What we talk about when we talk about risk: refining surgery's hazards in medical thought.
Current efforts to improve the cost-effectiveness of health care focus on assessing accurately the value of technologically complex, costly medical treatments for individual patients and society. These efforts universally acknowledge that the determination of such value should incorporate information regarding the risks posed by a given treatment for an individual, but they typically overlook the implications for medical decision making that inhere in how notions of risk are understood and used in contemporary medical discourse. To gain perspective on how the hazards of surgery have been defined and redefined in medical thought, we examine changes over time in notions of risk related to operative care. We reviewed historical writings on risk assessment and patient selection for surgical procedures published between 1957 and 1997 and conducted informal interviews with experts. To examine changes attributable to advances in research on risk assessment, we focused on the period surrounding the 1977 publication of an influential surgical risk-stratification index. Writings before 1977 demonstrate a summative, global approach to patients as "good" or "poor" risks, without quantifying the likelihood of specific postoperative events. Beginning in the early 1980s, assessments of operative risk increasingly emphasized quantitative estimates of the probability of dysfunction of a specific organ system after surgery. This new approach to establishing surgical risk was consistent with concurrent trends in other domains of medicine. In particular, it emphasized a more "scientific," standardized approach to medical decision making over an earlier focus on individual physicians' judgment and professional authority. Recent writings on operative risk reflect a viewpoint that is more specific and, at the same time, more generic and fragmented than earlier approaches. By permitting the separation of multiple component hazards implicit in surgical interventions, such a viewpoint may encourage a distinct, permissive standard for surgical interventions that conflicts with larger policy efforts to promote cost-effective decision making by physicians and patients.


Direct determination of the ionization energies of PtC, PtO, and PtO2 with VUV radiation.
Photoionization efficiency curves were measured for gas-phase PtC, PtO, and PtO2 using tunable vacuum ultraviolet (VUV) radiation at the Advanced Light Source. The molecules were prepared by laser ablation of a platinum tube, followed by reaction with CH4 or N2O and supersonic expansion. These measurements provide the first directly measured ionization energy for PtC, IE(PtC) = 9.45 +/- 0.05 eV. The direct measurement also gives greatly improved ionization energies for the platinum oxides, IE(PtO) = 10.0 +/- 0.1 eV and IE(PtO2) = 11.35 +/- 0.05 eV. The ionization energy connects the dissociation energies of the neutral and cation, leading to greatly improved 0 K bond dissociation energies for the neutrals: D0(Pt-C) = 5.95 +/- 0.07 eV, D0(Pt-O) = 4.30 +/- 0.12 eV, and D0(OPt-O) = 4.41 +/- 0.13 eV, as well as enthalpies of formation for the gas-phase molecules DeltaH(0)(f,0)(PtC(g)) = 701 +/- 7 kJ/mol, DeltaH(0)(f,0)(PtO(g)) = 396 +/- 12 kJ/mol, and DeltaH(0)(f,0)(PtO2(g)) = 218 +/- 11 kJ/mol. Much of the error in previous Knudsen cell measurements of platinum oxide bond dissociation energies is due to the use of thermodynamic second law extrapolations. Third law values calculated using statistical mechanical thermodynamic functions are in much better agreement with values obtained from ionization energies and ion energetics. These experiments demonstrate that laser ablation production with direct VUV ionization measurements is a versatile tool to measure ionization energies and bond dissociation energies for catalytically interesting species such as metal oxides and carbides.


Nanoscale structural characterization of epitaxial graphene grown on off-axis 4H-SiC (0001).
In this work, we present a nanometer resolution structural characterization of epitaxial graphene (EG) layers grown on 4H-SiC (0001) 8° off-axis, by annealing in inert gas ambient (Ar) in a wide temperature range (Tgr from 1600 to 2000°C). For all the considered growth temperatures, few layers of graphene (FLG) conformally covering the 100 to 200-nm wide terraces of the SiC surface have been observed by high-resolution cross-sectional transmission electron microscopy (HR-XTEM). Tapping mode atomic force microscopy (t-AFM) showed the formation of wrinkles with approx. 1 to 2 nm height and 10 to 20 nm width in the FLG film, as a result of the release of the compressive strain, which builds up in FLG during the sample cooling due to the thermal expansion coefficients mismatch between graphene and SiC. While for EG grown on on-axis 4H-SiC an isotropic mesh-like network of wrinkles interconnected into nodes is commonly reported, in the present case of a vicinal SiC surface, wrinkles are preferentially oriented in the direction perpendicular to the step edges of the SiC terraces. For each Tgr, the number of graphene layers was determined on very small sample areas by HR-XTEM and, with high statistics and on several sample positions, by measuring the depth of selectively etched trenches in FLG by t-AFM. Both the density of wrinkles and the number of graphene layers are found to increase almost linearly as a function of the growth temperature in the considered temperature range.


People with intellectual disability who offend or are involved with the criminal justice system.
This review assesses the impact of recent research on the field of offenders with intellectual disabilities. Research includes work on prevalence, developments in appropriate assessments and investigations into the effectiveness of treatment procedures. Methodological difficulties continued to beset studies on prevalence, with estimates ranging between 2 and 10% of the offender population having intellectual disabilities. Research on risk assessment has developed quickly in the last 7 years and current studies establish both the framework for assessment and new instruments that have been shown to predict offending incidents. There have been a number of promising studies on sex offender treatment and on the treatment of issues related to general offending. These studies continue to evaluate treatment progress in terms of improvements in behaviour, cognitive distortions and reductions of offending. One notable study had targeted reductions in sexual deviancy. With two exceptions, the main drawback in treatment studies continues to be the lack of control conditions. These research studies will aid clinicians in the implementation of the assessment reviews and treatment programs for offenders with intellectual disabilities.


Vascular endothelial growth factor promotes fibrosis resolution and repair in mice.
Vascular endothelial growth factor (VEGF)-induced angiogenesis is implicated in fibrogenesis and portal hypertension. However, the function of VEGF in fibrosis resolution has not been explored. We developed a cholecystojejunostomy procedure to reconstruct biliary flow after bile duct ligation in C57BL/6 mice to generate a model of fibrosis resolution. These mice were then given injections of VEGF-neutralizing (mcr84) or control antibodies, and other mice received an adenovirus that expressed mouse VEGF or a control vector. The procedure was also performed on macrophage fas-induced apoptosis mice, in which macrophages can be selectively depleted. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, vascular permeability, real-time polymerase chain reaction, and flow cytometry assays. VEGF-neutralizing antibodies prevented development of fibrosis but also disrupted hepatic tissue repair and fibrosis resolution. During fibrosis resolution, VEGF inhibition impaired liver sinusoidal permeability, which was associated with reduced monocyte migration, adhesion, and infiltration of fibrotic liver. Scar-associated macrophages contributed to this process by producing the chemokine (C-X-C motif) ligand 9 (CXCL9) and matrix metalloproteinase 13. Resolution of fibrosis was impaired in macrophage fas-induced apoptosis mice but increased after overexpression of CXCL9. In a mouse model of liver fibrosis resolution, VEGF promoted fibrogenesis, but was also required for hepatic tissue repair and fibrosis resolution. We observed that VEGF regulates vascular permeability, monocyte infiltration, and scar-associated macrophages function.


Concurrent deployment of visual attention and response selection bottleneck in a dual-task: Electrophysiological and behavioural evidence.
Visual attention and response selection are limited in capacity. Here, we investigated whether visual attention requires the same bottleneck mechanism as response selection in a dual-task of the psychological refractory period (PRP) paradigm. The dual-task consisted of an auditory two-choice discrimination Task 1 and a conjunction search Task 2, which were presented at variable temporal intervals (stimulus onset asynchrony, SOA). In conjunction search, visual attention is required to select items and to bind their features resulting in a serial search process around the items in the search display (i.e., set size). We measured the reaction time of the visual search task (RT2) and the N2pc, an event-related potential (ERP), which reflects lateralized visual attention processes. If the response selection processes in Task 1 influence the visual attention processes in Task 2, N2pc latency and amplitude would be delayed and attenuated at short SOA compared to long SOA. The results, however, showed that latency and amplitude were independent of SOA, indicating that visual attention was concurrently deployed to response selection. Moreover, the RT2 analysis revealed an underadditive interaction of SOA and set size. We concluded that visual attention does not require the same bottleneck mechanism as response selection in dual-tasks.


Prevalence and characteristics of non-syndromic orofacial clefts and the influence of consanguinity.
The Objective of this study was to identify the prevalence and describe the characteristics of non-syndromic orofacial cleft (NSOFC) in Jeddah, Saudi Arabia and examine the influence of consanguinity. Six hospitals were selected to represent Jeddah's five municipal districts. New born infants with NSOFC born between 1st of January 2010 to 31st of December 2011 were clinically examined and their number compared to the total number of infants born in these hospitals to calculate the prevalence of NSOFC types and sub-phenotypes. Referred Infants were included for the purpose of studying NSOFC characteristics and their relationship to consanguinity. Information on NSOFC infants was gathered through parents' interviews, infants 'files and patient examinations. Prospective surveillance of births resulted in identifying 37 NSOFC infants born between 1st of January 2010 to 31st of December 2011 giving a birth prevalence of 0.80/1000 living births. The total infants seen, including referred cases, were 79 children. Consanguinity among parents of cleft palate (CP) cases was statistically higher than that among cleft lip with or without cleft palate (CL/P) patients (P = 0.039). Although there appears to be a trend in the relationship between consanguinity and severity of CL/P sub-phenotype, it was not statistically significant (P = 0.248). Birth prevalence of NSOFC in Jeddah City was 0.8/1000 live births with CL/P: 0.68/1000 and CP: 0.13/1000. Both figures were low compared to the global birth prevalence (NSOFC: 1.25/1000, CL/P: 0.94/1000 and CP: 0.31/1000 live births). Consanguineous parents were statistically higher among CP cases than among other NSOFC phenotypes.


Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction.
The inflammatory response following myocardial infarction (MI) is prerequisite for proper healing of infarcted tissue, but can also have detrimental effects on cardiac function. Interleukin (IL)-1α and IL-1β are potent inflammatory mediators and their bioactivity is tightly regulated by IL-1 receptor antagonist (IL-1ra) and soluble (s) IL-1 receptors (R). We aimed to examine whether levels of soluble regulators of IL-1 signalling are changed during ST-elevation MI (STEMI) and their associations with parameters of cardiac injury and ventricular remodelling. Plasma levels of IL-1Ra, sIL-1R1, sIL-1R2 and sIL-1R accessory protein (sIL-1RAcP) were measured by immunoassays in repeated samples from patients with STEMI (n = 255) and compared to healthy controls (n = 65). IL-1Ra, sIL-1R1 and sIL-1R2 levels were all significantly elevated after STEMI, while levels of sIL-1RAcP were lower compared to controls. sIL-1R2 levels (at different time points) correlated positively with C-reactive protein, myocardial infarct size and change in indexed left ventricular end-diastolic and end-systolic volume (LVEDVi and LVESVi) measured by cardiac MR acutely and after 4 months, and negatively with LV ejection fraction. Patients with >median levels of sIL-1R2 in the acute phase were more likely to have increased change in LVEDVi and LVESVi. Importantly, sIL-1R2 remained significantly associated with change in LVEDVi and LVESVi also after adjustment for clinical covariates. Levels of sIL-1R2 are independently associated with parameters of LV adverse remodelling following STEMI.


Changes in sexuality and intimacy after the diagnosis and treatment of cancer: the experience of partners in a sexual relationship with a person with cancer.
Changes in sexuality and intimacy after cancer were examined using open-ended questionnaire responses with 156 informal carers who were partners of a person with cancer. Interviews were conducted with 20 participants to examine changes in depth. Seventy-six percent of partners of a person with "nonreproductive" cancer types and 84% of partners caring for a person with cancer involving "reproductive" sites reported an impact on their sexual relationship. Cessation or decreased frequency of sex and intimacy was reported by 59% of the women and 79% of the men. Renegotiation of sexuality and intimacy after cancer was reported by only 19% of the women and 14% of the men. Reasons for changes to sexuality after cancer were the impact of cancer treatments, exhaustion due to caring, and repositioning of the person with cancer as a patient, not a sexual partner. Changes to sexuality were associated with reports of self-blame, rejection, sadness, anger, and lack of sexual fulfillment. Positive consequences of changes included accepting the changed sexual relationship and having increased closeness and intimacy. These findings reinforce the need to acknowledge the sexual needs of partners as well as people with cancer, by healthcare professionals working in cancer and palliative care.


Benefits and Risks of Bariatric Surgery in Adults: A Review.
Severe obesity and its related diseases, such as type 2 diabetes, hypertension, dyslipidemia, and sleep apnea, are very common in the United States, but currently very few patients with these conditions choose to undergo bariatric surgery. Summaries of the expanding evidence for both the benefits and risks of bariatric surgery are needed to better guide shared decision-making conversations. There are approximately 252 000 bariatric procedures (per 2018 numbers) performed each year in the US, of which an estimated 15% are revisions. The 1991 National Institutes of Health guidelines recommended consideration of bariatric surgery in patients with a body mass index (calculated as weight in kilograms divided by height in meters squared) of 40 or higher or 35 or higher with serious obesity-related comorbidities. These guidelines are still widely used; however, there is increasing evidence that bariatric procedures should also be considered for patients with type 2 diabetes and a body mass index of 30 to 35 if hyperglycemia is inadequately controlled despite optimal medical treatment for type 2 diabetes. Substantial evidence indicates that surgery results in greater improvements in weight loss and type 2 diabetes outcomes, compared with nonsurgical interventions, regardless of the type of procedures used. The 2 most common procedures used currently, the sleeve gastrectomy and gastric bypass, have similar effects on weight loss and diabetes outcomes and similar safety through at least 5-year follow-up. However, emerging evidence suggests that the sleeve procedure is associated with fewer reoperations, and the bypass procedure may lead to more durable weight loss and glycemic control. Although safety is a concern, current data indicate that the perioperative mortality rates range from 0.03% to 0.2%, which has substantially improved since early 2000s. More long-term randomized studies are needed to assess the effect of bariatric procedures on cardiovascular disease, cancer, and other health outcomes and to evaluate emerging newer procedures. Modern bariatric procedures have strong evidence of efficacy and safety. All patients with severe obesity-and especially those with type 2 diabetes-should be engaged in a shared decision-making conversation about the risks and benefits of surgery compared with continuing usual medical and lifestyle treatment, and the decision about surgery should be driven primarily by informed patient preferences.


The Relationship Between Neurocognitive Functioning and Occupational Functioning in Bipolar Disorder: A Literature Review.
Neurocognitive impairment in Bipolar Disorder (BD) has been widely reported, even during remission. Neurocognitive impairment has been identified as a contributing factor towards unfavourable psychosocial functioning within this population. The objective of this review was to investigate the association between neurocognitive impairment and occupational functioning in BD. A literature review of English-language journal articles from January 1990 to November 2013 was undertaken utilising the PsychINFO, Scopus and Web of Knowledge databases. Studies that made specific reference to occupational outcomes were included, and those that reported on global psychosocial measures were excluded. Majority of the papers reviewed (20 out of 23) identified an association between neurocognitive impairment (particularly in executive functioning, verbal learning and memory, processing speed and attention) and occupational functioning. Several methodological issues were identified. There was a discrepancy in the measures used to assess neurocognitive function across studies and also the definition and measurement of occupational functioning. The clinical features of the samples varied across studies, and confounding variables were intermittently controlled. The review focused on English-language papers only and hence there is a bias toward the Western labour market. These limitations therefore influence the generalizability of the interpreted findings and the reliability of comparisons across studies. Neurocognitive impairment in BD appears to play a role in occupational outcomes. The findings of this review highlight the challenges for future research in this area, particularly in the measurement of neurocognitive and occupational functioning. Incorporating neurocognitive interventions in the treatment of BD, which has traditionally focussed solely on symptomatic recovery, may advance the vocational rehabilitation of these patients.


Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes.
Genome-wide association studies (GWASs) are regularly used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of 10 candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 participants. We discovered four rare variants that lowered T1D risk independently of each other (odds ratio = 0.51 to 0.74; P = 1.3 x 10(-3) to 2.1 x 10(-16)) in IFIH1 (interferon induced with helicase C domain 1), a gene located in a region previously associated with T1D by GWASs. These variants are predicted to alter the expression and structure of IFIH1 [MDA5 (melanoma differentiation-associated protein 5)], a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This finding firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWASs.


Meta-proteomics for the discovery of protein biomarkers of beef tenderness: An overview of integrated studies.
This meta-proteomics review focused on proteins identified as candidate biomarkers of beef tenderness by comparing extreme groups of tenderness using two-dimensional electrophoresis (2-DE) associated with mass spectrometry (MS). We reviewed in this integromics study the results of 12 experiments that identified protein biomarkers from two muscles, Longissimus thoracis (LT) and Semitendinosus (ST), of different types of cattle: young bulls, steers or cows from beef breeds (Charolais, Limousin, Blond d'Aquitaine), hardy breed (Salers) or mixed breed (PDO Maine-Anjou). Comparative proteomics of groups differing in their tenderness evaluated by instrumental Warner-Bratzler shear force (WBSF) or by sensory analysis using trained panelists, revealed 61 proteins differentially abundant (P < 0.05) between tender and tough groups. A higher number of discriminative proteins was observed for LT (50 proteins) compared to ST muscle (28 proteins). The Gene Ontology annotations showed that the proteins of structure and contraction, protection against oxidative stress and apoptosis, energy metabolism, 70 family HSPs and proteasome subunits are more involved in LT tenderness than in ST. Amongst the list of candidate biomarkers of tenderness some proteins such as HSPB1 are common between the two muscles whatever the evaluation method of tenderness, but some relationships with tenderness for other proteins (MYH1, TNNT3, HSPB6) were inversed. Muscle specificities were revealed in this meta-proteomics. For example, Parvalbumin (PVALB) appeared as a robust biomarker in ST muscle whatever the evaluation method of tenderness. HSPA1B seems to be a robust candidate for LT tenderness (with WBSF) regardless the animal type. Some gender specificities were further identified including similarities between cows and steers (MSRA and HSPA9) in contrast to bulls. The comparison of the 12 proteomic studies revealed strong dissimilarities to identify generic biomarkers of beef tenderness. This integrative analysis allowed better understanding of the biological processes involved in beef tenderness in two muscles and their variations according to the main factors underlying this quality. It allowed also proposing for the first time a comprehensive list of candidate biomarkers to be evaluated deeply to validate their relationships with tenderness on a large number of cattle and breeds.


Transfer of the left-side bias effect in perceptual expertise: The case of simplified and traditional Chinese character recognition.
The left-side bias (LSB) effect observed in face and expert Chinese character perception is suggested to be an expertise marker for visual object recognition. However, in character perception this effect is limited to characters printed in a familiar font (font-sensitive LSB effect). Here we investigated whether the LSB and font-sensitive LSB effects depend on participants' familiarity with global structure or local component information of the stimuli through examining their transfer effects across simplified and traditional Chinese scripts: the two Chinese scripts share similar overall structures but differ in the visual complexity of local components in general. We found that LSB in expert Chinese character processing could be transferred to the Chinese script that the readers are unfamiliar with. In contrast, the font-sensitive LSB effect did not transfer, and was limited to characters with the visual complexity the readers were most familiar with. These effects suggest that the LSB effect may be generalized to another visual category with similar overall structures; in contrast, effects of within-category variations such as fonts may depend on familiarity with local component information of the stimuli, and thus may be limited to the exemplars of the category that experts are typically exposed to.


