Intermittent explosive disorder subtypes in the general population: association with comorbidity, impairment and suicidality.
Intermittent explosive disorder (IED) is characterised by impulsive anger attacks that vary greatly across individuals in severity and consequence. Understanding IED subtypes has been limited by lack of large, general population datasets including assessment of IED. Using the 17-country World Mental Health surveys dataset, this study examined whether behavioural subtypes of IED are associated with differing patterns of comorbidity, suicidality and functional impairment. IED was assessed using the Composite International Diagnostic Interview in the World Mental Health surveys (n = 45 266). Five behavioural subtypes were created based on type of anger attack. Logistic regression assessed association of these subtypes with lifetime comorbidity, lifetime suicidality and 12-month functional impairment. The lifetime prevalence of IED in all countries was 0.8% (s.e.: 0.0). The two subtypes involving anger attacks that harmed people ('hurt people only' and 'destroy property and hurt people'), collectively comprising 73% of those with IED, were characterised by high rates of externalising comorbid disorders. The remaining three subtypes involving anger attacks that destroyed property only, destroyed property and threatened people, and threatened people only, were characterised by higher rates of internalising than externalising comorbid disorders. Suicidal behaviour did not vary across the five behavioural subtypes but was higher among those with (v. those without) comorbid disorders, and among those who perpetrated more violent assaults. The most common IED behavioural subtypes in these general population samples are associated with high rates of externalising disorders. This contrasts with the findings from clinical studies of IED, which observe a preponderance of internalising disorder comorbidity. This disparity in findings across population and clinical studies, together with the marked heterogeneity that characterises the diagnostic entity of IED, suggests that it is a disorder that requires much greater research.


Interruption of ghrelin signaling in the PVN increases high-fat diet intake and body weight in stressed and non-stressed C57BL6J male mice.
Chronic social stress has been associated with increased caloric intake and adiposity. These effects have been linked to stress induced changes in the secretion of ghrelin, a hormone that targets a number of brain regions to increase food intake and energy expenditure and promote increased body fat content. One of the brain sites targeted by ghrelin is the hypothalamic paraventricular nucleus (PVN), a region critical for both the regulation of the stress response and the regulation of energy balance. Given these data, we examined the contribution of ghrelin receptors in the PVN to the metabolic and behavioral changes that are seen during chronic social stress in mice. To do this, mice were implanted with cannulae attached to osmotic minipumps and delivering either vehicle or the ghrelin receptor (growth hormone secretagogue receptor) antagonist [D-Lys-3]-GHRP-6 (20 nmol/day/mouse). Following a week of recovery, half of the animals in each group were exposed to chronic social defeat stress for a period of 3 weeks whereas the other half were left undisturbed. During this time, all animals were given ad libitum access to standard laboratory chow and presented a high-fat diet for 4 h during the day. Results showed that the ghrelin receptor antagonism did not decrease stressed induced caloric intake, but paradoxically increased the intake of the high fat diet. This would suggest that ghrelin acts on the PVN to promote the intake of carbohydrate rich diets while decreasing fat intake and blockade of ghrelin receptors in the PVN leads to more consumption of foods that are high in fat.


Increasing volume of distribution to the brain with interstitial infusion: dose, rather than convection, might be the most important factor.
The volume of distribution in tissue (Vt) that can be achieved by direct interstitial infusion of therapeutic agents into brain is limited. The maintenance of a pressure gradient during interstitial infusion to establish fluid convection has been shown to increase the Vt of small, medium, and large molecules. We have used monocrystalline iron oxide nanocompounds, superparamagnetic particles of sizes the same order of magnitude as virions, to investigate the effect of dose, the volume of infusate, and the time of infusion on the distribution of large molecules in rodent brain. Our initial study in rats (n = 6) replicated the results of a previously described report of convection-enhanced delivery in cats. At a constant rate and concentration, the Vt increased in a linear fashion, proportional to the increases in time, volume, and dose. When using a constant rate and a constant concentration, however, it is unclear which variable or variables (dose, volume, infusion time) have the greatest influence on this effect. Therefore, we assessed each variable independently (n = 12). When the iron dose was increased from 5.3 to 26.5 micrograms, there was a three- to fivefold increase in the Vt, depending on the volume and time of infusion (2 Microliters/20 min, 24 microliters/20 min, or 24 microliters/120 min) (P < 0.001). When the volume of infusate was increased from 2 to 24 microliters, at an infusion time of 20 minutes and a dose of either 5.3 or 26.5 micrograms, there was a 43 or 52% decline in the Vt, respectively (P = 0.018). When the time for the infusion of 24 microliters was increased from 20 to 120 minutes, there was a 79% increase in the Vt at a dose of 26.5 micrograms but no change in the Vt at a dose of 5.3 micrograms. The effect associated with infusion time was not significant (P = 0.113). Magnetic resonance imaging was performed to document the distribution of monocrystalline iron oxide nanocompounds in vivo, and histochemical staining for iron was used to document the distribution of monocrystalline iron oxide nanocompounds in tissue sections. The Vt for both methods was calculated by computer image analysis, and the correlation between magnetic resonance and histological volumes was determined (r2 = 0.93). On the basis of this model, we suggest that dose, rather than convection, might be the most important variable in maximizing the Vt and improved distribution might be achieved by administering an increased concentration of agent.


Arylamine N-acetyltransferases: a pharmacogenomic approach to drug metabolism and endogenous function.
The arylamine N-acetyltransferases (NATs) are a unique family of enzymes that catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. The NATs have been shown to be important in drug detoxification and carcinogen activation, with humans possessing two isoenzymes encoded by polymorphic genes. This polymorphism has pharmacogenetic implications, leading to different rates of inactivation of drugs, including the anti-tubercular agent isoniazid and the anti-hypertensive drug hydralazine. Mice provide a good model for human NAT, allowing genetic manipulation of expression to explore possible endogenous roles of these enzymes. The first three-dimensional NAT structure was resolved for NAT from Salmonella typhimurium, and subsequently the structure of NAT from Mycobacterium smegmatis has been elucidated. These identified a 'Cys-His-Asp' catalytic triad (conserved in all NATs), which is believed to be responsible for the activation of the active site cysteine residue. As more genomic data become available, NAT homologues continue to be found in prokaryotic species, many of which are pathogenic, including Mycobacterium tuberculosis. The discovery of NAT in M. tuberculosis is particularly significant, since this enzyme participates in inactivation of isoniazid in the bacterium, with implications for isoniazid resistance. Structural studies on NAT proteins and phenotypic analyses of organisms (both mice and prokaryotes) following genetic modifications of the nat genes are leading to an understanding of the potentially diverse roles of NAT in endogenous and xenobiotic metabolism. These studies have indicated that NAT, particularly in Mycobacteria, has the potential to be a drug target. Combinatorial chemical approaches, together with in silico structural studies, will allow for advances in the identification of NAT substrates and inhibitors, both as experimental tools and as potential drugs.


Healthcare Policies for Stateless Populations in ASEAN Countries: A Scoping Review.
This study aimed at summarizing the existing health policies for stateless populations living in the 10 ASEAN countries: Brunei, Cambodia, Lao PDR, Indonesia, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Vietnam. We followed scoping review method recommended by Arksey and O'Malley. Our inclusion criteria were based on three concepts: populations (stateless and undocumented people), issues (healthcare policies and regulations), and settings (10 ASEAN countries). Our findings suggest that none of the ASEAN countries have explicit healthcare policies for stateless people except Thailand. We also observed that ratification of international human rights treaties relating to the right to health does not necessarily translate into the provision of healthcare policies for stateless population. Although Thailand seems like the only country among 10 ASIAN countries having health policies for stateless populations in the country, the question remains whether having a policy would lead to a proper implementation by ensuring right to health.


Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a marine model of airway sensitization.
To study the role of CD8+ T cells in allergic sensitization, we examined the effects of in vivo depletion of CD8+ T cells prior to sensitization on IgE production, immediate type cutaneous hypersensitivity and development of altered airway responsiveness. BALB/c mice were thymectomized and treated with anti-CD8 antibody resulting in depletion of CD8+ T cells (<1%) in spleen and lymphoid tissues. In these mice, sensitization to ovalbumin (OVA) via the airways still resulted in IgE anti-OVA responses and immediate cutaneous reactions to OVA, but the animals were unable to develop airway hyperresponsiveness, eosinophil infiltration of the lung parenchyma, or IL-5 production in the local lymph nodes of the airway. Transfer of CD8+ T cells from naive animals during sensitization (on day 8 of the 10-d protocol) fully restored the ability to develop airway hyperresponsiveness and this was accompanied by IL-5 production and eosinophil accumulation in the lung. These data indicate a critical role for CD8+ T cells in the production of IL-5 and the development of altered airway responsiveness after antigen sensitization through the airways.


Dietary intake of saturated fatty acids and mortality from cardiovascular disease in Japanese: the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) Study.
Prospective epidemiologic studies have generated mixed results regarding the association between saturated fatty acid (SFA) intake and risk of ischemic heart disease (IHD) and stroke. These associations have not been extensively studied in Asians. The aim of this study was to test the hypothesis that SFA intake is associated with the risk of cardiovascular disease mortality in Japanese whose average SFA intake is low. The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study) comprised 58,453 Japanese men and women who completed a food-frequency questionnaire. Participants were aged 40-79 y at baseline (1988-1990) and were followed up for 14.1 y. Associations of energy-adjusted SFA intake with mortality from stroke (intraparenchymal and subarachnoid hemorrhages and ischemic stroke) and heart diseases (IHD, cardiac arrest, and heart failure) were examined after adjustment for age, sex, and cardiovascular disease risk and dietary factors. We observed inverse associations of SFA intake with mortality from total stroke [n = 976; multivariable hazard ratio (95% CI) for highest compared with lowest quintiles: 0.69 (0.53, 0.89); P for trend = 0.004], intraparenchymal hemorrhage [n = 224; 0.48 (0.27, 0.85); P for trend = 0.03], and ischemic stroke [n = 321; 0.58 (0.37, 0.90); P for trend = 0.01]. No multivariable-adjusted associations were observed between SFA and mortality from subarachnoid hemorrhage [n = 153; 0.91 (0.46, 1.80); P for trend = 0.47] and heart disease [n = 836; 0.89 (0.68, 1.15); P for trend = 0.59]. SFA intake was inversely associated with mortality from total stroke, including intraparenchymal hemorrhage and ischemic stroke subtypes, in this Japanese cohort.


