[Evaluation of Post-traumatic Stress Disorder: validation of a measure, the PCLS].
Post-Traumatic Stress Disorder (PTSD) is a psychiatric disorder frequently found in psychiatric clinic and in the population of victims of traumatic events. PTSD, characterized by an intense fear, helplessness or horror, resulting from exposure to a traumatic event, is clinically manifested with three main syndromes: reexperiencing, avoidance behavior and numbing of emotion, and physiological hyperarousal. The Post-Traumatic Checklist Scale (PCLS) is a brief and self-report questionnaire for evaluating the severity of three main syndromes of PTSD. The scale can be divided into three sub-scores corresponding to the three main syndromes of the disorder: reexperiencing (items 1-5), avoidance (items 6-12) and hyperarousal (items 13-17). The validation studies in English version (Weathers et al., 1993, Blanchard et al., 1996) and French version (Ventureyra et al., 2001) showed that the PCLS possesses good psychometric properties. But the discriminating validation with another pathological group and the sensitivity of the scale to change of treatment have not yet been studied up to now. The aim of this study is the validation of the French version of the PCLS in Post-Traumatic Stress Disorder (PTSD) subjects compared with subjects suffering from other anxiety disorders and non-clinical subjects. The sensitivity of the PCLS after a cognitive behavioral therapy (CBT) for PTSD was studied for the first time. Fifty-seven outpatients suffering from PTSD according to DSM IV criteria, 23 patients suffering from other anxiety disorders and 28 non-clinical subjects were included in this study. All subjects were assessed with the PCLS. The Beck Depression Inventory--13 items (BDI-13) and the Fear Questionnaire (FQ) were used for the two groups of patients. Fifty-five PTSD patients were administered the PCLS twice over an interval of one to two weeks without any intervention in order to determine the test-retest reliability of the PCLS. And 24 PTSD patients were reassessed with the PCLS after 16 sessions of cognitive behavioral therapy (CBT) in order to study the sensitivity to treatment of the PCLS. The CBT technique for PTSD consisted of relaxation, exposition, recital, cognitive restructuration and stress management. The total score and the subscores on the PCLS were found to be significantly higher in PTSD patients than in two control groups: suffering from other anxiety disorders subjects (61.2/41.4, p<0.0001) and non-clinical subjects (61.2/28.8, p<0.0001). The correlation between the PCLS total score and the others measures showed that the PCLS correlated significantly with the depression measure, the BDI-13 (p<0.001), and the sub-scores of Fear Questionnaire (agoraphobia: p<0.001; anxiety-depression: p<0.001; distress: p<0.001), but not with the social phobia sub-score of the FQ. The PCLS showed a satisfactory test-retest reliability in 55 patients (the total score: r=0.75, p<0.0001; the sub-score of reexperiencing: r=0.844, p<0.0001; the sub-score of avoidance: r=0.702, p<0.0001; the sub-score of hyperarousal: r=0.712, p<0.0001). The t-test showed that the total score of the PCLS was significantly reduced in 24 patients after 16 sessions of CBT (the mean gain=13.1, t=5.63, p<0.0001). The results of our study confirm that the PCLS possesses good empirical and discriminating validity and a good sensitivity. The fact that the PTSD patients reported significantly higher total scores on the PCLS and its three subscores than other anxiety disorder subjects and non-clinical subjects indicates that the PCLS differentiates well the patients presenting PTSD from other anxiety disorder subjects and non-clinical subjects. The PCLS total score also correlates significantly with the other measures of psychopathology used in the study, such as measures of phobia (the Fear Questionnaire agoraphobia subscale), depression (the Beck Depression Inventory -13) and distress (the Fear Questionnaire distress subscale). This may be explained by the fact that some PTSD symptoms overlap with those of depression and of anxiety or phobia. The PCLS showed anxiety or phobia. The PCLS showed a satisfactory test-retest reliability. The PCLS is therefore a valid and effective measurement of PTSD. It may be a useful tool for screening and assessing PTSD in clinical practice and research in psychiatry.


Relation between serum creatinine and body mass index in elite athletes of different sport disciplines.
To document the relation between serum creatinine concentration and body mass index in elite athletes from five different sports, and to study potential differences among athletes performing different sports with different features and requirements. Before the start of the competitive season, serum creatinine was measured in 151 elite athletes from five different sports: rugby (n = 44), soccer (n = 27), alpine skiing (n = 34), sailing (n = 22), cycling (n = 24). Pearson's correlation analysis was used to evaluate the relation between serum creatinine and body mass index (BMI). Analysis of variance and unpaired Student's t test were used to compare creatinine concentration and BMI in different sport disciplines. In the whole group of athletes, a positive correlation between serum creatinine and BMI was found (r = 0.48, p<0.001). Significant differences in creatinine concentration and BMI were found between athletes competing in different sports: their mean (SD) values were respectively 1.31 (0.12) mg/dl and 28.83 (2.41) for rugby players, 1.27 mg/dl (0.10) and 23.10 (1.01) for soccer players, 1.15 (0.11) mg/dl and 25.8 (1.50) for skiers, 1.08 (0.11) mg/dl and 26.93 (2.36) for sailors, and 0.91 (0.07)mg/dl and 21.33 (1.21) for cyclists. There is a correlation between creatinine concentration and BMI in elite athletes competing in different sports characterised by different kinds of training, competitive season, and involvement of aerobic and anaerobic metabolism. Interpretation of creatinine concentrations in male athletes should consider professional status as well as the specific sport performed. All athletes should be monitored with consecutive creatinine assessments, using as the baseline the concentration determined before the start of training and the competitive season, but taking into consideration the specific sport performed and the BMI until equations that include creatinine and factors that affect its concentration are used.


Effectiveness of a Sensory-Enriched Early Intervention Group Program for Children With Developmental Disabilities.
The study's objective was to evaluate the effectiveness of the Interdisciplinary Sensory-Enriched Early Intervention (ISEEI) group program for children with developmental delays. We conducted a retrospective chart review of 63 children ages 18-36 mo who participated in ISEEI. We evaluated participants with the Bayley Scales of Infant and Toddler Development III (Bayley-III) and the Infant/Toddler Sensory Profile (ITSP) at enrollment and after 3-9 mo. We conducted a paired t test to examine changes in the Bayley-III between pre- and posttests. At enrollment, 70% of children presented atypical scores in two or more areas of sensory processing in the ITSP. Results revealed that children with sensory processing difficulties demonstrated significant improvement in all areas of development except fine motor skills; children without sensory processing difficulties showed significant improvement in language and cognition. The ISEEI group program is an effective method to ameliorate developmental delays.


Effect of coenzyme-q10 on Doxorubicin-induced nephrotoxicity in rats.
Nephrotoxicity is one of the limiting factors for using doxorubicin (Dox) as an anticancer chemotherapeutic. Here, we investigated possible protective effect of coenzyme-Q10 (CoQ10) on Dox-induced nephrotoxicity and the mechanisms involved. Two doses (10 and 100 mg/kg) of CoQ10 were administered orally to rats for 8 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of Dox (15 mg/kg) at day 4 of the experiment. Our results showed that the low dose of CoQ10 succeeded in reversing Dox-induced nephrotoxicity to control levels (e.g., levels of blood urea nitrogen and serum creatinine, concentrations of renal reduced glutathione (GSH) and malondialdehyde, catalase activity and caspase 3 expression, and renal histopathology). Alternatively, the high dose of CoQ10 showed no superior nephroprotection over the low dose, as there were no significant improvements in renal histopathology, catalase activity, or caspase 3 expression compared to the Dox-treated group. Interestingly, the high dose of CoQ10 alone significantly decreased renal GSH level as well as catalase activity and caused a mild induction of caspase 3 expression compared to control, probably due to a prooxidant effect at this dose of CoQ10. We conclude that CoQ10 protects from Dox-induced nephrotoxicity with a precaution to dosage adjustment.


Precisely tunable thickness of graphitic carbon nitride nanosheets for visible-light-driven photocatalytic hydrogen evolution.
Graphitic carbon nitride (GCN) nanosheets with unique physicochemical properties have received increasing attention in the area of photocatalysis, yet tunable thickness for the straightforward production of this graphite-like two-dimensional (2D) nanomaterial remains a challenge. In this work, GCN nanosheets with different thicknesses were firstly prepared by a direct calcination of melamine supramolecular aggregates (MSA) obtained from a hydrochloric acid (HCl)-induced hydrothermal assembly approach. The resultant nanosheets over nanometer scale thickness could be precisely controlled via simply adjusting the HCl concentration. Compared to the bulk GCN (BGCN), the thinner nanosheets possessed a high specific surface area, a large electronic-band structure, and fast charge separation ability. The thinnest nanosheets with a thickness of approximately 4 nm exhibited excellent visible-light-driven photocatalytic water splitting performance in hydrogen evolution (524 μmol h-1 g-1), which is over 9-fold higher than the BGCN powder. This work provides a thickness-dependent strategy for the preparation of metal-free GCN nanosheets and develops a promising 2D photocatalyst for application in solar energy conversion.


Elementary processes governing V2AlC chemical etching in HF.
The literature on MXenes, an important class of 2D materials discovered in 2011, is now abundant. Yet, the lack of well-defined structures, with definite crystal orientations, has so far hindered our capability to identify some key aspects ruling MXene's chemical exfoliation from their parent MAX phase. Herein the chemical exfoliation of V2AlC is studied by using well-defined square pillars with lateral sizes from 7 μm up to 500 μm, processed from centimeter-sized V2AlC single crystals. The MXene conversion kinetics are assessed with μm spatial resolution by combining Raman spectroscopy with scanning electron and optical microscopies. HF penetration, and the loss of the Al species, take place through the edges. At room temperature, and on a reasonable time scale, no etching can takes place by HF penetration through the basal planes, viz. normal to the basal planes. In defect-free pillars, etching through the edges is isotropic. Initially the etching rate is linear with a rate of 2.2 ± 0.3 μm h-1 at 25 °C. At a distance of ≈45 μm, the etching rate is greatly diminished.


