highly corrupted image sequences. Quantitative evaluations on standard artificially noise-corrupted image sequences demonstrate that our method outperforms other recent competitive methods. We also report convincing results on real noisy image sequences.


Towards personalized Internet health information: the STEPPS architecture.
STEPPS (STructured Evaluated Personalized Patient Support) proposes a strategy for integration of electronic patient records with Internet health-related content and its consequent use in personalized information retrieval for patient education. The application domain is the post-discharge support of burn patients in the Netherlands. We developed an electronic patient record interface for structured data collection in burn care. The system's thesaurus was projected to UMLS terms and the corresponding codes were incorporated in our software. A list of topics central to burn patient education was identified and a collection of related Web pages was compiled using meta-search software (Copernic2001Pro). The HTML pages were filed into catalogues by the Collexis indexing-matching software, using the UMLS Metathesaurus as indexing vocabulary. The bilingual (English and Dutch) structured data interface is currently used to create a database of retrospective patient data. Each patient's profile, i.e. set of characteristics employed to personalize information retrieval, can be automatically extracted. We have assembled a collection of more than 2500 Internet pages containing relevant information for burn patients. When patient data is available, the Collexis matching engine will accept the patient's profile as input and retrieve the most relevant HTML documents available in the catalogues. We have addressed some basic issues around the technical feasibility of linking electronic patient record data to online content. Although the functionality of STEPPS is not yet optimal, it contributes to the efforts towards improved relevance of information retrieval. Electronic patient record applications in conjunction with Internet resources can give a significant boost to the availability of tailored health education material. In this context, quality assurance of online health information is an indispensable element.


Social perception as induction and inference: an integrative model of intergroup differentiation, ingroup favoritism, and differential accuracy.
Three general properties of social stereotypes are the perception of differences between ingroups and outgroups (intergroup differentiation), the perception of ingroups as having more desirable attributes than outgroups (ingroup favoritism), and the greater accuracy of ingroup perceptions (differential accuracy). We present and test an inductive-reasoning model that accounts for all 3 phenomena, and we explicate the relations among them. Based on empirical evidence, the model assumes that most people have a positive self-image, that they project these self-images more strongly to ingroups than to outgroups, and that their self-images are valid cues for judgments about social groups. Two minimal-group experiments using a crossed-categorization paradigm support the model and provide new evidence for underlying psychological processes.


Defining quality improvement in public health.
Many industries commonly use quality improvement (QI) techniques to improve service delivery and process performance. Yet, there has been scarce application of these proven methods to public health settings and the public health field has not developed a set of shared principles or a common definition for quality improvement. This article discusses a definition of quality improvement in public health and describes a continuum of quality improvement applications for public health departments. Quality improvement is a distinct management process and set of tools and techniques that are coordinated to ensure that departments consistently meet the health needs of their communities.


Branched-chain amino acids in liver disease: new aspects of long known phenomena.
To provide an overview of findings on the role of branched-chain amino acids (BCAAs) in the pathophysiology, pathobiochemistry, and treatment of liver cirrhosis and its complications that have been published since or were not included in the last review on this topic in 2007 in this journal. There has been continued interest in the potential of oral BCAA supplements in improving energy metabolism, nitrogen metabolism, carbohydrate metabolism, insulin resistance, severity of liver disease, serum albumin levels, quality of serum albumin, or postoperative complication rates. Unfortunately, many trials suffer from lacking or inadequate controls or small sample size. In a fine example of scientific perseverance, Dutch researchers uncovered the long-known phenomenon of ingested blood being highly comagenic in patients with cirrhosis to be due to the low biologic value of blood protein. The absence of isoleucine and the abundance of leucine in the hemoglobin molecule by way of BCAA antagonism leads to impaired protein synthesis and azotemia paving the way for hepatic encephalopathy. Recognizing hypoisoleucinemia and BCAA antagonism following gastrointestinal bleeding, and its successful treatment by isoleucine infusion has advanced our understanding of the role of BCAA in liver cirrhosis.


Simultaneous enzymatic activity modulation and rapid determination of enzyme kinetics by highly crystalline graphite dots.
The research field in enzyme-based biotechnology urgently requires the discovery of new materials and methods with high-performance. Here we report that highly crystalline graphite dots (GDs) can modulate enzyme activities, and simultaneously allow for real-time measurements on enzyme kinetics in combination with mass spectrometry (MS). A well-defined modulation of lipolytic activities from inhibition to enhancement can be realized by selectively coupling lipase enzymes with GDs containing specific functional groups on the surface. As a unique feature of our approach, GDs in the enzyme reaction can simultaneously serve as a versatile matrix for rapid and sensitive detection of the residual enzyme substrate, the intermediate or final product of lipolytic digestion using MS technology. Therefore, enzyme kinetic data can be collected in a real-time, high-throughput format. This work provides a new platform for enzymological research in hybrid bio-catalytic processes with advanced nanotechnology.


Genetic testing in the workplace: the employer's coin toss.
A toss of the coin by the modern-day employer reveals two options regarding genetic testing in the workplace. The employer may choose to take advantage of increasingly precise, available, and affordable genetic testing in order to ascertain the genetic characteristics--and deficiencies--of its employees. This outcome exposes the employer to a vast array of potential litigation and liability relating to the Americans with Disabilities Act, the Fourth Amendment, Title VII of the Civil Rights Act, and state legislation designed to protect genetic privacy. Alternatively, the employer may neglect to indulge in this trend of genetic testing and may face liability for employer negligence, violations of federal legislation such as OSHA regulations, and increased costs associated with insuring the health of genetically endangered employees. In the rapidly developing universe of genetic intelligence, the employer is faced with a staggering dilemma.


Bulk Raman analysis of pharmaceutical tablets.
We compare and contrast two Raman collection geometries, backscattering and transmission, to identify their potential for monitoring the bulk chemical composition of turbid media. The experiments performed on pharmaceutical tablets confirm the expected strong bias of the backscattering Raman collection towards surface layers of the probed sample. However, this bias is largely absent with the transmission geometry, exhibiting gross insensitivity to the depth of impurities within the sample. The results are supported by Monte-Carlo simulations. The applicability of transmission geometry to tablets without any thinning is possible because of long migration times of Raman photons in non-absorbing powder media. The absolute measured intensity of the Raman signal was only 12 times lower in transmission geometry compared with backscattering geometry for a standard paracetamol tablet with a thickness of 3.9 mm. This makes detection relatively straightforward, and detectable Raman signals were observed even after propagation through three paracetamol tablets. Given its properties and instrumental simplicity, the transmission method is particularly well suited to the on-line analysis of bulk content of tablets in pharmaceutical applications.


Continued Increase of Axial Length and Its Risk Factors in Adults With High Myopia.
Pathologic myopia due to an excessive increase of axial length is associated with severe visual impairments. Systematic analyses to determine the rate of and the risk factors associated with the axial elongation in adults with high myopia based on long-term follow-up of a large population are needed. To determine the risk factors associated with axial elongation in adults with high myopia. This cohort study used the medical records of 43 201 patient visits in a single-hospital database that were collected from January 3, 2011, to December 28, 2018. A total of 15 745 medical records with the patients' sex, best-corrected visual acuity (BCVA), axial length, type of myopic maculopathy, and the presence or absence of choroidal neovascularization (CNV) were reviewed. Data were analyzed from April 3, 2019, to August 5, 2020. Changes in the axial length at each examination were calculated. The significance of the associations between the annual increase of the axial length and age, sex, baseline axial length, types of myopic maculopathy, and a history of CNV was determined. Generalized linear mixed models were used to evaluate the strength of the risk factors associated with an increase of the axial length in high myopia. Among 1877 patients with 9161 visits included in the analysis, the mean (SD) age was 62.10 (12.92) years, and 1357 (72.30%) were women. The mean (SD) axial length was 29.66 (2.20) mm with a mean (SD) growth rate of 0.05 (0.24) mm/y. Among the 9161 visits, 7096 eyes (77.46%) had myopic maculopathy and 2477 eyes (27.04%) had CNV. The odds ratio for inducing a severe elongation of the axial length was 1.46 (95% CI, 1.38-1.55) for female sex, 0.44 (95% CI, 0.35-0.56) to 0.63 (95% CI, 13 0.50-0.78) for older than 40 years, 1.33 (95% CI, 1.15-1.54) for BCVA of less than 20/400, 1.67 (95% CI, 1.54-1.81) to 2.67 (95% CI, 2.46-2.88) for baseline axial length of 28.15 mm or greater, 1.06 (95% CI, 0.96-1.17) to 1.39 (95% CI, 1.24-1.55) for the presence of maculopathy, and 1.37 (95% CI, 1.29-1.47) for prior CNV. This cohort study found continuing axial elongation in adults with high myopia. The risk factors for elongation do not appear to be modifiable, so prevention of myopia may be the best approach to reduce the incidence of pathologic myopia and its complications in the future.