Poly(ADP-ribose) reactivates stalled DNA topoisomerase I and Induces DNA strand break resealing.
Regulating the topological state of DNA is a vital function of the enzyme DNA topoisomerase I. However, when acting on damaged DNA, topoisomerase I may get trapped in a covalent complex with nicked DNA (stalled topoisomerase I), that, if unrepaired, may lead to genomic instability or cell death. Here we show that ADP-ribose polymers target specific domains of topoisomerase I and reprogram the enzyme to remove itself from cleaved DNA and close the resulting gap. Two members of the poly(ADP-ribose) polymerase family, PARP-1 and 2, act as poly(ADP-ribose) carriers to stalled topoisomerase I sites and induce efficient repair of enzyme-associated DNA strand breaks. Thus, by counteracting topoisomerase I-induced DNA damage, PARP-1 and PARP-2 act as positive regulators of genomic stability in eukaryotic cells.


Breast cancer version 3.2014.
Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. The NCCN Guidelines specific to management of large clinical stage II and III tumors are discussed in this article. These guidelines are the work of the members of the NCCN Breast Cancer Panel. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Although not stated at every decision point of the guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.


Daunomycin accumulation and induction of programmed cell death in rat hair follicles.
The anthracycline antibiotic daunomycin (DM) is useful for the treatment of leukemia but has side-effects such as alopecia. Using immunocytochemistry, we show that, after a single i.v. injection, DM accumulates in the nuclei of matrix cells and in the outer root sheath of hair follicles. DM-positive matrix cells are detectable up to 48 h after injection and exhibit a characteristic granular morphology, which is not observed in saline-injected controls. TUNEL-staining has revealed that DM injection induces programmed cell death (PCD) in rat hair follicles. Cells undergoing PCD are detectable as late as 5 days postinjection in both the matrix and outer root sheath. Newly developed double-staining has shown that some of the DM-positive matrix cell nuclei are also TUNEL-positive. Staining for activated caspase-3 has demonstrated immunopositive cells following DM administration both in the matrix and in the outer root sheath. Ultrastructural immunocytochemistry has shown the presence of DM-positive cells with two different types of morphology. About half of the immunopositive cells exhibit a morphology typical of classical apoptosis (PCD type 1), whereas the other half show signs of autophagic cell death (PCD type 2). Interestingly, little, if any, DM accumulation or apoptosis has been detected in the dermal hair papillae. This may have a bearing on potential regeneration of the hair follicles. Thus, DM accumulates in a characteristic pattern in hair follicles. This accumulation is associated with the induction of two morphologically distinct forms of PCD.


Prospective follow-up studies found no chromosomal mutagenicity of methylphenidate therapy in ADHD affected children.
Five to ten percent of all children suffer from attention-deficit/hyperactivity disorder (ADHD), which is often treated with the central nervous stimulant methylphenidate (MPH). In 2005 controversy arose due to a report of enhanced cytogenetic effects in 12 children after 3 months of MPH treatment. Since then, several prospective studies have been performed and published, which are summarized here. A table comparing the micronucleus frequencies, a marker investigated in all of these studies, is presented. An induction of cytogenetic effects by MPH was only reported in one, the 2005 study by El-Zein et al., while all other studies, with now altogether 110 MPH-exposed individuals, showed no elevation. To address the question of long-term use of MPH, we published the data of 30 chronically treated children and also saw no difference compared to untreated children. Here, we report as new follow-up data that an additional 12 months time point in a small group of 12 children who had begun MPH therapy within our published study also did not reveal elevated cytogenetic damage. Furthermore, a previously unpublished analysis of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG; a non-invasive biomarker for DNA-base oxidation and its repair) in 11 children before and after 3 months of MPH exposure yielded no significant difference. Since gene mutations may not necessarily manifest as chromosomal aberrations, micronuclei or SCEs, we discuss the available data from animal models, which also do not reveal a mutagenic potential of MPH. Although the only two available epidemiological studies do not report elevated risk for MPH exposure, the results are not conclusive yet, and further monitoring of exposed populations is suggested.


Toxicity evaluation of PEDOT/biomolecular composites intended for neural communication electrodes.
Electrodes coated with the conducting polymer poly(3,4-ethylene dioxythiophene) (PEDOT) possess attractive electrochemical properties for stimulation or recording in the nervous system. Biomolecules, added as counter ions in electropolymerization, could further improve the biomaterial properties, eliminating the need for surfactant counter ions in the process. Such PEDOT/biomolecular composites, using heparin or hyaluronic acid, have previously been investigated electrochemically. In the present study, their biocompatibility is evaluated. An agarose overlay assay using L929 fibroblasts, and elution and direct contact tests on human neuroblastoma SH-SY5Y cells are applied to investigate cytotoxicity in vitro. PEDOT:heparin was further evaluated in vivo through polymer-coated implants in rodent cortex. No cytotoxic response was seen to any of the PEDOT materials tested. The examination of cortical tissue exposed to polymer-coated implants showed extensive glial scarring irrespective of implant material (Pt:polymer or Pt). However, quantification of immunological response, through distance measurements from implant site to closest neuron and counting of ED1+ cell density around implant, was comparable to those of platinum controls. These results indicate that PEDOT:heparin surfaces were non-cytotoxic and show no marked difference in immunological response in cortical tissue compared to pure platinum controls.


Physical therapists' perspectives on practice errors in geriatric, neurologic, or orthopedic clinical settings.
While practice errors have been studied extensively in medicine and pharmacy, little research exists in physical therapy. The purpose of this study was to explore the phenomenon of physical therapy practice errors in geriatric, adult neurologic, and orthopedic clinical settings. Thirty physical therapists with three or more years of practice experience participated in the study, representing four geographically distinct regions of the United States. Four focus groups were conducted via guided discussion questions in four different states. Collected data were transcribed and analyzed by using constant comparative method. Data analysis yielded five major themes including: 1) taxonomy of error, 2) aversive outcomes, 3) individual and systematic causes, 4) post hoc actions, and 5) prevention of future errors. Because human errors are inevitable in physical therapy practice, understanding of causes and prevention strategies is necessary to minimize harm to patients. In addition, physical therapists must recognize their role and responsibility in creating a culture of error analysis and error prevention.


Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells.
MicroRNA (miRNA) transfer via exosomes may mediate cell-to-cell communication. Interestingly, specific miRNAs are enriched in exosomes in a cell-type-dependent fashion. However, the mechanisms whereby miRNAs are sorted to exosomes and the significance of miRNA transfer to acceptor cells are unclear. We used macrophages and endothelial cells (ECs) as a model of heterotypic cell communication in order to investigate both processes. RNA profiling of macrophages and their exosomes shows that miRNA sorting to exosomes is modulated by cell-activation-dependent changes of miRNA target levels in the producer cells. Genetically perturbing the expression of individual miRNAs or their targeted transcripts promotes bidirectional miRNA relocation from the cell cytoplasm/P bodies (sites of miRNA activity) to multivesicular bodies (sites of exosome biogenesis) and controls miRNA sorting to exosomes. Furthermore, the use of Dicer-deficient cells and reporter lentiviral vectors (LVs) for miRNA activity shows that exosomal miRNAs are transferred from macrophages to ECs to detectably repress targeted sequences.


Serial examination of an inducible and reversible dilated cardiomyopathy in individual adult Drosophila.
Recent work has demonstrated that Drosophila can be used as a model of dilated cardiomyopathy, defined as an enlarged cardiac chamber at end-diastole when the heart is fully relaxed and having an impaired systolic function when the heart is fully contracted. Gene mutations that cause cardiac dysfunction in adult Drosophila can result from abnormalities in cardiac development or alterations in post-developmental heart function. To clarify the contribution of transgene expression to post-developmental cardiac abnormalities, we applied strategies to examine the temporal and spacial effects of transgene expression on cardiac function. We engineered transgenic Drosophila based on the well-characterized temperature-sensitive Gal80 protein in the context of the bipartite Gal4/UAS transgenic expression system in Drosophila employing the cardiac specific driver, tinCDelta4-Gal4. Then, we developed a strategy using optical coherence tomography to serially measure cardiac function in the individual flies over time course of several days. As a proof of concept we examined the effects of the expression of a human mutant delta-sarcoglycan associated with familial heart failure and observed a reversible, post-developmental dilated cardiomyopathy in Drosophila. Our results show that the unique imaging strategy based on the non-destructive, non-invasive properties of optical coherence tomography can be applied to serially examine cardiac function in individual adult flies. Furthermore, the induction and reversal of cardiac transgene expression can be investigated in adult flies thereby providing insight into the post-developmental effects of transgene expression.