Supramolecular motifs in dynamic covalent PEG-hemiaminal organogels.
Dynamic covalent materials are stable materials that possess reversible behaviour triggered by stimuli such as light, redox conditions or temperature; whereas supramolecular crosslinks depend on the equilibrium constant and relative concentrations of crosslinks as a function of temperature. The combination of these two reversible chemistries can allow access to materials with unique properties. Here, we show that this combination of dynamic covalent and supramolecular chemistry can be used to prepare organogels comprising distinct networks. Two materials containing hemiaminal crosslink junctions were synthesized; one material is comprised of dynamic covalent junctions and the other contains hydrogen-bonding bis-hemiaminal moieties. Under specific network synthesis conditions, these materials exhibited self-healing behaviour. This work reports on both the molecular-level detail of hemiaminal crosslink junction formation as well as the macroscopic behaviour of hemiaminal dynamic covalent network (HDCN) elastomeric organogels. These materials have potential applications as elastomeric components in printable materials, cargo carriers and adhesives.


Reactive Astrocytes as Drug Target in Alzheimer's Disease.
Alzheimer's disease is a neurodegenerative disease characterized by deposition of extracellular amyloid-β, intracellular neurofibrillary tangles, and loss of cortical neurons. However, the mechanism underlying neurodegeneration in Alzheimer's disease (AD) remains to be explored. Many of the researches on AD have been primarily focused on neuronal changes. Current research, however, broadens to give emphasis on the importance of nonneuronal cells, such as astrocytes. Astrocytes play fundamental roles in several cerebral functions and their dysfunctions promote neurodegeneration and, eventually, retraction of neuronal synapses, which leads to cognitive deficits found in AD. Astrocytes become reactive as a result of deposition of Aβ, which in turn have detrimental consequences, including decreased glutamate uptake due to reduced expression of uptake transporters, altered energy metabolism, altered ion homeostasis (K+ and Ca+), increased tonic inhibition, and increased release of cytokines and inflammatory mediators. In this review, recent insights on the involvement of, tonic inhibition, astrocytic glutamate transporters and aquaporin in the pathogenesis of Alzheimer's disease are provided. Compounds which increase expression of GLT1 have showed efficacy for AD in preclinical studies. Tonic inhibition mediated by GABA could also be a promising target and drugs that block the GABA synthesizing enzyme, MAO-B, have shown efficacy. However, there are contradictory evidences on the role of AQP4 in AD.


Bacillus thuringiensis resistance influences European corn borer (Lepidoptera: Crambidae) larval behavior after exposure to Cry1Ab.
The behavior of pests targeted by Bacillus thuringiensis (Bt) crops has been recognized as an important factor to define resistance management plans. However, most data do not include the possible impact resistance may have on the behavior of pests. To examine whether resistance influences behavior of European corn borer, Ostrinia nubilalis (Hübner) (Lepidoptera: Crambidae), neonates after exposure to dietary Bt, the responses of Cry1Ab-resistant, -susceptible, and hybrid (F1) lines from two populations were compared in laboratory tests by using artificial diet mixed with 10-50% Cry1Ab or non-Bt isoline corn, Zea mays L., tissue. In no-choice tests, resistant (and usually hybrid) lines were less likely to be irritated (i.e., to move away after physical contact with diet containing Cry1Ab) than susceptible larvae after exposure to diets containing 10-50% Cry1Ab leaf tissue. Early in the no-choice tests (8 h), neonate O. nubilalis also were more likely to move off of diets that contained 10% non-Bt tissue compared with diets with 25 or 50% non-Bt tissue. In agreement with results from no-choice tests, choice tests with 10 or 25% tissue indicated that resistant (and sometimes hybrid) larvae were more likely than susceptible neonates to be found on diet with Cry1Ab. For choice tests, differences among lines seemed dependent on the amount of Cry1Ab tissue incorporated into diets. Results suggest differences in behavior are a result of reduced physiological susceptibility to Cry1Ab and are not an independent behavioral component to resistance.


Parameter estimates for genetic effects on carcass traits of Korean native cattle.
Data (n = 1,746) collected from 1985 through 1995 on Korean Native Cattle by the National Livestock Research Institute of Korea were used to estimate genetic parameters for marbling score, dressing percentage, and longissimus muscle area, with backfat thickness, slaughter age, or slaughter weight as covariates. Estimates were obtained with REML. Model 1 included animal genetic and residual random effects. Model 2 was extended to include an uncorrelated random effect of the dam. Model 3 was based on Model 1 but also included sire x region x year-season interaction effects. Model 4 combined Models 2 and 3. All models included fixed effects for region x year-season and age of dam x sex combinations. From single-trait analyses, estimates of heritability with covariates to adjust for backfat thickness, slaughter age, and slaughter weight from Model 4 were, respectively, .10, .08, and .01 for marbling score; .09, .12, and .16 for dressing percentage; and .18, .17, and .24 for longissimus muscle area. From three-trait analyses, estimates of genetic correlations between marbling score and dressing percentage, marbling score and longissimus muscle area, and dressing percentage and longissimus muscle area were, respectively, -.99, .20, and -.11 with backfat thickness as covariate; -.88, .47, and .01 with slaughter age as covariate; and -.03, .39, and .91 with slaughter weight as covariate. Results of this study suggest that choice of covariate (backfat thickness, slaughter age, or slaughter weight) for the model seems to be important for carcass traits for Korean Native Cattle. Including sire x region x year-season interaction effects in the model for marbling score and dressing percentage may be important because whether sire x region x year-season interaction effects were in the model affected estimates of other variance components for the three carcass traits. Whether the maternal effect was in the model had little effect on estimates of other parameters. With backfat thickness and slaughter age end points, selection for increasing marbling score would be expected to result in decreasing dressing percentage for Korean Native Cattle. With slaughter weight as a covariate for end point, increased longissimus muscle area would be associated with increased dressing percentage, and increased marbling score would be related to increased longissimus muscle area. The differences in estimates associated with choice of end point, however, need further study.


Quantification of variable functional-group densities of mixed-silane monolayers on surfaces via a dual-mode fluorescence and XPS label.
The preparation of aminated monolayers with a controlled density of functional groups on silica surfaces through a simple vapor deposition process employing different ratios of two suitable monoalkoxysilanes, (3-aminopropyl)diisopropylethoxysilane (APDIPES) and (3-cyanopropyl)dimethylmethoxysilane (CPDMMS), and advances in the reliable quantification of such tailored surfaces are presented here. The one-step codeposition process was carried out with binary silane mixtures, rendering possible the control over a wide range of densities in a single step. In particular, APDIPES constitutes the functional silane and CPDMMS the inert component. The procedure requires only small amounts of silanes, several ratios can be produced in a single batch, the deposition can be carried out within a few hours and a dry atmosphere can easily be employed, limiting self-condensation of the silanes. Characterization of the ratio of silanes actually bound to the surface can then be performed in a facile manner through contact angle measurements using the Cassie equation. The reliable estimation of the number of surface functional groups was approached with a dual-mode BODIPY-type fluorescence label, which allows quantification by fluorescence and XPS on one and the same sample. We found that fluorescence and XPS signals correlate over at least 1 order of magnitude, allowing for a direct linking of quantitative fluorescence analysis to XPS quantification. Employment of synchrotron-based methods (XPS; reference-free total reflection X-ray fluorescence, TXRF) made the traceable quantification of surface functional groups possible, providing an absolute reference for quantitative fluorescence measurements through a traceable measurement chain.


Highly parallel computation.
Highly parallel computing architectures are the only means to achieve the computational rates demanded by advanced scientific problems. A decade of research has demonstrated the feasibility of such machines, and current research focuses on which architectures are best suited for particular dasses of problems. The architectures designated as MIMD and SIMD have produced the best results to date; neither shows a decisive advantage for most near-homogeneous scientific problems. For scientific problems with many dissimilar parts, more speculative architectures such as neural networks or data flow may be needed.


Anterior chiasmal optic nerve avulsion.
In a case of traumatic avulsion of the optic nerve at the anterior chiasm, MR imaging provided highly specific images of the injury site, including the absence of the optic nerve within the optic canal and the point of transection at the anterior portion of the chiasm. This was confirmed clinically and histopathologically. MR imaging should be considered in cases of suspected chiasmal injury.


Energy expenditure and caloric balance after burn: increased feeding leads to fat rather than lean mass accretion.
Resting energy expenditure (REE) is commonly measured in critical illness to determine caloric "demands" and thus nutritive needs. The purpose of this study was to 1) determine whether REE is associated with clinical outcomes and 2) determine whether an optimal caloric delivery rate based on REE exists to offset erosion of lean mass after burn. From 1995 to 2001, REE was measured by indirect calorimetry in 250 survivors of 10 to 99%TBSA burns. Caloric intake and REE were correlated with muscle protein catabolism, length of stay, ventilator dependence, sepsis, and mortality. From 1998 to 2000, 42 patients (>60%TBSA burns) received continuous enteral nutrition at a spectrum of caloric balance between 1.0x REE kcal/d -1.8x REE kcal/d. Serial body composition was measured by dual energy x-ray absorptiometry. Lean mass, fat mass, morbidity, and mortality were determined. REE/predicted basal metabolic rate correlated directly with burn size, sepsis, ventilator dependence, and muscle protein catabolism (P <.05). Declining REE correlated with mortality (P <.05). 2) Erosion of lean body mass was not attenuated by increased caloric balance, however, fat mass increased with caloric supply (P <.05). In surviving burned patients, caloric delivery beyond 1.2 x REE results in increased fat mass without changes in lean body mass. Declining energy expenditure appears to be a harbinger of mortality in severely burned patients.