Slow diffusion of home HIV-specimen collection: provider concerns at odds with client preferences.
Home specimen collection and telephone counseling (HSCTC) may be a convenient new method for detection of HIV infection among cohorts at high-risk for HIV. To evaluate attitudes about HSCTC among participants, HIV counselors, and community advisory board members associated with a national multisite study of persons at high risk for HIV. Twelve focus groups and surveys were conducted at six sites among 126 counselors, community advisory board members, and cohort participants. Staff and community advisory board members raised concerns about the acceptability, feasibility, safety, and effectiveness of HSCTC. In contrast, participants (92%) reported a willingness to collect blood and oral samples on a frequent basis, and preferred telephone (73%) to office-based counseling. Home specimen collection and telephone counseling appear to be preferred by study participants at high risk of HIV infection. Staff and community advisory board members had stronger reservations than prospective users.


Effects of resistance training on the physical capacities of adolescent soccer players.
This study examined the effects of a progressive resistance training program in addition to soccer training on the physical capacities of male adolescents. Eighteen soccer players (age: 12-15 years) were separated in a soccer (SOC; n = 9) and a strength-soccer (STR; n = 9) training group and 8 subjects of similar age constituted a control group. All players followed a soccer training program 5 times a week for the development of technical and tactical skills. In addition, the STR group followed a strength training program twice a week for 16 weeks. The program included 10 exercises, and at each exercise, 2-3 sets of 8-15 repetitions with a load 55-80% of 1 repetition maximum (1RM). Maximum strength ([1RM] leg press, bench-press), jumping ability (squat jump [SJ], countermovement jump [CMJ], repeated jumps for 30 seconds) running speed (30 m, 10 x 5-m shuttle run), flexibility (seat and reach), and soccer technique were measured at the beginning, after 8 weeks, and at the end of the training period. After 16 weeks of training, 1RM leg press, 10 x 5-m shuttle run speed, and performance in soccer technique were higher (p < 0.05) for the STR and the SOC groups than for the control group. One repetition maximum bench press and leg press, SJ and CMJ height, and 30-m speed were higher (p < 0.05) for the STR group compared with SOC and control groups. The above data show that soccer training alone improves more than normal growth maximum strength of the lower limps and agility. The addition of resistance training, however, improves more maximal strength of the upper and the lower body, vertical jump height, and 30-m speed. Thus, the combination of soccer and resistance training could be used for an overall development of the physical capacities of young boys.


Nuclear genomic signals of the 'microturbellarian' roots of platyhelminth evolutionary innovation.
Flatworms number among the most diverse invertebrate phyla and represent the most biomedically significant branch of the major bilaterian clade Spiralia, but to date, deep evolutionary relationships within this group have been studied using only a single locus (the rRNA operon), leaving the origins of many key clades unclear. In this study, using a survey of genomes and transcriptomes representing all free-living flatworm orders, we provide resolution of platyhelminth interrelationships based on hundreds of nuclear protein-coding genes, exploring phylogenetic signal through concatenation as well as recently developed consensus approaches. These analyses robustly support a modern hypothesis of flatworm phylogeny, one which emphasizes the primacy of the often-overlooked 'microturbellarian' groups in understanding the major evolutionary transitions within Platyhelminthes: perhaps most notably, we propose a novel scenario for the interrelationships between free-living and vertebrate-parasitic flatworms, providing new opportunities to shed light on the origins and biological consequences of parasitism in these iconic invertebrates.


Insulin regulates neuronal M2 muscarinic receptor function in the ileum of diabetic rats.
Acetylcholine release from cholinergic nerves in the gastrointestinal tract is limited by neuronal M(2) muscarinic receptors. In diabetic animals, M(2) muscarinic receptor function in the ileum is increased, leading to decreased acetylcholine release and smooth muscle contraction in response to nerve stimulation. The mechanisms responsible for increased M(2) muscarinic receptor function are unknown but may contribute to the gastrointestinal dysmotility that occurs frequently in diabetics. In this study, we investigated whether insulin modulates M(2) muscarinic receptor function in the gastrointestinal tract of diabetic rats. M(2) muscarinic receptor function was tested by measuring the ability of an agonist, pilocarpine, to inhibit and an antagonist, methoctramine, to potentiate electrical field stimulation (EFS)-induced contraction of ileum in vitro. Insulin administration (0.2, 0.6, and 2 U s.c. daily for 7 days) reversed the diabetes-induced increase in M(2) muscarinic receptor function and restored normal contractions to EFS. Insulin had no effect on the function of postjunctional M(3) muscarinic receptors, determined by measuring contractile responses to acetylcholine. These data suggest that insulin tonically inhibits neuronal M(2) muscarinic receptors. Thus, loss of insulin removes this inhibition and increases M(2) muscarinic receptor function leading to decreased acetylcholine release and contraction to EFS. In nondiabetic rats, there was a trend that higher insulin doses (0.6 and 2 U) increased M(2) muscarinic receptor function, suggesting a bell-shaped concentration-response relationship for insulin. In conclusion, lack of insulin or excess insulin increases M(2) muscarinic receptor function in rat ileum. This mechanism may contribute to decreased acetylcholine release in the gastrointestinal tract of diabetics, resulting in dysmotility.


[Neuropsychological profile of frontotemporal lobar degeneration].
Frontotemporal lobar degeneration encompasses three different syndromes, with clinical and pathologic commonalities, making diagnosis difficult in early stages. Three subtypes are recognized: frontotemporal dementia and its three variants, corticobasal syndrome and supranuclear palsy syndrome. The objective of this study is to review the neuropsychological features of each syndrome in order to differentiate amongst subtypes as well as from other forms of dementia. We review multiple studies from the literature, highlighting the main clinical features, neuropathology and changes in brain imaging of each syndrome. Subsequently, we describe the neuropsychological profile compared to other dementias, and how it progresses over time. Although there is an overlap amongst the different subtypes of frontotemporal lobar degeneration, neuropsychological profiles can help identify subtypes and discriminate frontotemporal lobar degeneration from other forms of dementia.


Nanoscale Advancement Continues-From Catalysts and Reagents to Restructuring of Reaction Media.
Comprehensive studies dedicated to the search for specific properties of matter at the micro- and nanoscales have greatly enriched the fields of chemistry and materials science. From the point of view of synthetic chemistry, discoveries in the field of nanoscale catalysis, in which the size effects of active centers are used to accelerate the reactions, are of particular importance. However, another approach for the promotion of chemical transformations based on the micro- or nanoconfinement of reacting molecules or even on the structuring of the reaction media as a whole is gaining interest as a highly valuable tool. Herein, we highlight the example of an increase in the efficiency of phenol alkylation and tert-butylation of benzyl alcohol in reaction media based on ionic liquids by the creation of acidic microdomains in the presence of small molecule additives.


The Association Between Diabetes and Age-Related Macular Degeneration Among the Elderly in Taiwan.
To investigate the relationship between diabetes and future development of age-related macular degeneration (AMD). Longitudinal, retrospective cohort study data for the period between 1997 and 2012 were obtained from the Longitudinal Health Insurance Database (LHID) of Taiwan. The final available 71,904 patients with diabetes and 270,213 patients without diabetes ≥50 years of age were further matched by age, sex, and Charlson comorbidity index. In the end, 54,616 study subjects in each of the diabetes and nondiabetes groups were recruited. The stratified populations of patients with diabetes with diabetic retinopathy (DR) (n = 7,119) versus those with diabetes who do not have DR (n = 7,119) and populations of patients with proliferative DR (PDR) (n = 2,134) versus those with nonproliferative DR (NPDR) (n = 2,134) were also obtained. Competing risk regression models were used to assess the adjusted hazard ratio (HR) and 99% CI. The main outcome measures were the first-ever diagnosis of AMD during the observational period. The incidences of nonexudative AMD (HR 1.23; P = 0.108) and exudative AMD (HR 1.37; P = 0.023) were not significantly associated with cohorts of persons with diabetes compared with cohorts without diabetes. The stratified analysis showed that nonexudative AMD (HR 3.89; P = 0.001) and exudative AMD (HR 3.42; P < 0.001) were significantly correlated to diabetes with DR cohorts, compared with diabetes without DR cohorts. The incidences of nonexudative AMD (HR 0.53; P = 0.277) and exudative AMD (HR 2.27; P = 0.058) were not significantly different between PDR cohorts compared with NPDR cohorts. This study provides large-scale, population-based evidence that diabetes with retinopathy is independently associated with an increased risk of subsequent AMD development.


A filamentous growth response mediated by the yeast mating pathway.
Haploid cells of the budding yeast Saccharomyces cerevisiae respond to mating pheromones by arresting their cell-division cycle in G1 and differentiating into a cell type capable of locating and fusing with mating partners. Yeast cells undergo chemotactic cell surface growth when pheromones are present above a threshold level for morphogenesis; however, the morphogenetic responses of cells to levels of pheromone below this threshold have not been systematically explored. Here we show that MATa haploid cells exposed to low levels of the alpha-factor mating pheromone undergo a novel cellular response: cells modulate their division patterns and cell shape, forming colonies composed of filamentous chains of cells. Time-lapse analysis of filament formation shows that its dynamics are distinct from that of pseudohyphal growth; during pheromone-induced filament formation, daughter cells are delayed relative to mother cells with respect to the timing of bud emergence. Filament formation requires the RSR1(BUD1), BUD8, SLK1/BCK1, and SPA2 genes and many elements of the STE11/STE7 MAP kinase pathway; this response is also independent of FAR1, a gene involved in orienting cell polarization during the mating response. We suggest that mating yeast cells undergo a complex response to low levels of pheromone that may enhance the ability of cells to search for mating partners through the modification of cell shape and alteration of cell-division patterns.


