Comparing the Workload Perceptions of Identifying Patient Condition and Priorities of Care Among Burn Providers in Three Burn ICUs.
Multidisciplinary rounds (MDRs) in the burn intensive care unit serve as an efficient means for clinicians to assess patient status and establish patient care priorities. Both tasks require significant cognitive work, the magnitude of which is relevant because increased cognitive work of task completion has been associated with increased error rates. We sought to quantify this workload during MDR using the National Aeronautics and Space Administration Task Load Index (NASA-TLX). Research staff at three academic regional referral burn centers administered the NASA-TLX to clinicians during MDR. Clinicians assessed their workload associated with 1) "Identify(ing) if the patient is better, same, or worse than yesterday" and 2) "Identify(ing) the most important objectives of care for the patient today." Data were collected on clinician type, years of experience, and hours of direct patient care. Surveys were administered to 116 total clinicians, 41 physicians, 25 nurses, 13 medical students, and 37 clinicians in other roles. Clinicians with less experience reported more cognitive work when completing both tasks (P < .005). Clinicians in the "others" group (respiratory therapists, dieticians, pharmacists, etc.) reported less cognitive work than all other groups for both tasks (P < .05). The NASA-TLX was an effective tool for collecting perceptions of cognitive workload associated with MDR. Perceived cognitive work varied by clinician type and experience level when completing two key tasks. Less experience was associated with increased perceived work, potentially increasing mental error rates, and increasing risk to patients. Creating tools or work processes to reduce cognitive work may improve clinician performance.


A sensitive detection assay based on signal amplification technology for Alzheimer's disease's early biomarker in exosome.
Alzheimer's disease (AD) considered as the third health "killer" has seriously threatened the health of the elderly. However, the modern diagnostic strategies of AD present several disadvantages: the low accuracy and specificity resulting in some false-negative diagnoses, and the poor sensitivity leading to a delayed treatment. In view of this situation, a enzyme-free and target-triggered signal amplification strategy, based on graphene oxide (GO) and entropy-driven strand displacement reaction (ESDR) principle, was proposed. In this strategy, when the hairpin structure probes (H)specially binds with beta-amyloid-(1-42) oligomers (Aβ42 oligomers), it's structure will be opened, causing the bases complementary to FAM-labeled replacement probes R (R1 and R2) exposed. At this time, R1 and R2 will hybridize with H, resulting in the bound Aβ42 oligomers released. The released Aβ42 oligomers would participate in the next cycle reaction, making the signal amplified. As a quencher, GO could absorb the free single-stranded DNA R1 and R2 and quench their fluorescence; however, the DNA duplex still exists free and keeps its signal-on. Through the detection of Aβ42 oligomers in exosomes, this ultrasensitive detection method with the advantages of low limit of detection (LOD, 20 pM), great accuracy, excellent precision and convenience provides an excellent prospect for AD's early diagnosis.


The involvement of the Notch locus in Drosophila oogenesis.
The Notch gene in Drosophila encodes a transmembrane protein with homology to EGF that, in a variety of tissues, appears to mediate cell interactions necessary for cell fate choices. Here we demonstrate that oogenesis and spermatogenesis depend on Notch. We examine the phenotypes of the temperature-sensitive Notch allele, Nts1, and, using a monoclonal antibody, determine the cellular and subcellular distribution of Notch protein during oogenesis. We show that Nts1 is associated with a missense mutation in the extracellular, EGF homologous region of Notch and that at non-permissive temperatures oogenesis is blocked and the subcellular distribution of the protein is altered. In wild-type ovaries, Notch protein is found on the apical surface of somatically derived follicle cells, while in the germline-derived cells the protein is not polarized. These findings are discussed in view of the hypothesis that Notch acts as a multifunctional receptor to mediate developmentally important cell interactions.


Isoform-specific Ras signaling is growth factor dependent.
HRAS, NRAS, and KRAS isoforms are almost identical proteins that are ubiquitously expressed and activate a common set of effectors. In vivo studies have revealed that they are not biologically redundant; however, the isoform specificity of Ras signaling remains poorly understood. Using a novel panel of isogenic SW48 cell lines endogenously expressing wild-type or G12V-mutated activated Ras isoforms, we have performed a detailed characterization of endogenous isoform-specific mutant Ras signaling. We find that despite displaying significant Ras activation, the downstream outputs of oncogenic Ras mutants are minimal in the absence of growth factor inputs. The lack of mutant KRAS-induced effector activation observed in SW48 cells appears to be representative of a broad panel of colon cancer cell lines harboring mutant KRAS. For MAP kinase pathway activation in KRAS-mutant cells, the requirement for coincident growth factor stimulation occurs at an early point in the Raf activation cycle. Finally, we find that Ras isoform-specific signaling was highly context dependent and did not conform to the dogma derived from ectopic expression studies.


GSEA-InContext: identifying novel and common patterns in expression experiments.
Gene Set Enrichment Analysis (GSEA) is routinely used to analyze and interpret coordinate pathway-level changes in transcriptomics experiments. For an experiment where less than seven samples per condition are compared, GSEA employs a competitive null hypothesis to test significance. A gene set enrichment score is tested against a null distribution of enrichment scores generated from permuted gene sets, where genes are randomly selected from the input experiment. Looking across a variety of biological conditions, however, genes are not randomly distributed with many showing consistent patterns of up- or down-regulation. As a result, common patterns of positively and negatively enriched gene sets are observed across experiments. Placing a single experiment into the context of a relevant set of background experiments allows us to identify both the common and experiment-specific patterns of gene set enrichment. We compiled a compendium of 442 small molecule transcriptomic experiments and used GSEA to characterize common patterns of positively and negatively enriched gene sets. To identify experiment-specific gene set enrichment, we developed the GSEA-InContext method that accounts for gene expression patterns within a background set of experiments to identify statistically significantly enriched gene sets. We evaluated GSEA-InContext on experiments using small molecules with known targets to show that it successfully prioritizes gene sets that are specific to each experiment, thus providing valuable insights that complement standard GSEA analysis. GSEA-InContext implemented in Python, Supplementary results and the background expression compendium are available at: https://github.com/CostelloLab/GSEA-InContext.


Use of social networking sites in online sex crimes against minors: an examination of national incidence and means of utilization.
To describe the variety of ways social networking sites (SNSs) are used to facilitate the sexual exploitation of youth, as well as identify victim, offender, and case differences between arrests, with and without a SNS nexus. Mail surveys were sent to a nationally representative sample of over 2,500 local, state, and federal law enforcement agencies in the United States. Follow-up detailed telephone interviews were conducted for 1,051 individual cases ending in an arrest for Internet-related sex crimes against minors in 2006. In the United States, an estimated 2,322 arrests (unweighted n = 291) for Internet sex crimes against minors involved SNSs in some way, including an estimated 503 arrests (unweighted n = 93) in cases involving identified victims and the use of SNSs by offenders (the majority of arrests involved undercover operations undertaken by police). SNSs were used to initiate sexual relationships, to provide a means of communication between victim and offender, to access information about the victim, to disseminate information or pictures about the victim, and to get in touch with victim's friends. A considerable number of arrests for Internet sex crimes against minors have a SNS nexus to them. The findings support previous claims that prevention messages should target youth behaviors rather than specific online locations where these crimes occur. In targeting behaviors, youth can take this knowledge with them online, regardless of whether they are using SNSs, chat rooms, or instant messaging.


Pituitary adenoma apoplexy caused by rupture of an anterior communicating artery aneurysm: case report and literature review.
Pituitary adenoma combined with intracranial aneurysm is not rare. Some aneurysms are located inside pituitary adenomas, and most do not rupture. Pituitary apoplexy caused by aneurysm rupture is rare and is easily misdiagnosed as simple pituitary adenoma apoplexy. In this study, we report one case of rare pituitary adenoma apoplexy caused by the rupture of an anterior communicating artery aneurysm. The patient was a 49-year-old male who had an untreated pituitary adenoma for 3 years. The patient experienced a sudden headache; computed tomography (CT) and magnetic resonance imaging (MRI) revealed pituitary adenoma apoplexy and significant subarachnoid hemorrhage. Cranial CT angiography (CTA) showed a communicating artery aneurysm. Supratentorial intracranial aneurysm clipping and pituitary adenoma resection were performed. The aneurysm was a ruptured aneurysm located inside the pituitary adenoma. During the surgery, the aneurysm was clipped, and the majority of the tumor was resected. The patient recovered well after the surgery and received radiotherapy. This rare case demonstrates that when pituitary adenoma apoplexy is combined with subarachnoid hemorrhage, the possibility of a combined intrasellar aneurysm should be considered. During transsphenoidal tumor resection, aneurysm rupture should be avoided to prevent disastrous consequences.