Long-term dynamics of adaptive evolution in a globally important phytoplankton species to ocean acidification.
Marine phytoplankton may adapt to ocean change, such as acidification or warming, because of their large population sizes and short generation times. Long-term adaptation to novel environments is a dynamic process, and phenotypic change can take place thousands of generations after exposure to novel conditions. We conducted a long-term evolution experiment (4 years = 2100 generations), starting with a single clone of the abundant and widespread coccolithophore Emiliania huxleyi exposed to three different CO2 levels simulating ocean acidification (OA). Growth rates as a proxy for Darwinian fitness increased only moderately under both levels of OA [+3.4% and +4.8%, respectively, at 1100 and 2200 μatm partial pressure of CO2 (Pco2)] relative to control treatments (ambient CO2, 400 μatm). Long-term adaptation to OA was complex, and initial phenotypic responses of ecologically important traits were later reverted. The biogeochemically important trait of calcification, in particular, that had initially been restored within the first year of evolution was later reduced to levels lower than the performance of nonadapted populations under OA. Calcification was not constitutively lost but returned to control treatment levels when high CO2-adapted isolates were transferred back to present-day control CO2 conditions. Selection under elevated CO2 exacerbated a general decrease of cell sizes under long-term laboratory evolution. Our results show that phytoplankton may evolve complex phenotypic plasticity that can affect biogeochemically important traits, such as calcification. Adaptive evolution may play out over longer time scales (>1 year) in an unforeseen way under future ocean conditions that cannot be predicted from initial adaptation responses.


Patterns of ethanol intake in male rats with partial dopamine transporter deficiency.
Mesolimbic dopamine signaling plays a major role in alcohol and substance use disorders as well as comorbidities such as anxiety and depression. Growing evidence suggests that alcohol drinking is modulated by the function of the dopamine transporter (DAT), which tightly regulates extracellular dopamine concentrations. Adult male rats on a Wistar Han background (DAT+/+) and rats with a partial DAT deletion (DAT+/-) were used in this study. First, using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core from ethanol-naïve subjects, we measured greater evoked dopamine concentrations and slower dopamine reuptake in DAT+/- rats, consistent with increased dopamine signaling. Next, we measured ethanol drinking using the intermittent access two-bottle choice paradigm (20% v/v ethanol vs. water) across 5 weeks. DAT+/- rats voluntarily consumed less ethanol during its initial availability (the first 30 min), especially after longer periods of deprivation. In addition, DAT+/- males consumed less ethanol that was adulterated with the bitter tastant quinine. These findings suggest that partial DAT blockade and concomitant increase in brain dopamine levels has potential to reduce drinking and ameliorate alcohol use disorder (AUD).


Hospital-physician relations under hospital prepayment.
Fundamental changes now occurring in the field of health services may make it increasingly difficult to develop or maintain satisfactory hospital-physician relations. This paper examines the nature of hospital-physician relations following the introduction of an experimental hospital prepayment program that capped budgets in nine hospitals for a 5-year period. Results from longitudinal analyses based on data from key physicians, hospital administrators, and board members indicate generally positive "effects" on hospital-physician relations, except for increased strain in the system. In most respects, there were no adverse effects on the work relations of physicians, in the perceived quality of medical care, or in the institutional performance of physicians at the nine participating hospitals after the introduction of prepayment. Moreover, to some extent, the prepayment program appears to have been effective in controlling hospital costs and is perceived by the principal participants to have been successful.


[Macrophage activation syndrome associated with systemic juvenile idiopathic arthritis].
To describe the characteristics of macrophage activation syndrome associated with juvenile idiopathic arthritis. This is a retrospective study involving 462 patients with juvenile idiopathic arthritis. Seven (1.5%) of those patients suffered from systemic onset juvenile idiopathic arthritis and developed macrophage activation syndrome. The median age of the juvenile idiopathic arthritis onset was 3 years and 10 months and the median duration of juvenile idiopathic arthritis before macrophage activation syndrome was 8 years and 4 months. All of them presented with fever, jaundice, hepatosplenomegaly, bleeding, pancytopenia, abnormal liver function tests and abnormal coagulation profile. Three cases presented associated infections and one patient developed macrophage activation syndrome two weeks after the administration of sulfasalazine. Three patients died and the macrophage hemophagocytosis was present in five. The treatment of macrophage activation syndrome included pulse therapy with methylprednisolone in all of them, cyclosporine A in three, plasma exchange in two and intravenous immunoglobulin in two. Macrophage activation syndrome is a complication of the systemic onset juvenile idiopathic arthritis with a high morbidity and mortality rate.


Cross-resistance between biocides and antimicrobials: an emerging question.
The widespread use of biocides, and their resulting dissemination in the environment, can contribute to adaptations in bacteria leading to the development of low-level susceptibility to antibacterial agents. The mechanisms of resistance in bacteria are similar for both antimicrobials and biocides, and exposure to biocides can result in cross-resistance to antibacterial agents. Resistance mechanisms altering the activity of biocide and antibiotic molecules are discussed with regard to regulation and mode of action in the light of laboratory studies of induced resistance. It is clear that in order to preserve their activity and avoid the development of possible cross-resistance, prudent use of antibacterial agents is to be strongly recommended, not only in clinical settings but also in veterinary and agricultural and other applications.


Classification of nodal stations in gastric cancer.
The lymphatic drainage from the stomach is anatomically elaborate and it is very hard to predict the pattern of lymph node (LN) metastases from gastric cancer (GC). However, there are LN stations metastases that are more frequently observed depending on the tumor location. Furthermore, the incidence of metastasis to various regional LN stations depends on the depth of gastric-wall invasion. The Japanese Gastric Cancer Association (JGCA) classifies the regional LNs draining the stomach into 33 regional lymphatic stations. These are distinguished into three (N1-N3) groups with respect to the location of the primary tumor. The aim of this classification is to provide a common language for the clinical, surgical, and pathological description of GC.


One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain.
Spinal cord stimulation of the dorsal root ganglion (DRG-SCS) is a new therapy for treating chronic neuropathic pain. Previous work has demonstrated the effectiveness of DRG-SCS for pain associated with failed back surgery syndrome, complex regional pain syndrome, chronic postsurgical pain, and other etiologies through 6 months of treatment; this report describes the maintenance of pain relief, improvement in mood, and quality of life through 12 months. Subjects with intractable pain in the back and/or lower limbs were implanted with an active neurostimulator device. Up to four percutaneous leads were placed epidurally near DRGs. Subjects were tracked prospectively for 12 months. Overall, pain was reduced by 56% at 12 months post-implantation, and 60% of subjects reported greater than 50% improvement in their pain. Pain localized to the back, legs, and feet was reduced by 42%, 62%, and 80%, respectively. Measures of quality of life and mood were also improved over the course of the study, and subjects reported high levels of satisfaction. Importantly, excellent pain-paresthesia overlap was reported, remaining stable through 12 months. Despite methodological differences in the literature, DRG-SCS appears to be comparable to traditional SCS in terms of pain relief and associated benefits in mood and quality of life. Its benefits may include the ability to achieve precise pain-paresthesia concordance, including in regions that are typically difficult to target with SCS, and to consistently maintain that coverage over time.


The effect of radiotherapy in liver-confined but non-resectable Barcelona Clinic Liver Cancer stage C large hepatocellular carcinoma.
Clinical trials to determine the efficacy of radiotherapy (RT) in liver-confined but non-resectable Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) are scarce. We aimed to determine the benefit of RT in such tumors and investigated large HCC tumors. HCC data from the Korea Central Cancer Registry recorded from 2008 to 2010 were used. A total of 593 patients met our inclusion criteria; 67 were treated with RT while the remainder made up the non-RT group. Fifty-two RT recipients underwent combination treatments within 4 weeks after the first RT treatment, and were defined as the combination RT group. We performed propensity score matching (PSM) to compare the RT or combination RT groups with the non-RT group. The endpoint was overall survival (OS). Median follow-up time for surviving patients was 48 months. After PSM, there was no difference in OS between the RT and non-RT groups or between the combination RT and non-RT groups. However, the combination RT group had a longer median survival time (MST) (10.7 vs. 6.9 months, respectively). Next, we conducted PSM between the combination RT and non-RT groups in patients with tumor sizes ≥10 cm; MST was significantly longer in the former group (10.1 vs. 5.4 months, respectively; bootstrap 95% confidence interval of the difference in MST: 0.2-11.8). As a combined modality, RT is a plausible therapeutic option for liver-confined but non-resectable BCLC stage C large HCC patients.


Do we understand the evolution of genomic imprinting?
The conflict theory is the only hypothesis to have attracted any critical attention for the evolution of genomic imprinting. Although the earliest data appeared supportive, recent systematic analyses have not confirmed the model's predictions. The status of theory remains undecided, however, as post-hoc explanations can be provided as to why these predictions are not borne out.


Differential expression of keratins 10, 17, and 19 in normal cervical epithelium, cervical intraepithelial neoplasia, and cervical carcinoma.
To examine the value of immunohistochemistry in defining a keratin profile to aid cervical histopathological diagnosis. Immunohistochemical localisation of keratins 17, 10, and 19 was studied in 268 cervical biopsies from 216 women including normal epithelia (with and without human papilloma virus), low and high grade cervical intraepithelial neoplasia, and invasive carcinoma. The percentage of positive immunostaining was scored using a Kontron MOP videoplan image analyser. All major categories of cervical epithelia expressed these keratins to varying degrees. The median percentage of immunostaining for keratin 10 was 40% in normal tissue compared with just 1% in invasive carcinoma (p < 0.0001). The medians for keratin 17 were 0% in the normal group and 80% in carcinomas (p < 0.0001). By contrast, there was no significant difference in staining for keratin 19. Using a combination of the keratin 10 and 17 percentages, it was possible to separate the carcinomas from the benign conditions with a sensitivity of 100% and a specificity of 93%. Further analyses within the groups revealed more extensive staining for keratins 10 and 19 in reserve cell hyperplasia, immature squamous metaplasia, and congenital transformation zone. The morphological variety within the cervix is reflected, in part, by distinct keratin patterns. There are striking differences in the patterns of keratins 10 and 17 between infiltrating squamous carcinoma and normal cervical epithelia.