Cutaneous warming promotes sleep onset.
Sleep occurs in close relation to changes in body temperature. Both the monophasic sleep period in humans and the polyphasic sleep periods in rodents tend to be initiated when core body temperature is declining. This decline is mainly due to an increase in skin blood flow and consequently skin warming and heat loss. We have proposed that these intrinsically occurring changes in core and skin temperatures could modulate neuronal activity in sleep-regulating brain areas (Van Someren EJW, Chronobiol Int 17: 313-54, 2000). We here provide results compatible with this hypothesis. We obtained 144 sleep-onset latencies while directly manipulating core and skin temperatures within the comfortable range in eight healthy subjects under controlled conditions. The induction of a proximal skin temperature difference of only 0.78 +/- 0.03 degrees C (mean +/- SE) around a mean of 35.13 +/- 0.11 degrees C changed sleep-onset latency by 26%, i.e., by 3.09 minutes [95% confidence interval (CI), 1.91 to 4.28] around a mean of 11.85 min (CI, 9.74 to 14.41), with faster sleep onsets when the proximal skin was warmed. The reduction in sleep-onset latency occurred despite a small but significant decrease in subjective comfort during proximal skin warming. The induction of changes in core temperature (delta = 0.20 +/- 0.02 degrees C) and distal skin temperature (delta = 0.74 +/- 0.05 degrees C) were ineffective. Previous studies have demonstrated correlations between skin temperature and sleep-onset latency. Also, sleep disruption by ambient temperatures that activate thermoregulatory defense mechanisms has been shown. The present study is the first to experimentally demonstrate a causal contribution to sleep-onset latency of skin temperature manipulations within the normal nocturnal fluctuation range. Circadian and sleep-appetitive behavior-induced variations in skin temperature might act as an input signal to sleep-regulating systems.


Children's complex care needs: a systematic concept analysis of multidisciplinary language.
Complex care in the arena of child health is a growing phenomenon. Although considerable research is taking place, there remains limited understanding and agreement on the concept of complex care needs (CCNs), with potential for ambiguity. We conducted a systematic concept analysis of the attributes, antecedents, and consequences of children's CCNs from a multidisciplinary perspective. Our data sources included PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO. Inclusion criteria included publications in peer-reviewed journals between January 1990 and December 2017, written in the English language. One hundred and forty articles were included. We found that children's CCNs refer to multidimensional health and social care needs, in the presence of a recognized medical condition or where there is no unifying diagnosis.Conclusion: Children's CCNs are individual and contextualized, are continuing and dynamic, and are present across a range of settings, impacted by family and healthcare structures. There remain extensive challenges to caring for these children and their families, precluding the possibility that any one profession can possess the requisite knowledge or scope to singularly provide high-quality competent care. What is Known: • Complex care is a growing phenomenon and population prevalence figures show that there is an increasing number of children with complex care needs (CCNs). However, the concept has not been systematically analyzed before, leaving it generally ill-defined and at times confusing. What is New: • This is the first time this concept has been systematically analyzed and this analysis provides a much-needed theoretical framework for understanding the multidimensional nature of CCNs in children. • Children's CCNs refer to multidimensional health and social care needs in the presence of a recognized medical condition or where there is no unifying diagnosis. They are individual and contextualized, are continuing and dynamic, and are present across a range of settings, impacted by family and healthcare structures. It is clear that the very nature of CCNs precludes the possibility that any one profession or discipline can possess the requisite knowledge or scope for high-quality competent care for this population.


Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder.
Whilst professional bodies such as the Royal College and the American College of Obstetricians and Gynecologists have well-established standards for audit of management for most gynaecology disorders, such standards for premenstrual disorders (PMDs) have yet to be developed. The International Society of Premenstrual Disorders (ISPMD) has already published three consensus papers on PMDs covering areas that include definition, classification/quantification, clinical trial design and management (American College Obstetricians and Gynecologists 2011; Brown et al. in Cochrane Database Syst Rev 2:CD001396, 2009; Dickerson et al. in Am Fam Physician 67(8):1743-1752, 2003). In this fourth consensus of ISPMD, we aim to create a set of auditable standards for the clinical management of PMDs. All members of the original ISPMD consensus group were invited to submit one or more auditable standards to be eligible in the inclusion of the consensus. Ninety-five percent of members (18/19) responded with at least one auditable standard. A total of 66 auditable standards were received, which were returned to all group members who then ranked the standards in order of priority, before the results were collated. Proposed standards related to the diagnosis of PMDs identified the importance of obtaining an accurate history, that a symptom diary should be kept for 2 months prior to diagnosis and that symptom reporting demonstrates symptoms in the premenstrual phase of the menstrual cycle and relieved by menstruation. Regarding treatment, the most important standards were the use of selective serotonin reuptake inhibitors (SSRIs) as a first line treatment, an evidence-based approach to treatment and that SSRI side effects are properly explained to patients. A set of comprehensive standards to be used in the diagnosis and treatment of PMD has been established, for which PMD management can be audited against for standardised and improved care.


Predicting Anatomical Therapeutic Chemical (ATC) classification of drugs by integrating chemical-chemical interactions and similarities.
The Anatomical Therapeutic Chemical (ATC) classification system, recommended by the World Health Organization, categories drugs into different classes according to their therapeutic and chemical characteristics. For a set of query compounds, how can we identify which ATC-class (or classes) they belong to? It is an important and challenging problem because the information thus obtained would be quite useful for drug development and utilization. By hybridizing the informations of chemical-chemical interactions and chemical-chemical similarities, a novel method was developed for such purpose. It was observed by the jackknife test on a benchmark dataset of 3,883 drug compounds that the overall success rate achieved by the prediction method was about 73% in identifying the drugs among the following 14 main ATC-classes: (1) alimentary tract and metabolism; (2) blood and blood forming organs; (3) cardiovascular system; (4) dermatologicals; (5) genitourinary system and sex hormones; (6) systemic hormonal preparations, excluding sex hormones and insulins; (7) anti-infectives for systemic use; (8) antineoplastic and immunomodulating agents; (9) musculoskeletal system; (10) nervous system; (11) antiparasitic products, insecticides and repellents; (12) respiratory system; (13) sensory organs; (14) various. Such a success rate is substantially higher than 7% by the random guess. It has not escaped our notice that the current method can be straightforwardly extended to identify the drugs for their 2(nd)-level, 3(rd)-level, 4(th)-level, and 5(th)-level ATC-classifications once the statistically significant benchmark data are available for these lower levels.


Connexin 43-Mediated Gap Junction Communication Regulates Ameloblast Differentiation via ERK1/2 Phosphorylation.
Connexin 43 (Cx43) is an integral membrane protein that forms gap junction channels. These channels mediate intercellular transport and intracellular signaling to regulate organogenesis. The human disease oculodentodigital dysplasia (ODDD) is caused by mutations in Cx43 and is characterized by skeletal, ocular, and dental abnormalities including amelogenesis imperfecta. To clarify the role of Cx43 in amelogenesis, we examined the expression and function of Cx43 in tooth development. Single-cell RNA-seq analysis and immunostaining showed that Cx43 is highly expressed in pre-secretory ameloblasts, differentiated ameloblasts, and odontoblasts. Further, we investigated the pathogenic mechanisms of ODDD by analyzing Cx43-null mice. These mice developed abnormal teeth with multiple dental epithelium layers. The expression of enamel matrix proteins such as ameloblastin (Ambn), which is critical for enamel formation, was significantly reduced in Cx43-null mice. TGF-β1 induces Ambn transcription in dental epithelial cells. The induction of Ambn expression by TGF-β1 depends on the density of the cultured cells. Cell culture at low densities reduces cell-cell contact and reduces the effect of TGF-β1 on Ambn induction. When cell density was high, Ambn expression by TGF-β1 was enhanced. This induction was inhibited by the gap junction inhibitors, oleamide, and 18α-grycyrrhizic acid and was also inhibited in cells expressing Cx43 mutations (R76S and R202H). TGF-β1-mediated phosphorylation and nuclear translocation of ERK1/2, but not Smad2/3, were suppressed by gap junction inhibitors. Cx43 gap junction activity is required for TGF-β1-mediated Runx2 phosphorylation through ERK1/2, which forms complexes with Smad2/3. In addition to its gap junction activity, Cx43 may also function as a Ca2+ channel that regulates slow Ca2+ influx and ERK1/2 phosphorylation. TGF-β1 transiently increases intracellular calcium levels, and the increase in intracellular calcium over a short period was not related to the expression level of Cx43. However, long-term intracellular calcium elevation was enhanced in cells overexpressing Cx43. Our results suggest that Cx43 regulates intercellular communication through gap junction activity by modulating TGF-β1-mediated ERK signaling and enamel formation.


Ca2+ metabolism during cholinergic stimulation of acid secretion.
Carbachol-induced changes in 45Ca fluxes and cytosolic free Ca2+ were characterized in rabbit gastric glands and isolated dog parietal cells. Cholinergic stimulation was expressed as changes in the membrane permeability of the parietal cell to Ca2+ without Ca2+ release from intracellular stores. The changes in the membrane permeability to Ca2+ were sustained as long as the cells were exposed to carbachol, independent of extracellular Ca2+, and had the properties of a passive pathway across which Ca2+ distributed according to its chemical gradient. As a consequence of the changes in membrane permeability to Ca2+, carbachol caused a sustained increase in free cytosolic Ca2+ from a resting level of 134 +/- 11 to 533 +/- 81 nM (n = 14). After carbachol stimulation, calcium ions were sequestered in mitochondrial and probably nonmitochondrial compartments. When cell stimulation was terminated by atropine or La3+, the cells restored the resting level of the intracellular Ca2+ activity ([Ca2+]in), independent of uncoupling of mitochondrial oxidation phosphorylation. Reduction in [Ca2+]in was mainly through Ca2+ efflux across the plasma membrane of the parietal cell. Manipulation of intracellular Na+ ion activity in intact cells and studies with basal-lateral membrane vesicles from gastric mucosa indicated the absence of extracellular Na+-intracellular Ca2+ exchange activity in the plasma membrane of the parietal cell. A calmodulin-regulated, ATP-dependent Ca2+ pump that could maintain active Ca2+ extrusion from parietal cells was found in the basal-lateral membrane of the parietal cells.


Inline holographic coherent anti-Stokes Raman microscopy.
We demonstrate a simple approach for inline holographic coherent anti-Stokes Raman scattering (CARS) microscopy, in which a layer of uniform nonlinear medium is placed in front of a specimen to be imaged. The reference wave created by four-wave mixing in the nonlinear medium can interfere with the CARS signal generated in the specimen to result in an inline hologram. We experimentally and theoretically investigate the inline CARS holography and show that it has chemical selectivity and can allow for three-dimensional imaging.