Reduced-calorie orange juice beverage with plant sterols lowers C-reactive protein concentrations and improves the lipid profile in human volunteers.
Dietary plant sterols effectively reduce LDL cholesterol when incorporated into fat matrices. We showed previously that supplementation with orange juice containing plant sterols (2 g/d) significantly reduced LDL cholesterol. Inflammation is pivotal in atherosclerosis. High-sensitivity C-reactive protein (hs-CRP), the prototypic marker of inflammation, is a cardiovascular disease risk marker; however, there is a paucity of data on the effect of plant sterols on CRP concentrations. The aim of this study was to examine whether plant sterols affect CRP concentrations and the lipoprotein profile when incorporated into a reduced-calorie (50 calories/240 mL) orange juice beverage. Seventy-two healthy subjects were randomly assigned to receive a reduced-calorie orange juice beverage either without (Placebo Bev) or with (1 g/240 mL; Sterol Bev) plant sterols twice a day with meals for 8 wk. Fasting blood was obtained at baseline and after 8 wk of Placebo Bev or Sterol Bev supplementation. Sterol Bev supplementation significantly reduced total cholesterol (5%; P < 0.01) and LDL cholesterol (9.4%; P < 0.001) compared with both baseline and Placebo Bev (P < 0.05). HDL cholesterol increased significantly with Sterol Bev (P < 0.02). No significant changes in triacylglycerol, glucose, or liver function tests were observed with Sterol Bev. Sterol Bev supplementation resulted in no significant change in vitamin E and carotenoid concentrations. Sterol Bev supplementation resulted in a significant reduction of CRP concentrations compared with baseline and Placebo Bev (median reduction: 12%; P < 0.005). Supplementation with a reduced-calorie orange juice beverage containing plant sterols is effective in reducing CRP and LDL cholesterol and could be incorporated into the dietary portion of therapeutic lifestyle changes.


Target renal damage: the microvascular associations of increased aortic stiffness in patients with COPD.
Although renal impairment has been described in COPD, there is opportunity to evaluate further to determine nature and consider optimal management. Increased aortic stiffness, as seen in COPD, leads to reduced buffering of pulsatile flow. We hypothesised that urinary albumin creatinine ratio (UACR) would reflect glomerular damage related to aortic stiffness. Patients with COPD and controls underwent spirometry, blood pressure, arterial stiffness - aortic pulse wave velocity (PWV) and provided a spot urine sample for UACR, with other renal biomarkers measured. The UACR was increased in patients (n = 52): 0.80 mg/mmol compared to controls (n = 34): 0.46 mg/mmol, p < 0.05. Aortic PWV was related to log10 UACR in all subjects (r = 0.426, p < 0.001) and COPD patients alone. Aortic PWV was a significant variable for UACR with oxygen saturations, after accounting for potential confounders. Eight subjects (7 patients) reached a defined clinical microalbuminuria threshold, with aortic PWV greater in these patients compared to those patients without, although albuminuria is a continuum. Proximal tubular damage biomarkers, unlike the glomerular marker, were not different between patients and controls. There is glomerular damage in patients with COPD evidenced by increased UACR, related to increased aortic stiffness. Besides the macrovascular prognostic implications of increased aortic stiffness, the microvascular state in COPD management should be considered.


Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials.
To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential publication bias in trials of reboxetine. Systematic review and meta-analysis including unpublished data. Bibliographic databases (Medline, Embase, PsycINFO, BIOSIS, and Cochrane Library), clinical trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin). Double blind, randomised, controlled trials of acute treatment (six weeks or more) with reboxetine versus placebo or SSRIs in adults with major depression. Remission and response rates (benefit outcomes), as well as rates of patients with at least one adverse event and withdrawals owing to adverse events (harm outcomes). The procedures for data extraction and assessment of risk of bias were always conducted by one person and checked by another. If feasible, data were pooled by meta-analyses (random effects model). Publication bias was measured by comparing results of published and unpublished trials. We analysed 13 acute treatment trials that were placebo controlled, SSRI controlled, or both, which included 4098 patients. Data on 74% (3033/4098) of these patients were unpublished. In the reboxetine versus placebo comparison, no significant differences in remission rates were shown (odds ratio 1.17, 95% confidence interval 0.91 to 1.51; P=0.216). Substantial heterogeneity (I(2)=67.3%) was shown in the meta-analysis of the eight trials that investigated response rates for reboxetine versus placebo. A sensitivity analysis that excluded a small inpatient trial showed no significant difference in response rates between patients receiving reboxetine and those receiving placebo (OR 1.24, 95% CI 0.98 to 1.56; P=0.071; I(2)=42.1%). Reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram) for remission rates (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 95% CI 0.67 to 0.95; P=0.01). Reboxetine was inferior to placebo for both harm outcomes (P<0.001 for both), and to fluoxetine for withdrawals owing to adverse events (OR 1.79, 95% CI 1.06 to 3.05; P=0.031). Published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm. Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.


Association of Pharmacist Prescription of Hormonal Contraception With Unintended Pregnancies and Medicaid Costs.
To estimate unintended pregnancies averted and the cost effectiveness of pharmacist prescription of hormonal contraception. A decision-analytic model was developed to determine the cost effectiveness of expanding the scope of pharmacists to prescribe hormonal contraception compared with the standard of care and contraceptive access in clinics. Our perspective was that of the payor, Oregon Medicaid. Our primary outcome was unintended pregnancies averted. Secondary outcomes included: costs and quality-adjusted life years (QALYs). Model inputs were obtained from an analysis of Medicaid claims for the first 24 months after policy implementation in Oregon, and the literature. Univariate and bivariate sensitivity analyses, as well as a Monte Carlo simulation, were performed. Among Oregon's Medicaid population at risk for unintended pregnancy, the policy expanding the scope of pharmacists to prescribe hormonal contraception averted an estimated 51 unintended pregnancies and saved $1.6 million dollars. Quality of life was also improved, with 158 QALYs gained per 198,000 women. Sensitivity analysis demonstrated that the model was most sensitive to the effect on contraceptive continuation rates. If contraceptive continuation rates among women receiving care from a pharmacist are 10% less than among clinicians, than pharmacist prescription of hormonal contraception will not avert unintended pregnancies. Pharmacist prescription of hormonal contraception averts unintended pregnancies and is cost effective. Full implementation of the policy is needed for maximum benefits. Prospective data on the effect of the policy on contraceptive continuation rates are needed.


Curcumin-induced GADD153 upregulation: modulation by glutathione.
As we reported previously, GADD153 is upregulated in colon cancer cells exposed to curcumin. In the present study, we ascertained the involvement of glutathione and certain sulfhydryl enzymes associated with signal transduction in mediating the effect of curcumin on GADD153. Curcumin-induced GADD153 gene upregulation was attenuated by reduced glutathione (GSH) or N-acetylcysteine (NAC) and potentiated by the glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). Additionally, GSH and NAC decreased the intracellular content of curcumin. Conversely, curcumin decreased intracellular glutathione and also increased the formation of reactive oxygen species (ROS) in cells, but either GSH or NAC prevented both of these effects of curcumin. In affecting the thiol redox status, curcumin caused activation of certain sulfhydryl enzymes involved in signal transduction linked to GADD153 expression. Curcumin increased the expression of the phosphorylated forms of PTK, PDK1, and PKC-delta, which was attenuated by either GSH or NAC and potentiated by BSO. Furthermore, selective inhibitors of PI3K and PKC-delta attenuated curcumin-induced GADD153 upregulation. Collectively, these findings suggest that a regulatory thiol redox-sensitive signaling cascade exists in the molecular pathway leading to induction of GADD153 expression as caused by curcumin.


Teaching pathology via online digital microscopy: positive learning outcomes for rurally based medical students.
Technology has revolutionised teaching. Teaching pathology via digital microscopy (DM) is needed to overcome increasing student numbers, a shortage of pathology academics in regional medical schools, and difficulties with teaching students on rural clinical placement. To identify whether an online DM approach, combining digital pathology software, Web-based slides and classroom management software, delivers effective, practical pathology teaching sessions to medical students located both on campus and on rural placement. An online survey collected feedback from fourth and fifth year undergraduate James Cook University medical students on the importance of 16 listed benefits and challenges of using online DM to teach pathology, via a structured five-point Likert survey. Fifty-three students returned the survey (response rate = 33%). Benefits of online DM to teach pathology rated as 'very important' or 'extremely important' by over 50% of students included: higher quality images; faster learning; more convenient; better technology; everyone sees the same image; greater accessibility; helpful annotations on slides; cost savings; and more opportunity for self-paced learning out-of-hours and for collaborative learning in class. Challenges of online DM rated as 'very important' or 'extremely important' by over 50% of students included: Internet availability in more remote locations and potential problems using online technology during class. Nearly all medical students welcomed learning pathology via online digital technology. DM should improve the quantity, quality, cost and accessibility of pathology teaching by regional medical schools, and has significant implications for the growing emphasis in Australia for decentralised medical education and rural clinical placements.