The safety assessment of foods from transgenic and cloned animals using the comparative approach.
The comparative approach to food safety assessment is based on the idea that the safety of a new food can largely be determined by its comparison to the benchmark of commonly consumed foods already in the food supply (also called the 'conventional counterpart'). Any differences between the new food and its conventional counterpart are evaluated to determine their relevance to human health and safety. In this way it is possible to conclude whether a new food is 'as safe as' conventional food already in the food supply. This approach, first developed primarily for use in the safety assessment of food from transgenic plants, is now generally accepted for food from both transgenic and cloned animals as well. This article outlines the basic principles behind the comparative approach, discusses some of the potential food safety concerns associated with transgenic and cloned animals, and describes important elements of the comparative approach and how these might be applied to assessing the safety of food from animals.


Prevalence and correlates of quitline awareness and utilization in the United States: an update from the 2009-2010 National Adult Tobacco Survey.
Tobacco quitlines are evidence-based cessation resources that have been underutilized. The purpose of this study is to provide population-level data about quitline awareness and utilization in the United States and to assess correlates of awareness and utilization. Data were from the 2009-2010 National Adult Tobacco Survey. Descriptive statistics were produced for national- and state-level quitline awareness and for national quitline utilization. Bivariate and multivariable logistic regressions were used to identify correlates of quitline awareness and utilization. Quitline awareness among the total sample was 33.9% (current smokers 53.9%, former smokers 34.0%, never-smokers 27.0%). Awareness varied by state (range: 35.8%-84.6% for current smokers). Among current smokers who tried to quit in the past year, correlates of lower awareness included being Black, non-Hispanic, and making <$50,000 annually; correlates of higher awareness included having seen a health professional, higher state tobacco program expenditures, and being female. Among smokers who made at least one quit attempt in the previous year and were aware of the quitline, quitline utilization was 7.8%. Higher state tobacco program expenditure, health professional advice, and being Black, non-Hispanic were correlated with higher utilization; older age was correlated with lower utilization. Awareness was significantly associated with use at the state level (r = .98, p < .01). Although the majority of smokers in the United States are aware of quitlines, only a small percentage of those trying to quit utilize them. State tobacco program expenditures and receipt of advice from a health professional were associated with both higher quitline awareness and higher utilization.


The Effect of Plant Age on Resistance to Colletotrichum truncatum in Lens culinaris.
Anthracnose, caused by Colletotrichum truncatum, is a major disease of lentil (Lens culinaris) on the Canadian prairies. Age-dependent resistance to the pathogen was elucidated on (i) the partially resistant line 'CDC Redberry' compared with both resistant (LR59-81) and susceptible ('Eston') lines at different ages across the life cycle of the plant, and (ii) a range of lines with varying resistance at key ages, using both races of the pathogen (races Ct0 and Ct1). CDC Redberry appears moderately susceptible when inoculated at a young age and is more resistant when inoculated 19 to 26 days after planting. The highest disease levels were observed on the oldest plants studied (inoculated at podding stage, 47 days after planting). This pattern of age-dependent resistance in CDC Redberry was the same after inoculation with either race of the pathogen and indicated that the best differentiation occurs when plants are inoculated at the podding stage. 'CDC Robin' showed consistent separation between races at all ages but the most substantial differences were observed on plants inoculated at 47 days of age. Resistant lines LR59-81 and VIR 421 were relatively unaffected by age or by race of C. truncatum compared with partially resistant and susceptible lines. Overall, results suggest that differentiation between resistant and susceptible lines is optimal using older, adult-phased plants.


Developing a reporting guideline for social and psychological intervention trials.
Understanding randomized controlled trials of complex social and psychological interventions requires a detailed description of the interventions tested and the methods used to evaluate them. However, randomized controlled trial reports often omit, or inadequately report, this information. Incomplete and inaccurate reporting hinders the optimal use of research, wastes resources, and fails to meet ethical obligations to research participants and consumers. We explain how reporting guidelines have improved the quality of reports in medicine, and describe the ongoing development of a new reporting guideline for randomized controlled trials: an extension of the Consolidated Standards of Reporting Trials for social and psychological interventions. We invite readers to participate in the project by visiting our Web site, to help us reach the best-informed consensus on these guidelines ( http://tinyurl.com/consort-study ).


Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.
Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.


7-Deaza-2'-deoxyadenosine-5'-triphosphate as an alternative nucleotide for the pyrosequencing technology.
A new adenosine nucleotide analog suitable for the Pyrosequencing method is presented. The new analog, 7-deaza-2'-deoxyadenosine-5'-triphosphate (c7dATP), has virtually the same low substrate specificity for luciferase as the currently used analog, 2'-deoxyadenosine-5'-O-(1-thiotriphosphate) (dATPalphaS). The inhibitory effect dATPalphaS displays on the nucleotide degrading activity of apyrase was reduced significantly by substituting the c7dATP for the dATPalphaS. Both analogs show high stability after long time storage at + 8 degrees C. Furthermore, with the new nucleotide a read length of up to 100 bases was obtained for several templates from fungi, bacteria and viruses.


Angiotensin converting enzyme inhibitors and progressive renal insufficiency. Current experience and future directions.
To review the rationale for using angiotensin converting enzyme (ACE) inhibitors in progressive renal disease, and to evaluate the experience with these agents in patients with hypertension and renal insufficiency. Experimental and clinical studies published from January 1977 to November 1988 were identified by searching the literature and by extensive hand searching of bibliographies of identified articles. Experimental studies of glomerular function during therapy with ACE inhibitors or other antihypertensive regimens were reviewed. Series using ACE inhibitors for treating hypertensive patients with renal disease were evaluated and reports of adverse events were studied. Experimentally, ACE inhibitors seem to decrease glomerular injury by reducing both systemic and glomerular hypertension. Clinically, ACE inhibitors reduce systemic blood pressure in hypertensive patients with diabetic and nondiabetic renal disease without causing dramatic changes in glomerular filtration rate or renal blood flow. Most studies of nondiabetic renal insufficiency suggest that proteinuria is reduced in most patients. However, no long-term controlled study on the effect of ACE inhibitors on the progression rate of nondiabetic renal disease has been completed. ACE inhibitors have not yet been approved by the Food and Drug Administration (FDA) for treating or preventing progressive renal disease. Such use would therefore be considered "innovative" therapy. ACE inhibitors are tolerated by azotemic patients, although transient reductions in renal function can occur. Patients with bilateral renal insufficiency or low cardiac output are at increased risk for developing reversible acute renal insufficiency. Hyperkalemia may occur, particularly in patients with diabetes or severe renal insufficiency. In many patients with renal disease, ACE inhibitors dramatically reduce proteinuria, but whether they also reduce the rate of progression of renal disease remains unproved.


Oxidized low density lipoproteins potentiate vasoconstrictions to various agonists by direct interaction with vascular smooth muscle.
In hypercholesterolemia, low density lipoproteins (LDLs) may be oxidized by monocytes/macrophages in the arterial wall. Therefore, we investigated the effect of LDL and its oxidative derivatives (ox-LDL) on vascular tone in isolated perfused rabbit femoral arteries. Perfusion of endothelium-intact and endothelium-denuded segments with ox-LDL (80 micrograms protein/ml) caused no or only weak vasoconstrictions in the absence of contractile agonists. However, in the presence of ox-LDL, vasoconstrictions to threshold concentrations of norepinephrine, serotonin, phenylephrine, or potassium were significantly enhanced. This enhancement correlated with the degree of oxidation. When ox-LDL was administered at higher concentrations (greater than 200 micrograms protein/ml), it evoked moderate vasoconstrictions even in the absence of contractile agonists. Native LDL had no effect on vascular tone. Preincubation with verapamil, diltiazem, and nitrendipine inhibited vasoconstrictions evoked by ox-LDL, both in the presence and in the absence of a contractile agonist. The contractile responses to ox-LDL were significantly greater in endothelium-denuded segments than in endothelium-intact segments. At the above concentrations, ox-LDL had no influence on endothelium-derived relaxing factor-mediated vasodilations. These data indicate that ox-LDL enhances agonist-induced vasoconstrictions by a direct effect on the vascular smooth muscle. We therefore suggest that ox-LDL is an important factor that may increase the risk of inappropriate vasoconstriction in hypercholesterolemia, independent of its putative cytotoxic effect on the endothelium.


High-resolution AFM imaging of intact and fractured trabecular bone.
Nanoscale structural analyses of biomineralized materials can frequently help elucidate important structure-function relationships in these complex organic-inorganic composites. Atomic force microscope (AFM) imaging of the exterior surface of trabecular bone reveals a densely woven structure of collagen fibrils, banded with a 67-nm periodicity, and densely packed mineral plates. The mineral plates on the collagen fibrils overlap and exhibit a large range of plate diameters from 30 to 200 nm. On the collagen fibrils, small nodular features, spaced 20-30 nm, run perpendicular to the fibrils. In some cases, these nodules are also seen on filaments extending between collagen fibrils. We hypothesize that these protrusions are noncollagenous proteins such as proteoglycans and may have collapsed into compact structures when the sample was dried. AFM images of pristine fractured surfaces reveal a dense array of mineral plates. In a few isolated locations, short sections of bare collagen fibrils are visible. In other regions, the existence of the underlying collagen fibrils can be inferred from the linear patterns of the mineral plates. Fractured samples, rinsed to remove mineral plates, reveal separated collagen fibrils on the fractured surfaces. These fibrils are often covered with protrusions similar to those observed on the exterior surfaces but are less organized. In addition, as on the exterior surfaces, there are sometimes small filaments extending between neighboring collagen fibrils. These studies provide important insights into the nanostructured architecture of this complex biocomposite.