The recognition of a viral antigenic moiety by class I MHC-restricted cytolytic T lymphocytes is limited by the availability of the endogenously processed antigen.
The transmembrane hydrophobic domain of the type A influenza A/JAPAN/305/57 (H2N2) hemagglutinin (HA) contains an immunodominant site encompassing amino acids 523-545 (J523-545) recognized by class I MHC-restricted cytolytic T lymphocytes (CTL). Class I CTL of two fine specificity subsets map to this transmembrane (TM) site. One of these CTL subpopulations is subtype specific. These T lymphocytes recognize the site generated during infection of target cells with A/JAPAN/305/57 virus (H2N2) but not target cells expressing the comparable TM site of the influenza A/PR/8/34 virus (H1N1) hemagglutinin (P527-549) after infection with this virus. The other CTL subpopulation is cross-reactive and recognizes the TM site of the A/JAPAN/305/57 HA and the A/PR/8/34 HA with similar efficiency. Analyses of the critical amino acids in the TM site necessary for CTL recognition with the use of synthetic peptides unexpectedly revealed reactivity for the A/PR/8 HA TM site by subtype-specific CTL. This reactivity was only observed with truncated peptides corresponding to a limited portion of the A/PR/8 HA TM site but also required peptide concentrations greater than 10(-7) M. These results suggested either that the endogenously processed A/PR/8 HA TM site generated during infection was larger than the site defined by the truncated cross-reactive peptides or that the concentration of endogenously processed TM site produced during infection was limiting. To distinguish between these possibilities, we expressed in target cells synthetic minigenes encoding only the portion of the A/PR/8 HA transmembrane sites defined by the synthetic peptides. Unlike the peptides, the "preprocessed" endogenous minigene products were not recognized by subtype-specific CTL. These data suggest that the level of available endogenously processed Ag rather than selectivity in the site of fragmentation of newly synthesized Ag may play a critical role in determining whether the complex of the antigenic moiety and class I MHC is efficiently presented to and recognized by class I CTL.


The Citrobacter rodentium type III secretion system effector EspO affects mucosal damage repair and antimicrobial responses.
Infection with Citrobacter rodentium triggers robust tissue damage repair responses, manifested by secretion of IL-22, in the absence of which mice succumbed to the infection. Of the main hallmarks of C. rodentium infection are colonic crypt hyperplasia (CCH) and dysbiosis. In order to colonize the host and compete with the gut microbiota, C. rodentium employs a type III secretion system (T3SS) that injects effectors into colonic intestinal epithelial cells (IECs). Once injected, the effectors subvert processes involved in innate immune responses, cellular metabolism and oxygenation of the mucosa. Importantly, the identity of the effector/s triggering the tissue repair response is/are unknown. Here we report that the effector EspO ,an orthologue of OspE found in Shigella spp, affects proliferation of IECs 8 and 14 days post C. rodentium infection as well as secretion of IL-22 from colonic explants. While we observed no differences in the recruitment of group 3 innate lymphoid cells (ILC3s) and T cells, which are the main sources of IL-22 at the early and late stages of C. rodentium infection respectively, infection with ΔespO was characterized by diminished recruitment of sub-mucosal neutrophils, which coincided with lower abundance of Mmp9 and chemokines (e.g. S100a8/9) in IECs. Moreover, mice infected with ΔespO triggered significantly lesser nutritional immunity (e.g. calprotectin, Lcn2) and expression of antimicrobial peptides (Reg3β, Reg3γ) compared to mice infected with WT C. rodentium. This overlapped with a decrease in STAT3 phosphorylation in IECs. Importantly, while the reduced CCH and abundance of antimicrobial proteins during ΔespO infection did not affect C. rodentium colonization or the composition of commensal Proteobacteria, they had a subtle consequence on Firmicutes subpopulations. EspO is the first bacterial virulence factor that affects neutrophil recruitment and secretion of IL-22, as well as expression of antimicrobial and nutritional immunity proteins in IECs.


Coupling mechanism of a GPCR and a heterotrimeric G protein during chemoattractant gradient sensing in Dictyostelium.
The coupling of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) with G proteins is fundamental for GPCR signaling; however, the mechanism of coupling is still debated. Moreover, how the proposed mechanisms affect the dynamics of downstream signaling remains unclear. Here, through experiments involving fluorescence recovery after photobleaching and single-molecule imaging, we directly measured the mobilities of cyclic adenosine monophosphate (cAMP) receptor 1 (cAR1), a chemoattractant receptor, and a G protein βγ subunit in live cells. We found that cAR1 diffused more slowly in the plasma membrane than did Gβγ. Upon binding of ligand to the receptor, the mobility of cAR1 was unchanged, whereas the speed of a fraction of the faster-moving Gβγ subunits decreased. Our measurements showed that cAR1 was relatively immobile and Gβγ diffused freely, suggesting that chemoattractant-bound cAR1 transiently interacted with G proteins. Using models of possible coupling mechanisms, we computed the temporal kinetics of G protein activation. Our fluorescence resonance energy transfer imaging data showed that fully activated cAR1 induced the sustained dissociation of G protein α and βγ subunits, which indicated that ligand-bound cAR1 activated G proteins continuously. Finally, simulations indicated that a high-affinity coupling of ligand-bound receptors and G proteins was essential for cAR1 to translate extracellular gradient signals into directional cellular responses. We suggest that chemoattractant receptors use a ligand-induced coupling rather than a precoupled mechanism to control the activation of G proteins during chemotaxis.


Population level impact of an imperfect prophylactic vaccine for herpes simplex virus-2.
The continuation of developing Herpes simplex virus type-2 (HSV-2) prophylactic vaccines requires parallel mathematical modeling to quantify the effect on the population of these vaccines. Using mathematical modeling we derived 3 summary measures for the population effect of imperfect HSV-2 vaccines as a function of their efficacies in reducing susceptibility (VES), genital shedding (VEP), and infectivity during shedding (VEI). In addition, we studied the population level effect of vaccine intervention using representative vaccine efficacies. A vaccine with limited efficacy of reducing shedding frequency (VEP = 10%) and infectivity (VEI = 0%) would need to reduce susceptibility by 75% (VES = 75%) to substantially reduce the sustainability of HSV-2 infection in a population. No reduction in susceptibility would be required to reach this target in a vaccine that decreased shedding by 75% (VES = 0%, VEP = 75%, VEI = 0%). Mass vaccination using a vaccine with imperfect efficacies (VES = 30%, VEP = 75%, and VEI = 0%) in Kisumu, Kenya, in 2010 would decrease prevalence and incidence in 2020 by 7% and 30%, respectively. For lower prevalence settings, vaccination is predicted to have a lower effect on prevalence. A vaccine with substantially high efficacy of reducing HSV-2 shedding frequency would have a desirable effect at the population level. The vaccine's short-term impact in a high prevalence setting in Africa would be a substantial decrease in incidence, whereas its immediate impact on prevalence would be small and would increase slowly over time.


Weaning from mechanical ventilation.
Patients that require positive pressure ventilation to maintain sufficient alveolar ventilation or pulmonary gas exchange may eventually reach a point in the course of their care wherein mechanical ventilation is no longer necessary. This process of transferring the work of breathing from the ventilator back to the patient is referred to as ventilator weaning. The term "ventilator weaning" may be used to refer to all methods by which this transfer of workload may be accomplished. In many patients, particularly those with short-lasting or readily correctable causes of respiratory insufficiency (e.g., general anesthesia), the discontinuation of positive pressure ventilation may be easily achieved. Indeed, in patients awakening from general anesthesia, the axiom "awake enough to blink, awake enough to breath" may prove to be a sufficient guideline. However, in those patients requiring long-term mechanical ventilatory support, the process can prove to be both frustrating and exceptionally challenging. It is of crucial importance to identify those patients that may be successfully weaned because of both the financial impact of prolonged intensive care unit hospitalization and the risks imposed on the patient by the process of positive pressure ventilation. To be able to predict which patients may be ready to be weaned from the ventilator requires an understanding of the balance between the work of breathing (ventilatory load) and the ability of the patient's respiratory pump to meet those needs (ventilatory capacity). The management of patients experiencing difficulty during the weaning process requires that the clinician recognize imbalances between ventilatory load and capacity and to correct these imbalances once identified.