Bayesian robust principal component analysis.
A hierarchical Bayesian model is considered for decomposing a matrix into low-rank and sparse components, assuming the observed matrix is a superposition of the two. The matrix is assumed noisy, with unknown and possibly non-stationary noise statistics. The Bayesian framework infers an approximate representation for the noise statistics while simultaneously inferring the low-rank and sparse-outlier contributions; the model is robust to a broad range of noise levels, without having to change model hyperparameter settings. In addition, the Bayesian framework allows exploitation of additional structure in the matrix. For example, in video applications each row (or column) corresponds to a video frame, and we introduce a Markov dependency between consecutive rows in the matrix (corresponding to consecutive frames in the video). The properties of this Markov process are also inferred based on the observed matrix, while simultaneously denoising and recovering the low-rank and sparse components. We compare the Bayesian model to a state-of-the-art optimization-based implementation of robust PCA; considering several examples, we demonstrate competitive performance of the proposed model.


Brain Citrullination Patterns and T Cell Reactivity of Cerebrospinal Fluid-Derived CD4+ T Cells in Multiple Sclerosis.
Immune responses to citrullinated peptides have been described in autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). We investigated the post-translational modification (PTM), arginine to citrulline, in brain tissue of MS patients and controls (C) by proteomics and subsequently the cellular immune response of cerebrospinal fluid (CSF)-infiltrating T cells to citrullinated and unmodified peptides of myelin basic protein (MBP). Using specifically adapted tissue extraction- and combined data interpretation protocols we could establish a map of citrullinated proteins by identifying more than 80 proteins with two or more citrullinated peptides in human brain tissue. We report many of them for the first time. For the already described citrullinated proteins MBP, GFAP, and vimentin, we could identify additional citrullinated sites. The number of modified proteins in MS white matter was higher than control tissue. Citrullinated peptides are considered neoepitopes that may trigger autoreactivity. We used newly identified epitopes and previously reported immunodominant myelin peptides in their citrullinated and non-citrullinated form to address the recognition of CSF-infiltrating CD4+ T cells from 22 MS patients by measuring proliferation and IFN-γ secretion. We did not detect marked responses to citrullinated peptides, but slightly more strongly to the non-modified version. Based on these data, we conclude that citrullination does not appear to be an important activating factor of a T cell response, but could be the consequence of an immune- or inflammatory response. Our approach allowed us to perform a deep proteome analysis and opens new technical possibilities to analyze complex PTM patterns on minute quantities of rare tissue samples.


Reporting and evaluating wait times for urgent hip fracture surgery in Ontario, Canada.
Although a delay of 24 hours for hip fracture repair is associated with medical complications and costs, it is unknown how long patients wait for surgery for hip fracture. We describe novel methods for measuring exact urgent and emergent surgical wait times (in hours) and the factors that influence them. Adults aged 45 years and older who underwent surgery for hip fracture (the most common urgently performed procedure) in Ontario, Canada, between 2009 and 2014 were eligible. Validated data from linked health administrative databases were used. The primary outcome was the time elapsed from hospital arrival recorded in the National Ambulatory Care Reporting System until the time of surgery recorded in the Discharge Abstract Database (in hours). The influence of patient, physician and hospital factors on wait times was investigated using 3-level, hierarchical linear regression models. Among 42 230 patients with hip fracture, the mean (SD) wait time for surgery was 38.76 (28.84) hours, and 14 174 (33.5%) patients underwent surgery within 24 hours. Variables strongly associated with delay included time for hospital transfer (adjusted increase of 26.23 h, 95% CI 25.38 to 27.01) and time for preoperative echocardiography (adjusted increase of 18.56 h, 95% CI 17.73 to 19.38). More than half of the hospitals (37 of 72, 51.4%), compared with 4.8% of surgeons and 0.2% of anesthesiologists, showed significant differences in the risk-adjusted likelihood of delayed surgery. Exact wait times for urgent and emergent surgery can be measured using Canada's administrative data. Only one-third of patients received surgery within the safe time frame (24 h). Wait times varied according to hospital and physician factors; however, hospital factors had a larger impact.


Encoding and decoding spikes for dynamic stimuli.
Naturally occurring sensory stimuli are dynamic. In this letter, we consider how spiking neural populations might transmit information about continuous dynamic stimulus variables. The combination of simple encoders and temporal stimulus correlations leads to a code in which information is not readily available to downstream neurons. Here, we explore a complex encoder that is paired with a simple decoder that allows representation and manipulation of the dynamic information in neural systems. The encoder we present takes the form of a biologically plausible recurrent spiking neural network where the output population recodes its inputs to produce spikes that are independently decodeable. We show that this network can be learned in a supervised manner by a simple local learning rule.


SUSTAINED ISOMETRIC SHOULDER CONTRACTION ON MUSCULAR STRENGTH AND ENDURANCE: A RANDOMIZED CLINICAL TRIAL.
The Advanced Throwers Ten Exercise Program incorporates sustained isometric contractions in conjunction with dynamic shoulder movements. It has been suggested that incorporating isometric holds may facilitate greater increases in muscular strength and endurance. However, no objective evidence currently exists to support this claim. The purpose of this research was to compare the effects of a sustained muscle contraction resistive training program (Advanced Throwers Ten Program) to a more traditional exercise training protocol to determine if increases in shoulder muscular strength and endurance occur in an otherwise healthy population. It was hypothesized that utilizing a sustained isometric hold during a shoulder scaption exercise from the Advanced Throwers Ten would produce greater increases in shoulder strength and endurance as compared to a traditional training program incorporating a isotonic scapular plane abduction (scaption) exercise. Randomized Clinical Trial. Fifty healthy participants were enrolled in this study, of which 25 were randomized into the traditional training group (age: 26 ± 8, height:172 ± 10 cm, weight: 73 ± 13 kg, Marx Activity Scale: 11 ± 4) and 25 were randomized to the Advanced Throwers Ten group (age: 28 ± 9, height: 169 ± 23 cm, weight: 74 ± 16 kg, Marx Activity Scale: 11 ± 5). No pre-intervention differences existed between the groups (P>0.05). Arm endurance and strength data were collected pre and post intervention using a portable load cell (BTE Evaluator, Hanover, MD). Both within and between group analyses were done in order to investigate average torque (strength) and angular impulse (endurance) changes. The traditional and Advanced Throwers Ten groups both significantly improved torque and angular impulse on both the dominant and non-dominant arms by 10-14%. There were no differences in strength or endurance following the interventions between the two training groups (p>0.75). Both training approaches increased strength and endurance as the muscle loads were consistent between protocols indicating that either approach will have positive effects. Level 2.


Sex roles and mutual mate choice matter during mate sampling.
The roles of females and males in mating competition and mate choice have lately proven more variable, between and within species, than previously thought. In nature, mating competition occurs during mate search and is expected to be regulated by the numbers of potential mates and same-sex competitors. Here, we present the first study to test how a temporal change in sex roles affects mating competition and mate choice during mate sampling. Our model system (the marine fish Gobiusculus flavescens) is uniquely suitable because of its change in sex roles, from conventional to reversed, over the breeding season. As predicted from sex role theory, courtship was typically initiated by males and terminated by females early in the breeding season. The opposite pattern was observed late in the season, at which time several females often simultaneously courted the same male. Mate-searching females visited more males early than late in the breeding season. Our study shows that mutual mate choice and mating competition can have profound effects on female and male behavior. Future work needs to consider the dynamic nature of mating competition and mate choice if we aim to fully understand sexual selection in the wild.