Behavior of Listeria monocytogenes during the Manufacture, Ripening, and Cold Storage of Afuega'l Pitu Cheese.
Afuega'l Pitu is an artisanal acid-coagulated cheese manufactured in Asturias (northern Spain) and mainly consumed between the 3rd and the 30th day of ripening. Six cheese-making trials were performed in a pilot plant by using pasteurized whole milk inoculated with Listeria monocytogenes (strain L2 [serotype 1/2a], L39, or L41 [serotype 4b]) to ca. 2.7 log CFU/ml. A starter containing three strains, Lactococcus lactis subsp. lactis IPLA 947, Lactococcus lactis subsp. lactis biovar diacetylactis IPLA 838, and Leuconostoc citreum IPLA 616, grown separately in milk and combined in the volumetric proportion 3:1:1.3 was used. During the acidification L. monocytogenes counts increased 2.78- to 7.03-fold, depending on the strain, and remained within the curd; from this time counts decreased abruptly and were not detected in cheeses beyond the 7th day. The average pH in the curd was 4.43, and it decreased to around 4.0 in 5- to 7-day-old cheeses. These pH values were near the tolerance limit for L. monocytogenes and probably caused cell damage. Although moisture, aw, and NaCl levels were not limiting for the growth and survival of L. monocytogenes , salt content must be considered as a contributing factor in L. monocytogenes inactivation. Finally, the L2 strain grew better in curd and was slightly more resistant to low pH and refrigeration than strain L39 or L41. The manufacture of Afuega'l Pitu cheese from pasteurized milk and the design of a specific starter from the autochthonous lactic microbiota can lead to a safer product that can be consumed after very short ripening periods.


The experience of Chinese physicians in the national health diplomacy programme deployed to Sudan.
Chinese Medical Teams have been working in developing countries since 1963 as a health diplomacy strategy. In 2010, 1252 Chinese medical personnel were assigned to 48 countries. We conducted a review of Chinese literature and governmental websites to describe the history and current distribution of Chinese Medical Teams around the world. In addition, we interviewed members of a 36-member Chinese Medical Team deployed to Sudan (primarily about their motivations to join the programme and the challenges and benefits they face), along with their Sudanese hosts. The most significant challenge health workers described was homesickness. Most members said they were able to maintain motivation through their curiosity and the doctor-friendly environment. All but two rated their own working performance as 'good' or 'very good', while their Sudanese colleagues consistently rated them even higher. Participants reported conflicting beliefs regarding the perceived responsibilities of the team and challenges around communication. Three pillars support the Chinese Medical Team programme in Sudan: bilateral government commitment, the professionalism of the Medical Teams, and the welcoming medical environment. Future success of this or similar Chinese programmes depend on the willingness of both governments to participate, the ongoing commitment of younger Chinese doctors, and the hospitality of physicians in the host country. There are also some threats to the programme, including a potentially diminishing need for Chinese doctors to support increasingly well-trained host country physicians.


Sleep in children with attention-deficit/hyperactivity disorder: meta-analysis of subjective and objective studies.
To perform a meta-analysis of subjective (i.e., based on questionnaires) and objective (i.e., using polysomnography or actigraphy) studies comparing sleep in children with attention-deficit/hyperactivity disorder (ADHD) versus controls. We searched for subjective and objective sleep studies (1987-2008) in children with ADHD (diagnosed according to standardized criteria). Studies including subjects pharmacologically treated or with comorbid anxiety/depressive disorders were excluded. Sixteen studies, providing 9 subjective and 15 objective parameters and including a total pooled sample of 722 children with ADHD versus 638 controls, were retained. With regard to subjective items, the meta-analysis indicated that children with ADHD had significantly higher bedtime resistance (z = 6.94, p <.001), more sleep onset difficulties (z = 9.38, p <.001), night awakenings (z = 2.15, p =.031), difficulties with morning awakenings (z = 5.19, p <.001), sleep disordered breathing (z = 2.05, p =.040), and daytime sleepiness (z = 1.96, p =.050) compared with the controls. As for objective parameters, sleep onset latency (on actigraphy), the number of stage shifts/hour sleep, and the apnea-hypopnea index were significantly higher in the children with ADHD compared with the controls (z = 3.44, p =.001; z = 2.43, p =.015; z = 3.47, p =.001, respectively). The children with ADHD also had significantly lower sleep efficiency on polysomnography (z = 2.26, p =.024), true sleep time on actigraphy (z = 2.85, p =.004), and average times to fall asleep for the Multiple Sleep Latency Test (z = 6.37, p <.001) than the controls. The children with ADHD are significantly more impaired than the controls in most of the subjective and some of the objective sleep measures. These results lay the groundwork for future evidence-based guidelines on the management of sleep disturbances in children with ADHD.


A review of functional imaging studies on category specificity.
A review of 20 functional imaging studies that compared visual processing of natural objects and artifacts in normal subjects is presented. The studies included fulfilled three criteria: (i) they used pictures as stimuli, (ii) they were based on direct contrasts between categories, and (iii) they reported findings in Talairach space. Not a single area is consistently activated for a given category across all studies. In contrast, 11 out of 29 regions are reported activated by both artifacts and natural objects. It is argued that the inconsistency is unlikely to reflect differences between studies in task requirements alone. Rather, the most likely causes of the inconsistency are: (i) adoption of liberal statistical thresholds that may yield false-positive activations, (ii) limited sensitivity due to few observations, and (iii) failure to match categories on confounding variables such as familiarity and visual complexity. Of the most consistent activations found, none appear to be selective for natural objects or artifacts. The findings reviewed are compatible with theories of category specificity that assume a widely distributed conceptual system not organized by category.


Change in Dysfunctional Beliefs About Sleep in Behavior Therapy, Cognitive Therapy, and Cognitive-Behavioral Therapy for Insomnia.
As part of a larger randomized controlled trial, 188 participants were randomized to behavior therapy (BT), cognitive therapy (CT), or cognitive-behavioral therapy (CBT) for insomnia. The aims of this study were threefold: (a) to determine whether change in dysfunctional beliefs about sleep was related to change in sleep, insomnia symptoms, and impairment following treatment; (b) to determine whether BT, CT, and CBT differ in their effects on dysfunctional beliefs; and (c) to determine whether the treatments differ in their effects on particular kinds of dysfunctional beliefs. Beliefs, sleep, insomnia symptoms, and sleep-related psychosocial impairment were assessed at pretreatment, posttreatment, and 6- and 12-month follow-up. Greater change in dysfunctional beliefs occurring over the course of BT, CT, or CBT was associated with greater improvement in insomnia symptoms and impairment at posttreatment and both follow-ups. All groups experienced a significant decrease in dysfunctional beliefs during treatment, which were sustained through 6- and 12-month follow-up. Compared with the BT group, a greater proportion of participants in the CT and/or CBT groups endorsed dysfunctional beliefs below a level considered clinically significant at posttreatment and 12-month follow-up. The results demonstrate the importance of targeting dysfunctional beliefs in insomnia treatment, suggest that beliefs may be significantly modified with BT alone, and indicate that cognitive interventions may be particularly powerful in enhancing belief change.


An Update of the Systematic Appraisal of the Accuracy and Utility of Discography in Chronic Spinal Pain.
The intervertebral disc has been implicated as a major cause of chronic spinal pain based on clinical, basic science, and epidemiological research. There is, however, a lack of consensus regarding the diagnosis and treatment of intervertebral disc disorders. Based on controlled evaluations, lumbar intervertebral discs have been shown to be the source of chronic back pain without disc herniation in 26% to 39% of patients, and in 16% to 53% of patients with pain in the cervical spine. Lumbar, cervical, and thoracic provocation discography, which includes disc stimulation and morphological evaluation, is often used to distinguish a painful disc from other potential sources of pain. Despite the extensive literature on point, intense debate continues about lumbar discography as a diagnostic tool. A systematic review of the diagnostic accuracy of lumbar, cervical, and thoracic provocation and analgesic discography literature. To systematically assess and re-evaluate the diagnostic accuracy of lumbar, cervical, and thoracic discography. The available literature on discography was reviewed. A methodological quality assessment of included studies was performed using the Quality Appraisal of Reliability Studies (QAREL) checklist. Only diagnostic accuracy studies meeting at least 50% of the designated inclusion criteria were included in the analysis. To assess the level of evidence, a modified grading of qualitative evidence criteria was utilized, with grading of evidence into 5 categories from Level I to Level V incorporating evidence obtained from multiple high quality diagnostic accuracy studies for Level I and opinion or consensus of a large group of clinicians and/or scientists for Level V. Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to June 2017, and manual searches of the bibliographies of known primary and review articles. Over 100 manuscripts were considered for inclusion. Of these, 8 studies met inclusion criteria for diagnostic accuracy and prevalence with 5 studies assessing lumbar provocation discography and 3 studies assessing cervical discography. The results showed variable prevalence from 16.9% to 26% for discogenic pain and 16.9% to 42% for internal disc disruption. The cervical discogenic pain prevalence ranged from 16% to 53%. Based on methodological quality assessment criteria the strength of evidence for lumbar provocation discography is Level III and for cervical discogenic pain is Level IV. Despite multiple publications in the lumbar spine, value and validity of discography continues to be debated. In reference to cervical and thoracic discography, the available literature and value and validity continues to be low. This systematic review illustrates that lumbar provocation discography performed according to the International Association for the Study of Pain (IASP) criteria may be a useful tool for evaluating chronic lumbar discogenic pain. The evidence is weaker for cervical and nonexistent for thoracic discography. Lumbar intervertebral disc, cervical intervertebral disc, thoracic intervertebral disc, discography, provocation discography, analgesic discography, diagnostic accuracy, prevalence.