The comparison between motor imagery and verbal rehearsal on the learning of sequential movements.
Mental practice refers to the cognitive rehearsal of a physical activity. It is widely used by athletes to enhance their performance and its efficiency to help train motor function in people with physical disabilities is now recognized. Mental practice is generally based on motor imagery (MI), i.e., the conscious simulation of a movement without its actual execution. It may also be based on verbal rehearsal (VR), i.e., the silent rehearsal of the labels associated with an action. In this study, the effect of MI training or VR on the learning and retention of a foot-sequence task was investigated. Thirty right-footed subjects, aged between 22 and 37 years old (mean: 27.4 ± 4.1 years) and randomly assigned to one of three groups, practiced a serial reaction time task involving a sequence of three dorsiflexions and three plantar flexions with the left foot. One group (n = 10) mentally practiced the sequence with MI for 5 weeks, another group (n = 10) mentally practiced the sequence with VR of the foot positions for the same duration, and a control group (n = 10) did not practice the sequence mentally. The time to perform the practiced sequence as well as an unpracticed sequence was recorded before training, immediately after training and 6 months after training (retention). The main results showed that the speed improvement after training was significantly greater in the MI group compared to the control group and tended to be greater in the VR group compared to the control group. The improvement in performance did not differ in the MI and VR groups. At retention, however, no difference in response times was found among the three groups, indicating that the effect of mental practice did not last over a long period without training. Interestingly, this pattern of results was similar for the practiced and non-practiced sequence. Overall, these results suggest that both MI training and VR help to improve motor performance and that mental practice may induce non-specific effects.


MAG2, a Toxoplasma gondii Bradyzoite Stage-Specific Cyst Matrix Protein.
Toxoplasma gondii causes a chronic infection that affects a significant portion of the world's population, and this latent infection is the source of reactivation of toxoplasmosis. An attribute of the slowly growing bradyzoite stage of the parasite is the formation of a cyst within infected cells, allowing the parasite to escape the host's immune response. In this study, a new bradyzoite cyst matrix antigen (MAG) was identified through a hybridoma library screen. This cyst matrix antigen, matrix antigen 2 (MAG2), contains 14 tandem repeats consisting of acidic, basic, and proline residues. Immunoblotting revealed that MAG2 migrates at a level higher than its predicted molecular weight, and computational analysis showed that the structure of MAG2 is highly disordered. Cell fractionation studies indicated that MAG2 was associated with both insoluble and soluble cyst matrix material, suggesting that it interacts with the intracyst network (ICN). Examination of the kinetics of MAG2 within the cyst matrix using fluorescence recovery after photobleaching (FRAP) demonstrated that MAG2 does not readily diffuse within the cyst matrix. Kinetic studies of MAG1 demonstrated that this protein has different diffusion kinetics in tachyzoite and bradyzoite vacuoles and that its mobility is not altered in the absence of MAG2. In addition, deletion of MAG2 does not influence growth, cystogenesis, or cyst morphology.IMPORTANCE This report expands on the list of characterized Toxoplasma gondii cyst matrix proteins. Using fluorescence recovery after photobleaching (FRAP), we have shown that matrix proteins within the cyst matrix are not mainly in a mobile state, providing further evidence of how proteins behave within the cyst matrix. Understanding the proteins expressed during the bradyzoite stage of the parasite reveals how the parasite functions during chronic infection.


Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials.
There is currently no effective treatment for recurrent hepatitis C after orthotopic liver transplantation (OLT). We therefore performed two randomized, controlled trials--a prophylaxis trial and a treatment trial--to evaluate the safety and efficacy of peginterferon alfa-2a in patients who had undergone OLT. The prophylaxis trial enrolled 54 patients within 3 weeks after OLT, and the treatment trial enrolled 67 patients 6 to 60 months after OLT. In each trial, patients were randomized to treatment with once weekly injections of 180 microg peginterferon alfa-2a or no antiviral treatment for 48 weeks and were followed up for 24 weeks thereafter. Peginterferon alfa-2a treated patients had significantly lower hepatitis C virus RNA levels and more favorable changes in hepatic histological features compared with untreated controls. However, only 2 treated patients in the prophylaxis trial (8%) and 3 in the treatment trial (12%) achieved a sustained virological response. In the prophylaxis trial, 8 patients (31%) in the peginterferon alfa-2a group and 9 (32%) in the untreated group were withdrawn prematurely; whereas in the treatment trial, 10 patients (30%) in the peginterferon alfa-2a group and 6 (19%) in the untreated group were withdrawn prematurely. The incidence of acute rejection was similar in the treated and untreated groups in both the prophylaxis (12% vs. 21%; P = .5) and treatment (12% vs. 0%; P = .1) trials. In conclusion, peginterferon alfa-2a treatment for 48 weeks is safe and tolerable and offers some efficacy in the post-OLT setting. Randomized controlled studies are needed to establish the efficacy of pegylated interferon and ribavirin in patients who have undergone OLT.


The global burden of dengue: an analysis from the Global Burden of Disease Study 2013.
Dengue is the most common arbovirus infection globally, but its burden is poorly quantified. We estimated dengue mortality, incidence, and burden for the Global Burden of Disease Study 2013. We modelled mortality from vital registration, verbal autopsy, and surveillance data using the Cause of Death Ensemble Modelling tool. We modelled incidence from officially reported cases, and adjusted our raw estimates for under-reporting based on published estimates of expansion factors. In total, we had 1780 country-years of mortality data from 130 countries, 1636 country-years of dengue case reports from 76 countries, and expansion factor estimates for 14 countries. We estimated an average of 9221 dengue deaths per year between 1990 and 2013, increasing from a low of 8277 (95% uncertainty estimate 5353-10 649) in 1992, to a peak of 11 302 (6790-13 722) in 2010. This yielded a total of 576 900 (330 000-701 200) years of life lost to premature mortality attributable to dengue in 2013. The incidence of dengue increased greatly between 1990 and 2013, with the number of cases more than doubling every decade, from 8·3 million (3·3 million-17·2 million) apparent cases in 1990, to 58·4 million (23·6 million-121·9 million) apparent cases in 2013. When accounting for disability from moderate and severe acute dengue, and post-dengue chronic fatigue, 566 000 (186 000-1 415 000) years lived with disability were attributable to dengue in 2013. Considering fatal and non-fatal outcomes together, dengue was responsible for 1·14 million (0·73 million-1·98 million) disability-adjusted life-years in 2013. Although lower than other estimates, our results offer more evidence that the true symptomatic incidence of dengue probably falls within the commonly cited range of 50 million to 100 million cases per year. Our mortality estimates are lower than those presented elsewhere and should be considered in light of the totality of evidence suggesting that dengue mortality might, in fact, be substantially higher. Bill & Melinda Gates Foundation.


Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors.
The protozoan parasite Toxoplasma gondii blocks the innate aversion of rats for cat urine, instead producing an attraction to the pheromone; this may increase the likelihood of a cat predating a rat. This is thought to reflect adaptive, behavioral manipulation by Toxoplasma in that the parasite, although capable of infecting rats, reproduces sexually only in the gut of the cat. The "behavioral manipulation" hypothesis postulates that a parasite will specifically manipulate host behaviors essential for enhancing its own transmission. However, the neural circuits implicated in innate fear, anxiety, and learned fear all overlap considerably, raising the possibility that Toxoplasma may disrupt all of these nonspecifically. We investigated these conflicting predictions. In mice and rats, latent Toxoplasma infection converted the aversion to feline odors into attraction. Such loss of fear is remarkably specific, because infection did not diminish learned fear, anxiety-like behavior, olfaction, or nonaversive learning. These effects are associated with a tendency for parasite cysts to be more abundant in amygdalar structures than those found in other regions of the brain. By closely examining other types of behavioral patterns that were predicted to be altered we show that the behavioral effect of chronic Toxoplasma infection is highly specific. Overall, this study provides a strong argument in support of the behavioral manipulation hypothesis. Proximate mechanisms of such behavioral manipulations remain unknown, although a subtle tropism on part of the parasite remains a potent possibility.


Prescribing Competency of Medical Students: National Survey of Medical Education Leaders.
Introduction Evidence suggests that newly licensed physicians are not adequately prepared to prescribe safely. There is currently no national pre-licensure prescribing competency assessment required in North America. This study's purpose was to survey Canadian medical school leaders for their interest in and perceived need for a nationwide prescribing assessment for final year medical students. Method In spring of 2015, surveys were disseminated online to medical education leaders in all 17 Canadian medical schools. The survey included questions on perceived prescribing competency in medical schools, and interest in integration of a national assessment into medical school curricula and licensing. Results 372 (34.6 %) faculty from all 17 Canadian medical schools responded. 277 (74.5%) respondents were residency directors, 33 (8.9%) vice deans of medical education or equivalent, and 62 (16.7%) clerkship coordinators. Faculty judged 23.4% (SD 22.9%) of their own graduates' prescribing knowledge to be unsatisfactory and 131 (44.8%) felt obligated to provide close supervision to more than a third of their new residents due to prescribing concerns. 239 (73.0%) believed that an assessment process would improve their graduates' quality, 262 (80.4%) thought it should be incorporated into their medical school curricula and 248 (76.0%) into the national licensing process. Except in regards to close supervision due to concerns, there were no significant differences between schools' responses. Conclusions Amongst Canadian medical school leadership, there is a perceived inadequacy in medical student prescribing competency as well as support for a standardized prescribing competency assessment in curricula and licensing processes.