Chemotherapy and adverse cardiovascular events in colorectal cancer patients undergoing surgical resection.
Colorectal cancer patients undergoing surgical resection are at increased short-term risk of post-operative adverse events. However, specific predictors for long-term major adverse cardiac and cerebrovascular events (MACCE) are unclear. We hypothesised that patients who receive chemotherapy are at higher risk of MACCE than those who did not. In this retrospective study, 412 patients who underwent surgical resection for newly diagnosed colorectal cancer from January 2013 to April 2015 were grouped according to chemotherapy status. MACCE was defined as a composite of cardiovascular death, myocardial infarction, stroke, unplanned revascularisation, hospitalisation for heart failure or angina. Predictors of MACCE were identified using competing risks regression, with non-cardiovascular death a competing risk. There were 200 patients in the chemotherapy group and 212 patients in the non-chemotherapy group. The overall prevalence of prior cardiovascular disease was 20.9%. Over a median follow-up duration of 5.1 years from diagnosis, the incidence of MACCE was 13.3%. Diabetes mellitus and prior cardiovascular disease were associated with an increased risk of MACCE (subdistribution hazard ratio, 2.56; 95% CI, 1.48-4.42) and 2.38 (95% CI, 1.36-4.18) respectively. The chemotherapy group was associated with a lower risk of MACCE (subdistribution hazard ratio, 0.37; 95% CI, 0.19-0.75) compared to the non-chemotherapy group. Amongst colorectal cancer patients undergoing surgical resection, there was a high incidence of MACCE. Diabetes mellitus and prior cardiovascular disease were associated with an increased risk of MACCE. Chemotherapy was associated with a lower risk of MACCE, but further research is required to clarify this association.


Mitochondrial Single Nucleotide Polymorphisms in Ceratitis capitata (Diptera: Tephritidae) Can Distinguish Sterile, Released Flies from Wild Flies in Various Regions of the World.
In areas infested with pest species such as the Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), many programs rely heavily on the sterile insect technique (SIT) as a form of biological control. However, when SIT treatments are used both for control of established infestations and for occasional outbreaks, for several reasons, programs are often unable to adequately quantify the success of this approach. Chief among these are difficulties associated with reliably and rapidly determining the strain of origin of males recaptured during and after the SIT program. In this study, we describe the use of a DNA-based marker that can be used to rapidly and reliably distinguish males originating from the two sterile strains that are most widely used in SIT rearing facilities from males originating from wild strains of various regions of the world. This method uses polymerase chain reaction amplification of material from individual specimens to directly analyze DNA sequence variants found within a portion of the mitochondrial ND4 subunit 4 (ND4) gene to identify single nucleotide polymorphisms (SNPs) that are diagnostic of different strains. Specifically, the SNPs described here reliably distinguish individual flies originating from the Vienna 7 and Vienna 8 strains used for sterile release from wild flies infesting various areas including Western Australia, Guatemala, and Hawaii. The availability of such markers for determination of the strain of origin of specimens, either from whole specimens or body parts (including their sperm), has great potential to improve the ability to monitor and quantify the success of any sterile release program.


Mechanisms of B cell autoimmunity in SLE.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is known to be associated with polyclonal B-cell hyperreactivity. The underlying causes of the diffuse B-cell over-reactivity are unclear, but potential candidates include (a) intrinsic hyper-reactivity leading to polyclonal B-cell activation with disturbed activation thresholds and ineffective negative selection; (b) lack of immunoregulatory functions; (c) secondary effects of an overactive inflammatory environment, such as overactive germinal center and ectopic follicular activity; and/or (d) disturbed cytokine production by non-B immune cells. These mechanisms are not mutually exclusive and may operate to varying extents and at varying times in SLE. Phenotypic and molecular studies as well as the results of recent clinical trials have begun to provide new insights to address these possibilities. Of importance, new information has made it possible to distinguish between the contribution played by abnormalities in central checkpoints that could lead to a pre-immune repertoire enriched in autoreactive B cells, on the one hand, and the possibility that autoimmunity arises in the periphery from somatic hypermutation and abnormal selection during T cell-dependent B-cell responses on the other. There is an intriguing possibility that apoptotic material bound to the surface of follicular dendritic cells positively selects autoreactive B cells that arise from non-autoreactive B-cell precursors as a result of somatic hypermutation and thereby promotes the peripheral emergence of autoimmunity.


Interventional studies for preventing surgical site infections in sub-Saharan Africa - A systematic review.
There is a great need for safe surgical services in sub-Saharan Africa, but a major difficulty of performing surgery in this region is the high risk of post-operative surgical site infection (SSI). We aimed to systematically review which interventions had been tested in sub-Saharan Africa to reduce the risk of SSI and to synthesize their findings. We searched Medline, Embase and Global Health databases for studies published between 1995 and 2010 without language restrictions and extracted data from full-text articles. We identified 24 relevant articles originating from nine countries in sub-Saharan Africa. The methodological quality of these publications was diverse, with inconsistency in definitions used for SSI, period and method of post-operative follow-up and classification of wound contamination. Although it was difficult to synthesise information between studies, there was consistent evidence that use of single-dose pre-operative antibiotic prophylaxis could reduce, sometimes dramatically, the risk of SSI. Several studies indicated that alcohol-based handrubs could provide a low-cost alternative to traditional surgical hand-washing methods. Other studies investigated the use of drains and variants of surgical technique. There were no African studies found relating to several other promising SSI prevention strategies, including use of checklists and SSI surveillance. There is extremely limited research from sub-Saharan Africa on interventions to curb the occurrence of SSI. Although some of the existing studies are weak, several high-quality studies have been published in recent years. Standard methodological approaches to this subject are needed.


"Can we walk?" Environmental supports for physical activity in India.
India is currently facing a non-communicable disease epidemic. Physical activity (PA) is a preventative factor for non-communicable diseases. Understanding the role of the built environment (BE) to facilitate or constrain PA is essential for public health interventions to increase population PA. The objective of this study was to understand BEs associations with PA occurring in two major life domains or life areas-travel and leisure-in urban India. Between December 2014 and April 2015, in-person surveys were conducted with participants (N=370; female=47.2%) in Chennai, India. Perceived BE characteristics regarding residential density, land use mix-diversity, land use mix-access, street connectivity, infrastructure for walking and bicycling, aesthetics, traffic safety, and safety from crime were measured using the adapted Neighborhood Environment Walkability Scale-India (NEWS-India). Self-reported PA was measured the International Physical Activity Questionnaire. High residential density was associated with greater odds of travel PA (aOR=1.9, 95% CI=1.2, 3.2). Land use mix-diversity was positively related to travel PA (aOR=2.1, 95%CI=1.2, 3.6), but not associated with leisure or total PA. The aggregate NEWS-India score predicted a two-fold increase in odds of travel PA (aOR=1.9, 95% CI=1.1, 3.1) and a 40% decrease in odds of leisure PA (aOR=0.6, 95% CI=0.4, 1.0). However, the association of the aggregated score with leisure PA was not significant. Results suggest that relationships between BE and PA in low-and-middle income countries may be context-specific, and may differ markedly from higher income countries. Findings have public health implications for India suggesting that caution should be taken when translating evidence across countries.


Development and validation of a screening instrument to assess the types and quality of foods served at home meals.
Although there is growing interest in assessing the home food environment, no easy-to-use, low cost tools exist to assess the foods served at home meals, making it difficult to assess the meal component of the food environment. The aim of this study was to develop and validate a user-friendly screener to assess the types of foods served at home meals. Primary food preparing adults (n = 51) participated in a validation study in their own homes. Staff and participants independently completed a screener as participants cooked dinner. The screener assessed the types of foods offered, method(s) of preparation, and use of added fats. Two scale scores were created: 1) to assess offerings of foods in five food groups (meat and other protein, milk, vegetables, fruit, grains), 2) to assess the relative healthfulness of foods based on types offered, preparation method, and added fats. Criterion validity was assessed comparing staff and participant reports of individual foods (kappa (k)) and scale scores (Spearman correlations). Criterion validity was high between participants' and staffs' record of whether major food categories (meat and other protein, bread and cereal, salad, vegetables, fruits, dessert) were served (k = 0.79-1.0), moderate for reports of other starches (e.g., rice) being served (k = 0.52), and high for the Five Food Group and Healthfulness scale scores (r = 0.75-0.85, p < .001). This new meal screening tool has high validity and can be used to assess the types of foods served at home meals allowing a more comprehensive assessment of the home food environment.


Argonaute-based programmable RNase as a tool for cleavage of highly-structured RNA.
The recent identification and development of RNA-guided enzymes for programmable cleavage of target nucleic acids offers exciting possibilities for both therapeutic and biotechnological applications. However, critical challenges such as expensive guide RNAs and inability to predict the efficiency of target recognition, especially for highly-structured RNAs, remain to be addressed. Here, we introduce a programmable RNA restriction enzyme, based on a budding yeast Argonaute (AGO), programmed with cost-effective 23-nucleotide (nt) single-stranded DNAs as guides. DNA guides offer the advantage that diverse sequences can be easily designed and purchased, enabling high-throughput screening to identify optimal recognition sites in the target RNA. Using this DNA-induced slicing complex (DISC) programmed with 11 different guide DNAs designed to span the sequence, sites of cleavage were identified in the 352-nt human immunodeficiency virus type 1 5'-untranslated region. This assay, coupled with primer extension and capillary electrophoresis, allows detection and relative quantification of all DISC-cleavage sites simultaneously in a single reaction. Comparison between DISC cleavage and RNase H cleavage reveals that DISC not only cleaves solvent-exposed sites, but also sites that become more accessible upon DISC binding. This study demonstrates the advantages of the DISC system for programmable cleavage of highly-structured, functional RNAs.


A congruent solution to arthropod phylogeny: phylogenomics, microRNAs and morphology support monophyletic Mandibulata.
While a unique origin of the euarthropods is well established, relationships between the four euarthropod classes-chelicerates, myriapods, crustaceans and hexapods-are less clear. Unsolved questions include the position of myriapods, the monophyletic origin of chelicerates, and the validity of the close relationship of euarthropods to tardigrades and onychophorans. Morphology predicts that myriapods, insects and crustaceans form a monophyletic group, the Mandibulata, which has been contradicted by many molecular studies that support an alternative Myriochelata hypothesis (Myriapoda plus Chelicerata). Because of the conflicting insights from published molecular datasets, evidence from nuclear-coding genes needs corroboration from independent data to define the relationships among major nodes in the euarthropod tree. Here, we address this issue by analysing two independent molecular datasets: a phylogenomic dataset of 198 protein-coding genes including new sequences for myriapods, and novel microRNA complements sampled from all major arthropod lineages. Our phylogenomic analyses strongly support Mandibulata, and show that Myriochelata is a tree-reconstruction artefact caused by saturation and long-branch attraction. The analysis of the microRNA dataset corroborates the Mandibulata, showing that the microRNAs miR-965 and miR-282 are present and expressed in all mandibulate species sampled, but not in the chelicerates. Mandibulata is further supported by the phylogenetic analysis of a comprehensive morphological dataset covering living and fossil arthropods, and including recently proposed, putative apomorphies of Myriochelata. Our phylogenomic analyses also provide strong support for the inclusion of pycnogonids in a monophyletic Chelicerata, a paraphyletic Cycloneuralia, and a common origin of Arthropoda (tardigrades, onychophorans and arthropods), suggesting that previous phylogenies grouping tardigrades and nematodes may also have been subject to tree-reconstruction artefacts.