Anticoagulation for cerebral venous sinus thrombosis.
Treatment of cerebral venous sinus thrombosis with anticoagulants has been controversial. Anticoagulants may prevent new venous infarcts, neurologic deterioration and pulmonary embolism but may also promote haemorrhages. To assess the effectiveness and safety of anticoagulant therapy in patients with confirmed cerebral venous sinus thrombosis. We searched the Cochrane Stroke Group Trials Register (last searched August 2010), MEDLINE (1950 to August 2010), EMBASE (1980 to August 2010) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011 Issue 1). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers and reference lists of relevant articles, and contacted authors. Unconfounded randomised controlled trials in which anticoagulant therapy was compared with placebo or open control in patients with cerebral venous sinus thrombosis (confirmed by intra-arterial contrast, or venography with magnetic resonance, or venography with computed tomography imaging). Two review authors independently extracted outcomes for each of the two treatment groups (anticoagulant treatment and control). The outcome data for each patient were analysed in the treatment group to which the patient was originally allocated (intention-to-treat analysis). We calculated a weighted estimate of the treatment effects across trials (relative risk, absolute risk reduction). We included two small trials involving 79 patients. One trial (20 patients) examined the efficacy of intravenous, adjusted dose unfractionated heparin. The other trial (59 patients) examined high dose, body weight adjusted, subcutaneous, low-molecular weight heparin (nadroparin). Anticoagulant therapy was associated with a pooled relative risk of death of 0.33 (95% confidence interval (CI) 0.08 to 1.21) and of death or dependency of 0.46 (95% CI 0.16 to 1.31). The absolute reduction in the risk of death or dependency was 13% (95% CI 30% to -3%). No new symptomatic intracerebral haemorrhages were observed. One major gastro-intestinal haemorrhage occurred after anticoagulant treatment. Two control patients (placebo) had a diagnosis of probable pulmonary embolism (one fatal). Based upon the limited evidence available, anticoagulant treatment for cerebral venous sinus thrombosis appeared to be safe and was associated with a potentially important reduction in the risk of death or dependency which did not reach statistical significance.


CMOS-compatible dense arrays of Ge quantum dots on the Si(001) surface: hut cluster nucleation, atomic structure and array life cycle during UHV MBE growth.
We report a direct observation of Ge hut nucleation on Si(001) during UHV molecular beam epitaxy at 360°C. Nuclei of pyramids and wedges were observed on the wetting layer (WL) (M × N) patches starting from the coverage of 5.1 Å and found to have different structures. Atomic models of nuclei of both hut species have been built as well as models of the growing clusters. The growth of huts of each species has been demonstrated to follow generic scenarios. The formation of the second atomic layer of a wedge results in rearrangement of its first layer. Its ridge structure does not repeat the nucleus. A pyramid grows without phase transitions. A structure of its vertex copies the nucleus. Transitions between hut species turned out to be impossible. The wedges contain point defects in the upper corners of the triangular faces and have preferential growth directions along the ridges. The derived structure of the {105} facet follows the paired dimer model. Further growth of hut arrays results in domination of wedges, and the density of pyramids exponentially drops. The second generation of huts arises at coverages >10 Å; new huts occupy the whole WL at coverages ~14 Å. Nanocrystalline Ge 2D layer begins forming at coverages >14 Å.


The Potential of the MAGIC TOM Parental Accessions to Explore the Genetic Variability in Tomato Acclimation to Repeated Cycles of Water Deficit and Recovery.
Episodes of water deficit (WD) during the crop cycle of tomato may negatively impact plant growth and fruit yield, but they may also improve fruit quality. Moreover, a moderate WD may induce a plant "memory effect" which is known to stimulate plant acclimation and defenses for upcoming stress episodes. The objective of this study was to analyze the positive and negative impacts of repeated episodes of WD at the plant and fruit levels. Three episodes of WD (-38, -45, and -55% of water supply) followed by three periods of recovery ("WD treatments"), were applied to the eight parents of the Multi-Parent Advanced Generation Inter-Cross population which offers the largest allelic variability observed in tomato. Predawn and midday water potentials, chlorophyll a fluorescence, growth and fruit quality traits [contents in sugars, acids, carotenoids, and ascorbic acid (AsA)] were measured throughout the experiment. Important genotypic variations were observed both at the plant and fruit levels and variations in fruit and leaf traits were found not to be correlated. Overall, the WD treatments were at the origin of important osmotic regulations, reduction of leaf growth, acclimation of photosynthetic functioning, notably through an increase in the chlorophyll content and in the quantum yield of the electron transport flux until PSI acceptors (J 0 (RE1)/J (ABS)). The effects on fruit sugar, acid, carotenoid and AsA contents on a dry matter basis ranged from negative to positive to nil depending on genotypes and stress intensity. Three small fruit size accessions were richer in AsA on a fresh matter basis, due to concentration effects. So, fruit quality was improved under WD mainly through concentration effects. On the whole, two accessions, LA1420 and Criollo appeared as interesting genetic resources, cumulating adaptive traits both at the leaf and fruit levels. Our observations show that the complexity involved in plant responses, when considering a broad range of physiological traits and the variability of genotypic effects, represent a true challenge for upcoming studies aiming at taking advantage of, not just dealing with WD.


Evolution of the Rdr1 TNL-cluster in roses and other Rosaceous species.
The resistance of plants to pathogens relies on two lines of defense: a basal defense response and a pathogen-specific system, in which resistance (R) genes induce defense reactions after detection of pathogen-associated molecular patterns (PAMPS). In the specific system, a so-called arms race has developed in which the emergence of new races of a pathogen leads to the diversification of plant resistance genes to counteract the pathogens' effect. The mechanism of resistance gene diversification has been elucidated well for short-lived annual species, but data are mostly lacking for long-lived perennial and clonally propagated plants, such as roses. We analyzed the rose black spot resistance gene, Rdr1, in five members of the Rosaceae: Rosa multiflora, Rosa rugosa, Fragaria vesca (strawberry), Malus x domestica (apple) and Prunus persica (peach), and we present the deduced possible mechanism of R-gene diversification. We sequenced a 340.4-kb region from R. rugosa orthologous to the Rdr1 locus in R. multiflora. Apart from some deletions and rearrangements, the two loci display a high degree of synteny. Additionally, less pronounced synteny is found with an orthologous locus in strawberry but is absent in peach and apple, where genes from the Rdr1 locus are distributed on two different chromosomes. An analysis of 20 TIR-NBS-LRR (TNL) genes obtained from R. rugosa and R. multiflora revealed illegitimate recombination, gene conversion, unequal crossing over, indels, point mutations and transposable elements as mechanisms of diversification.A phylogenetic analysis of 53 complete TNL genes from the five Rosaceae species revealed that with the exception of some genes from apple and peach, most of the genes occur in species-specific clusters, indicating that recent TNL gene diversification began prior to the split of Rosa from Fragaria in the Rosoideae and peach from apple in the Spiraeoideae and continued after the split in individual species. Sequence similarity of up to 99% is obtained between two R. multiflora TNL paralogs, indicating a very recent duplication. The mechanisms by which TNL genes from perennial Rosaceae diversify are mainly similar to those from annual plant species. However, most TNL genes appear to be of recent origin, likely due to recent duplications, supporting the hypothesis that TNL genes in woody perennials are generally younger than those from annuals. This recent origin might facilitate the development of new resistance specificities, compensating for longer generation times in woody perennials.


MSM: a new flexible framework for Multimodal Surface Matching.
Surface-based cortical registration methods that are driven by geometrical features, such as folding, provide sub-optimal alignment of many functional areas due to variable correlation between cortical folding patterns and function. This has led to the proposal of new registration methods using features derived from functional and diffusion imaging. However, as yet there is no consensus over the best set of features for optimal alignment of brain function. In this paper we demonstrate the utility of a new Multimodal Surface Matching (MSM) algorithm capable of driving alignment using a wide variety of descriptors of brain architecture, function and connectivity. The versatility of the framework originates from adapting the discrete Markov Random Field (MRF) registration method to surface alignment. This has the benefit of being very flexible in the choice of a similarity measure and relatively insensitive to local minima. The method offers significant flexibility in the choice of feature set, and we demonstrate the advantages of this by performing registrations using univariate descriptors of surface curvature and myelination, multivariate feature sets derived from resting fMRI, and multimodal descriptors of surface curvature and myelination. We compare the results with two state of the art surface registration methods that use geometric features: FreeSurfer and Spherical Demons. In the future, the MSM technique will allow explorations into the best combinations of features and alignment strategies for inter-subject alignment of cortical functional areas for a wide range of neuroimaging data sets.