Influence of epidural mixture and surgery on bladder function after open renal surgery: a randomized clinical trial.
In a previous observational study, thoracic epidural analgesia (TEA) after open renal surgery resulted in clinically relevant postvoid residuals (PVRs). This study aimed to investigate the individual contribution of epidurally administrated drugs and surgery in bladder dysfunction. In this single-center, parallel-group, randomized (computer-generated list), double-blind superiority trial, 40 patients undergoing open renal surgery were equally allocated to receive epidural bupivacaine (0.125%) alone or with fentanyl (2 µg/ml). Patients underwent urodynamic investigations before TEA and during TEA preoperatively and postoperatively. Primary outcome was the difference (Δ) in PVR between before TEA and postoperatively during TEA. Secondary outcomes were changes in detrusor pressure at maximum flow rate, bladder compliance, and ΔPVR between different time points. Median ΔPVR (ml) from baseline to postoperatively was 180 (range, -85 to 645; P = 0.001) in the bupivacaine group and 235 (range, 0-580; P value less than 0.001) in the bupivacaine/fentanyl group, with no difference between groups (95% confidence interval, -167 to 103; P = 0.634). Detrusor pressure at maximum flow rate (cm H(2)O) from baseline was more pronounced in the bupivacaine/fentanyl than that in the bupivacaine group preoperatively (-10; range, -64 to -2; P value less than 0.001 vs. -3; range, -35 to 13; P = 0.397) (P = 0.045) and postoperatively (-18; range, -64 to 0; P value less than 0.001 vs. -12; range, -34 to 22; P = 0.006) (P = 0.135). Surgery did not affect PVRs, but a decreased bladder compliance was observed in both groups. No adverse events occurred. Thoracic epidurally administrated bupivacaine resulted in clinically relevant PVRs based on impaired detrusor function. The addition of fentanyl enhanced this effect without generating greater PVRs. After surgery, the voiding phase was not further impaired; however, bladder compliance was decreased.


Measurement of a reaction-diffusion crossover in exciton-exciton recombination inside carbon nanotubes using femtosecond optical absorption.
Exciton-exciton recombination in isolated semiconducting single-walled carbon nanotubes was studied using femtosecond transient absorption. Under sufficient excitation to saturate the optical absorption, we observed an abrupt transition between reaction- and diffusion-limited kinetics, arising from reactions between incoherent localized excitons with a finite probability of ~0.2 per encounter. This represents the first experimental observation of a crossover between classical and critical kinetics in a 1D coalescing random walk, which is a paradigm for the study of nonequilibrium systems.


Stuttering in English-Mandarin bilingual speakers: the influence of language dominance on stuttering severity.
English and Mandarin are the 2 most spoken languages in the world, yet it is not known how stuttering manifests in English-Mandarin bilinguals. In this research, the authors investigated whether the severity and type of stuttering is different in English and Mandarin in English-Mandarin bilinguals, and whether this difference was influenced by language dominance. Thirty English-Mandarin bilinguals who stutter (BWS), ages 12-44 years, were categorized into 3 groups (15 English-dominant, 4 Mandarin-dominant, and 11 balanced bilinguals) using a self-report classification tool. Three 10-min conversations in English and Mandarin were assessed by 2 English-Mandarin bilingual clinicians for percent syllables stuttered (%SS), perceived stuttering severity (SEV), and types of stuttering behaviors using the Lidcombe Behavioral Data Language (LBDL; Packman & Onslow, 1998; Teesson, Packman, & Onslow, 2003). English-dominant and Mandarin-dominant BWS exhibited higher %SS and SEV scores in their less dominant language, whereas the scores for the balanced bilinguals were similar for both languages. The difference in the percentage of stutters per LBDL category between English and Mandarin was not markedly different for any bilingual group. Language dominance appeared to influence the severity but not the types of stuttering behaviors in BWS. Clinicians working with BWS need to assess language dominance when diagnosing stuttering severity in bilingual clients.


Linking environmental filtering and disequilibrium to biogeography with a community climate framework.
We present a framework to measure the strength of environmental filtering and disequilibrium of the species composition of a local community across time, relative to past, current, and future climates. We demonstrate the framework by measuring the impact of climate change on New World forests, integrating data for climate niches of more than 14000 species, community composition of 471 New World forest plots, and observed climate across the most recent glacial-interglacial interval. We show that a majority of communities have species compositions that are strongly filtered and are more in equilibrium with current climate than random samples from the regional pool. Variation in the level of current community disequilibrium can be predicted from Last Glacial Maximum climate and will increase with near-future climate change.


Humor as a character strength among the elderly: theoretical considerations.
Positive psychology is a scientific approach within psychology that focuses on research on what is best in people. Within this framework, humor is understood as a character strength. The article gives a brief overview on positive psychology and implications for aging (positive aging, successful aging) with an emphasis on the contribution of humor. Humor as a strength of character and its measurement by various approaches are discussed. It is argued that there is a lack of empirical data about humor in the elderly. Potential benefits of considering humor in research but also in practice are discussed.


Oscillatory mode coupling and electrically strobed gratings in photorefractive quantum-well diodes.
Oscillatory mode coupling between two coherent laser beams is produced when an interference pattern moves against a quasi-static electrically strobed grating in a photorefractive AlGaAs/GaAs multiple-quantum-well diode operated in the quantum-confined Stark geometry. The oscillation frequency is equal to the frequency difference between the two laser beams and provides a method to measure high-frequency Doppler shifts or large surface displacements for laser-based ultrasound. Combined photorefractive gains (normally forbidden by symmetry in the Stark geometry) and absorptive gains approach 1200cm(-1)during two-wave mixing using moving gratings.


Problem-elephant translocation: translocating the problem and the elephant?
Human-elephant conflict (HEC) threatens the survival of endangered Asian elephants (Elephas maximus). Translocating "problem-elephants" is an important HEC mitigation and elephant conservation strategy across elephant range, with hundreds translocated annually. In the first comprehensive assessment of elephant translocation, we monitored 16 translocations in Sri Lanka with GPS collars. All translocated elephants were released into national parks. Two were killed within the parks where they were released, while all the others left those parks. Translocated elephants showed variable responses: "homers" returned to the capture site, "wanderers" ranged widely, and "settlers" established home ranges in new areas soon after release. Translocation caused wider propagation and intensification of HEC, and increased elephant mortality. We conclude that translocation defeats both HEC mitigation and elephant conservation goals.


Site-directed mutagenesis of a loop at the active site of E1 (alpha2beta2) of the pyruvate dehydrogenase complex. A possible common sequence motif.
Limited proteolysis of the pyruvate decarboxylase (E1, alpha2beta2) component of the pyruvate dehydrogenase (PDH) multienzyme complex of Bacillus stearothermophilus has indicated the importance for catalysis of a site (Tyr281-Arg282) in the E1alpha subunit (Chauhan, H.J., Domingo, G.J., Jung, H.-I. & Perham, R.N. (2000) Eur. J. Biochem. 267, 7158-7169). This site appears to be conserved in the alpha-subunit of heterotetrameric E1s and multiple sequence alignments suggest that there are additional conserved amino-acid residues in this region, part of a common pattern with the consensus sequence -YR-H-D-YR-DE-. This region lies about 50 amino acids on the C-terminal side of a 30-residue motif previously recognized as involved in binding thiamin diphosphate (ThDP) in all ThDP-dependent enzymes. The role of individual residues in this set of conserved amino acids in the E1alpha chain was investigated by means of site-directed mutagenesis. We propose that particular residues are involved in: (a) binding the 2-oxo acid substrate, (b) decarboxylation of the 2-oxo acid and reductive acetylation of the tethered lipoyl domain in the PDH complex, (c) an "open-close" mechanism of the active site, and (d) phosphorylation by the E1-specific kinase (in eukaryotic PDH and branched chain 2-oxo acid dehydrogenase complexes).


Genetic differences between five European populations.
We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences. We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ(2) test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p < 10(-45). We found 40,593 SNPs which are genome-wide significantly (p ≤ 10(-8)) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation (HERC2, EXOC2, IRF4), the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, FOXP2, implicated in speech development. Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci.


Cooperation and competition shape ecological resistance during periodic spatial disturbance of engineered bacteria.
Cooperation is fundamental to the survival of many bacterial species. Previous studies have shown that spatial structure can both promote and suppress cooperation. Most environments where bacteria are found are periodically disturbed, which can affect the spatial structure of the population. Despite the important role that spatial disturbances play in maintaining ecological relationships, it remains unclear as to how periodic spatial disturbances affect bacteria dependent on cooperation for survival. Here, we use bacteria engineered with a strong Allee effect to investigate how the frequency of periodic spatial disturbances affects cooperation. We show that at intermediate frequencies of spatial disturbance, the ability of the bacterial population to cooperate is perturbed. A mathematical model demonstrates that periodic spatial disturbance leads to a tradeoff between accessing an autoinducer and accessing nutrients, which determines the ability of the bacteria to cooperate. Based on this relationship, we alter the ability of the bacteria to access an autoinducer. We show that increased access to an autoinducer can enhance cooperation, but can also reduce ecological resistance, defined as the ability of a population to resist changes due to disturbance. Our results may have implications in maintaining stability of microbial communities and in the treatment of infectious diseases.