Clinical and microbiological characteristics of community-onset Clostridium difficile infection in The Netherlands.
To elucidate the prevalence, characteristics and risk factors of community-onset Clostridium difficile infection (CO-CDI), an uncontrolled prospective study was performed. For 3 months in 2007-2008, three laboratories in The Netherlands tested all unformed stool samples submitted by general practitioners (GPs) for C. difficile by enzyme immunoassay for toxins A and B, irrespective of whether GPs specifically requested this. Patients with positive results were asked to complete a questionnaire. Positive stool samples were cultured for C. difficile, and isolates were characterized. In all, 2443 stool samples from 2423 patients were tested, and 37 patients (1.5%) with positive toxin test results were identified. Mixed infections were not found. Age varied from 1 to 92 years, and 18% were under the age of 20 years. Diarrhoea was typically frequent and watery, sometimes with admixture of blood or fever. Eight of 28 patients (29%) suffered recurrences. Among 31 patients with toxin-positive stool samples for whom information was available, 20 (65%) had not been admitted to a healthcare institution in the year before, 13 (42%) had not used antibiotics during the 6 months before, and eight (26%) had neither risk factor. A separate analysis for patients whose samples were both toxin-positive and culture-positive produced similar results. Cultured C. difficile isolates belonged to 13 different PCR ribotypes, and 24% of the isolates were non-typeable (rare or new) PCR ribotypes. In conclusion, CO-CDI can affect all age groups, and many patients do not have known risk factors. Several PCR ribotypes not encountered in hospital-associated outbreaks were found, suggesting the absence of a direct link between outbreaks and community-onset cases.


A fluorescein-based chemosensor for relay fluorescence recognition of Cu(ii) ions and biothiols in water and its applications to a molecular logic gate and living cell imaging.
Relay recognition of copper(ii) ions and biothiols via a fluorescence "on-off-on" cascade was designed and realized as a new sequential combination of cations and small molecules. Probe 1 bearing a fluorescein skeleton was thus synthesized, which performed well in 100% HEPES buffer (pH = 7.0) solution, as a highly sensitive, selective fluorescence sensor for Cu2+. The limit of detection (LOD, 0.017 ppm) was obtained, and this value is much lower than 1.3 ppm, allowed by US EPA. The 1 : 1 complex generated from fast sensing of Cu2+ when excited at 491 nm, showed good relay recognition for biothiols (i.e., Cys, Hcy and GSH with low detection limits of 0.12 μM, 0.036 μM and 0.024 μM, respectively) via remarkable fluorescence enhancement. The origin of this relay process was disclosed through ESI-MS and corresponding density functional theory (DFT) computations. Notably, probe 1 can be utilized for the construction of a molecular logic gate with the IMPLICATION function by using the above fluorescence changes. Moreover, this relay recognition was also applied to HepG2 cell imaging successfully.


Local anergy rather than systemic anti-tumour immunity to explain tumour growth in an animal model of oral squamous cell carcinoma.
A chemically induced syngeneic hamster tumour model of human oral squamous cell carcinoma (OSCC) was used to investigate the possible influence of locally transplanted growing rumours on the immune system of the recipient. Cell activation and cell cytotoxicity assays were performed in vitro using the colorimetric MTT assay to measure any possible changes. The fast growing nature of the tumour model if grafted locally as a fragment was confirmed but not if injected as a single cell suspension (SCS). Stimulation (Concanavalin A) of spleen cells from normal and from tumour bearing animals showed that there was a minor though statistically significant decrease in the mitogenic response of the latter. Thus, the respective stimulatory indices (SI) were 4.06+/-1.61 and 2.06+/-0.87 (0.02
0.01). No significant difference was observed when spleen cells were stimulated with interleukin-2 (IL-2), although there was a similar trend. Pre-immunisation of animals with irradiated autologous SCS three weeks prior to grafting, resulted in a significant decrease in the tumour growth rate of subsequently grafted tumour. Thus, the mean If: SD (weight of takes in mg) for the successful takes of untreated (n=10) and treated (n=9) groups were 52.0+/-52.2 and 25.7+/-19.4 (0.02
0.05) respectively. The number of cases with no tumour takes were 2 of 10 (20%) and 6 of 9 (66%) respectively. In a separate experiment groups of 5 animals were immunized with an increasing number of cells as irradiated SCS, the results of which demonstrated an inverse correlation between the rate of tumour growth and the number of injected tumour cells. The addition of irradiated SCS to IL-2 activated normal spleen cells (LAK cells) in vitro led to a dose-related decrease in the efficiency of cytotoxicity of latter when tested against an xenogeneic super-sensitive surrogate tumour target cell line (Fen cells). Thus, the percent killing by IL-2-activated normal spleen cells was 56.4%. The corresponding mean values for IL-2 activated normal spleen cells in the presence of tumour SCS at 25/1 and 50/1 ratios were 35.9% (p<0.05) and 11.9% (p<0.001) respectively. Ln an attempt to establish the presence of T suppressor cells, spleen cells from tumour bearing animals were injected concomitantly with SCS into 5 recipients. After four weeks no tumour growth had occurred. In conclusion we demonstrated that the presence of injected or grafted tumour had only a minor effect on systemic immune function but induced a strong local anergic effect. This local anergic effect was demonstrable as blocking of LAK activity and thus perhaps allowed suppression of the functional activities of incoming immunocompetent cells.


Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the antithrombotic effect of the VKAs, the monitoring of anticoagulation intensity, and the clinical applications of VKA therapy and provides specific management recommendations. Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh the risks, burdens, and costs. Grade 2 recommendations suggest that the individual patient's values may lead to different choices. (For a full understanding of the grading, see the "Grades of Recommendation" chapter by Guyatt et al, CHEST 2008; 133:123S-131S.) Among the key recommendations in this article are the following: for dosing of VKAs, we recommend the initiation of oral anticoagulation therapy, with doses between 5 mg and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 1B); we suggest against pharmacogenetic-based dosing until randomized data indicate that it is beneficial (Grade 2C); and in elderly and other patient subgroups who are debilitated or malnourished, we recommend a starting dose of < or = 5 mg (Grade 1C). The article also includes several specific recommendations for the management of patients with nontherapeutic INRs, with INRs above the therapeutic range, and with bleeding whether the INR is therapeutic or elevated. For the use of vitamin K to reverse a mildly elevated INR, we recommend oral rather than subcutaneous administration (Grade 1A). For patients with life-threatening bleeding or intracranial hemorrhage, we recommend the use of prothrombin complex concentrates or recombinant factor VIIa to immediately reverse the INR (Grade 1C). For most patients who have a lupus inhibitor, we recommend a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 1A]. We recommend that physicians who manage oral anticoagulation therapy do so in a systematic and coordinated fashion, incorporating patient education, systematic INR testing, tracking, follow-up, and good patient communication of results and dose adjustments [Grade 1B]. In patients who are suitably selected and trained, patient self-testing or patient self-management of dosing are effective alternative treatment models that result in improved quality of anticoagulation management, with greater time in the therapeutic range and fewer adverse events. Patient self-monitoring or self-management, however, is a choice made by patients and physicians that depends on many factors. We suggest that such therapeutic management be implemented where suitable (Grade 2B).


Maximizing CRISPR/Cas9 phenotype penetrance applying predictive modeling of editing outcomes in Xenopus and zebrafish embryos.
CRISPR/Cas9 genome editing has revolutionized functional genomics in vertebrates. However, CRISPR/Cas9 edited F0 animals too often demonstrate variable phenotypic penetrance due to the mosaic nature of editing outcomes after double strand break (DSB) repair. Even with high efficiency levels of genome editing, phenotypes may be obscured by proportional presence of in-frame mutations that still produce functional protein. Recently, studies in cell culture systems have shown that the nature of CRISPR/Cas9-mediated mutations can be dependent on local sequence context and can be predicted by computational methods. Here, we demonstrate that similar approaches can be used to forecast CRISPR/Cas9 gene editing outcomes in Xenopus tropicalis, Xenopus laevis, and zebrafish. We show that a publicly available neural network previously trained in mouse embryonic stem cell cultures (InDelphi-mESC) is able to accurately predict CRISPR/Cas9 gene editing outcomes in early vertebrate embryos. Our observations can have direct implications for experiment design, allowing the selection of guide RNAs with predicted repair outcome signatures enriched towards frameshift mutations, allowing maximization of CRISPR/Cas9 phenotype penetrance in the F0 generation.


Autophagic degradation of GZMB/granzyme B: a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis.
The crucial issue for defining successful natural killer (NK)-based anticancer therapy is the ability of tumor cells to activate resistance mechanisms leading to escape from NK-mediated killing. It is now well established that such mechanisms are likely evolved under hypoxia in the tumor microenvironment. Here, we show that hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis and that this impairment is reverted by targeting autophagy. We provide evidence that activation of autophagy in hypoxic cells is involved in selective degradation of the pro-apoptotic NK-derived serine protease GZMB/granzyme B, thereby blocking NK-mediated target cell apoptosis. Our in vivo data validate the concept that targeting autophagy in cancer cells promotes tumor regression by facilitating their elimination by NK cells. This study provides a cutting-edge advance in our understanding of how hypoxia-induced autophagy impairs NK-mediated lysis and might pave the way for formulating more effective NK-based antitumor therapy by combining autophagy inhibitors.