Wound-healing properties of nut oil from Pouteria lucuma.
Cell migration, angiogenesis, inflammation, and extracellular matrix remodeling are key events in wound healing. Natural products, including fatty acids (FAs), can accelerate wound healing by modulating the aforementioned events. This study aims to evaluate the effect of lucuma (Pouteria lucuma O Kezte) nut oil (LNO) on fibroblasts migration, angiogenesis, inflammation, bacterial and fungal growth, and wound healing. Methods GC-MS analysis of FAs methyl esters (FAMES) was used for chemical characterization of LNO. In vitro studies were carried out with LNO investigating the induction of cell migration, cytoskeleton remodeling of human fibroblasts, inhibition of LPS-induced nitric oxide production in macrophages, and antibacterial and antifungal effects. Two in vivo studies were carried out to study LNO's effect on angiogenesis and wound healing: (i) tail fin regeneration in transgenic zebrafish larvae expressing enhanced green fluorescent protein (EGFP) in vascular endothelial cells was used to study vessel sprouting and wound healing and (ii) the closure of wounds was evaluated in CD-1 mice after topical applications of LNO-containing formulations. Lucuma nut oil is a mixture of FAs, 99.7% of which were characterized. Major components of LNO (w/w) are linoleic acid (38.9%), oleic acid (27.9%), palmitic acid (18.6%), stearic acid (8.9%), and γ linolenic acid (2.9%). In vitro studies showed that LNO significantly promoted migration and vinculin expression in human fibroblasts. LNO decreased LPS-induced nitric oxide production and did not display significant antibacterial or antifungal effects. LNO induced tail fin regeneration in transgenic zebrafish larvae 48 h after tail fin amputation and significantly accelerated cutaneous wound closure in CD-1 mice. Natural FAs from P. lucuma nut promote skin regeneration and, thus, may have applications in medicine and skin care.


Recent advances in managing HIV-associated cryptococcal meningitis.
The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in cryptococcal meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated cryptococcal meningitis.


Surgery for patients with drug-resistant tuberculosis: report of 121 cases receiving community-based treatment in Lima, Peru.
While most patients with tuberculosis (TB) can be successfully treated using short-course medical chemotherapy, thoracic surgery is an important adjunctive strategy for many patients with drug-resistant disease. The need for physical, technical and financial resources presents a potential challenge to implementing surgery as a component of treatment for multidrug-resistant TB (MDR-TB) in resource-poor settings. However, a cohort of patients with severe MDR-TB in Lima, Peru underwent surgery as part of their treatment. 121 patients underwent pulmonary surgery for drug-resistant tuberculosis between May 1999 and January 2004. Surgery was performed by a team of thoracic surgeons under the Ministry of Health. Patient demographic data, clinical characteristics, surgical procedures and surgical outcomes were studied. Most of the patients had failed multiple TB regimens and were resistant to a median of seven drugs. The median time of follow-up after surgery was 33 months. 79.3% of patients were culture-positive before surgery, and sustained culture-negative status among survivors was achieved in 74.8% of patients. 63% of those followed up for at least 6 months after surgery were either cured or probably cured. Postoperative complications, observed in 22.6% of patients, were associated with preoperative haemoptysis, vital capacity <50% and low forced expiratory volume in 1 s. This is one of the largest cohorts with MDR-TB to be treated with surgery, and the first from a resource-poor country. Although surgery is not often considered an option for patients in resource-poor settings, the findings of this study support the argument that adjunctive surgery should be considered an integral component of MDR-TB treatment programmes, even in poor countries such as Peru.


Nonvasculitic autoimmune inflammatory meningoencephalitis.
Caselli and colleagues described five cases with encephalopathy, progressive cognitive decline, ataxia, abnormal CSF studies and steroid responsiveness, and proposed the term non-vasculitic autoimmune inflammatory meningoencephalitis (NAIM). Many of these cases had brain biopsy showing mild leptomeningeal perivascular lymphocytic inflammation, however, none of the cases had a post-mortem. Nonvasculitic autoimmune mediated meningoencephalitis has been described in patients with Sjogren's syndrome, systemic lupus erythematosus and, more recently, with Hashimoto's disease. The present study is the first post-mortem report of a case with a clinical diagnosis of NAIM. Neuropathological examination revealed a panencephalitis with intact vessel walls. T and B immunostaining showed a mixture of T and B cells. The findings were not consistent with other reported findings in collagen vascular diseases including Sjogren's syndrome, CNS vasculitis or Hashimoto's encephalopathy. There was no evidence of neoplasia, bacteria, acid-fast bacilli, fungi or atypical infectious agents. This is the first post-mortem report of a case with a clinical diagnosis of NAIM and demonstrates a panencephalitis without evidence of a vasculitis. The pathology seems unique, however, Sjogren and Hashimoto's encephalopathy might be variants of NAIM.


Rutin-Enriched Extract from Coriandrum sativum L. Ameliorates Ionizing Radiation-Induced Hematopoietic Injury.
Hematopoietic injury is a major cause of mortality in radiation accidents and a primary side effect in patients undergoing radiotherapy. Ionizing radiation (IR)-induced myelosuppression is largely attributed to the injury of hematopoietic stem and progenitor cells (HSPCs). Coriander is a culinary herb with multiple pharmacological effects and has been widely used in traditional medicine. In this study, flavonoids were identified as the main component of coriander extract with rutin being the leading compound (rutin-enriched coriander extract; RE-CE). We evaluated the radioprotective effect of RE-CE against IR-induced HSPCs injury. Results showed that RE-CE treatment markedly improved survival, ameliorated organ injuries and myelosuppression, elevated HSPCs frequency, and promoted differentiation and proliferation of HSPCs in irradiated mice. The protective role of RE-CE in hematopoietic injury is probably attributed to its anti-apoptotic and anti-DNA damage effect in irradiated HSPCs. Moreover, these changes were associated with reduced reactive oxygen species (ROS) and enhanced antioxidant enzymatic activities in irradiated HSPCs. Collectively, these findings demonstrate that RE-CE is able to ameliorate IR-induced hematopoietic injury partly by reducing IR-induced oxidative stress.


Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS).
Cardiac troponins and natriuretic peptides are established for risk stratification in light-chain amyloidosis. Data on cardiac biomarkers in transthyretin amyloidosis (ATTR) are lacking. Patients (n = 1617) with any of the following cardiac biomarkers, BNP (n = 1079), NT-proBNP (n = 550), troponin T (n = 274), and troponin I (n = 108), available at baseline in the Transthyretin Amyloidosis Outcomes Survey (THAOS) were analyzed for differences between genotypes and phenotypes and their association with survival. Median level of BNP was 68.0 pg/mL (IQR 30.5-194.9), NT-proBNP 337.9 pg/mL (IQR 73.0-2584.0), troponin T 0.03 μg/L (IQR 0.01-0.05), and troponin I 0.08 μg/L (IQR 0.04-0.13). NT-proBNP and BNP were higher in wild-type than mutant-type ATTR, troponin T and I did not differ, respectively. Non-Val30Met patients had higher BNP, NT-proBNP and troponin T levels than Val30Met patients, but not troponin I. Late-onset Val30Met was associated with higher levels of troponin I and troponin T compared with early-onset. 115 patients died during a median follow-up of 1.2 years. Mortality increased with increasing quartiles (BNP/NT-proBNP Q1 = 1.7%, Q2 = 5.2%, Q3 = 21.7%, Q4 = 71.3%; troponin T/I Q1 = 6.5%, Q2 = 14.5%, Q3 = 33.9%, Q4 = 45.2%). Three-year overall-survival estimates for BNP/NT-proBNP and troponin T/I quartiles differed significantly (p<0.001). Stepwise risk stratification was achieved by combining NT-proBNP/BNP and troponin T/I. From Cox proportional hazards model, age, modified body mass index, mutation (Val30Met vs. Non-Val30Met) and BNP/NT-proBNP (Q1-Q3 pooled vs. Q4) were identified as independent predictors of survival in patients with mutant-type ATTR. In this ATTR patient cohort, cardiac biomarkers were abnormal in a substantial percentage of patients irrespective of genotype. Along with age, mBMI, and mutation (Val30Met vs. Non-Val30Met), cardiac biomarkers were associated with surrogates of disease severity with BNP/NT-proBNP identified as an independent predictor of survival in ATTR. ClinicalTrials.gov NCT00628745.