Alcohol consumption among pregnant women in a Swedish sample and its effects on the newborn outcomes.
Little is known about the effects of low levels of maternal alcohol intake on the neuropsychological development of the child. This study is part of an ongoing investigation on maternal drinking and presents data on demographic variables, maternal alcohol use, and birth outcomes from that study. The sample comprised 2,264 women from a Swedish antenatal clinic. Retrospective self-report data were collected on alcohol consumption before and during pregnancy, using the Alcohol Use Disorders Identification Test (AUDIT), and on nicotine use. Specific alcohol biomarkers for excessive drinking, carbohydrate-deficient transferrin (CDT) in serum and phosphatidylethanol (PEth) in whole blood, were determined during mid-pregnancy in a subsample of the women. Data on labor and early characteristics of the child were also assessed. Before pregnancy, 89% of the women regularly consumed alcohol and 49% reported occasional or frequent binge drinking. Nicotine was used by 15% before and by 5% during pregnancy. During pregnancy, 12% continued using alcohol and 5% also admitted binge drinking. However, all alcohol biomarker values were below the reporting limits (CDT ≤ 1.7% disialotransferrin; total PEth < 0.1 μmol/L). Self-reported drinking during pregnancy was associated with a higher AUDIT score before pregnancy, nicotine use at the time of the first prenatal visit, older age, and previous legal abortions. The AUDIT questionnaire and 2 specific alcohol biomarkers were used in routine maternity care to collect information about drinking during pregnancy and thereby to identify children at risk for alcohol-related complications. While the AUDIT results suggested that a significant number of women continued using alcohol during pregnancy, implying a risk for fetal disorders, the biomarkers showed negative test values thus indicating only modest drinking levels.


Handedness in captive gorillas (Gorilla gorilla).
Species-level right handedness is frequently presented as a marker of human uniqueness. Handedness also has implications for the evolution of language and cognition. In this study, we examined handedness in 22 captive gorillas (Gorilla gorilla) across a range of behaviours that were part of their daily routine. Ten individuals showed no preferences for any of the behaviours performed, and the majority of the remaining individuals showed a preference for only one behaviour. These results lend support to the theory that species-level handedness is unique to humans. It is hoped that these results will contribute to investigations into the evolution of handedness, which can ultimately be used to further our understanding of the evolution of human language and cognition.


The Rehabilitation of Patients With Advanced Heart Failure After Left Ventricular Assist Device Placement: A Narrative Review.
Because more patients with advanced heart failure are receiving a left ventricular assist device (LVAD) as destination therapy or a bridge to transplantation, there is increasing attention on functional outcomes and quality of life after LVAD implantation. Rehabilitation providers in the acute inpatient rehabilitation setting increasingly will treat patients with an LVAD and should understand the exercise physiology, medical management, rehabilitation considerations, and outcomes after rehabilitation for patients with an LVAD. The purpose of this article is to provide the physiatrist with a comprehensive understanding of the rehabilitation of patients with advanced heart failure and LVAD implantation. Changes in relevant organ system physiology and exercise physiology after LVAD are summarized. Safety of rehabilitation and program considerations for acute inpatient rehabilitation are reviewed. Recommendations for medical management and prevention of secondary complications seen in patients with an LVAD are outlined. A discussion of outcomes after acute inpatient rehabilitation, the dual diagnosis of stroke and LVAD placement, and long-term cognitive, functional, and quality-of-life outcomes after LVAD placement is presented.


Avian photoreceptor patterns represent a disordered hyperuniform solution to a multiscale packing problem.
Optimal spatial sampling of light rigorously requires that identical photoreceptors be arranged in perfectly regular arrays in two dimensions. Examples of such perfect arrays in nature include the compound eyes of insects and the nearly crystalline photoreceptor patterns of some fish and reptiles. Birds are highly visual animals with five different cone photoreceptor subtypes, yet their photoreceptor patterns are not perfectly regular. By analyzing the chicken cone photoreceptor system consisting of five different cell types using a variety of sensitive microstructural descriptors, we find that the disordered photoreceptor patterns are "hyperuniform" (exhibiting vanishing infinite-wavelength density fluctuations), a property that had heretofore been identified in a unique subset of physical systems, but had never been observed in any living organism. Remarkably, the patterns of both the total population and the individual cell types are simultaneously hyperuniform. We term such patterns "multihyperuniform" because multiple distinct subsets of the overall point pattern are themselves hyperuniform. We have devised a unique multiscale cell packing model in two dimensions that suggests that photoreceptor types interact with both short- and long-ranged repulsive forces and that the resultant competition between the types gives rise to the aforementioned singular spatial features characterizing the system, including multihyperuniformity. These findings suggest that a disordered hyperuniform pattern may represent the most uniform sampling arrangement attainable in the avian system, given intrinsic packing constraints within the photoreceptor epithelium. In addition, they show how fundamental physical constraints can change the course of a biological optimization process. Our results suggest that multihyperuniform disordered structures have implications for the design of materials with novel physical properties and therefore may represent a fruitful area for future research.


Esophageal cancer related gene-4 is a choroid plexus-derived injury response gene: evidence for a biphasic response in early and late brain injury.
By virtue of its ability to regulate the composition of cerebrospinal fluid (CSF), the choroid plexus (CP) is ideally suited to instigate a rapid response to traumatic brain injury (TBI) by producing growth regulatory proteins. For example, Esophageal Cancer Related Gene-4 (Ecrg4) is a tumor suppressor gene that encodes a hormone-like peptide called augurin that is present in large concentrations in CP epithelia (CPe). Because augurin is thought to regulate senescence, neuroprogenitor cell growth and differentiation in the CNS, we evaluated the kinetics of Ecrg4 expression and augurin immunoreactivity in CPe after CNS injury. Adult rats were injured with a penetrating cortical lesion and alterations in augurin immunoreactivity were examined by immunohistochemistry. Ecrg4 gene expression was characterized by in situ hybridization. Cell surface augurin was identified histologically by confocal microscopy and biochemically by sub-cellular fractionation. Both Ecrg4 gene expression and augurin protein levels were decreased 24-72 hrs post-injury but restored to uninjured levels by day 7 post-injury. Protein staining in the supraoptic nucleus of the hypothalamus, used as a control brain region, did not show a decrease of auguin immunoreactivity. Ecrg4 gene expression localized to CPe cells, and augurin protein to the CPe ventricular face. Extracellular cell surface tethering of 14 kDa augurin was confirmed by cell surface fractionation of primary human CPe cells in vitro while a 6-8 kDa fragment of augurin was detected in conditioned media, indicating release from the cell surface by proteolytic processing. In rat CSF however, 14 kDa augurin was detected. We hypothesize the initial release and proteolytic processing of augurin participates in the activation phase of injury while sustained Ecrg4 down-regulation is dysinhibitory during the proliferative phase. Accordingly, augurin would play a constitutive inhibitory function in normal CNS while down regulation of Ecrg4 gene expression in injury, like in cancer, dysinhibits proliferation.


[Prevalence of chronic kidney disease and its association with lifestyle factors in adults from 10 regions of China].
Objective: To investigate the distribution of chronic kidney disease (CKD) in participants from the China Kadoorie Biobank (CKB) study and evaluate the association between lifestyle risk factors and CKD. Methods: Based on the baseline survey data and follow-up data (as of December 31, 2018) of the CKB study, the differences in CKD cases' area and population distributions were described. Cox proportional hazards regression model was used to estimate the association between lifestyle risk factors and the risk of CKD. Results: A total of 505 147 participants, 4 920 cases of CKD were recorded in 11.26 year follow up with a incidence rate of 83.43/100 000 person-years. Glomerulonephropathy was the most common type. The incidence of CKD was higher in the urban area, men, and the elderly aged 60 years and above (87.83/100 000 person-years, 86.37/100 000 person-years, and 132.06/100 000 person-years). Current male smokers had an increased risk for CKD compared with non-smokers or occasional smokers (HR=1.18, 95%CI: 1.05-1.31). The non-obese population was used as a control group, both general obesity determined by BMI (HR=1.19, 95%CI: 1.10-1.29) and central obesity determined by waist circumference (HR=1.27, 95%CI: 1.19-1.35) were associated with higher risk for CKD. Conclusion: The risks for CKD varied with area and population in the CKB cohort study, and the risk was influenced by multiple lifestyle factors.