Changes in epidermal growth factor receptor expression during chemotherapy in non-small cell lung cancer.
Antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab, may potentially improve outcome in non-small cell lung cancer (NSCLC) patients with high EGFR expression. The EGFR expression may be heterogeneously distributed within tumors, and small biopsies may thus not accurately reveal the EGFR expression. In addition, EGFR expression may also change during chemotherapy. The current study investigates the magnitude of these two issues. EGFR expression in diagnostic biopsies and resection specimen was compared in 53 NSCLC patients stage T1-4N0-1M0 treated with surgery without preceding chemotherapy (OP group), and 65 NSCLC patients stage T1-3N0-2M0 (NAC group) treated with preoperative carboplatin and paclitaxel in order to evaluate the discordance of EGFR expression between samples. Discordance between tumors dichotomized according to EGFR expression (high: H-score ≥200; low: H-score <200) in diagnostic biopsies and immediate resection specimens was 25 % in the OP group and 33 % in the NAC group (p = 0.628). Five (9 %) of primary tumors in the OP group and 4 (13 %) in the NAC group had increased EGFR expression in the resection specimens as compared to the diagnostic biopsies (p = 0.583). A decrease in EGFR expression was observed in 6 (11 %) in the OP group and 7 (23 %) in the NAC group (p = 0.148). EGFR expression in 25 % of diagnostic biopsies may potentially not be accurate compared to the prevailing pattern in the whole tumor based on the larger resection specimens. This may potentially be an obstacle for proper use of antibodies targeting the EGFR in NSCLC. EGFR expression does, however, not change significantly during paclitaxel and carboplatin and rebiopsies in order to decide on anti-EGFR antibody therapy following chemotherapy do not seem warranted.


The Relationship Between School Holidays and Transmission of Influenza in England and Wales.
School closure is often considered as an influenza control measure, but its effects on transmission are poorly understood. We used 2 approaches to estimate how school holidays affect the contact parameter (the per capita rate of contact sufficient for infection transmission) for influenza using primary care data from England and Wales (1967-2000). Firstly, we fitted an age-structured susceptible-infectious-recovered model to each year's data to estimate the proportional change in the contact parameter during school holidays as compared with termtime. Secondly, we calculated the percentage difference in the contact parameter between holidays and termtime from weekly values of the contact parameter, estimated directly from simple mass-action models. Estimates were combined using random-effects meta-analysis, where appropriate. From fitting to the data, the difference in the contact parameter among children aged 5-14 years during holidays as compared with termtime ranged from a 36% reduction to a 17% increase; estimates were too heterogeneous for meta-analysis. Based on the simple mass-action model, the contact parameter was 17% (95% confidence interval: 10, 25) lower during holidays than during termtime. Results were robust to the assumed proportions of infections that were reported and individuals who were susceptible when the influenza season started. We conclude that school closure may reduce transmission during influenza outbreaks.


Use of a 3-D dispersion model for calculation of distribution of horse allergen and odor around horse facilities.
The interest in equestrian sports has increased substantially during the last decades, resulting in increased number of horse facilities around urban areas. In Sweden, new guidelines for safe distance have been decided based on the size of the horse facility (e.g., number of horses) and local conditions, such as topography and meteorology. There is therefore an increasing need to estimate dispersion of horse allergens to be used, for example, in the planning processes for new residential areas in the vicinity of horse facilities. The aim of this study was to develop a method for calculating short- and long-term emissions and dispersion of horse allergen and odor around horse facilities. First, a method was developed to estimate horse allergen and odor emissions at hourly resolution based on field measurements. Secondly, these emission factors were used to calculate concentrations of horse allergen and odor by using 3-D dispersion modeling. Results from these calculations showed that horse allergens spread up to about 200 m, after which concentration levels were very low (<2 U/m³). Approximately 10% of a study-group detected the smell of manure at 60m, while the majority--80%-90%--detected smell at 60 m or shorter distance from the manure heap. Modeling enabled horse allergen exposure concentrations to be determined with good time resolution.


Wolbachia divergence and the evolution of cytoplasmic incompatibility in Culex pipiens.
Many insect species harbor Wolbachia bacteria that induce cytoplasmic incompatibility (CI), i.e. embryonic lethality in crosses between infected males and uninfected females, or between males and females carrying incompatible Wolbachia strains. The molecular mechanism of CI remains unknown, but the available data are best interpreted under a modification-rescue model, where a mod function disables the reproductive success of infected males' sperm, unless the eggs are infected and express a compatible resc function. Here we examine the evolution of CI in the mosquito Culex pipiens, harbouring a large number of closely related Wolbachia strains structured in five distinct phylogenetic groups. Specifically, we used a worldwide sample of mosquito lines to assess the hypothesis that genetic divergence should correlate with the divergence of CI properties on a low evolutionary scale. We observed a significant association of Wolbachia genetic divergence with CI patterns. Most Wolbachia strains from the same group were compatible whereas those from different groups were often incompatible. Consistently, we found a strong association between Wolbachia groups and their mod-resc properties. Finally, lines from the same geographical area were rarely incompatible, confirming the conjecture that the spatial distribution of Wolbachia compatibility types should be constrained by selection. This study indicates a clear correlation between Wolbachia genotypes and CI properties, paving the way toward the identification of the molecular basis of CI through comparative genomics.


Hormonal response to carbohydrate supplementation at rest and after resistance exercise.
This investigation examined the anabolic-hormone response to carbohydrate (CHO) supplementation at rest and after resistance exercise. Nine recreationally trained men randomly underwent 4 testing conditions: rest with placebo (RPL), rest with CHO (RCHO), resistance exercise with placebo (EPL), and resistance exercise with CHO (ECHO). The resistance-exercise protocol was four sets of Smith machine squats with a 10-repetition-maximum load, with 90-s rests between sets. Participants then consumed either a placebo or CHO (24% CHO, 1.5 g/kg) drink. Blood was taken before exercise (Pre), immediately after testing (Post), and then 15 (15P), 30 (30P), and 60 (60P) min after drink ingestion. Blood was analyzed for cortisol, glucose, insulin, and total testosterone (TTST). Cortisol did not change significantly in any condition. Glucose concentrations increased significantly from Pre to 15P and 30P during RCHO and Pre to 15P, 30P, and 60P in ECHO (p <or= .05). Insulin concentrations increased significantly from Pre to 15P, 30P, and 60P in the RCHO and ECHO conditions (p <or= .05). There were no significant changes in TTST concentrations during RPL or RCHO. Both EPL and ECHO demonstrated a significant elevation in TTST concentrations from Pre to Post (p <or= .05). During ECHO, TTST concentrations at 60P were significantly lower than Pre levels (p <or= .05), but there were no significant treatment differences in TTST concentrations at any time point during the EPL and ECHO conditions. Ingesting CHO after resistance exercise resulted in decreased TTST concentrations during recovery, although the mechanism is unclear.


Genetic variation in glutathione-related genes and body burden of methylmercury.
Exposure to toxic methylmercury (MeHg) through fish consumption is a large problem worldwide, and it has led to governmental recommendations of reduced fish consumption and blacklisting of mercury-contaminated fish. The elimination kinetics of MeHg varies greatly among individuals. Knowledge about the reasons for such variation is of importance for improving the risk assessment for MeHg. One possible explanation is hereditary differences in MeHg metabolism. MeHg is eliminated from the body as a glutathione (GSH) conjugate. We conducted this study to assess the influence of polymorphisms in GSH-synthesizing [glutamyl-cysteine ligase modifier subunit (GCLM-588) and glutamyl-cysteine ligase catalytic subunit (GCLC-129)] or GSH-conjugating [glutathione S-transferase pi 1 (GSTP1-105 and GSTP1-114)] genes on MeHg retention. Based on information obtained from questionnaires, 292 subjects from northern Sweden had a high consumption of fish (lean/fat fish two to three times per week or more). We measured total Hg in erythrocytes (Ery-Hg) and long-chain n-3 polyunsaturated fatty acids in plasma (P-PUFA; an exposure marker for fish intake). The GSTP1 genotype modified Ery-Hg; effects were seen for GSTP1-105 and -114 separately, and combining them resulted in stronger effects. We found evidence of effect modification: individuals with zero or one variant allele demonstrated a steeper regression slope for Ery-Hg (p=0.038) compared with individuals with two or more variant alleles. The GCLM-588 genotype also influenced Ery-Hg (p=0.035): Individuals with the GCLM-588 TT genotype demonstrated the highest Ery-Hg, but we saw no evidence of effect modification with increasing P-PUFA. These results suggest a role of GSH-related polymorphisms in MeHg metabolism.


Opening the 'implementation black-box' of the user fee exemption policy for caesarean section in Benin: a realist evaluation.
To improve access to maternal health services, Benin introduced in 2009 a user fee exemption policy for caesarean sections. Similar to other low- and middle-income countries, its implementation showed mixed results. Our study aimed at understanding why and in which circumstances the implementation of this policy in hospitals succeeded or failed. We adopted the realist evaluation approach and tested the initial programme theory through a multiple embedded case study design. We selected two hospitals with contrastive outcomes. We used data from 52 semi-structured interviews, a patient exit survey, a costing study of caesarean section and an analysis of financial flows. In the analysis, we used the intervention-context-actor-mechanism-outcome configuration heuristic. We identified two main causal pathways. First, in the state-owned hospital, which has a public-oriented but administrative management system, and where citizens demand accountability through various channels, the implementation process was effective. In the non-state-owned hospital, managers were guided by organizational financial interests more than by the inherent social value of the policy, there was a perceived lack of enforcement and the implementation was poor. We found that trust, perceived coercion, adherence to policy goals, perceived financial incentives and fairness in their allocation drive compliance, persuasion, positive responses to incentives and self-efficacy at the operational level to generate the policy implementation outcomes. Compliance with the policy depended on enforcement by hierarchical authority and bottom-up pressure. Persuasion depended on the alignment of the policy with personal and organizational values. Incentives may determine the adoption if they influence the local stakeholder's revenue are trustworthy and perceived as fairly allocated. Failure to anticipate the differential responses of implementers will prevent the proper implementation of user fee exemption policies and similar universal health coverage reforms.