A multivariate brain signature for reward.
The processing of reinforcers and punishers is crucial to adapt to an ever changing environment and its dysregulation is prevalent in mental health and substance use disorders. While many human brain measures related to reward have been based on activity in individual brain regions, recent studies indicate that many affective and motivational processes are encoded in distributed systems that span multiple regions. Consequently, decoding these processes using individual regions yields small effect sizes and limited reliability, whereas predictive models based on distributed patterns yield larger effect sizes and excellent reliability. To create such a predictive model for the processes of rewards and losses, termed the Brain Reward Signature (BRS), we trained a model to predict the signed magnitude of monetary rewards on the Monetary Incentive Delay task (MID; N = 39) and achieved a highly significant decoding performance (92% for decoding rewards versus losses). We subsequently demonstrate the generalizability of our signature on another version of the MID in a different sample (92% decoding accuracy; N = 12) and on a gambling task from a large sample (73% decoding accuracy, N = 1084). We further provided preliminary data to characterize the specificity of the signature by illustrating that the signature map generates estimates that significantly differ between rewarding and negative feedback (92% decoding accuracy) but do not differ for conditions that differ in disgust rather than reward in a novel Disgust-Delay Task (N = 39). Finally, we show that passively viewing positive and negatively valenced facial expressions loads positively on our signature, in line with previous studies on morbid curiosity. We thus created a BRS that can accurately predict brain responses to rewards and losses in active decision making tasks, and that possibly relates to information seeking in passive observational tasks.


Determination of the Pretibial Soft Tissue Thickness in Children: Are Intraosseous Infusion Needles Long Enough?
The EZ-IO intraosseous (IO) needle is available in 2 needle sizes for children based on the patient weight. To date, there is no published evidence validating the use of weight-based scaling in children. We hypothesized that pretibial subcutaneous tissue thickness (PSTT) does not correspond with patient weight but rather with age and body mass index (BMI). Our objective was to describe the relationship of a patient's PSTT to their weight, age, and BMI in children less than 40 kg. One hundred patients who weighed less than 40 kg were recruited prospectively from October 2013 to April 2015 at a tertiary care pediatric emergency department. All sonographic assessments were performed by 1 of 2 emergency physicians certified in point-of-care ultrasound. A single sonographic image was taken over the proximal tibia corresponding to the site of IO insertion. In patients where both sonographers performed independent measurements, a Pearson correlation coefficient was determined. Univariate linear regression was performed to determine the relationship between age, weight, and BMI with PSTT. One hundred participants were recruited and ranged in age from 10 days to 14 years (mean [SD], 5.01 [3.14] years). Fifty-seven percent of participants were male. Patients' weights ranged from 3.5 to 39.3 kg (mean [SD], 21.42 [9.12] kg), and BMI ranged from 12.1 to 45.0 kg/m (mean [SD], 17.31 [4.00]). The mean (SD) PSTT across participants was 0.68 (0.2) cm. The intraclass correlation coefficient for agreement between the 2 sonographers was moderate (intraclass correlation coefficient, 0.602 [confidence interval, 0.385-0.757]). There were significant positive correlations between BMI and PSTT (r = 0.562, P = <0.001) as well as weight and PSTT (r = 0.293, P < 0.003). There was a weak correlation between age and PSTT (0.065, P = 0.521). Pretibial subcutaneous tissue thickness correlates most strongly with BMI, followed by weight, and weakly with age. Our findings suggest that current IO needle length recommendations should be based on BMI rather than weight. This would suggest that clinicians need to be aware that young patients in particular with large BMIs may pose problems with current weight-based needle length recommendations.


Isotropic single-objective microscopy: theory and experiment.
Isotropic single-objective (ISO) microscopy is a recently proposed imaging technique that can theoretically exhibit the same axial and transverse resolutions as 4Pi microscopy while using a classical single-objective confocal microscope. This achievement is obtained by placing the sample on a mirror and shaping the illumination beam so that the interference of the incident and mirror-reflected fields yields a quasi-spherical spot. In this work, we model the image formation in the ISO fluorescence microscope and simulate its point spread function. Then, we describe the experimental implementation and discuss its practical difficulties.


The dynamics and impact of foot and mouth disease in smallholder farming systems in South-East Asia: a case study in Laos.
There is a general lack of data on the different patterns of dynamics and impact of foot and mouth disease (FMD) in South-East Asia and the impact the disease has on different sectors, in particular the smallholder sector in which livestock play such an important role. A pilot study was conducted of a recent outbreak of FMD that swept across the southern part of Laos during the second half of 1999. The main objectives of the study were to investigate the possible routes of transmission of the disease and the impact of FMD on the predominantly smallholder rice/livestock production system of Savannakhet Province. The study was performed by group interviews of farmers in ten villages, located in five districts across the width of the Province, and of district and provincial veterinary officials. Results suggested that the infection had probably been introduced from the eastern border and had spread rapidly west, along a principal trading route of pigs, cattle and buffalo. In the process, many villages adjacent to this trading route became infected and the disease spread rapidly within infected villages. The disease had a significant impact on the agricultural system, but the impact would have been much greater had the epidemic occurred during the season of paddy field preparation. Mortality was observed in young buffalo, cattle and pigs, and long periods of morbidity were observed in buffalo, often requiring extended treatment. The sale of livestock for cash was severely restricted, creating additional repercussions on that sector. It was concluded that the most appropriate approach to FMD control would be to prevent infected animals from entering the principal trading routes for pigs, cattle and buffalo. This will require the involvement of all the stakeholders of the livestock industry, including traders and veterinary authorities. A further tactic to be considered would be to protect livestock systems adjacent to these trading routes by vaccination. An economic study of the market incentives of both traders and smallholders is recommended and this approach is advocated in other parts of South-East Asia where livestock trading routes present the major risk of FMD outbreaks.


Two cases of periodic fever syndrome with coexistent mevalonate kinase and Mediterranean fever gene mutations.
Çakan M, Aktay-Ayaz N, Keskindemirci G, Karadağ ŞG. Two cases of periodic fever syndrome with coexistent mevalonate kinase and Mediterranean fever gene mutations. Turk J Pediatr 2017; 59: 467-470. The periodic fever syndromes are autoinflammatory diseases that present with recurrent fever, serositis and rash. Familial Mediterranean fever is the most common periodic fever syndrome and characterized by recurrent attacks of fever, arthritis, peritonitis, pleuritis that typically last 1-3 days. Hyperimmunoglobulinemia D syndrome is another example of periodic fever syndromes and patients have recurrent fever attacks for 3-7 days accompanied by abdominal pain, rash, vomiting, diarrhea, arthralgia, arthritis, aphthous ulcers, and cervical lymphadenopathy. In some cases the clinical picture of the patient does not fit to one autoinflammatory syndrome because of the digenic inheritance. This may cause to overlap or atypical clinical features or an unexpected response to treatment. Herein we report two cases of hyperimmunoglobulinemia D syndrome that also had MEFV gene mutations and familial Mediterranean fever phenotype.


The value of (18)F-FDG PET/CT for the detection of distant metastases in high-risk patients with head and neck squamous cell carcinoma.
The aims of this study were to assess a cohort of patients with head and neck squamous cell carcinoma (HNSCC) for: (1) the prevalence of synchronous distant metastases (DM) as detected by the initial staging by using (18)F-FDG PET/CT, (2) the prevalence of metachronous DM, and (3) the validity of published risk factors with special emphasis on the maximum standardized uptake value (SUV max) for the prediction of DM. Two hundred and ninety nine patients with advanced HNSCC were included. Following risk factors at the time of diagnosis and during follow-up were analyzed: advanced T/N stage, poor histological differentiation, level IV/Vb lymph nodes, primary site in the larynx/hypopharynx, and SUV max. The prevalence of DM at initial staging and during follow-up was 10% and 11%, respectively. At initial staging, primary site in the larynx/hypopharynx and neck nodes in level IV/Vb, and during follow-up only level IV/Vb nodes achieved statistical significance. The sensitivity for (18)F-FDG PET/CT with regard to the detection of DM was 96.8%, the specificity 95.4%, the positive predictive value (PV) 69.8%, and the negative PV 99.6%. Patients without DM showed a significantly better overall survival (OS) than patients developing DM (p<0.001). There was no significant difference in OS with regard to the time of diagnosis of DM. The prevalence for synchronous and metachronous DM in advanced HNSCC is considerable. (18)F-FDG PET/CT is highly accurate for initial staging and follow-up. DM carries a bad prognosis regardless of the time of diagnosis.


Impact of foliar herbivory on the development of a root-feeding insect and its parasitoid.
The majority of studies exploring interactions between above- and below-ground biota have been focused on the effects of root-associated organisms on foliar herbivorous insects. This study examined the effects of foliar herbivory by Pieris brassicae L. (Lepidoptera: Pieridae) on the performance of the root herbivore Delia radicum L. (Diptera: Anthomyiidae) and its parasitoid Trybliographa rapae (Westwood) (Hymenoptera: Figitidae), mediated through a shared host plant Brassica nigra L. (Brassicaceae). In the presence of foliar herbivory, the survival of D. radicum and T. rapae decreased significantly by more than 50%. In addition, newly emerged adults of both root herbivores and parasitoids were significantly smaller on plants that had been exposed to foliar herbivory than on control plants. To determine what factor(s) may have accounted for the observed results, we examined the effects of foliar herbivory on root quantity and quality. No significant differences in root biomass were found between plants with and without shoot herbivore damage. Moreover, concentrations of nitrogen in root tissues were also unaffected by shoot damage by P. brassicae larvae. However, higher levels of indole glucosinolates were measured in roots of plants exposed to foliar herbivory, suggesting that the development of the root herbivore and its parasitoid may be, at least partly, negatively affected by increased levels of these allelochemicals in root tissues. Our results show that foliar herbivores can affect the development not only of root-feeding insects but also their natural enemies. We argue that such indirect interactions between above- and below-ground biota may play an important role in the structuring and functioning of communities.


Classification of personality disorder.
An interview schedule was used to record the personality traits of 130 psychiatric patients, 65 with a primary clinical diagnosis of personality disorder and 65 with other diagnoses. The results were analysed by factor analysis and three types of cluster analysis. Factor analysis showed a similar structure of personality variables in both groups of patients, supporting the notion that personality disorders differ only in degree from the personalities of other psychiatric patients. Cluster analysis revealed five discrete categories; sociopathic, passive-dependent, anankastic, schizoid and a non-personality-disordered group. Of all the personality-disordered patients 63 per cent fell into the passive-dependent or sociopathic category. The results suggest that the current classification of personality disorder could be simplified.