Use of sustained release dextroamphetamine for the treatment of stimulant use disorder in the setting of injectable opioid agonist treatment in Canada: a case report.
For people with opioid use disorder who are not responding to oral opioid agonist treatment, evidence supports the effectiveness of injectable opioid agonist treatment with injectable hydromorphone (an opioid analgesic) and diacetylmorphine (pharmaceutical grade heroin). While this treatment is effective at reducing illicit opioid use, concurrent cocaine use is prevalent. Dextroamphetamine (a central nervous system stimulant) has been found to be a safe and effective treatment for cocaine dependence among people receiving injectable opioid agonist treatment in Europe. We present the first report of dextroamphetamine prescribing offered for the treatment of stimulant use disorder among a patient receiving iOAT outside of a clinical trial. This case report can be used to inform clinical practice in the treatment of cocaine use disorder, an area where interventions are currently lacking. Dextroamphetamine was prescribed to a 51-year-old male who was diagnosed with concurrent opioid and stimulant use disorder in an injectable opioid agonist treatment clinic in Vancouver, Canada. He reported smoking crack cocaine daily for more than two decades and was experiencing health consequences associated with this use. He presented to his routine physician visit with the goal of reducing his cocaine use and was prescribed dextroamphetamine for the treatment of stimulant use disorder. After 4-weeks the patient was tolerating the medication with no observed adverse events and was achieving his therapeutic goal of reducing his cocaine use. Dextroamphetamine can be prescribed to support patients with stimulant use disorder to reduce or stop their use of cocaine. The case demonstrated that when dextroamphetamine was prescribed, a significant reduction in cocaine use was experienced among a patient that had been regularly using cocaine on a daily basis for many years. Daily contact with care for the opioid medication promoted adherence to the stimulant medication and allowed for monitoring of dose and tolerance. Settings where patients are in regular contact with care such as oral and injectable opioid agonist treatment clinics serve as a suitable location to integrate dextroamphetamine prescribing for patients that use illicit stimulants to reduce use and associated harms.


Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation.
Irradiated or injured cells enter apoptosis, and in turn, promote proliferation of surrounding unaffected cells. In Drosophila, apoptotic cells have an active role in proliferation, where the caspase Dronc and p53 induce mitogen expression and growth in the surrounding tissues. The Drosophila p53 gene structure is conserved and encodes at least two protein isoforms: a full-length isoform (Dp53) and an N-terminally truncated isoform (DΔNp53). Historically, DΔNp53 was the first p53 isoform identified and was thought to be responsible for all p53 biological activities. It was shown that DΔNp53 induces apoptosis by inducing the expression of IAP antagonists, such as Reaper. Here we investigated the roles of Dp53 and DΔNp53 in apoptosis and apoptosis-induced proliferation. We found that both isoforms were capable of activating apoptosis, but that they each induced distinct IAP antagonists. Expression of DΔNp53 induced Wingless (Wg) expression and enhanced proliferation in both 'undead cells' and in 'genuine' apoptotic cells. In contrast to DΔNp53, Dp53 did not induce Wg expression in the absence of the endogenous p53 gene. Thus, we propose that DΔNp53 is the main isoform that regulates apoptosis-induced proliferation. Understanding the roles of Drosophila p53 isoforms in apoptosis and in apoptosis-induced proliferation may shed new light on the roles of p53 isoforms in humans, with important implications in cancer biology.


Parallel driving and modulatory pathways link the prefrontal cortex and thalamus.
Pathways linking the thalamus and cortex mediate our daily shifts from states of attention to quiet rest, or sleep, yet little is known about their architecture in high-order neural systems associated with cognition, emotion and action. We provide novel evidence for neurochemical and synaptic specificity of two complementary circuits linking one such system, the prefrontal cortex with the ventral anterior thalamic nucleus in primates. One circuit originated from the neurochemical group of parvalbumin-positive thalamic neurons and projected focally through large terminals to the middle cortical layers, resembling 'drivers' in sensory pathways. Parvalbumin thalamic neurons, in turn, were innervated by small 'modulatory' type cortical terminals, forming asymmetric (presumed excitatory) synapses at thalamic sites enriched with the specialized metabotropic glutamate receptors. A second circuit had a complementary organization: it originated from the neurochemical group of calbindin-positive thalamic neurons and terminated through small 'modulatory' terminals over long distances in the superficial prefrontal layers. Calbindin thalamic neurons, in turn, were innervated by prefrontal axons through small and large terminals that formed asymmetric synapses preferentially at sites with ionotropic glutamate receptors, consistent with a driving pathway. The largely parallel thalamo-cortical pathways terminated among distinct and laminar-specific neurochemical classes of inhibitory neurons that differ markedly in inhibitory control. The balance of activation of these parallel circuits that link a high-order association cortex with the thalamus may allow shifts to different states of consciousness, in processes that are disrupted in psychiatric diseases.


Rouleaux red blood cells splitting in microscopic thin blood smear images via local maxima, circles drawing, and mapping with original RBCs.
Splitting the rouleaux RBCs from single RBCs and its further subdivision is a challenging area in computer-assisted diagnosis of blood. This phenomenon is applied in complete blood count, anemia, leukemia, and malaria tests. Several automated techniques are reported in the state of art for this task but face either under or over splitting problems. The current research presents a novel approach to split Rouleaux red blood cells (chains of RBCs) precisely, which are frequently observed in the thin blood smear images. Accordingly, this research address the rouleaux splitting problem in a realistic, efficient and automated way by considering the distance transform and local maxima of the rouleaux RBCs. Rouleaux RBCs are splitted by taking their local maxima as the centres to draw circles by mid-point circle algorithm. The resulting circles are further mapped with single RBC in Rouleaux to preserve its original shape. The results of the proposed approach on standard data set are presented and analyzed statistically by achieving an average recall of 0.059, an average precision of 0.067 and F-measure 0.063 are achieved through ground truth with visual inspection.


Association of puberty timing with type 2 diabetes: A systematic review and meta-analysis.
Emerging studies have investigated the association between puberty timing, particularly age at menarche (AAM), and type 2 diabetes. However, whether this association is independent of adiposity is unclear. We aimed to systematically review published evidence on the association between puberty timing and type 2 diabetes (T2D) or impaired glucose tolerance (IGT), with and without adjustment for adiposity, and to estimate the potential contribution of puberty timing to the burden of T2D in the United Kingdom (UK). We searched PubMed, Medline, and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-variance-weighted random-effects meta-analysis was used to pool reported estimates, and meta-regression was used to explore sources of heterogeneity. Twenty-eight observational studies were identified. All assessed AAM in women (combined N = 1,228,306); only 1 study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was lower per year later AAM (relative risk [RR] = 0.91, 95% CI 0.89-0.93, p < 0.001, 11 estimates, n = 833,529, I2 = 85.4%) and higher for early versus later menarche (RR = 1.39, 95% CI 1.25-1.55, p < 0.001, 23 estimates, n = 1,185,444, I2 = 87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR = 0.97 per year, 95% CI 0.95-0.98, p < 0.001, 12 estimates, n = 852,268, I2 = 51.8%; early menarche: RR = 1.19, 95% CI 1.11-1.28, p < 0.001, 21 estimates, n = 890,583, I2 = 68.1%). Associations were stronger among white than Asian women, and in populations with earlier average AAM. The estimated population attributable risk of T2D in white UK women due to early menarche unadjusted and adjusted for adiposity was 12.6% (95% CI 11.0-14.3) and 5.1% (95% CI 3.6-6.7), respectively. Findings in this study are limited by residual and unmeasured confounding, and self-reported AAM. Earlier AAM is consistently associated with higher T2D/IGT risk, independent of adiposity. More importantly, this research has identified that a substantial proportion of T2D in women is related to early menarche, which would be expected to increase in light of global secular trends towards earlier puberty timing. These findings highlight the need to identify the underlying mechanisms linking early menarche to T2D/IGT risk.


Risk factors for absence seizures: a population-based case-control study in Rochester, Minnesota.
To our knowledge, this is the first population-based case-control study of risk factors for absence seizures (AS). Diagnosis of AS was based on clinical criteria. The complete medical history of potential cases, available through the records-linkage system for residents of Rochester, MN, was independently reviewed by three neurologists who agreed upon the diagnosis. All AS patients who were residents of Rochester at time of diagnosis between 1935 and 1979, and who were born in this community, were included (N = 30). Two population controls (born in Rochester) were matched to each patient, and for both patients and controls, the records-linkage system was used to obtain information about possible risk factors. The only factor significantly more common in cases than in controls was a history of febrile seizures (odds ratio = 12; p less than 0.01). We suggest that these febrile seizures represent either an early manifestation of the convulsive diathesis or the symptom of a preexisting brain dysfunction. None of the other factors investigated reached statistical significance, including those that have been previously suggested such as twin pregnancy, breech presentation at delivery, being first-born, and perinatal asphyxia. Sample size limitations should be considered in interpreting these findings.