Prenatal high-fat diet alters the cerebrovasculature and clearance of β-amyloid in adult offspring.
Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides in the extracellular spaces of the brain as plaques and in the walls of blood vessels as cerebral amyloid angiopathy (CAA). Failure of perivascular drainage of Aβ along cerebrovascular basement membranes contributes to the development of CAA. Mid-life hypercholesterolaemia is a risk factor for the development of AD. Maternal obesity is associated with the development of obesity, hypertension and hypercholesterolaemia in adulthood, suggesting that the risk for AD and CAA may also be influenced by the early-life environment. In the present study, we tested the hypothesis that early-life exposure to a high-fat diet results in changes to the cerebrovasculature and failure of Aβ clearance from the brain. We also assessed whether vascular Aβ deposition is greater in the brains of aged humans with a history of hyperlipidaemia, compared to age-matched controls with normal lipidaemia. Using a mouse model of maternal obesity, we found that exposure to a high-fat diet during gestation and lactation induced changes in multiple components of the neurovascular unit, including a down-regulation in collagen IV, fibronectin and apolipoprotein E, an up-regulation in markers of astrocytes and perivascular macrophages and altered blood vessel morphology in the brains of adult mice. Sustained high-fat diet over the entire lifespan resulted in additional decreases in levels of pericytes and impaired perivascular clearance of Aβ from the brain. In humans, vascular Aβ load was significantly increased in the brains of aged individuals with a history of hypercholesterolaemia. These results support a critical role for early dietary influence on the brain vasculature across the lifespan, with consequences for the development of age-related cerebrovascular and neurodegenerative diseases.


Promoting diabetes self-management among African Americans: an educational intervention.
Diabetes is a major national health problem that affects African Americans more seriously than other population groups. The purpose of this project was to increase knowledge and self-management of diabetes among African American adults 40 years of age and older diagnosed with type II diabetes. A quasi-experimental pre-test/post-test comparison group design was used. Three educational sessions were provided to participants in the intervention group. Content included information about diabetes and its complications, risk factors, proper diet, recommendations for exercise, medications, and monitoring blood glucose. Teaching strategies included discussion, games, and demonstrations. Patient navigators provided follow-up by phone at the scheduled intervals. Preliminary results indicated significantly increased knowledge among intervention group participants between the pre- and post-test and the pre-test and follow-up. Findings for HbA1c values, body mass index, and weight were not significant.


Variation in restorer genes and primary sexual investment in gynodioecious Plantago coronopus: the trade-off between male and female function.
In many gynodioecious species the nuclear inheritance of male fertility is complex and involves multiple (restorer) genes. In addition to restoring plants from the female (male sterile) to the hermaphrodite (male fertile) state, these genes are also thought to play a role in the determination of the quantity of pollen produced by hermaphrodites. The more restorer alleles a hermaphroditic plant possesses, the higher the pollen production. To test this hypothesis I combined the results of crossing studies of the genetics of male sterility with phenotypic data on investment in stamens and ovules among the progeny of plants involved in these studies. The sex ratio (i.e. the frequency of hermaphrodites among the progeny), being a measure of the number of restorer alleles of the maternal plant, was positively related to the investment in pollen (male function), but negatively related to the investment in ovules (female function), in both field and greenhouse experiments. Consequently, a negative correlation between male and female function was observed (trade-off) and it is suggested that antagonistic pleiotropic effects of restorer genes might be the cause. Phenotypic gender, a measure combining investment in both pollen and ovules, was highly repeatable between field and greenhouse, indicating genetic determination of a more male- or female-biased allocation pattern among the studied plants.


Self-association of a DNA loop creates a quadruplex: crystal structure of d(GCATGCT) at 1.8 A resolution.
The flexibility of DNA enables it to adopt three interconvertible types of duplex termed the A-, B- and Z-forms. It can also produce hairpin loops, triplex structures and guanine-rich quadruplex structures. Conformational flexibility assists in the tight packaging of DNA, for example in chromosomes. This is important given the large quantity of genetic information that must be packaged efficiently. Moreover, the ability of DNA to specifically self-associate or interact with complementary sequences is fundamental to many biological processes. Structural studies provide information about DNA conformation and DNA-DNA interactions and suggest features that might be relevant to how the molecule performs its biological role. We have characterized the structure of a synthetic heptanucleotide that folds into a novel loop structure. The loop is stabilized by association with a cation, by intra-strand hydrogen bonds between guanine and cytosine that are distinct from the normal Watson-Crick hydrogen bonds, and by van der Waals interactions. Two loops associate through the formation of four G.C pairs that exhibit pronounced base-stacking interactions. The formation of a symmetric A.A base pair further stabilizes loop dimerization. Stacking of the A.A pair on a symmetry-related A.A pairing assists the formation of a four-stranded assembly. A T.T pairing is also observed between symmetry-related loops. This analysis provides a rare example of an experimentally determined non-duplex DNA structure. It provides conformational detail relevant to the tight packaging or folding of a DNA strand and illustrates how a cation might modulate phosphate-phosphate repulsion in a tightly packed structure. The observation of base quartets involving G.C base pairs suggests a further structure to be considered in DNA-DNA interactions. The structure also provides detailed geometries for A.A and T.T base pairs.


Adaptive dielectric liquid lens.
A tunable-focus liquid lens using dielectrophoretic effect is demonstrated. When a voltage is applied to a dielectric liquid droplet, the generated electric field inside the droplet is inhomogeneous. As a result, the liquid bears a dielectric force and its surface profile can be reshaped which causes the focal length to change. Adaptive lenses with different apertures are fabricated and their performances evaluated. In comparison to the patterned-electrode liquid lenses, our lens uses continuous electrode which is much simpler for fabrication.


From Efficacy to Global Impact: Lessons Learned About What Not to Do in Translating Our Research to Reach.
Although members of the Association for Behavioral and Cognitive Therapies have made significant strides toward the collective goals outlined in our mission statement, we routinely acknowledge that our ability to develop empirically supported treatments exceeds our success in improving dissemination and implementation of said interventions. Further, as noted by Kazdin and Blase (2011), even if we succeeded in having every clinician worldwide administer our best treatments with excellent competency, we still would be unsuccessful in markedly impacting the worldwide burden of mental illness because most treatments require intensive labor by expensive providers. To this end, Kazdin and Blase and others call for increased use of alternative strategies. Examples include increased attention toward prevention; use of lower-cost, simplified interventions; task shifting; train-the-trainer models; community participatory research methodology; and identification of novel funding sources. The Body Project is an empirically supported, cognitive dissonance-based prevention intervention that targets body image, a well-established risk factor for eating disorders, negative affect, unhealthy weight control behaviors, smoking behavior, and decreased physical activity. Supported by a global village of researchers, community activists, and organizational partners, the Body Project is currently being implemented in 125 countries. The aim of this paper is to share lessons our team has learned in taking a prevention intervention from early testing to widespread implementation and connect these back to broader conversations occurring in our field regarding the importance of scalability and new directions in improving global mental health.


Phosphorus index as a phosphorus awareness tool: documented phosphorus use reduction in New York state.
In 1999, New York introduced its concentrated animal feeding operation (CAFO) permit followed, in 2001, by release of the New York phosphorus index (NY-PI) and establishment of a statewide on-farm research partnership. State policy requires that the Natural Resources Conservation Service's 590 nutrient management standard, and therefore the NY-PI, be implemented on all CAFO farms as well as animal feeding operations (AFOs) receiving state or federal cost share funds for manure storage and other related practices. Since the introduction of the NY-PI, P fertilizer sales (farm use) declined from 14,470 Mg in 2001 (8.6 kg P ha) to 7,376 Mg in 2009 (5.0 kg P ha). Cost of fertilizer was not a significant covariate for the reduction in P use over time. Certified nutrient management planners were surveyed in 2011 to evaluate their perceptions of drivers for changes in P use. In addition, whole farm P balances were recorded for 54 New York dairy farms. The survey data illustrate key ingredients for success: (i) statewide awareness of environmental challenges through both regulations and extension programming; (ii) science-based, user-friendly tools that allow for farm-specific responses to the challenges; (iii) risk assessment of management alternatives through on-farm research; (iv) enforcement of regulations; and (v) existence of economically feasible alternatives. Whole farm balances showed a reduction in P surplus of 44%, averaged across farms, whereas milk production increased, further illustrating the willingness and economic potential to make changes that improve production efficiency and reduce risk of nutrient loss to the environment.


Local calcium transients triggered by single L-type calcium channel currents in cardiac cells.
Excitation-contraction coupling was studied in mammalian cardiac cells in which the opening probability of L-type calcium (Ca2+) channels was reduced. Confocal microscopy during voltage-clamp depolarization revealed distinct local transients in the concentration of intracellular calcium ions ([Ca2+]i). When voltage was varied, the latency to occurrence and the relative probability of occurrence of local [Ca2+]i transients varied as predicted if Ca2+ release from the sarcoplasmic reticulum (SR) was linked tightly to Ca2+ flux through L-type Ca2+ channels but not to that through the Na-Ca exchanger or to average [Ca2+]i. Voltage had no effect on the amplitude of local [Ca2+]i transients. Thus, the most efficacious "Ca2+ signal" for activating Ca2+ release from the SR may be a transient microdomain of high [Ca2+]i beneath an individual, open L-type Ca2+ channel.


Roles of ESCRT in autophagy-associated neurodegeneration.
Autophagy is a regulated pathway for bulk degradation of cytoplasmic contents and organelles, an important process involved in many physiological and pathological conditions in multiple organs, including the nervous system. It has been proposed that developing autophagosomes fuse with late endosomal compartments before their fusion with lysosomes; however, little is known about the functional relationship between the autophagy and endocytic pathways. In the endosomal-lysosomal pathway, a key step in sorting transmembrane cargo proteins is regulated by multimeric complexes called ESCRT (endosomal sorting complex required for transport). We recently reported that dysfunction of ESCRT-III, either by depletion of its essential subunit mSnf7-2 or by expression of a mutant CHMP2B protein associated with frontotemporal dementia linked to chromosome 3 (FTD3), caused autophagosome accumulation and dendritic retraction before neurodegeneration in cultured mature cortical neurons. This defect is likely a result of an abnormal fusion process between autophagosomes and endosomal compartments or lysosomes. This study suggests that defects in the late steps of the autophagy pathway may contribute to the pathogenesis of FTD and potentially other neurodegenerative diseases.


Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis.
There is a lack of consensus on the role of selective cannabinoids for the treatment of neuropathic pain (NP). Guidelines from national and international pain societies have provided contradictory recommendations. The primary objective of this systematic review and meta-analysis (SR-MA) was to determine the analgesic efficacy and safety of selective cannabinoids compared to conventional management or placebo for chronic NP. We reviewed randomized controlled trials that compared selective cannabinoids (dronabinol, nabilone, nabiximols) with conventional treatments (eg, pharmacotherapy, physical therapy, or a combination of these) or placebo in patients with chronic NP because patients with NP may be on any of these therapies or none if all standard treatments have failed to provide analgesia and or if these treatments have been associated with adverse effects. MEDLINE, EMBASE, and other major databases up to March 11, 2016, were searched. Data on scores of numerical rating scale for NP and its subtypes, central and peripheral, were meta-analyzed. The certainty of evidence was classified using the Grade of Recommendations Assessment, Development, and Evaluation approach. Eleven randomized controlled trials including 1219 patients (614 in selective cannabinoid and 605 in comparator groups) were included in this SR-MA. There was variability in the studies in quality of reporting, etiology of NP, type and dose of selective cannabinoids. Patients who received selective cannabinoids reported a significant, but clinically small, reduction in mean numerical rating scale pain scores (0-10 scale) compared with comparator groups (-0.65 points; 95% confidence interval, -1.06 to -0.23 points; P = .002, I = 60%; Grade of Recommendations Assessment, Development, and Evaluation: weak recommendation and moderate-quality evidence). Use of selective cannabinoids was also associated with improvements in quality of life and sleep with no major adverse effects. Selective cannabinoids provide a small analgesic benefit in patients with chronic NP. There was a high degree of heterogeneity among publications included in this SR-MA. Well-designed, large, randomized studies are required to better evaluate specific dosage, duration of intervention, and the effect of this intervention on physical and psychologic function.


D-penicillamine for primary sclerosing cholangitis.
Primary sclerosing cholangitis is a cholestatic disease. D-penicillamine is suggested as a treatment option due to its copper reducing and immunomodulatory potential. To evaluate the beneficial and harmful effects of D-penicillamine for patients with primary sclerosing cholangitis. Eligible trials were identified through searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (August 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 3, 2005), MEDLINE (1950 to August 2005), EMBASE (1980 to August 2005), Science Citation Index EXPANDED (1945 to August 2005), and reference lists of relevant articles. Authors of trials and pharmaceutical companies known to produce D-penicillamine were also contacted. Randomised clinical trials comparing D-penicillamine in any dose, duration, and route of administration versus placebo, no intervention, or other intervention(s). Trials were included irrespective of publication status, year of publication, language, or blinding. Both authors selected the trials, extracted data, and evaluated the methodological quality of the trials with respect to the generation of allocation sequence, allocation concealment, blinding, and follow-up. The results were reported by intention-to-treat analysis. The outcomes were presented as relative risk (RR) or weighted mean difference (WMD), both with 95% confidence intervals (CI). One randomised trial was identified and included in the review. It was of low methodological quality. The trial compared D-penicillamine versus placebo in 70 patients with primary sclerosing cholangitis. Compared with placebo, D-penicillamine therapy had no significant effect on mortality (RR 1.14, 95% CI 0.49 to 2.64), liver transplantation (RR 1.11, 95% CI 0.39 to 3.17), hepatic histologic progression (RR 1.17, 95% CI 0.79 to 1.74), or cholangiographic deterioration (RR 0.87, 95% CI 0.43 to 1.79). D-penicillamine led to a significant improvement in the serum aspartate aminotransferase (WMD -23.00 U/L; 95% CI -30.66 to -15.34), but not in serum bilirubin level (WMD 0.40 mg/L; 95% CI -0.19 to 0.99) and serum alkaline phosphatases activity (WMD 44.00 U/L; 95% CI -37.89 to 125.89). There were significantly more adverse events in patients receiving D-penicillamine (P = 0.013). There is not sufficient evidence to support or refute the use of D-penicillamine for patients with primary sclerosing cholangitis. We do not recommend the use of D-penicillamine for patients with primary sclerosing cholangitis outside randomised trials.


Identification of an Upper Limit of Tumor Burden for Downstaging in Candidates with Hepatocellular Cancer Waiting for Liver Transplantation: A West-East Collaborative Effort.
Abstract: Since the introduction of Milan Criteria, all scoring models describing the prognosis of hepatocellular cancer (HCC) after liver transplantation (LT) have been exclusively based on characteristics available at surgery, therefore neglecting the intention-to-treat principles. This study aimed at developing an intention-to-treat model through a competing-risk analysis. Using data available at first referral, an upper limit of tumor burden for downstaging was identified beyond which successful LT becomes an unrealistic goal. Twelve centers in Europe, United States, and Asia (Brussels, Sapienza Rome, Padua, Columbia University New York, Innsbruck, Medanta-The Medicity Dehli, Hong Kong, Kyoto, Kaohsiung Taiwan, Mainz, Fukuoka, Shulan Hospital Hangzhou) created a Derivation (n = 2318) and a Validation Set (n = 773) of HCC patients listed for LT between January2000-March 2017. In the Derivation Set, the competing-risk analysis identified two independent covariables predicting post-transplant HCC-related death: combined HCC number and diameter (SHR = 1.15; p < 0.001) and alpha-fetoprotein (AFP) (SHR = 1.80; p < 0.001). WE-DS Model showed good diagnostic performances at internal and external validation. The identified upper limit of tumor burden for downstaging was AFP ≤ 20 ng/mL and up-to-twelve as sum of HCC number and diameter; AFP = 21-200 and up-to-ten; AFP = 201-500 and up-to-seven; AFP = 501-1000 and up-to-five. The WE-DS Model proposed here, based on morphologic and biologic data obtained at first referral in a large international cohort of HCC patients listed for LT, allowed identifying an upper limit of tumor burden for downstaging beyond which successful LT, following downstaging, results in a futile transplantation.


Effects of High Intensity Interval Training on Pregnant Rats, and the Placenta, Heart and Liver of Their Fetuses.
To investigate the effects of high intensity interval training (HIIT) on the maternal heart, fetuses and placentas of pregnant rats. Female Sprague-Dawley rats were randomly assigned to HIIT or sedentary control groups. The HIIT group was trained for 6 weeks with 10 bouts of high intensity uphill running on a treadmill for four minutes (at 85-90% of maximal oxygen consumption) for five days/week. After three weeks of HIIT, rats were mated. After six weeks (gestational day 20 in pregnant rats), echocardiography was performed to evaluate maternal cardiac function. Real-time PCR was performed for the quantification of gene expression, and oxidative stress and total antioxidant capacity was assessed in the tissue samples. Maternal heart weight and systolic function were not affected by HIIT or pregnancy. In the maternal heart, expression of 11 of 22 genes related to cardiac remodeling was influenced by pregnancy but none by HIIT. Litter size, fetal weight and placental weight were not affected by HIIT. Total antioxidant capacity, malondialdehyde content, peroxidase and superoxide dismutase activity measured in the placenta, fetal heart and liver were not influenced by HIIT. HIIT reduced the expression of eNOS (p = 0.03), hypoxia-inducible factor 1α (p = 0.04) and glutathione peroxidase 4.2 (p = 0.02) in the fetal liver and increased the expression of vascular endothelial growth factor-β (p = 0.014), superoxide dismutase 1 (p = 0.001) and tissue inhibitor of metallopeptidase 3 (p = 0.049) in the fetal heart. Maternal cardiac function and gene expression was not affected by HIIT. Although HIIT did not affect fetal growth, level of oxidative stress and total antioxidant capacity in the fetal tissues, some genes related to oxidative stress were altered in the fetal heart and liver indicating that protective mechanisms may be activated.


Revival of the genus Lentzea and proposal for Lechevalieria gen. nov.
The genus Saccharothrix is phylogenetically heterogeneous on the basis of analysis of almost complete 16S rDNA sequences. An evaluation of chemotaxonomic, morphological and physiological properties in the light of the molecular phylogeny data revealed that several species are misclassified. Saccharothrix aerocolonigenes NRRL B-3298T and Saccharothrix flava NRRL B-16131T constitute a lineage distinct from Saccharothrix and separate from Lentzea. The genus Lechevalieria gen. nov. is proposed for these species. Lechevalieria aerocolonigenes comb. nov. is the type species and S. flava is transferred as Lechevalieria flava comb. nov. Although Lentzea albidocapillata, the type species of the genus Lentzea, was transferred recently to the genus Saccharothrix, the revival of Lentzea is clearly supported by molecular phylogenetic and chemotaxonomic data. The description of the revived genus is emended to include galactose, mannose and traces of ribose as diagnostic whole-cell sugars and MK-9(H4) as the principal menaquinone and elimination of tuberculostearic acid as a diagnostic component in the fatty acid profile. Saccharothrix waywayandensis NRRL B-16159T, S. aerocolonigenes NRRL B-16137 and 'Asiosporangium albidum' IFO 16102 are members of the amended genus Lentzea on the basis of phylogenetic and chemotaxonomic properties. S. waywayandensis is transferred to Lentzea as Lentzea waywayandensis comb. nov., while the new species Lentzea californiensis sp. nov. and Lentzea albida sp. nov. are described for S. aerocolonigenes NRRL B-16137 and 'A. albidum' IFO 16102, respectively. Nucleotide signatures in the 16S rDNA sequences are defined that are diagnostic for the genera Lechevalieria, Lentzea and Saccharothrix.