Combining experimental strategies for successful target deconvolution.
Investment in phenotypic drug discovery has led to increased demand for rapid and robust target deconvolution to aid successful drug development. Although methods for target identification and mechanism of action (MoA) discovery are flourishing, they typically lead to lists of putative targets. Validating which target(s) are involved in the therapeutic mechanism of a compound poses a significant challenge, requiring direct binding, target engagement, and functional studies in relevant physiological contexts. A combination of orthogonal approaches can allow target identification beyond the proteome as well as aid prioritisation for resource-intensive target validation studies.


Tailoring the diameter and density of self-catalyzed GaAs nanowires on silicon.
Nanowire diameter has a dramatic effect on the absorption cross-section in the optical domain. The maximum absorption is reached for ideal nanowire morphology within a solar cell device. As a consequence, understanding how to tailor the nanowire diameter and density is extremely important for high-efficient nanowire-based solar cells. In this work, we investigate mastering the diameter and density of self-catalyzed GaAs nanowires on Si(111) substrates by growth conditions using the self-assembly of Ga droplets. We introduce a new paradigm of the characteristic nucleation time controlled by group III flux and temperature that determine diameter and length distributions of GaAs nanowires. This insight into the growth mechanism is then used to grow nanowire forests with a completely tailored diameter-density distribution. We also show how the reflectivity of nanowire arrays can be minimized in this way. In general, this work opens new possibilities for the cost-effective and controlled fabrication of the ensembles of self-catalyzed III-V nanowires for different applications, in particular in next-generation photovoltaic devices.


Dietary pattern and asthma: a systematic review and meta-analysis.
The literature on the relationship between diet and asthma has largely focused on individual nutrients, with conflicting results. People consume a combination of foods from various groups that form a dietary pattern. Studying the role of dietary patterns in asthma is an emerging area of research. The purpose of this study was to systematically review dietary patterns and asthma outcomes in adults and children, to review maternal diet and child asthma, and to conduct a meta-analysis on the association between asthma prevalence and dietary patterns in adults. We searched Medline, Scopus, and ISI Web of Knowledge up to January 2014. Two researchers independently reviewed studies meeting the inclusion criteria using the American Dietetic Association quality criteria. A linear mixed model was used to derive the pooled effect size (95% confidence interval) for each of three dietary pattern categories (healthy, unhealthy, and neutral). Thirty-one studies were identified (16 cross-sectional, one case-control, 13 cohort, and one randomized controlled trial), including 12 in adults, 13 in children, five in pregnant woman-child pairs, and one in both children and pregnant woman-child pairs. Six of the 12 adult studies reported significant associations between dietary patterns and asthma outcomes (eg, ever asthma and forced expiratory volume in one second). Seven of ten studies examining the Mediterranean diet showed protective effects on child asthma and/or wheeze. Four of the six studies in mother-child pairs showed that maternal dietary patterns during pregnancy were not associated with child asthma or wheeze. The meta-analysis including six adult studies, the primary outcome of which was the prevalence of current or ever asthma, showed no association with healthy, unhealthy, or neutral dietary patterns. The evidence suggests no association of dietary patterns with asthma prevalence in adults or of maternal diet with child asthma or wheeze. The Mediterranean diet in children may prevent asthma or wheeze, but randomized controlled trials are lacking.


Neural synchrony in mother-child conversation: Exploring the role of conversation patterns.
Conversations are an essential form of communication in daily family life. Specific patterns of caregiver-child conversations have been linked to children's socio-cognitive development and child-relationship quality beyond the immediate family environment. Recently, interpersonal neural synchronization has been proposed as a neural mechanism supporting conversation. Here, we present a functional near-infrared spectroscopy (fNIRS) hyperscanning study looking at the temporal dynamics of neural synchrony during mother-child conversation. Preschoolers (20 boys and 20 girls, M age 5;07 years) and their mothers (M age 36.37 years) were tested simultaneously with fNIRS hyperscanning while engaging in a free verbal conversation lasting for 4 min. Neural synchrony (using wavelet transform coherence analysis) was assessed over time. Furthermore, each conversational turn was coded for conversation patterns comprising turn-taking, relevance, contingency and intrusiveness. Results from linear mixed-effects modeling revealed that turn-taking, but not relevance, contingency or intrusiveness predicted neural synchronization during the conversation over time. Results are discussed to point out possible variables affecting parent-child conversation quality and the potential functional role of interpersonal neural synchronization for parent-child conversation.


Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion.
Elevated blood triacylglycerol (TG) is a significant contributing factor to the current epidemic of obesity-related health disorders, including type-2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The observation that mice lacking the enzyme sn-glycerol-3-phosphate acyltransferase are protected from insulin resistance suggests the possibility that the regulation of TG synthesis be a target for therapy. Five-week-old Zucker Diabetic Fatty (ZDF) rats were fed a diet containing (R)-alpha-lipoic acid (LA, approximately 200mg/kg body weight per day) for 5 weeks. LA offset the rise in blood and liver TG by inhibiting liver lipogenic gene expression (e.g. sn-glycerol-3-phosphate acyltransferase-1 and diacylglycerol O-acyltransferase-2), lowering hepatic TG secretion, and stimulating clearance of TG-rich lipoproteins. LA-induced TG lowering was not due to the anorectic properties of LA, as pair-fed rats developed hypertriglyceridemia. Livers from LA-treated rats exhibited elevated glycogen content, suggesting dietary carbohydrates were stored as glycogen rather than becoming lipogenic substrate. Although AMP-activated protein kinase (AMPK) reportedly mediates the metabolic effects of LA in rodents, no change in AMPK activity was observed, suggesting LA acted independently of this kinase. The hepatic expression of peroxisome proliferator activated receptor alpha (PPARalpha) target genes involved in fatty acid beta-oxidation was either unchanged or decreased with LA, indicating a different mode of action than for fibrate drugs. Given its strong safety record, LA may have potential clinical applications for the treatment or prevention of hypertriglyceridemia and diabetic dyslipidemia.


Future directions in the management of epithelial ovarian cancer.
Epithelial ovarian cancer can be a difficult malignancy to manage, partially owing to its heterogenous biology. Whilst desirable, screening designed to reduce mortality has not yet proven effective, though results of ongoing studies are awaited. In this brief review, we attempt to highlight some important issues in the current management of primary and recurrent ovarian cancer, and to place these issues in the context of cutting-edge approaches to targeted therapy and its combination with chemotherapy, as well as other novel treatment strategies. It is hoped that this will lead to further improvements in progression-free and overall survival for patients with ovarian cancer, whilst maintaining their quality of life for as much of the disease journey as possible.


Taeniasis and cysticercosis in housemaids working in affluent neighborhoods in Lima, Peru.
Taenia solium taeniasis/cysticercosis is endemic in most developing countries, where it is an important cause of epileptic seizures and other neurologic symptoms. In industrialized countries, cysticercosis results from travel or immigration of tapeworm carriers from endemic areas. In both endemic and nonendemic countries, housemaids commonly immigrate from cysticercosis-endemic areas and can transmit the infection if they carry the adult tapeworm. Between July 2001 and July 2002, 1,178 housemaids (961 of them work in the top five most affluent districts of Lima, a metropolis of 8 million inhabitants considered nonendemic for cysticercosis) were evaluated for serum antibodies to Taenia solium and stool microscopy for taeniasis and cysticercosis. The serosurvey revealed a prevalence of cysticercosis-specific antibodies of 14.6% (95% CI: 12.6-16.6%), and stool microscopy detected 12 T. solium tapeworm carriers, for a prevalence of taeniasis of 1.2% (95% CI: 0.6-1.8%). A nonrandom sample of 26 seropositive housemaids was examined by brain CT and 50% of them had brain lesions compatible with neurocysticercosis, mainly calcifications. From the families who used a tapeworm-carrier housemaid, cysticercosis antibodies were detected in 6 (23%) of 26 persons who agreed to participate. One seropositive member of the employer families was symptomatic for seizures and had brain calcifications. The prevalence of tapeworm infections in this housemaid group is similar to levels in endemic areas, constituting a source of neurocysticercosis infection.


Blue light filtered white light induces depression-like responses and temporary spatial learning deficits in rats.
Ambient light has a vital impact on mood and cognitive functions. Blue light has been previously reported to play a salient role in the antidepressant effect via melanopsin. Whether blue light filtered white light (BFW) affects mood and cognitive functions remains unclear. The present study aimed to investigate whether BFW led to depression-like symptoms and cognitive deficits including spatial learning and memory abilities in rats, and whether they were associated with the light-responsive function in retinal explants. Male Sprague-Dawley albino rats were randomly divided into 2 groups (n = 10) and treated with a white light-emitting diode (LED) light source and BFW light source, respectively, under a standard 12 : 12 h L/D condition over 30 days. The sucrose consumption test, forced swim test (FST) and the level of plasma corticosterone (CORT) were employed to evaluate depression-like symptoms in rats. Cognitive functions were assessed by the Morris water maze (MWM) test. A multi-electrode array (MEA) system was utilized to measure electro-retinogram (ERG) responses induced by white or BFW flashes. The effect of BFW over 30 days on depression-like responses in rats was indicated by decreased sucrose consumption in the sucrose consumption test, an increased immobility time in the FST and an elevated level of plasma CORT. BFW led to temporary spatial learning deficits in rats, which was evidenced by prolonged escape latency and swimming distances in the spatial navigation test. However, no changes were observed in the short memory ability of rats treated with BFW. The micro-ERG results showed a delayed implicit time and reduced amplitudes evoked by BFW flashes compared to the white flash group. BFW induces depression-like symptoms and temporary spatial learning deficits in rats, which might be closely related to the impairment of light-evoked output signals in the retina.