The whereabouts of a morphogen: direct evidence for short- and graded long-range activity of hedgehog signaling peptides.
Sonic Hedgehog (Shh) and Indian Hedgehog (Ihh) are members of the Hedgehog (Hh) family of signaling molecules known to be involved in embryonic patterning and morphogenesis. The Hh proteins undergo an autocatalytic cleavage to yield an N-terminal and a C-terminal peptide, with the signaling capacities confined to the N peptide. Drosophila Hh-N has been shown to act via both short- and long-range signaling. In vertebrates, however, attempts to directly demonstrate Shh (SHH) or Ihh (IHH) proteins at a distance from producing cells have been largely unsuccessful. Furthermore, the fact that the Hh N peptides occur in a cholesterol-modified, membrane-tethered form is not easily reconciled with long-range signaling. This study used optimized immunohistochemistry combined with tissue separation and biochemical analyses in vivo and in vitro to determine the range of action of SHH and IHH in the mouse embryo. In all embryonic structures studied, we detect signaling peptides in producing cells, but we also find that ligands move over considerable distances depending on the tissue. These data provide direct evidence for the presence of Hedgehog signaling peptides in target compartments, suggesting a direct long-range action without a need for secondary mediators. Visualization of Hedgehog proteins in target tissues was achieved only under conditions that allowed proteoglycan/glycosaminoglycan (PG/GAG) preservation. Furthermore, we show that induced changes of the composition of PG/GAG in the tooth alter SHH signaling. These data suggest a crucial role for PG/GAGs in Hedgehog movement.


Long Persistence of a Streptococcus pneumoniae 23F Clone in a Cystic Fibrosis Patient.
Streptococcus pneumoniae isolates of serotype 23F with intermediate penicillin resistance were recovered on seven occasions over a period of 37 months from a cystic fibrosis patient in Berlin. All isolates expressed the same multilocus sequence type (ST), ST10523. The genome sequences of the first and last isolates, D122 and D141, revealed the absence of two phage-related gene clusters compared to the genome of another ST10523 strain, D219, isolated earlier at a different place in Germany. Genomes of all three strains carried the same novel mosaic penicillin-binding protein (PBP) genes, pbp2x, pbp2b, and pbp1a; these genes were distinct from those of other penicillin-resistant S. pneumoniae strains except for pbp1a of a Romanian S. pneumoniae isolate. All PBPs contained mutations that have been associated with the penicillin resistance phenotype. Most interestingly, a mosaic block identical to an internal pbp2x sequence of ST10523 was present in pbp2x of Streptococcus mitis strain B93-4, which was isolated from the same patient. This suggests interspecies gene transfer from S. pneumoniae to S. mitis within the host. Nearly all genes expressing surface proteins, which represent major virulence factors of S. pneumoniae and are typical for this species, were present in the genome of ST10523. One exception was the hyaluronidase gene hlyA, which contained a 12-nucleotide deletion within the promoter region and an internal stop codon. The lack of a functional hyaluronidase might contribute to the ability to persist in the host for an unusually long period of time. IMPORTANCEStreptococcus pneumoniae is a common resident in the human nasopharynx. However, carriage can result in severe diseases due to a unique repertoire of pathogenicity factors that are rare in closely related commensal streptococci. We investigated a penicillin-resistant S. pneumoniae clone of serotype 23F isolated from a cystic fibrosis patient on multiple occasions over an unusually long period of over 3 years that was present without causing disease. Genome comparisons revealed an apparent nonfunctional pneumococcus-specific gene encoding a hyaluronidase, supporting the view that this enzyme adds to the virulence potential of the bacterium. The 23F clone harbored unique mosaic genes encoding penicillin resistance determinants, the product of horizontal gene transfer involving the commensal S. mitis as donor species. Sequences identical to one such mosaic gene were identified in an S. mitis strain from the same patient, suggesting that in this case S. pneumoniae played the role of donor.


Impact of residual platelet reactivity on reperfusion in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.
Whether high platelet reactivity (HPR) immediately after diagnostic angiography is associated with worse coronary reperfusion prior to and after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) is unknown. This study aimed to assess the impact of P2Y12-mediated HPR on angiographic outcomes in patients with STEMI undergoing PPCI. STEMI patients undergoing PPCI and pretreated with a P2Y12 receptor antagonist underwent platelet function testing with the VerifyNow™ assay at the time of angiography. Light transmission aggregometry (LTA) was performed in a subgroup. HPR was defined according to expert consensus definitions. Pre-PCI coronary patency, thrombotic burden and indices of impaired post-PCI reperfusion were compared between HPR and non-HPR patients. Among 164 patients, the prevalence of VerifyNow™-derived HPR was 71.3% at a median (interquartile range (IQR)) of 55 (40-75) minutes after a P2Y12 inhibitor loading dose. Compared with non-HPR patients, those with HPR had significantly lower rates of pre-PCI Thrombolysis in Myocardial Infarction (TIMI) flow grades 2 or 3 (51.1% vs. 32.5%, p = 0.04), higher rates of thrombus score (TS) grade 3/4 (29.8% vs. 52.1%, p = 0.015) and 4 (14.9% vs. 32.5%, p = 0.037) and lower median (IQR) corrected TIMI frame count (cTFC; 23.2 (15.8-32.5) vs. 26.0 (21.0-35.0), p = 0.02), respectively. These findings were consistent using LTA-based data. HPR and TS grade 4 were predictors of higher cTFC. In patients with STEMI undergoing PPCI pretreated with P2Y12 receptor inhibitors, pre-PPCI HPR was found to be associated with lower pre-PCI coronary patency, higher thrombotic burden and a worse index of post-PCI coronary reperfusion.


Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice.
Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here, we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21, or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.


The utility of high-resolution melting analysis of SNP nucleated PCR amplicons--an MLST based Staphylococcus aureus typing scheme.
High resolution melting (HRM) analysis is gaining prominence as a method for discriminating DNA sequence variants. Its advantage is that it is performed in a real-time PCR device, and the PCR amplification and HRM analysis are closed tube, and effectively single step. We have developed an HRM-based method for Staphylococcus aureus genotyping. Eight single nucleotide polymorphisms (SNPs) were derived from the S. aureus multi-locus sequence typing (MLST) database on the basis of maximized Simpson's Index of Diversity. Only G↔A, G↔T, C↔A, C↔T SNPs were considered for inclusion, to facilitate allele discrimination by HRM. In silico experiments revealed that DNA fragments incorporating the SNPs give much higher resolving power than randomly selected fragments. It was shown that the predicted optimum fragment size for HRM analysis was 200 bp, and that other SNPs within the fragments contribute to the resolving power. Six DNA fragments ranging from 83 bp to 219 bp, incorporating the resolution optimized SNPs were designed. HRM analysis of these fragments using 94 diverse S. aureus isolates of known sequence type or clonal complex (CC) revealed that sequence variants are resolved largely in accordance with G+C content. A combination of experimental results and in silico prediction indicates that HRM analysis resolves S. aureus into 268 "melt types" (MelTs), and provides a Simpson's Index of Diversity of 0.978 with respect to MLST. There is a high concordance between HRM analysis and the MLST defined CCs. We have generated a Microsoft Excel key which facilitates data interpretation and translation between MelT and MLST data. The potential of this approach for genotyping other bacterial pathogens was investigated using a computerized approach to estimate the densities of SNPs with unlinked allelic states. The MLST databases for all species tested contained abundant unlinked SNPs, thus suggesting that high resolving power is not dependent upon large numbers of SNPs.


Discovering transcription and splicing networks in myelodysplastic syndromes.
More and more transcription factors and their motifs have been reported and linked to specific gene expression levels. However, focusing only on transcription is not sufficient for mechanism research. Most genes, especially in eukaryotes, are alternatively spliced to different isoforms. Some of these isoforms increase the biodiversity of proteins. From this viewpoint, transcription and splicing are two of important mechanisms to modulate expression levels of isoforms. To integrate these two kinds of regulation, we built a linear regression model to select a subset of transcription factors and splicing factors for each co-expressed isoforms using least-angle regression approach. Then, we applied this method to investigate the mechanism of myelodysplastic syndromes (MDS), a precursor lesion of acute myeloid leukemia. Results suggested that expression levels of most isoforms were regulated by a set of selected regulatory factors. Some of the detected factors, such as EGR1 and STAT family, are highly correlated with progression of MDS. We discovered that the splicing factor SRSF11 experienced alternative splicing switch, and in turn induced different amino acid sequences between MDS and controls. This splicing switch causes two different splicing mechanisms. Polymerase Chain Reaction experiments also confirmed that one of its isoforms was over-expressed in MDS. We analyzed the regulatory networks constructed from the co-expressed isoforms and their regulatory factors in MDS. Many of these networks were enriched in the herpes simplex infection pathway which involves many splicing factors, and pathways in cancers and acute or chronic myeloid leukemia.