Analgesic effects and the mechanisms of anti-inflammation of ergostatrien-3beta-ol from Antrodia camphorata submerged whole broth in mice.
Ergostatrien-3beta-ol (ST1), an active and major ingredient from Antrodia camphorata (AC) submerged whole broth was evaluated for the analgesic and anti-inflammatory effects. Treatment of male imprinting control region (ICR) mice with ST1 (1, 5, and 10 mg/kg) significantly inhibited the numbers of acetic-acid-induced writhing response in 10 min. Also, our result showed that ST1 (10 mg/kg) significantly inhibited the formalin-induced pain in the late phase (p < 0.001). In the anti-inflammatory test, ST1 (10 mg/kg) decreased the paw edema at 4 and 5 h after lambda-carrageenin (Carr) administration and increased the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the liver tissue. We also demonstrated that ST1 significantly attenuated the malondialdehyde (MDA) level in the edema paw at 5 h after Carr injection. ST1 (1, 5, and 10 mg/kg) decreased the nitric oxide (NO) levels on both the edema paw and serum level at 5 h after Carr injection. Also, ST1 (5 and 10 mg/kg) diminished the serum tumor necrosis factor (TNF-alpha) at 5 h after Carr injection. Western blotting revealed that ST1 (10 mg/kg) decreased Carr-induced inducible nitric oxide synthase (iNOS), and cycloxyclase (COX-2) expressions at 5 h in the edema paw. An intraperitoneal (ip) injection treatment with ST1 also diminished neutrophil infiltration into sites of inflammation, as did indomethacin (Indo). The anti-inflammatory mechanisms of ST1 might be related to the decrease in the level of MDA, iNOS, and COX-2 in the edema paw via increasing the activities of CAT, SOD, and GPx in the liver through the suppression of TNF-alpha and NO.


Healthier than thou? "Practicing what you preach" backfires by increasing anticipated devaluation.
[Correction Notice: An Erratum for this article was reported in Vol 112(5) of Journal of Personality and Social Psychology (see record 2017-17124-001). In the article, the beginning phrase of the second paragraph of the Internal Meta-Analysis of Studies 3 Through 5 section is incorrect. It should instead begin as follows: Across the three studies. The Monin et al. (2014) reference in both the References list and in text is included in error. The correct citation should read as follows: Monin, B., & Oppenheimer, D. M. (2014). The limits of direct replications and the virtues of stimulus sampling: Commentary on Klein et al., 2014. Social Psychology, 45, 299-300.] Should experts always practice what they preach? When an expert displays exemplary behavior, individuals who fear negative devaluation sometimes anticipate that this expert will look down on them. As a result, displays of excellence can paradoxically turn off the very people they are trying to inspire. Five studies document this in the medical domain, showing that individuals who are overweight or obese and concerned about their weight avoid physicians who advertise their fitness, for fear that these doctors will judge them negatively. People (erroneously) believe that doctors have healthier habits than other individuals (Study 1), doctors advertise healthy habits (Study 2), and overweight individuals anticipate devaluation from, and thus avoid and feel less comfortable with, doctors who portray themselves as fitness-focused (Study 3). Studies 4 and 5 test strategies for physicians to emphasize their own fitness without turning off weight-sensitive patients. This work demonstrates that it is critical to take into account ego-defensive processes when attempting to lead by example. (PsycINFO Database Record


The effect of tuberculin skin test and BCG vaccination on the expansion of PPD-specific IFN-gamma producing cells ex vivo.
Understanding the immunogenicity of BCG in a population where it has failed will facilitate the design of new TB vaccines. We assessed the immunogenicity of M. bovis BCG over 12 months by ELISPOT assay. Forty-one adolescents and young Gambian male adults received a tuberculin skin test (TST) which was followed one week later by BCG vaccination, but the 23 control subjects received neither of these. TST alone significantly induced PPD-specific IFN-gamma producing cells. Twenty-three percent of subjects did not respond to BCG, which was associated with higher pre-existing ex vivo response to PPD. Paradoxically, amongst BCG responders there was a correlation between pre-existing response and subsequent response to BCG. We conclude that BCG is immunogenic, but this effector response is short-lived and can be limited in higher pre-existing anti-mycobacterial immunity, suggesting a possible threshold beyond which BCG immunogenicity is inhibited.


Deletion of the MAG1 DNA glycosylase gene suppresses alkylation-induced killing and mutagenesis in yeast cells lacking AP endonucleases.
DNA base excision repair (BER) is initiated by DNA glycosylases that recognize and remove damaged bases. The phosphate backbone adjacent to the resulting apurinic/apyrimidinic (AP) site is then cleaved by an AP endonuclease or glycosylase-associated AP lyase to invoke subsequent BER steps. We have used a genetic approach in Saccharomyces cerevisiae to address whether AP sites are blocks to DNA replication and the biological consequences if AP sites persist in the genome. We found that yeast cells deficient in the two AP endonucleases (apn1 apn2 double mutant) are extremely sensitive to killing by methyl methanesulfonate (MMS), a model DNA alkylating agent. Interestingly, this sensitivity can be reduced up to 2500-fold by deleting the MAG1 3-methyladenine DNA glycosylase gene, suggesting that Mag1 not only removes lethal base lesions, but also benign lesions and possibly normal bases, and that the resulting AP sites are highly toxic to the cells. This rescuing effect appears to be specific for DNA alkylation damage, since the mag1 mutation reduces killing effects of two other DNA alkylating agents, but does not alter the sensitivity of apn cells to killing by UV, gamma-ray or H(2)O(2). Our mutagenesis assays indicate that nearly half of spontaneous and almost all MMS-induced mutations in the AP endonuclease-deficient cells are due to Mag1 DNA glycosylase activity. Although the DNA replication apparatus appears to be incapable of replicating past AP sites, Polzeta-mediated translesion synthesis is able to bypass AP sites, and accounts for all spontaneous and MMS-induced mutagenesis in the AP endonuclease-deficient cells. These results allow us to delineate base lesion flow within the BER pathway and link AP sites to other DNA damage repair and tolerance pathways.


Fossil Forests of Ocu, Panama.
Silicified woods, the remains of mid-Tertiary tropical forests, are abundant in the vicinity of Ocú, Panama. Initial identifications reveal plant taxa not previously recorded as fossil woods. The plants identified can be found today in moist forests of tropical America, but not in the savanna-like vegetation now growing at the fossil site.


The obligation of physicians to medical outliers: a Kantian and Hegelian synthesis.
Patients who present to medical practices without health insurance or with serious co-morbidities can become fiscal disasters to those who care for them. Their consumption of scarce resources has caused consternation among providers and institutions, especially as it concerns the amount and type of care they should receive. In fact, some providers may try to avoid caring for them altogether, or at least try to limit their institutional or practice exposure to them. We present a philosophical discourse, with emphasis on the writings of Immanuel Kant and G.F.W. Hegel, as to why physicians have the moral imperative to give such "outliers" considerate and thoughtful care. Outliers are defined and the ideals of morality, responsibility, good will, duty, and principle are applied to the care of patients whose financial means are meager and to those whose care is physiologically futile. Actions of moral worth, unconditional good will, and doing what is right are examined. Outliers are a legitimate economic concern to individual practitioners and institutions, however this should not lead to an evasion of care. These patients should be identified early in their course of care, but such identification should be preceded by a well-planned recognition of this burden and appropriate staffing and funding should be secured. A thoughtful team approach by medical practices and their institutions, involving both clinicians and non-clinicians, should be pursued.


Phylogenetic patterns of trait and trait plasticity evolution: Insights from amphibian embryos.
Environmental variation favors the evolution of phenotypic plasticity. For many species, we understand the costs and benefits of different phenotypes, but we lack a broad understanding of how plastic traits evolve across large clades. Using identical experiments conducted across North America, we examined prey responses to predator cues. We quantified five life-history traits and the magnitude of their plasticity for 23 amphibian species/populations (spanning three families and five genera) when exposed to no cues, crushed-egg cues, and predatory crayfish cues. Embryonic responses varied considerably among species and phylogenetic signal was common among the traits, whereas phylogenetic signal was rare for trait plasticities. Among trait-evolution models, the Ornstein-Uhlenbeck (OU) model provided the best fit or was essentially tied with Brownian motion. Using the best fitting model, evolutionary rates for plasticities were higher than traits for three life-history traits and lower for two. These data suggest that the evolution of life-history traits in amphibian embryos is more constrained by a species' position in the phylogeny than is the evolution of life history plasticities. The fact that an OU model of trait evolution was often a good fit to patterns of trait variation may indicate adaptive optima for traits and their plasticities.


Plasmonic antenna coupling to hyperbolic phonon-polaritons for sensitive and fast mid-infrared photodetection with graphene.
Integrating and manipulating the nano-optoelectronic properties of Van der Waals heterostructures can enable unprecedented platforms for photodetection and sensing. The main challenge of infrared photodetectors is to funnel the light into a small nanoscale active area and efficiently convert it into an electrical signal. Here, we overcome all of those challenges in one device, by efficient coupling of a plasmonic antenna to hyperbolic phonon-polaritons in hexagonal-BN to highly concentrate mid-infrared light into a graphene pn-junction. We balance the interplay of the absorption, electrical and thermal conductivity of graphene via the device geometry. This approach yields remarkable device performance featuring room temperature high sensitivity (NEP of 82 pW[Formula: see text]) and fast rise time of 17 nanoseconds (setup-limited), among others, hence achieving a combination currently not present in the state-of-the-art graphene and commercial mid-infrared detectors. We also develop a multiphysics model that shows very good quantitative agreement with our experimental results and reveals the different contributions to our photoresponse, thus paving the way for further improvement of these types of photodetectors even beyond mid-infrared range.


Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.


Smoking and survival after breast cancer diagnosis: a prospective observational study and systematic review.
The association of smoking with outcomes following breast cancer prognosis is not well understood. In a cohort study called Life After Cancer Epidemiology (LACE), 2,265 women diagnosed with breast cancer were followed for a median of 12 years. We used multivariable proportional-hazards models to determine whether smoking, assessed approximately two years post-diagnosis, was associated with risk of death among these women. We also undertook a systematic review of all cohort studies to date that have examined the association between smoking and breast cancer mortality. Compared with never smokers, women who were current smokers had a twofold higher rate of dying from breast cancer [hazard ratio (HR) = 2.01, 95 % confidence interval (CI) 1.27-3.18] and an approximately fourfold higher rate of dying from competing (non-breast cancer) causes (HR = 3.84, 95 % CI 2.50-5.89). Among seven studies that met the inclusion criteria in the systematic review, three studies and our own reported significantly increased risk of breast cancer death with current smoking. We found little evidence of an association between former smoking and breast cancer mortality (HR = 1.24, 95 % CI 0.94-1.64). Consistent with findings from our prospective observational study, the systematic review of seven additional studies indicates positive association of current smoking with breast cancer mortality, but weak association with former smoking. Women who smoke following breast cancer diagnosis and treatment are at higher risk of death both from breast cancer and other causes.