Fifty Years of the Panel Study of Income Dynamics: Past, Present, and Future.
The Panel Study of Income Dynamics (PSID) is the world's longest running household panel survey. Beginning in 1968, it has collected data on the same families and their descendants, making it an essential part of America's data infrastructure for empirically based social science research. PSID arose from the War on Poverty as a tool for evaluating poverty dynamics, and this year marks 50 years of data collection. Because of its long history and distinctive design of following adult children as they form their own households, PSID is uniquely positioned to address emerging social and behavioral research questions and related policy issues. This overview presents the design and structural aspects and its evolution over the past 50 years, the successes of the current survey, possible future directions, and the value of using the PSID to understand the challenges facing American families.


Towards a taxonomy for integrated care: a mixed-methods study.
Building integrated services in a primary care setting is considered an essential important strategy for establishing a high-quality and affordable health care system. The theoretical foundations of such integrated service models are described by the Rainbow Model of Integrated Care, which distinguishes six integration dimensions (clinical, professional, organisational, system, functional and normative integration). The aim of the present study is to refine the Rainbow Model of Integrated Care by developing a taxonomy that specifies the underlying key features of the six dimensions. First, a literature review was conducted to identify features for achieving integrated service delivery. Second, a thematic analysis method was used to develop a taxonomy of key features organised into the dimensions of the Rainbow Model of Integrated Care. Finally, the appropriateness of the key features was tested in a Delphi study among Dutch experts. The taxonomy consists of 59 key features distributed across the six integration dimensions of the Rainbow Model of Integrated Care. Key features associated with the clinical, professional, organisational and normative dimensions were considered appropriate by the experts. Key features linked to the functional and system dimensions were considered less appropriate. This study contributes to the ongoing debate of defining the concept and typology of integrated care. This taxonomy provides a development agenda for establishing an accepted scientific framework of integrated care from an end-user, professional, managerial and policy perspective.


Parental feeding practices and concerns related to child underweight, picky eating, and using food to calm differ according to ethnicity/race, acculturation, and income.
The purpose of this study was to examine differences in parental feeding practices according to ethnicity/race, household income, parent education level, acculturation (for Hispanic participants only), and participation in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program among parents living in a southern state in the United States. For this cross-sectional study, parents of children ages 1-5 years living throughout Texas were recruited through random digit dialing with screening questions during Fall 2006. Eligible parents who agreed to participate completed the Preschooler Feeding Questionnaire (PFQ) and a demographic questionnaire over the phone in either English or Spanish. The PFQ included five subscales: child overeating concerns, child underweight concerns, difficulty with picky eating, using food to calm, and pushing child to eat. Demographic questions assessed ethnicity/race, household income, parent education level, acculturation, and WIC participation. Structural Equation Modeling (SEM), with the demographic variables as predictors, was used to predict the five PFQ subscales. Complete data were obtained from 721 parents, 50% of whom were Hispanic. Significant differences for the PFQ subscales were noted for ethnicity/race, acculturation, and income level. Spanish-speaking Hispanic participants were significantly more worried about their child being underweight than English-speaking Hispanic participants. High-income non-WIC respondents were more likely to report that they have difficulty with picky eaters compared to WIC respondents. Spanish-speaking Hispanics and Black respondents were more likely than English-speaking Hispanics to use food to calm the child. Health practitioners need to be aware of differences in parental feeding practices and concerns among parents of diverse demographic backgrounds. Results from this study can be used to tailor health programs that promote healthy feeding practices among parents.


Physiology of desiccation resistance in Anopheles gambiae and Anopheles arabiensis.
Desiccation resistance and water balance were studied in the adult female mosquitoes Anopheles arabiensis and Anopheles gambiae sensu stricto. When the two species were reared from egg to adult under identical conditions, An. arabiensis had significantly higher desiccation resistance than did An. gambiae. Data are presented that indicate that this difference in desiccation resistance is associated with a higher body water content prior to desiccation in An. arabiensis. No differences in rate of water loss during desiccation or water content at death were observed. Measurements of metabolic rate and respiratory pattern also showed no statistically significant differences between the species. This study provides the first physiologic measurements of desiccation resistance in adults of these species and offers insights into the physiologic differences associated with differential resistance to desiccation stress.


High-Resolution Transfer Printing of Graphene Lines for Fully Printed, Flexible Electronics.
Pristine graphene inks show great promise for flexible printed electronics due to their high electrical conductivity and robust mechanical, chemical, and environmental stability. While traditional liquid-phase printing methods can produce graphene patterns with a resolution of ∼30 μm, more precise techniques are required for improved device performance and integration density. A high-resolution transfer printing method is developed here capable of printing conductive graphene patterns on plastic with line width and spacing as small as 3.2 and 1 μm, respectively. The core of this method lies in the design of a graphene ink and its integration with a thermally robust mold that enables annealing at up to ∼250 °C for precise, high-performance graphene patterns. These patterns exhibit excellent electrical and mechanical properties, enabling favorable operation as electrodes in fully printed electrolyte-gated transistors and inverters with stable performance even following cyclic bending to a strain of 1%. The high resolution coupled with excellent control over the line edge roughness to below 25 nm enables aggressive scaling of transistor dimensions, offering a compelling route for the scalable manufacturing of flexible nanoelectronic devices.


Targeting suboptimal prescribing in the elderly: a review of the impact of pharmacy services.
To review the currently available literature on the impact of interventions by pharmacists on suboptimal prescribing in the elderly. MEDLINE, EMBASE, and International Pharmaceutical Abstracts databases were searched for studies published between January 1992 and December 2008. Key words included medication review, drug regimen review, pharmaceutical services, pharmaceutical care, pharmacists, medications, appropriateness, suboptimal, underuse, aged, elderly, randomized controlled trial, inappropriate, prescribing, and intervention. To be included in the review, studies must have been conducted in patients 65 years or older, published in English, randomized and controlled, and must have included an intervention delivered by a pharmacist or had a pharmacist as a member of the intervention team. From each relevant study, the following data were extracted: study duration, country, number of patients, year of publication, objective, type and impact of the intervention, method used to assess suboptimal prescribing, and data concerning the quality of the study. A total of 38 articles were identified, of which 12 matched our inclusion criteria. Seven articles included interventions initiated by pharmacists, and the remaining 5 described interventions in which the pharmacist was a part of the multidisciplinary team. A broad range of tools was used to measure prescribing appropriateness; we found that a consensus on the best approach has not been reached. Most of the studies involving pharmacists showed significant improvement in suboptimal prescribing at one or more time points. However, most of these interventions were directed toward reducing the overuse or misuse of medications. Pharmacy services to reduce suboptimal prescribing have shown promising and noteworthy improvements. More research is needed to address the underutilization of medications in the elderly and healthcare impact of reducing suboptimal prescribing.


3D-QSAR study of c-Src kinase inhibitors based on docking.
Cancer is a significant world health problem for which efficient therapies are in urgent demand. c-Src has emerged as an attractive target for drug discovery efforts toward antitumor therapies. Toward this target several series of c-Src inhibitors that showed activity in the assay have been reported. In this article, 3D-QSAR models have been built with 156 anilinoquinazoline and quinolinecarbonitrile derivative inhibitors by using CoMFA and CoMSIA methods. These studies indicated that the QSAR models were statistically significant with high predictabilities (CoMFA model, q(2) = 0.590, r(2) = 0.855; CoMSIA model, q(2) = 0.538, r(2) = 0.748). The details of c-Src kinase/inhibitor binding interactions in the crystal structure of complex provided new information for the design of new inhibitors. As a result, docking simulations were also conducted on the series of potent inhibitors. The flexible docking method, which was performed by the DOCK program, positioned all of the inhibitors into the active site to determine the probable binding conformation. The CoMFA and CoMSIA models based on the flexible docking conformations also yielded statistically significant and highly predictive QSAR models (CoMFA model, q(2) = 0.507, r(2) = 0.695; CoMSIA model, q(2) = 0.463, r(2) = 0.734). Our models would offer help to better comprehend the structure-activity relationships that exist for this class of compounds and also facilitate the design of novel inhibitors with good chemical diversity.


Protection against Mitochondrial and Metal Toxicity Depends on Functional Lipid Binding Sites in ATP13A2.
The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson's disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. ATP13A2 interacts at the N-terminus with the signaling lipids phosphatidic acid (PA) and phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate ATP13A2 activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or ATP13A2 mutants in which three N-terminal lipid binding sites (LBS1-3) were mutated. We explored the regulatory role of LBS1-3 in the cellular protection by ATP13A2 against mitochondrial stress induced by rotenone and found that the LBS2-3 mutants displayed an abrogated protective effect. Moreover, in contrast to WT, the LBS2 and LBS3 mutants responded poorly to pharmacological inhibition of, respectively, PI(3,5)P2 and PA formation. We further demonstrate that PA and PI(3,5)P2 are also required for the ATP13A2-mediated protection against the toxic metals Mn(2+), Zn(2+), and Fe(3+), suggesting a general lipid-dependent activation mechanism of ATP13A2 in various PD-related stress conditions. Our results indicate that the ATP13A2-mediated protection requires binding of PI(3,5)P2 to LBS2 and PA to LBS3. Thus, targeting the N-terminal lipid binding sites of ATP13A2 might offer a therapeutic approach to reduce cellular toxicity of various PD insults including mitochondrial stress.


Literacy and memory decline among ethnically diverse elders.
Literacy may be a more powerful indicator of brain reserve than years of education. Literacy level may be a proxy for native intellectual capacity or life experience that can compensate for brain damage or provide brain reserve. Alternately, the experience of acquiring literacy skills may in itself change the organization of the brain and increase protection against cognitive decline. However, because people with low levels of literacy obtain poor scores on most cognitive measures, only longitudinal studies can elucidate the role of reading ability in reserve. We determined whether literacy skills could predict cognitive change in a sample of 136 English-speaking African American, Caucasian, and Hispanic elders selected from a longitudinal aging study in New York City. According to a physician's independent examination, all participants were nondemented throughout the four longitudinal assessments. Literacy level was assessed using the WRAT-3 reading subtest. After accounting for age at baseline and years of education, GEE analyses showed that elders with low levels of literacy had a steeper decline in both immediate and delayed recall of a word list over time as compared to high literacy elders. Our findings suggest that literacy skills are protective against memory decline among nondemented elders.