Utilization of HER2 genetic testing in a multi-institutional observational study.
Human epidermal growth factor receptor 2 (HER2) expression is amplified in about 20% of breast cancer tumors, and evaluation of HER2 status should influence therapy selection. A critical gap in our knowledge is the real-world implementation of HER2 testing and its impact on treatment decisions for women diagnosed with breast cancer. To assess use of HER2 testing, to describe characteristics of patients who do or do not receive HER2 testing, to describe which HER2 tests were used (fluorescence in situ hybridization or immunohistochemistry), and to evaluate trastuzumab use as a function of HER2 results. The population included 6460 women diagnosed with invasive breast cancer between 1999 and 2007 at 8 geographically distributed Cancer Research Network healthcare delivery systems in the United States. Electronic records were used to identify patient and tumor characteristics and treatment with trastuzumab. Chart abstraction was performed for 400 women (50 per site) to identify receipt of HER2 testing and results. More than 90% of study participants received HER2 testing. Everyone who received trastuzumab had a HER2 test, and nearly all (>95%) who received trastuzumab had a positive HER2 test result recorded in their medical chart. Most (77%) eligible patients with a positive HER2 test result diagnosed after 2005 received trastuzumab. This study expands upon previous work in individual health plans. HER2 status has been successfully incorporated into medical practice to guide treatment decisions for breast cancer patients in diverse integrated healthcare delivery settings.


Bilateral iliopsoas muscle contracture and spinous process impingement in a German Shepherd dog.
To report diagnosis and treatment of bilateral iliopsoas muscle contracture in a dog with spinous process impingement. Case report. German Shepherd dog. A dog with chronic progressive lameness, flexion contracture of the coxofemoral joints, severe pain, and decreased femoral reflexes had severe spondylosis bridging the vertebral bodies from L1 to L4 and enlarged dorsal spinous processes from T8 to L6 with impingement and bony proliferation. Ultrasonographic and magnetic resonance imaging (MRI) findings were consistent with fibrosis, mineralization, and atrophy of the iliopsoas muscles bilaterally which was treated by staged tenectomy of the insertions of the iliopsoas muscles. Because of severe perivascular fibrosis, the femoral vessels required ligation. Bilateral iliopsoas muscle tenectomy improved gait and provided pain relief. Histologic findings were consistent with fibrotic myopathy. Slow progression of severe clinical signs observed bilaterally in this dog differs from previous reports of iliopsoas myopathy. Findings were similar to the fibrotic myopathy of the gracilis or semitendinosus muscles described in dogs. Iliopsoas muscle abnormalities should be considered in dogs with limited hip extension and pain. MRI is useful for diagnosing muscle fibrosis. Iliopsoas tenectomy may improve clinical function in dogs with fibrotic myopathy.


Human coronaviruses: insights into environmental resistance and its influence on the development of new antiseptic strategies.
The Coronaviridae family, an enveloped RNA virus family, and, more particularly, human coronaviruses (HCoV), were historically known to be responsible for a large portion of common colds and other upper respiratory tract infections. HCoV are now known to be involved in more serious respiratory diseases, i.e. bronchitis, bronchiolitis or pneumonia, especially in young children and neonates, elderly people and immunosuppressed patients. They have also been involved in nosocomial viral infections. In 2002-2003, the outbreak of severe acute respiratory syndrome (SARS), due to a newly discovered coronavirus, the SARS-associated coronavirus (SARS-CoV); led to a new awareness of the medical importance of the Coronaviridae family. This pathogen, responsible for an emerging disease in humans, with high risk of fatal outcome; underline the pressing need for new approaches to the management of the infection, and primarily to its prevention. Another interesting feature of coronaviruses is their potential environmental resistance, despite the accepted fragility of enveloped viruses. Indeed, several studies have described the ability of HCoVs (i.e. HCoV 229E, HCoV OC43 (also known as betacoronavirus 1), NL63, HKU1 or SARS-CoV) to survive in different environmental conditions (e.g. temperature and humidity), on different supports found in hospital settings such as aluminum, sterile sponges or latex surgical gloves or in biological fluids. Finally, taking into account the persisting lack of specific antiviral treatments (there is, in fact, no specific treatment available to fight coronaviruses infections), the Coronaviridae specificities (i.e. pathogenicity, potential environmental resistance) make them a challenging model for the development of efficient means of prevention, as an adapted antisepsis-disinfection, to prevent the environmental spread of such infective agents. This review will summarize current knowledge on the capacity of human coronaviruses to survive in the environment and the efficacy of well-known antiseptic-disinfectants against them, with particular focus on the development of new methodologies to evaluate the activity of new antiseptic-disinfectants on viruses.


The experiences of working carers of older people regarding access to a web-based family care support network offered by a municipality.
Policy makers in Sweden and other European Member States pay increasing attention as to how best support working carers; carers juggling providing unpaid family care for older family members while performing paid work. Exploring perceived benefits and challenges with web-based information and communication technologies as a means of supporting working carers' in their caregiving role, this paper draws on findings from a qualitative study. The study aimed to describe working carers' experiences of having access to the web-based family care support network 'A good place' (AGP) provided by the municipality to support those caring for an older family member. Content analysis of interviews with nine working carers revealed three themes: A support hub, connections to peers, personnel and knowledge; Experiencing ICT support as relevant in changing life circumstances; and Upholding one's personal firewall. Findings indicate that the web-based family care support network AGP is an accessible, complementary means of support. Utilising support while balancing caregiving, work obligations and responsibilities was made easier with access to AGP; enabling working carers to access information, psychosocial support and learning opportunities. In particular, it provided channels for carers to share experiences with others, to be informed, and to gain insights into medical and care issues. This reinforced working carers' sense of competence, helping them meet caregiving demands and see positive aspects in their situation. Carers' low levels of digital skills and anxieties about using computer-based support were barriers to utilising web-based support and could lead to deprioritising of this support. However, to help carers overcome these barriers and to better match web-based support to working carers' preferences and situations, web-based support must be introduced in a timely manner and must more accurately meet each working carer's unique caregiving needs.


Suitability Analysis and Projected Climate Change Impact on Banana and Coffee Production Zones in Nepal.
The Government of Nepal has identified opportunities in agricultural commercialization, responding to a growing internal demand and expansion of export markets to reduce the immense trade deficit. Several cash crops, including coffee and bananas, have been identified in the recently approved Agriculture Development Strategy. Both of these crops have encouraged smallholder farmers to convert their subsistence farming practices to more commercial cultivation. Identification of suitable agro-ecological zones and understanding climate-related issues are important for improved production and livelihoods of smallholder farmers. Here, the suitability of coffee and banana crops is analyzed for different agro-ecological zones represented by Global Environmental Stratification (GEnS). Future shifts in these suitability zones are also predicted. Plantation sites in Nepal were geo-referenced and used as input in species distribution modelling. The multi-model ensemble model suggests that climate change will reduce the suitable growing area for coffee by about 72% across the selected emission scenarios from now to 2050. Impacts are low for banana growing, with a reduction in suitability by about 16% by 2050. Bananas show a lot of potential for playing an important role in Nepal as a sustainable crop in the context of climate change, as this study indicates that the amount of area suited to banana growing will grow by 40% by 2050. Based on our analysis we recommend possible new locations for coffee plantations and one method for mitigating climate change-related problems on existing plantations. These findings are expected to support planning and policy dialogue for mitigation and support better informed and scientifically based decision-making relating to these two crops.


Tiresias: A low-cost networked UWB radar system for in-home monitoring of dementia patients.
This paper describes Tiresias, a low-cost, unobtrusive networked radar system designed to monitor vulnerable patients in domestic environments and provide high quality behavioural and health data. Dementia is a disease that affects millions worldwide and progressively degrades an individual's ability to care for themselves. Eventually most people living with dementia will need to reside in assisted living facilities as they become unable to care for themselves. Understanding the effects dementia has on ability to self-care and extending the length of time people living with dementia can remain living independently are key goals of dementia research and care. The networked radar system proposed in this paper is designed to provide high quality behavioural and health data from domestic environments. This is achieved using multiple radar sensors networked together with their data outputs integrated and processed to produce high confidence measures of position and movement. It is hoped the data produced by this system will both provide insights into how dementia progresses, and also help monitor vulnerable individuals in their own homes, allowing them to remain independent longer than would otherwise be possible.