SCHNEL: scalable clustering of high dimensional single-cell data.
Single cell data measures multiple cellular markers at the single-cell level for thousands to millions of cells. Identification of distinct cell populations is a key step for further biological understanding, usually performed by clustering this data. Dimensionality reduction based clustering tools are either not scalable to large datasets containing millions of cells, or not fully automated requiring an initial manual estimation of the number of clusters. Graph clustering tools provide automated and reliable clustering for single cell data, but suffer heavily from scalability to large datasets. We developed SCHNEL, a scalable, reliable and automated clustering tool for high-dimensional single-cell data. SCHNEL transforms large high-dimensional data to a hierarchy of datasets containing subsets of data points following the original data manifold. The novel approach of SCHNEL combines this hierarchical representation of the data with graph clustering, making graph clustering scalable to millions of cells. Using seven different cytometry datasets, SCHNEL outperformed three popular clustering tools for cytometry data, and was able to produce meaningful clustering results for datasets of 3.5 and 17.2 million cells within workable time frames. In addition, we show that SCHNEL is a general clustering tool by applying it to single-cell RNA sequencing data, as well as a popular machine learning benchmark dataset MNIST. Implementation is available on GitHub (https://github.com/biovault/SCHNELpy). All datasets used in this study are publicly available. Supplementary data are available at Bioinformatics online.


Effect of intermittent high-intensity exercise on gastric emptying in man.
The effect on gastric emptying of brief intermittent high-intensity sprints and a moderate-intensity steady-state cycle exercise was studied. Eight healthy male subjects were each studied at rest (R), during steady-state exercise at a constant power output corresponding to 66% of their VO(2max) (C66), during intermittent high-intensity exercise at a power output averaging 66% of their VO(2max) (I66), and during intermittent high-intensity exercise at a power output averaging 75% of their VO(2max) (I75). Gastric emptying was measured using the double-sampling gastric aspiration technique. Subjects ingested 600 mL of a 6% carbohydrate-electrolyte solution immediately before exercise or seated rest. The volume of test solution in the stomach was less at all time points on trial I66 than on trial I75 (P = 0.023). The rate of gastric emptying, expressed as the median (range) time (minutes) taken to empty half the test meal volume (t(1/2)), was not different on trials R (20 (7--30)) and C66 (21 (7--49)), and was faster than on trial I75 (62 (27--100); P = 0.003 and P = 0.005, respectively). Median t(1/2) was faster on trial R than on trial I66 (30 (15--74) min; P = 0.019), but no difference was detected between C66 and I66 or between I66 and I75. However, over the initial 30 min period after ingestion, the median (range) volume of test drink delivered to the duodenum was faster (P < 0.01) on trials R (387 (296--541) mL) and C66 (389 (165--584) mL) than on trials I66 (331 (191--494) mL) or I75 (249 (79-335) mL). The data demonstrate that gastric emptying of liquids is slowed during brief intermittent high-intensity exercise compared with rest or steady-state moderate exercise.


Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease.
Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23. Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks. ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events. Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.


Factors of importance for patients' decision time in acute coronary syndrome.
Not much is known about the patients' decision time in acute coronary syndrome (ACS). The aim of the survey was therefore to describe patients' decision time and factors associated with this parameter in ACS. We conducted a national survey comprising intensive cardiac care units at 11 hospitals in Sweden in which patients with ACS diagnosis and symptoms onset outside hospital participated. Main outcome measures were patients' decision time and factors associated with patients' decision time. In all, 1939 patients took part in the survey. The major factors associated with a shorter patient decision time were: 1) ST-elevation ACS, 2) associated symptoms such as vertigo or near syncope, 3) interpreting the symptoms as cardiac in origin, 4) pain appearing suddenly and reaching a maximum within minutes, 5) having knowledge of the importance of quickly seeking medical care and 6) experiencing the symptoms as frightening. The following aspects of the disease were associated with a longer decision time: 1) pain was localised in the back and 2) symptom onset at home when alone. A number of factors, including the type of ACS, the type and localisation of symptoms, the place where symptoms occurred, patients' interpretation of symptoms and knowledge were all associated with patients' decision time in connection with ACS.


A Cross Cultural Comparison of Attitude of Mental Healthcare Professionals Towards Involuntary Treatment Orders.
The purpose of this study was to investigate East-West cultural attitudes of mental healthcare professionals (MHPs) towards Involuntary Treatment Orders (ITOs) among Taiwan, England, Wales, and New Zealand. Data on Taiwanese MHPs' views of ITO regime were collected from the National Psychiatric Disease Mandatory Assessment and Community Care Review Committee (N = 176). A national survey instrument was designed to assess the level of support for ITOs among senior clinicians and to determine their views on the importance of various factors in decision-making, the mechanisms through which coercion may work, impediments to its use, and its perceived impact on patients and therapeutic relationships. A descriptive analysis was carried out with data presented as appropriate for the distribution and a t-test was used to detect any differences by respondents. Risk reduction was ranked the most important factor in use of ITOs and reasons for discharging an order. Female respondents had higher approval ratings, with 85 % of agreeing that ITOs were of benefit to the therapeutic relationship, assured long-term stability, and increased medication compliance. The results suggest that clinicians decide the use of ITOs largely based on the risk management, both in terms of starting and ending an order. However, the use of ITOs vary which reflected in the practice. Given this variation in the use of enabling legislation, multidisciplinary input in decision-making is an essential safety mechanism.


Studies on the Virome of the Entomopathogenic Fungus Beauveria bassiana Reveal Novel dsRNA Elements and Mild Hypervirulence.
The entomopathogenic fungus Beauveria bassiana has a wide host range and is used as a biocontrol agent against arthropod pests. Mycoviruses have been described in phytopathogenic fungi while in entomopathogenic fungi their presence has been reported only rarely. Here we show that 21.3% of a collection of B. bassiana isolates sourced from worldwide locations, harbor dsRNA elements. Molecular characterization of these elements revealed the prevalence of mycoviruses belonging to the Partitiviridae and Totiviridae families, the smallest reported virus to date, belonging to the family Narnaviridae, and viruses unassigned to a family or genus. Of particular importance is the discovery of members of a newly proposed family Polymycoviridae in B. bassiana. Polymycoviruses, previously designated as tetramycoviruses, consist of four non-conventionally encapsidated capped dsRNAs. The presence of additional non-homologous genomic segments in B. bassiana polymycoviruses and other fungi illustrates the unprecedented dynamic nature of the viral genome. Finally, a comparison of virus-free and virus-infected isogenic lines derived from an exemplar B. bassiana isolate revealed a mild hypervirulent effect of mycoviruses on the growth of their host isolate and on its pathogenicity against the greater wax moth Galleria mellonella, highlighting for the first time the potential of mycoviruses as enhancers of biocontrol agents.


Assessing accuracy of an electronic provincial medication repository.
Jurisdictional drug information systems are being implemented in many regions around the world. British Columbia, Canada has had a provincial medication dispensing record, PharmaNet, system since 1995. Little is known about how accurately PharmaNet reflects actual medication usage. This prospective, multi-centre study compared pharmacist collected Best Possible Medication Histories (BPMH) to PharmaNet profiles to assess accuracy of the PharmaNet profiles for patients receiving a BPMH as part of clinical care. A review panel examined the anonymized BPMHs and discrepancies to estimate clinical significance of discrepancies. 16% of medication profiles were accurate, with 48% of the discrepant profiles considered potentially clinically significant by the clinical review panel. Cardiac medications tended to be more accurate (e.g. ramipril was accurate >90% of the time), while insulin, warfarin, salbutamol and pain relief medications were often inaccurate (80-85% of the time). 1215 sequential BPMHs were collected and reviewed for this study. The PharmaNet medication repository has a low accuracy and should be used in conjunction with other sources for medication histories for clinical or research purposes. This finding is consistent with other, smaller medication repository accuracy studies in other jurisdictions. Our study highlights specific medications that tend to be lower in accuracy.


Extent, intensity and drivers of mammal defaunation: a continental-scale analysis across the Neotropics.
Neotropical mammal diversity is currently threatened by several chronic human-induced pressures. We compiled 1,029 contemporary mammal assemblages surveyed across the Neotropics to quantify the continental-scale extent and intensity of defaunation and understand their determinants based on environmental covariates. We calculated a local defaunation index for all assemblages-adjusted by a false-absence ratio-which was examined using structural equation models. We propose a hunting index based on socioenvironmental co-variables that either intensify or inhibit hunting, which we used as an additional predictor of defaunation. Mammal defaunation intensity across the Neotropics on average erased 56.5% of the local source fauna, with ungulates comprising the most ubiquitous losses. The extent of defaunation is widespread, but more incipient in hitherto relatively intact major biomes that are rapidly succumbing to encroaching deforestation frontiers. Assemblage-wide mammal body mass distribution was greatly reduced from a historical 95th-percentile of ~ 14 kg to only ~ 4 kg in modern assemblages. Defaunation and depletion of large-bodied species were primarily driven by hunting pressure and remaining habitat area. Our findings can inform guidelines to design transnational conservation policies to safeguard native vertebrates, and ensure that the "empty ecosystem" syndrome will be deterred from reaching much of the New World tropics.