Quantum electronics. Probing Johnson noise and ballistic transport in normal metals with a single-spin qubit.
Thermally induced electrical currents, known as Johnson noise, cause fluctuating electric and magnetic fields in proximity to a conductor. These fluctuations are intrinsically related to the conductivity of the metal. We use single-spin qubits associated with nitrogen-vacancy centers in diamond to probe Johnson noise in the vicinity of conductive silver films. Measurements of polycrystalline silver films over a range of distances (20 to 200 nanometers) and temperatures (10 to 300 kelvin) are consistent with the classically expected behavior of the magnetic fluctuations. However, we find that Johnson noise is markedly suppressed next to single-crystal films, indicative of a substantial deviation from Ohm's law at length scales below the electron mean free path. Our results are consistent with a generalized model that accounts for the ballistic motion of electrons in the metal, indicating that under the appropriate conditions, nearby electrodes may be used for controlling nanoscale optoelectronic, atomic, and solid-state quantum systems.


Fungi that Infect Humans.
Fungi must meet four criteria to infect humans: growth at human body temperatures, circumvention or penetration of surface barriers, lysis and absorption of tissue, and resistance to immune defenses, including elevated body temperatures. Morphogenesis between small round, detachable cells and long, connected cells is the mechanism by which fungi solve problems of locomotion around or through host barriers. Secretion of lytic enzymes, and uptake systems for the released nutrients, are necessary if a fungus is to nutritionally utilize human tissue. Last, the potent human immune system evolved in the interaction with potential fungal pathogens, so few fungi meet all four conditions for a healthy human host. Paradoxically, the advances of modern medicine have made millions of people newly susceptible to fungal infections by disrupting immune defenses. This article explores how different members of four fungal phyla use different strategies to fulfill the four criteria to infect humans: the Entomophthorales, the Mucorales, the Ascomycota, and the Basidiomycota. Unique traits confer human pathogenic potential on various important members of these phyla: pathogenic Onygenales comprising thermal dimorphs such as Histoplasma and Coccidioides; the Cryptococcus spp. that infect immunocompromised as well as healthy humans; and important pathogens of immunocompromised patients-Candida, Pneumocystis, and Aspergillus spp. Also discussed are agents of neglected tropical diseases important in global health such as mycetoma and paracoccidiomycosis and common pathogens rarely implicated in serious illness such as dermatophytes. Commensalism is considered, as well as parasitism, in shaping genomes and physiological systems of hosts and fungi during evolution.


Master resilience training and its relationship to individual well-being and stress buffering among army national guard soldiers.
To better enable soldiers to adapt to stressors of military life, Master Resilience Training has been offered to soldiers since 2009. Few studies have examined whether the training achieves its intended effects. To fill this gap, resilience-trained Army National Guard soldiers and civilians (N = 611) completed online questionnaires about their resilience training experience (72% completion rate, N = 441). Respondents (92% or more) indicated the training was helpful and improved resilience competencies that enhanced coping with stressful circumstances. Respondents (97% or more) indicated that these competencies were subsequently used in their military and civilian jobs. A measure of resilience competencies was developed and showed self-reported changes largely pertained to increased self-awareness and strength of character, including improved optimism, mental agility, and connection with others. Self-reported change in resilience competencies was associated with fewer behavioral health symptoms, especially, for those reporting more current stressful events (known as the buffering effect). Findings are discussed in terms of resilience's potency of training, content of the training, and the need to elaborate on resilience's relationship to specific stressors.


Enhanced autophagy in pulmonary endothelial cells on exposure to HIV-Tat and morphine: Role in HIV-related pulmonary arterial hypertension.
Intravenous drug use is one of the major risk factors for HIV-infection in HIV-related pulmonary arterial hypertension patients. We previously demonstrated exaggerated pulmonary vascular remodeling with enhanced apoptosis followed by increased proliferation of pulmonary endothelial cells on simultaneous exposure to both opioids and HIV protein(s). Here we hypothesize that the exacerbation of autophagy may be involved in the switching of endothelial cells from an early apoptotic state to later hyper-proliferative state. Treatment of human pulmonary microvascular endothelial cells (HPMECs) with both the HIV-protein Tat and morphine resulted in an oxidative stress-dependent increase in the expression of various markers of autophagy and formation of autophagosomes when compared to either Tat or morphine monotreatments as demonstrated by western blot, transmission electron microscopy and immunofluorescence. Autophagy flux experiments suggested increased formation rather than decreased clearance of autolysosomes. Inhibition of autophagy resulted in a significant increase in apoptosis and reduction in proliferation of HPMECs with combined morphine and Tat (M+T) treatment compared to monotreatments whereas stimulation of autophagy resulted in opposite effects. Significant increases in the expression of autophagy markers as well as the number of autophagosomes and autolysosomes was observed in the lungs of SIV-infected macaques and HIV-infected humans exposed to opioids. Overall our findings indicate that morphine in combination with viral protein(s) results in the induction of autophagy in pulmonary endothelial cells that may lead to an increase in severity of angio-proliferative remodeling of the pulmonary vasculature on simian and human immunodeficiency virus infection in the presence of opioids.


Magnetic-resonance-imaging-derived indices for the normalization of left ventricular morphology by body size.
Scaling left ventricular (LV) mass and other cardiac dimensions to account for individual body size is important. The traditional method of simple ratio scaling using, for example, body surface area (BSA) assumes a linear and proportional relationship and accurate measurement of both LV mass and BSA. These assumptions can be questioned; hence, we examined the appropriateness of methods and different indices using highly accurate magnetic resonance imaging scans. Cardiac and whole-body scans were performed in 172 young, healthy, male subjects (age range, 17-28 years) to assess LV mass, volume, linear dimensions, lean body mass and fat mass. Height, body mass and BSA were determined anthropometrically. Relationships were examined for linearity and closeness of fit using log-log least-squares linear regression to determine the slope exponent b (where 1.0 indicates linearity). The relationship between LV mass and lean body mass (b=.90+/-.15; r(2)=.66) was linear and geometrically consistent. This was also the case for LV end-diastolic volume (b=.70), although the confidence intervals were broader (+/-0.32) and the r(2) (.31) smaller. The relationships between LV mass, volume and other variables were generally not linear or geometrically consistent. LV linear dimensions did not demonstrate any linear relationships, and in particular, those with BSA were extremely poor (r(2)=.02-.09). In summary, the traditional scaling of LV measurements to BSA does not remove the influence of body size and other techniques should be considered. Lean body mass was the most appropriate variable for simple indexing of LV mass. No body size variable had a linear and proportional relationship with LV linear dimensions, and the use of simple ratio scaling for these is seriously questioned.


The Cdc34/SCF ubiquitination complex mediates Saccharomyces cerevisiae cell wall integrity.
To identify novel functions for the Cdc34/SCF ubiquitination complex, we analyzed genomewide transcriptional profiles of cdc53-1 and cdc34-2 Saccharomyces cerevisiae mutants. This analysis revealed altered expression for several gene families, including genes involved in the regulation of cell wall organization and biosynthesis. This led us to uncover a role for the Cdc34/SCF complex in the regulation of cell wall integrity. In support of this, cdc53-1 and cdc34-2 mutants exhibit phenotypes characteristic of cell wall integrity mutants, such as SDS sensitivity and temperature-sensitive suppression by osmotic stabilizers. Examination of these mutants revealed defects in their induction of Slt2 phosphorylation, indicating defects in Pkc1-Slt2 MAPK signaling. Consistent with this, synthetic genetic interactions were observed between the genes encoding the Cdc34/SCF complex and key components of the Pck1-Slt2 MAPK pathway. Further analysis revealed that Cdc34/SCF mutants have reduced levels of active Rho1, suggesting that these defects stem from the deregulated activity of the Rho1 GTPase. Altering the activity of Rho1 via manipulation of the Rho1-GAPs LRG1 or SAC7 affected Cdc34/SCF mutant growth. Strikingly, however, deletion of LRG1 rescued the growth defects associated with Cdc34/SCF mutants, whereas deletion of SAC7 enhanced these defects. Given the differential roles that these GAPs play in the regulation of Rho1, these observations indicate the importance of coordinating Cdc34/SCF activity with specific Rho1 functions.