Clinical and Patient-reported Outcome Measures in Men Referred for Consideration of Surgery to Treat Lower Urinary Tract Symptoms: Baseline Results and Diagnostic Findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM).
Clinical evaluation of male lower urinary tract symptoms (MLUTS) in secondary care uses a range of assessments. It is unknown how MLUTS evaluation influences outcome of therapy recommendations and choice, notably urodynamics (UDS; filling cystometry and pressure flow studies). To report participants' sociodemographic and clinical characteristics, and initial diagnostic findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM). UPSTREAM is a randomised controlled trial evaluating whether symptoms are noninferior and surgery rates are lower if UDS is included. A total of 820 men (≥18 yr of age) seeking treatment for bothersome LUTS were recruited from 26 National Health Service hospital urology departments. Care pathway based on routine, noninvasive tests (control) or routine care plus UDS (intervention arm). The primary outcome is International Prostate Symptom Score (IPSS) and the key secondary outcome is surgery rates 18 mo after randomisation. International Consultation on Incontinence Questionnaires were captured for MLUTS, sexual function, and UDS satisfaction. Baseline clinical and patient-reported outcome measures (PROMs), and UDS findings were informally compared between arms. Trends across age groups for urinary and sexual PROMs were evaluated with a Cuzick's test, and questionnaire items were compared using Pearson's correlation coefficient. Storage LUTS, notably nocturia, and impaired sexual function are prominent in men being assessed for surgery. Sociodemographic and clinical evaluations were similar between arms. Overall mean IPSS and quality of life scores were 18.94 and 4.13, respectively. Trends were found across age groups, with older men suffering from higher rates of incontinence, nocturia, and erectile dysfunction, and younger men suffering from increased daytime frequency and voiding symptoms. Men undergoing UDS testing expressed high satisfaction with the procedure. Men being considered for surgery have additional clinical features that may affect treatment decision making and outcomes, notably storage LUTS and impaired sexual function. We describe initial assessment findings from a large clinical study of the treatment pathway for men suffering with bothersome urinary symptoms who were referred to hospital for further treatment, potentially including surgery. We report the patient characteristics and diagnostic test results, including symptom questionnaires, bladder diaries, flow rate tests, and urodynamics.


A global perspective of radiation-induced signal transduction pathways in cancer therapeutics.
Radiation is a well established therapeutic modality for the treatment of solid tumors. By merging molecular biological approaches with radiation biology, a significant number of signaling events elicited by ionizing radiation have been delineated. These signaling pathways include events leading to cell cycle arrest, apoptosis or cell survival. There are two major signaling events that affect radiation response. One is the intrinsic/constitutive pro-survival signaling event that is present in proliferating tumor cells while the other is "induced pro-survival event" in response to radiation, both of these events confer resistance to the killing effects of radiation. In this review, signaling pathways that lead to either apoptosis or survival of cells following ionizing radiation are discussed in detail. In addition, mechanisms of action for gene/drug based inhibitors that modulate the expression and function of various genes and gene products involved in pro-survival signaling pathways are described. Further, novel strategies to abrogate the "induced radiation resistance" leading to enhanced therapeutic efficacy of ionizing radiation have been proposed. These novel strategies include the use of radio-gene therapy, low dose fractionated radiation therapy as a chemopotentiator and therapeutic utility of high radiation dose induced bystander effect. The complete understanding of the molecular pathways leading to apoptosis/survival of cells following ionizing radiation will help in tailoring more effective novel strategies and treatment modalities for complete eradication of cancer.


Studies of the mechanistic details of the pH-dependent association of botulinum neurotoxin with membranes.
Botulinum neurotoxin (BoNT) belongs to a large class of toxic proteins that act by enzymatically modifying cytosolic substrates within eukaryotic cells. The process by which a catalytic moiety is transferred across a membrane to enter the cytosol is not understood for any such toxin. BoNT is known to form pH-dependent pores important for the translocation of the catalytic domain into the cytosol. As a first step toward understanding this process, we investigated the mechanism by which the translocation domain of BoNT associates with a model liposome membrane. We report conditions that allow pH-dependent proteoliposome formation and identify a sequence at the translocation domain C terminus that is protected from proteolytic degradation in the context of the proteoliposome. Fluorescence quenching experiments suggest that residues within this sequence move to a hydrophobic environment upon association with liposomes. EPR analyses of spin-labeled mutants reveal major conformational changes in a distinct region of the structure upon association and indicate the formation of an oligomeric membrane-associated intermediate. Together, these data support a model of how BoNT orients with membranes in response to low pH.


Radical Generation from the Gas-Phase Activation of Ionized Lipid Ozonides.
Reaction products from the ozonolysis of unsaturated lipids at gas-liquid interfaces have the potential to significantly influence the chemical and physical properties of organic aerosols in the atmosphere. In this study, the gas-phase dissociation behavior of lipid secondary ozonides is investigated using ion-trap mass spectrometry. Secondary ozonides were formed by reaction between a thin film of unsaturated lipids (fatty acid methyl esters or phospholipids) with ozone before being transferred to the gas phase as [M + Na]+ ions by electrospray ionization. Activation of the ionized ozonides was performed by either energetic collisions with helium buffer-gas or laser photolysis, with both processes yielding similar product distributions. Products arising from the decomposition of the ozonides were characterized by their mass-to-charge ratio and subsequent ion-molecule reactions. Product assignments were rationalized as arising from initial homolysis of the ozonide oxygen-oxygen bond with subsequent decomposition of the nascent biradical intermediate. In addition to classic aldehyde and carbonyl oxide-type fragments, carbon-centered radicals were identified with a number of decomposition pathways that indicated facile unimolecular radical migration. These findings reveal that photoactivation of secondary ozonides formed by the reaction of aerosol-bound lipids with tropospheric ozone may initiate radical-mediated chemistry within the particle resulting in surface modification. Graphical Abstract .


Cost-effectiveness of diagnostic strategies prior to carotid endarterectomy.
The main objective of this study was to assess the long-term cost-effectiveness of five alternative diagnostic strategies for identification of severe carotid stenosis in recently symptomatic patients. A decision-analytical model with Markov transition states was constructed. Data sources included a prospective study involving 167 patients who had screening Doppler ultrasound (DUS), confirmatory contrast-enhanced magnetic resonance angiography (CEMRA) and confirmatory digital subtraction angiography (DSA), individual patient data from the European Carotid Surgery Trial and other published clinical and cost data. A "selective" strategy, whereby all patients receive DUS and CEMRA (only proceeding to DSA if the CEMRA is positive and the DUS is negative), was most cost-effective. This was both the cheapest imaging and treatment strategy (35,205 dollars per patient) and yielded 6.1590 quality-adjusted life years (QALYs), higher than three alternative imaging strategies. Probabilistic sensitivity analysis demonstrated that there was less than a 10% probability that imaging with either DUS or DSA alone are cost-effective at the conventional 50,000 dollars/QALY threshold. In conclusion, DSA is not cost-effective in the routine diagnostic workup of most patients. DUS, with additional imaging in the form of CEMRA, is recommended, with a strategy of "CEMRA and selective DUS review" being shown to be the optimal imaging strategy.


A functional chaperone triad on the yeast ribosome.
The chaperones RAC (ribosome-associated complex), consisting of Ssz1p and zuotin, and Ssb1/2p are associated with ribosomes of yeast. Ssb1/2p was previously shown to form a crosslink product to polypeptides trapped in ribosome-nascent chain complexes (RNCs) in vitro. Here we show that an efficient crosslink of the nascent chain to Ssb1/2p depends on the presence of functional RAC. The crosslink to Ssb1/2p was significantly diminished if (i) RAC was removed from RNCs: a process reversed by addition of purified RAC; (ii) RAC carried a mutation in the J-domain of zuotin, leading to its inactivation in vivo; (iii) RAC's Ssz1p subunit was absent because RNCs were generated in a Deltassz1-derived translation extract. In vivo the same specific set of growth defects caused by the absence of any of the three chaperones was also displayed by a Deltassb1/2Deltassz1Deltazuo1 strain. The combination of in vitro and in vivo data supports a model in which Ssb1/2p, Ssz1p, and zuotin act in concert on nascent chains while they are being synthesized.


Piriformis electromyography activity during prone and side-lying hip joint movement.
[Purpose] To measure electromyographic activity of the piriformis using fine-wire electrodes during 7 hip movements. [Subjects and Methods] Eleven healthy men, without severe low back pain or lower limb injury, participated in this study. Fine-wire electrodes were inserted into the piriformis and surface electrodes were attached to the muscles in the hip region and the trunk muscles on the dominant arm side. Electromyographic signal amplitude was measured during 7 hip movements: side-lying external rotation in hip neutral position, side-lying abduction in hip neutral position, side-lying abduction in hip external rotation, side-lying abduction in hip internal rotation, prone extension in hip neutral position, prone extension in hip external rotation, and prone extension in hip internal rotation. Repeated-measures one-way analysis of variance was used to examine electromyographic activity in each of the 7 hip movements. [Results] Piriformis electromyographic activity was highest during prone hip extension in external rotation. Both the superior and inferior portions of the gluteus maximus were also highly activated during prone hip extension in external rotation. [Conclusion] Prone hip extension in external rotation induced high electromyographic activity in the piriformis and superior and inferior gluteus maximus muscles.