The role of clinician emotion in clinical reasoning: Balancing the analytical process.
This review paper identifies and describes the role of clinicians' memory, emotions and physical responses in clinical reasoning processes. Clinical reasoning is complex and multi-factorial and key models of clinical reasoning within musculoskeletal physiotherapy are discussed, highlighting the omission of emotion and subsequent physical responses and how these can impact upon a clinician when making a decision. It is proposed that clinicians should consider the emotions associated with decision-making, especially when there is concern surrounding a presentation. Reflecting on practice in the clinical environment and subsequently applying this to a patient presentation should involve some acknowledgement of clinicians' physical responses, emotions and how they may play a part in any decision made. Presenting intuition and gut-feeling as separate reasoning methods and how these processes co-exist with other more accepted reasoning such as hypothetico-deductive is also discussed. Musculoskeletal physiotherapy should consider the elements of feelings, emotions and physical responses when applying reflective practice principles. Furthermore, clinicians dealing with difficult and challenging presentations should look at the emotional as well as the analytical experience when justifying decisions and learning from practice.


Novel markers of cell kinetics to evaluate progression from cirrhosis to hepatocellular carcinoma.
We investigated cell cycle kinetics of nodular lesions in cirrhosis to differentiate hepatocellular carcinoma (HCC) from its precursor lesions. Twelve small HCC, 10 regenerative (RN), six large regenerative (LRN), and five dysplastic nodules (DN), identified in explant cirrhotic livers of five consecutive patients transplanted at Royal Free Hospital in 2002. Immunoperoxidase for MCM2, geminin and Ki67 was performed and the percentage of positive cells counted. The proportion of cells expressing MCM2 was more than those expressing Ki67, which in turn was more than those expressing geminin (overall median=16%, 2% and 0.5%, respectively, P<0.001). There was a statistically significant trend of increasing Ki67 expression (P=0.006), from RN to HCC; this trend was not statistically significant for geminin (P=0.18) or MCM2 (P=0.51). The median percentage of cells expressing Ki67 was 1% in RN, 0.5% in LRN, 2.2% in DN and 5.4% in HCC. The combination of these markers identified four different cell kinetics patterns: 'resting' (G0 cells: MCM2 -ve, Ki67 -ve, geminin -ve); 'licensed' (MCM2 +ve, Ki67 -ve, geminin -ve); 'slowly growing' (G1 phase arrest, MCM2 +ve, Ki67 +ve, low (0.4%) geminin) and expanding (MCM2 +ve, Ki67 +ve, geminin +ve) nodules. The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of HCC progression in cirrhosis.


Inequality in access to cultural ecosystem services from protected areas in the Chilean biodiversity hotspot.
Experiences with nature through visits to protected areas provide important cultural ecosystem services that have the potential to strengthen pro-environmental attitudes and behavior. Understanding accessibility to protected areas and likely preferences for enjoying the benefits of nature visits are key factors in identifying ways to reduce inequality in access and inform the planning and management for future protected areas. We develop, at a regional scale, a novel social media database of visits to public protected areas in part of the Chilean biodiversity hotspot using geotagged photographs and assess the inequality of access using the home locations of the visitors and socio-economic data. We find that 20% of the population of the region make 87% of the visits to protected areas. The larger, more biodiverse protected areas were the most visited and provided most cultural ecosystem services. Wealthier people tend to travel further to visit protected areas while people with lower incomes tend to visit protected areas that are closer to home. By providing information on the current spatial flows of people to protected areas, we demonstrate the need to expand the protected area network, especially in lower income areas, to reduce inequality in access to the benefits from cultural ecosystem services provided by nature to people.


Autophosphorylation of type II CaM kinase in hippocampal neurons: localization of phospho- and dephosphokinase with complementary phosphorylation site-specific antibodies.
We have visualized the distribution of autophosphorylated type II CaM kinase in neural tissue with the use of two complementary antibodies: a monoclonal antibody that binds to the alpha and beta subunits of the kinase only when they are autophosphorylated at threonine-286 (287 in beta) and affinity-purified rabbit antibodies that bind to both subunits only when they are not phosphorylated at these residues. We used these antibodies to double-label organotypic hippocampal cultures, detecting the mouse monoclonal antibody with rhodamine and the rabbit polyclonal antibodies with fluorescein. In double-exposed photographs, the ratios of intensities of the two fluorophores revealed the relative proportion of autophosphorylated and nonphosphorylated kinase in individual neurons throughout the cultures. We found that autophosphorylated and nonphosphorylated kinase are colocalized throughout most neurons rather than segregated within distinct cells or subcellular domains. However, the variations in intensity of the two fluorophores indicated that the proportion of autophosphorylated kinase is consistently higher in neuronal somas than in the neuropil. Incubation of the cultures in Ca2+ free medium dramatically reduced both the level of autophosphorylated kinase detected biochemically and the relative intensity of fluorescent staining with the phosphokinase specific monoclonal antibody. These results support the hypothesis that regulation of Ca(2+)-independent CaM kinase activity in vivo occurs by a dynamic equilibrium between autophosphorylation and dephosphorylation and that this equilibrium is maintained, at varying steady-state levels, in all parts of neurons.


Sexually dimorphic aggression indicates male gray wolves specialize in pack defense against conspecific groups.
Aggression directed at conspecific groups is common among gregarious, territorial species, and for some species such as gray wolves (Canis lupus) intraspecific strife is the leading cause of natural mortality. Each individual in a group likely has different measures of the costs and benefits associated with a group task, such as an aggressive attack on another group, which can alter motivation and behavior. We observed 292 inter-pack aggressive interactions in Yellowstone National Park between 1 April 1995 and 1 April 2011 (>5300days of observation) in order to determine the role of both sexes, and the influence of pack, age, and other traits on aggression. We recorded the behaviors and characteristics of all individuals present during the interactions (n=534 individuals) and which individuals participated in each step (i.e. chase, attack, kill, flight) of the interaction. Overall, all wolves were more likely to chase rivals if they outnumbered their opponent, suggesting packs accurately assess their opponent's size during encounters and individuals adjust their behavior based on relative pack size. Males were more likely than females to chase rival packs and gray-colored wolves were more aggressive than black-colored wolves. Male wolves and gray-colored wolves also recorded higher cortisol levels than females and black-colored wolves, indicating hormonal support for more intense aggressive behavior. Further, we found a positive correlation between male age and probability of chasing, while age-specific participation for females remained constant. Chasing behavior was influenced by the sex of lone intruders, with males more likely to chase male intruders. This difference in behavior suggests male and female wolves may have different strategies and motivations during inter-pack aggressive interactions related to gray wolf mating systems. A division of labor between pack members concerning resource and territory defense suggests selection for specific traits related to aggression is an adaptive response to intense competition between groups of conspecifics.


Evaluation of Minimal Change Lesions Using Linked Color Imaging in Patients With Nonerosive Reflux Esophagitis.
High prevalence of minimal change lesion (MCL) in nonerosive reflux esophagitis (NERD) patients is commonly recognized by many endoscopists. However, it is difficult to detect MCL with conventional white-light imaging (WLI) endoscopy. Linked color imaging (LCI), a novel image-enhanced endoscopy technology with strong, unique color enhancement, is used for easy recognition of early gastric cancer and detection of Helicobacter pylori infection. The aim of the study was to compare the efficacy of LCI and WLI endoscopy in evaluating MCL in patients with NER. Forty-one patients with NERD and 38 subjects with nongastroesophageal reflux disease (non-GERD) were recruited in this study between August 2017 and July 2018. During upper gastrointestinal endoscopy, the distal 5 cm of the esophageal mucosal morphology at the squamocolumnar junction was visualized using WLI followed by LCI. MCL was defined as areas of erythema, blurring of the Z-line, friability, decreased vascularity, white turbid discoloration, and edema or accentuation of the mucosal folds. Three experienced endoscopists evaluated the color patterns for MCL on WLI images and on WLI combined with LCI images in both groups. A biopsy was taken 2 cm above the esophagogastric junction. Histologic slides were scored by a pathologist in a blinded manner. The proportion of MCL was higher in the patients with NERD (70.7%, 29/41) than in patients with non-GERD (39.5%, 15/38) using WLI combined with LCI. In 12 patients with NERD, both WLI and LCI showed normal mucosa. The MCL detection rate was significantly higher when using WLI combined with LCI than when using WLI (70.7% vs. 51.2%, P=0.039) in patients with NERD. The histopathologic score of MCL (+) was significantly higher than that of MCL (-) patients in both the NERD group (4.59±0.32 vs. 2.36±0.34, P<0.01) and the non-GERD group (3.47±0.50 vs. 2.00±0.28, P<0.01). The intraobserver reproducibility levels and interobserver agreement were better with LCI than with WLI alone. Frequency of MCL was higher in patients with NERD than in those with non-GERD. MCL can be identified by using WLI combined with LCI in patients with NERD. By enhancing endoscopic images, LCI is more sensitive in detecting MCL compared with WLI.


Using a Discourse Task to Explore Semantic Ability in Persons With Cognitive Impairment.
This paper uses a discourse task to explore aspects of semantic production in persons with various degree of cognitive impairment and healthy controls. The purpose of the study was to test if an in-depth semantic analysis of a cognitive-linguistic challenging discourse task could differentiate persons with a cognitive decline from those with a stable cognitive impairment. Both quantitative measures of semantic ability, using tests of oral lexical retrieval, and qualitative analysis of a narrative were used to detect semantic difficulties. Besides group comparisons a classification experiment was performed to investigate if the discourse features could be used to improve classification of the participants who had a stable cognitive impairment from those who had cognitively declined. In sum, both types of assessment methods captured difficulties between the groups, but tests of oral lexical retrieval most successfully differentiated between the cognitively stable and the cognitively declined group. Discourse features improved classification accuracy and the best combination of features discriminated between participants with a stable cognitive impairment and those who had cognitively declined with an area under the curve (AUC) of 0.93.