Exploring conceptual and theoretical frameworks for nurse practitioner education: a scoping review protocol.
The objective of this review is to examine conceptual and/or theoretical frameworks that are relevant to nurse practitioner education.The specific review question is: What conceptual and/or theoretical frameworks are available that are relevant to the structuring of nurse practitioner education? The use of conceptual and theoretical frameworks to organize the educational curriculum of nursing programs is essential to protect and preserve the focus and clarity of nursing's distinct contribution to health care. Conceptual frameworks of nursing provide a means to look at nursing in relationship to external factors, thereby assigning meaning to the practice. Graduate level nursing education in the preparation of Nurse Practitioners (NPs) specifically and Advanced Practice Nurses (APNs) in general, is significantly compromised by the tendency to conceptualize the learning in these complex programs as being primarily related to skills-based tasks and competencies alone. According to Baumann, advanced nursing education must focus on the uniqueness of the NP position, in contrast to other health care professions. To do this, Baumann suggests using a conceptual nursing model and nursing theory as opposed to a strictly biomedical model. This allows NPs to interpret information in a way that differs from the strict biomedical model, providing opportunities for the NPs to be truly present in the lives of their patients.Canadian Nurse Practitioner (NP) practice competency documents are based primarily on the Canadian Nurses Association (CNA) Nurse Practitioner (NP) Core Competency Framework. This document defines the core set of entry-level competencies required for all NPs to practice in all Canadian jurisdictions, settings and client populations. The Core Competencies in the CNA NP Framework are organized within four main categories: professional role, responsibility and accountability; health assessment and diagnosis; therapeutic management; and health promotion and prevention of illness and injury. Although vital to the organization of provincial entry-level registration standards, this framework provides little direction to educational providers for curricula organization and philosophical perspectives.The Canadian Association of Schools of Nursing developed a national framework for NP education following a multi-phase consultation and literature and curriculum synthesis project. While the task force addressed the guiding principles and essential components of NP education along with contextual factors that impact on the delivery of curricula in Canadian jurisdictions, the philosophical approaches guiding and organizing the education were not addressed.A similar set of documents has been created in the United States by the National Organization of Nurse Practitioner Faculties (NONPF). These documents are organized by six population level foci (including the specialty of family/individual across the lifespan) and outline core competencies for entry to practice and registration and educational standards. The Core Competency documents provided by the NONPF are presented in the same manner as the CNA NP Framework and likewise, do not provide a guiding or organizing framework or philosophy for NP education.A full curriculum overhaul based on the NONPF competency requirements was performed at a university center in Oregon. The new curriculum was based on competencies that students must acquire, rather than learning objectives. While the NONPF Framework does provide an extensive list of entry-level requirements for NPs, the challenges faced by the institution as it aimed to incorporate the framework into the curriculum clearly provide evidence that these overarching frameworks need to include both a philosophical and organizational component to help guide educators.Conceptual frameworks are useful for establishing a congruent relationship between program curricula, objectives and content. Walker and Avant advance the utility of conceptual frameworks as providing the logic behind the interrelationships of terms and variables, and improving explanation and understanding. Gold, Haas & King assert that conceptual frameworks facilitate grounding of a nursing lens in the curricula of advanced practice nursing programs. It has been noted that newly practicing NPs have demonstrated an allegiance withmedical model thinking, second only in importance to wellness/health promotion considerations. Blasdell and colleagues surveyed 188 practicing NPs to investigate the relationship between education and the use of theory in clinical practice. Educated graduate NPs rated the importance of nursing theory to the NP practice role significantly higher than did diploma and baccalaureate degree NPs (4.05±2.06 versus 2.65±1.69, p<.001) but both groups rated the nursing models as less important for practice than a medical model approach.Huckabay highlighted the need for the use of a harmonized nursing model at the undergraduate level to ensure that students have a thorough understanding of what nursing is and what nursing care entails. At the graduate level, Huckabay suggested the use of multiple nursing models, depending on specialty. Regardless of the educational level, a conceptual framework used for education must enable nurse educators to have sufficient guidelines to construct a curriculum and determine what knowledge and skills are needed by the nursing students. Further, Furlong identified the need for Advanced Practice Nursing (APN) curriculae to be innovative and critically reflective, preparing students to be readily adaptable to challenges in the work place. Furlong suggests that to do this, the curriculum must rely upon an interdisciplinary framework to deliver content. Gold, Haas & King suggest that core curricula based on a medical model or a skill-related task list do not reflect the critical thinking of nurses, nor the uniqueness of the profession. Thus, conceptual models used for curricula development must: encompass the distinct nursing worldview, promote learning, and be efficient and comprehensive.Frameworks have been proposed and tested to guide the development and implementation of inter-professional education (IPE) and collaborative practice curricula for NP and medical students. A qualitative assessment of a framework guided IPE module illustrated the benefit of improving the focus on role awareness in participating students. However, this particular curriculum was limited to a two-week period and not presented as a pervasive approach to the educational programs of each discipline.In education, an overarching philosophy can provide a road map for goal identification, teaching material development and the formulation of evaluation methods. For instance, when creating a curriculum that was a result of the collaboration of three different post-secondary institutions, the SHARE (students, humor, administrative support, resources, and educational technology) model was used. This model brings together resources, students and faculty, surrounding them with humor, which was viewed as a fundamental part of the process while the program was still in its early stages. According to the authors, the program has been widely successful and the reliance on humor as an underlying philosophy has enabled the students and faculty to deal with problems arising in the new program.Focusing on evaluation, Kapborg & Fischbein promoted the use of the Education Interaction Model. The model identifies how educational influences can interact with abilities of students and how the consequences of this interaction can be evaluated by observing changes in both students and programs. The authors argue that, while the educational interaction model is effective, it is not the only model that can be used to carry out evaluations. The authors stress that the model chosen to perform an evaluation should be based upon what or who is going to be evaluated.The standards outlined in the CNA NP framework are an essential part of organizing the education process for NPs and ensuring that NPs have acquired the necessary skills to practice in Canada as an NP. However, the framework is lacking philosophy and organization regarding NP education programs to ensure that the curriculum is preparing the NPs for the ever-changing work environment.An Australian survey of NP education documents from relevant universities as well as interviews with NPs and academic conveners from Australia and New Zealand found that, while NP educational programs need to have strong clinical and science based learning components, student directed and flexible learning models act to ensure the capability of NPs as they strive to adapt to practice situations. Capability, as an approach to the learning process, includes the flexibility to respond to the specific, self-identified learning needs of students. Knowing how to learn, having high self-efficacy, applying competencies to new tasks, collaborating with others, and being creative are all signs of a capable practitioner. Gardner et al. emphasized the need for a program that fosters both competent and capable NPs. In a follow-up study, using the same data, Gardner et al. confirmed that NPs viewed the attributes of a capable NP as imperative to practice. Thus, a framework for NP education must include both competency building elements, such as those currently found in the CNA NP framework and capability building elements which can be fostered through self-directed learning.Similarly, Schaefer investigated the role of caring in nursing practice through a class for APN students in which the students reflected on their narratives of caring for patients. This qualitative study revealed that when APN students provide care by meeting the complex needs of suffering patients, the art and science of nursing combine. (ABSTRACT TRUNCATED)


Regional cerebral blood flow in monozygotic twins discordant and concordant for schizophrenia.
We addressed several questions regarding hypofunction of the prefrontal cortex ("hypofrontality") in schizophrenia by measuring regional cerebral blood flow during three different cognitive conditions in monozygotic twins who were discordant or concordant for schizophrenia or who were both normal. These questions included the prevalence of hypofrontality, the importance of genetic predisposition, and the role of long-term neuroleptic treatment. Significant differences between affected and unaffected discordant twins were found only during a task linked to the prefrontal cortex, the Wisconsin Card Sorting Test. During this condition, all of the twins with schizophrenia were hypofrontal compared with their unaffected co-twins, suggesting that, if appropriate cognitive conditions and control groups are used, hypofrontality can be demonstrated in the majority of, if not all, patients with schizophrenia. When unaffected co-twins of patients with schizophrenia were compared with twins who were both normal, no differences were observed, suggesting that nongenetic factors are important in the cause of the prefrontal physiologic deficit that appears to characterize schizophrenia. When concordant twins with a high- vs a low-dose lifetime history of neuroleptic treatment were compared, the twin receiving the higher dose was more hyperfrontal in six of eight pairs, suggesting that long-term neuroleptic treatment does not play a major role in hypofrontality.