Obesity and insulin resistance are associated with reduced activity in core memory regions of the brain.
Increasing research in animals and humans suggests that obesity may be associated with learning and memory deficits, and in particular with reductions in episodic memory. Rodent models have implicated the hippocampus in obesity-related memory impairments, but the neural mechanisms underlying episodic memory deficits in obese humans remain undetermined. In the present study, lean and obese human participants were scanned using fMRI while completing a What-Where-When episodic memory test (the "Treasure-Hunt Task") that assessed the ability to remember integrated item, spatial, and temporal details of previously encoded complex events. In lean participants, the Treasure-Hunt task elicited significant activity in regions of the brain known to be important for recollecting episodic memories, such as the hippocampus, angular gyrus, and dorsolateral prefrontal cortex. Both obesity and insulin resistance were associated with significantly reduced functional activity throughout the core recollection network. These findings indicate that obesity is associated with reduced functional activity in core brain areas supporting episodic memory and that insulin resistance may be a key player in this association.


An enquiry into scientific and media discourse in the MMR controversy: authority and factuality.
In this paper, we investigate two scientific articles at opposite ends of the MMR debate-Wakefield et al. (1998) (which started the debate) and Taylor et al. (1999)-and four media articles published to inform the public of the results of these two scientific studies. Because people need to assess truth claims about health risks, communicators seek to establish their believability in two ways: authority (i.e., the attribution of scientific claims to sources that may be perceived as believable because of their status) and factuality (i.e., the moderating, limiting, or highlighting of truth claims). The importance of authority was confirmed by the media texts' preference for direct quotes and messages about what people ought to do, especially at the beginning of the debate. Our most significant find, however, relates to two important indicators of factuality: avoidance of vague references and high use of epistemic modals, where Wakefield et al. displays a pattern not at all different from the media texts and opposite to that expected from a scientific text. That Wakefield et al. stands out in the majority of indicators investigated is of interest in view of its controversial position in the MMR debate and worthy of further study.


Theta burst stimulation improves overt visual search in spatial neglect independently of attentional load.
Visual neglect is considerably exacerbated by increases in visual attentional load. These detrimental effects of attentional load are hypothesised to be dependent on an interplay between dysfunctional inter-hemispheric inhibitory dynamics and load-related modulation of activity in cortical areas such as the posterior parietal cortex (PPC). Continuous Theta Burst Stimulation (cTBS) over the contralesional PPC reduces neglect severity. It is unknown, however, whether such positive effects also operate in the presence of the detrimental effects of heightened attentional load. Here, we examined the effects of cTBS on neglect severity in overt visual search (i.e., with eye movements), as a function of high and low visual attentional load conditions. Performance was assessed on the basis of target detection rates and eye movements, in a computerised visual search task and in two paper-pencil tasks. cTBS significantly ameliorated target detection performance, independently of attentional load. These ameliorative effects were significantly larger in the high than the low load condition, thereby equating target detection across both conditions. Eye movement analyses revealed that the improvements were mediated by a redeployment of visual fixations to the contralesional visual field. These findings represent a substantive advance, because cTBS led to an unprecedented amelioration of overt search efficiency that was independent of visual attentional load.


Factors Affecting the Decision to Initiate Anticoagulation After Spine Surgery: Findings From the AOSpine Anticoagulation Global Initiative.
Cross-sectional, international survey. To identify factors influencing pharmacologic anticoagulation initiation after spine surgery based on the AOSpine Anticoagulation Global Survey. This survey was distributed to the international membership of AOSpine (n = 3805). A Likert-type scale described grade practice-specific factors on a scale from low (1) to high (5) importance, and patient-specific factors a scale from low (0) to high (3) importance. Analysis was performed to determine which factors were significant in the decision making surrounding the initiation of pharmacologic anticoagulation. A total of 316 spine surgeons from 64 countries completed the survey. In terms of practice-specific factors considered to initiate treatment, expert opinion was graded the highest (mean grade ± SD = 3.2 ± 1.3), followed by fellowship training (3.2 ± 1.3). Conversely, previous studies (2.7 ± 1.2) and unspecified guidelines were considered least important (2.6 ± 1.6). Patient body mass index (2.0 ± 1.0) and postoperative mobilization (2.3 ± 1.0) were deemed most important and graded highly overall. Those who rated estimated blood loss with greater importance in anticoagulation initiation decision making were more likely to administer thromboprophylaxis at later times (hazard ratio [HR] = 0.68-0.71), while those who rated drain output with greater importance were likely to administer thromboprophylaxis at earlier times (HR = 1.32-1.43). Among our global cohort of spine surgeons, certain patient factors (ie, patient mobilization and body mass index) and practice-specific factors (ie, expert opinion and fellowship training) were considered to be most important when considering anticoagulation start times.


Cognitive reserve moderates the negative effect of brain atrophy on cognitive efficiency in multiple sclerosis.
According to the cognitive reserve hypothesis, neuropsychological expression of brain disease is attenuated among persons with higher education or premorbid intelligence. The current research examined cognitive reserve in multiple sclerosis (MS) by investigating whether the negative effect of brain atrophy on information processing (IP) efficiency is moderated by premorbid intelligence. Thirty-eight persons with clinically definite MS completed a vocabulary-based estimate of premorbid intelligence (Wechsler Vocabulary) and a composite measure of IP efficiency (Symbol Digit Modalities Test and Paced Auditory Serial Addition Task). Brain atrophy was estimated from measurements of third ventricle width using high-resolution anatomical brain magnetic resonance imaging (magnetization-prepared rapid gradient echo). In a hierarchical regression analysis controlling for age and depressive symptomatology, brain atrophy predicted worse IP efficiency (R2 = .23, p = .003) and cognitive reserve predicted better IP efficiency (R2 = .13, p = .013), but these effects were moderated by an Atrophy x Cognitive Reserve interaction (R2 = .15, p = .004). The negative effect of brain atrophy on IP efficiency was attenuated at higher levels of reserve, such that MS subjects with higher reserve were better able to withstand MS neuropathology without suffering cognitive impairment. Results help explain the incomplete and inconsistent relationship between brain atrophy and IP efficiency in previous research.


Sleepiness and prediction of driver impairment in simulator studies using a Cox proportional hazard approach.
Cox proportional hazard models were used to study relationships between the event that a driver is leaving the lane caused by sleepiness and different indicators of sleepiness. In order to elucidate different indicators' performance, five different models developed by Cox proportional hazard on a data set from a simulator study were used. The models consisted of physiological indicators and indicators from driving data both as stand alone and in combination. The different models were compared on two different data sets by means of sensitivity and specificity and the models' ability to predict lane departure was studied. In conclusion, a combination of blink indicators based on the ratio between blink amplitude and peak closing velocity of eyelid (A/PCV) (or blink amplitude and peak opening velocity of eyelid (A/POV)), standard deviation of lateral position and standard deviation of lateral acceleration relative road (ddy) was the most sensitive approach with sensitivity 0.80. This is also supported by the fact that driving data only shows the impairment of driving performance while blink data have a closer relation to sleepiness. Thus, an effective sleepiness warning system may be based on a combination of lane variability measures and variables related to eye movements (particularly slow eye closure) in order to have both high sensitivity (many correct warnings) and acceptable specificity (few false alarms).


Highly efficient nonradiative energy transfer mediated light harvesting in water using aqueous CdTe quantum dot antennas.
We present light harvesting of aqueous colloidal quantum dots to nonradiatively transfer their excitonic excitation energy efficiently to dye molecules in water, without requiring ligand exchange. These as-synthesized CdTe quantum dots that are used as donors to serve as light-harvesting antennas are carefully optimized to match the electronic structure of Rhodamine B molecules used as acceptors for light harvesting in aqueous medium. By varying the acceptor to donor concentration ratio, we measure the light harvesting factor, along with substantial lifetime modifications of these water-soluble quantum dots, from 25.3 ns to 7.2 ns as a result of their energy transfer with efficiency levels up to 86%. Such nonradiative energy transfer mediated light harvesting in aqueous medium holds great promise for future quantum dot multiplexed dye biodetection systems.


The transition from bee-to-fly dominated communities with increasing elevation and greater forest canopy cover.
Insect pollinator communities are thought to transition from bee-dominated communities at low elevations to fly-dominated communities at high elevations. We predicted that increased tree canopy cover and a subsequent decrease in meadows and flowering plants would limit bees but not flies at higher elevations. We tested and supported this prediction by examining changes in both abundance and species richness for 128 bee species and 96 fly species at key points along an elevational gradient in Northern Arizona represented by distinct vegetation life zones. In addition to an increase in fly species and abundance relative to bees with increasing elevation, there were changes in community structure). To better understand factors that might influence this transition we examined how tree canopy cover changed along the elevational gradient and how this influenced the change in insect pollinator communities. While bee communities were progressively divergent between forest and meadow habitats with increasing elevation and tree canopy cover, there was no significant pattern with flies between meadow and forest habitats. However, fly abundance did increase with increasing elevation relative to bees. Along a comparable elevational gradient on an adjacent mountain with no tree canopy cover (i.e., a fire burned mountain), the bee-to-fly transition did not occur; bees persisted as the dominant pollinator into the highest life zone. This suggests that tree canopy cover can in part explain the transition from bee-to fly-dominated communities. In conclusion, this is the first study in North America to document a bee-fly transition for both abundance and species richness and show that tree canopy cover may play a role in determining pollinator community composition, by restricting bees to open meadow habitats.