A prospective study of the responsiveness of depression and suicidal ideation in acne patients to different phases of isotretinoin therapy.
The degree and manner to which isotretinoin affects the mental health of acne patients has not been extensively researched, despite reports of possible associations between isotretinoin and depression. In this study, 33 patients with acne were prescribed a standard 16-week treatment regime with isotretinoin. At the initiation of isotretinoin treatment, week 8 review and termination of treatment, patients completed validated measures of depression, hopelessness and self-rated dermatological severity and were also assessed dermatologically using an acne grading protocol. When the first phase of isotretinoin treatment (week 1 to week 8) was compared to the second phase (week 9 to week 16), patients reported significant improvements in the cognitive-affective features of depression during the first phase of treatment, but not during the second phase. Corresponding improvements in the somatic symptoms of depression and hopelessness were not found. The implications of the research are discussed in relation to methodological design issues in this area.


Plasma proteome profiling of freshwater and seawater life stages of rainbow trout (Oncorhynchus mykiss).
The sea-run phenotype of rainbow trout (Oncorhynchus mykiss), like other anadromous salmonids, present a juvenile stage fully adapted to life in freshwater known as parr. Development in freshwater is followed by the smolt stage, where preadaptations needed for seawater life are developed making fish ready to migrate to the ocean, after which event they become post-smolts. While these three life stages have been studied using a variety of approaches, proteomics has never been used for such purpose. The present study characterised the blood plasma proteome of parr, smolt and post-smolt rainbow trout using a gel electrophoresis liquid chromatography tandem mass spectrometry approach alone or in combination with low-abundant protein enrichment technology (combinatorial peptide ligand library). In total, 1,822 proteins were quantified, 17.95% of them being detected only in plasma post enrichment. Across all life stages, the most abundant proteins were ankyrin-2, DNA primase large subunit, actin, serum albumin, apolipoproteins, hemoglobin subunits, hemopexin-like proteins and complement C3. When comparing the different life stages, 17 proteins involved in mechanisms to cope with hyperosmotic stress and retinal changes, as well as the downregulation of nonessential processes in smolts, were significantly different between parr and smolt samples. On the other hand, 11 proteins related to increased growth in post-smolts, and also related to coping with hyperosmotic stress and to retinal changes, were significantly different between smolt and post-smolt samples. Overall, this study presents a series of proteins with the potential to complement current seawater-readiness assessment tests in rainbow trout, which can be measured non-lethally in an easily accessible biofluid. Furthermore, this study represents a first in-depth characterisation of the rainbow trout blood plasma proteome, having considered three life stages of the fish and used both fractionation alone or in combination with enrichment methods to increase protein detection.


Delta neutrophil index as a prognostic marker of early mortality in gram negative bacteremia.
Sepsis is a syndrome that results in high morbidity and mortality. We investigated the delta neutrophil index (DN) as a predictive marker of early mortality in patients with gram-negative bacteremia. We conducted a retrospective study at a tertiary referral hospital in South Korea from November 2010 to March 2011. The DN was measured at onset of bacteremia and 24 hours and 72 hours later. The DN was calculated using an automatic hematology analyzer. Factors associated with 10-day mortality were assessed using logistic regression. A total of 172 patients with gram-negative bacteremia were included in the analysis; of these, 17 patients died within 10 days of bacteremia onset. In multivariate analysis, Sequental organ failure assessment scores (odds ratio [OR]: 2.24, 95% confidence interval [CI]: 1.31 to 3.84; P = 0.003), DN-day 1 ≥ 7.6% (OR: 305.18, 95% CI: 1.73 to 53983.52; P = 0.030) and DN-day 3 ≥ DN-day 1 (OR: 77.77, 95% CI: 1.90 to 3188.05; P = 0.022) were independent factors associated with early mortality in gram-negative bacteremia. Of four multivariate models developed and tested using various factors, the model using both DN-day 1 ≥ 7.6% and DN-day 3 ≥ DN-day 1 was most predictive early mortality. DN may be a useful marker of early mortality in patients with gram-negative bacteremia. We found both DN-day 1 and DN trend to be significantly associated with early mortality.


A Degree-Day Model for the Latent Period of Stagonospora nodorum Blotch in Winter Wheat.
Stagonospora nodorum blotch (SNB), which is caused by Stagonospora nodorum, occurs frequently in the southeastern United States, and severe epidemics can lead to substantial yield losses. To develop a model for the progress of SNB based on the effects of temperature on the latent period of the pathogen, batches of two winter wheat cultivars, AGS 2000 and USG 3209, were inoculated with S. nodorum at weekly intervals for 16 weeks. After 72 h of incubation, inoculated plants were exposed to outdoor conditions where temperatures ranged from -6.6 to 35.8°C, with a mean batch temperature ranging from 9.7 to 24.7°C. Latent period, expressed as time from inoculation until the first visible lesions with pycnidia, ranged from 13 to 34 days. The relationship between the inverse of the latent period and mean temperature was best described by a linear model, and the estimated thermal time required for the completion of the latent period was 384.6 degree-days. A shifted cumulative gamma distribution model with a base temperature of 0.5°C significantly (P < 0.0001) described the relationship between increasing number of lesions with pycnidia and accumulated thermal time. When latent period was defined as time to 50% of the maximum number of lesions with pycnidia (L50), the model estimated L50 as 336 and 326 degree-days above 0.5°C for AGS 2000 and USG 3209, respectively. The relationship between 1/L50 and mean temperature was also best described using a linear model (r2 = 0.93, P < 0.001). This study provides data that link disease progress with wheat growth, which facilitates accurate identification of thresholds for timing of fungicide applications.


Sexual-risk behaviour, self-perceived risk and knowledge of sexually transmissible infections among young Australians attending a music festival.
Prevalences of sexually transmissible infections (STI), unsafe sex and abortions are increasing in Australia and people aged 16 to 29 are particularly at risk. We conducted a survey of behaviour, knowledge and perceptions of STI risk among young people attending a longstanding annual music festival called the Big Day Out. A structured questionnaire was administered to a cross-sectional sample of people aged 16 to 29 years attending a music festival (Big Day Out). Completed questionnaires were collected from 939 participants (507 females, 432 males) whose median age was 20 years. Of the participants, 751 (80%) had ever had vaginal or anal sex. In the previous year, 48% had multiple partners and in the past 3 months 66% had a new partner. Of these, 224 (39%; 30% of those who had ever had sex) did not use condoms all or most of the time and were classified as being at risk of STI; however, only 24% of those so classified perceived that they were at risk of an STI. In total, 43% of all sexually experienced participants had not used a condom because they reported being drunk or high at the time. STI knowledge was poor overall and male participants, those living in non-metropolitan regions, those under the age of 20 and those with less schooling scored relatively poorly. Our data suggest that young men and women who attend the Big Day Out are sexually active young adults with limited knowledge of STI and blood-borne viruses who regularly engage in behaviours that put them at risk of infection.


Prolonged grief disorder: clinical utility of ICD-11 diagnostic guidelines.
The World Health Organization (WHO) International Classification of Disease (ICD-11) is expected to include a new diagnosis for prolonged grief disorder (ICD-11PGD). This study examines the validity and clinical utility of the ICD-11PGD guideline by testing its performance in a well-characterized clinical sample and contrasting it with a very different criteria set with the same name (PGDPLOS). We examined data from 261 treatment-seeking participants in the National Institute of Mental Health (NIMH)-sponsored multicenter clinical trial to determine the rates of diagnosis using the ICD-11PGD guideline and compared these with diagnosis using PGDPLOS criteria. The ICD-11PGD guideline identified 95.8% [95% confidence interval (CI) 93.3-98.2%] of a treatment-responsive cohort of patients with distressing and impairing grief. PGDPLOS criteria identified only 59.0% (95% CI 53.0-65.0%) and were more likely to omit those who lost someone other than a spouse, were currently married, bereaved by violent means, or not diagnosed with co-occurring depression. Those not diagnosed by PGDPLOS criteria showed the same rate of treatment response as those who were diagnosed. The ICD-11PGD diagnostic guideline showed good performance characteristics in this sample, while PGDPLOS criteria did not. Limitations of the research sample used to derive PGDPLOS criteria may partly explain their poor performance in a more diverse clinical sample. Clinicians and researchers need to be aware of the important difference between these two identically named diagnostic methods.


On the hormonal control of posterior regeneration in the annelid Platynereis dumerilii.
Regeneration is the process by which many animals are able to restore lost or injured body parts. After amputation of the posterior part of its body, the annelid Platynereis dumerilii is able to regenerate the pygidium, the posteriormost part of its body that bears the anus, and a subterminal growth zone containing stem cells that allows the subsequent addition of new segments. The ability to regenerate their posterior part (posterior regeneration) is promoted, in juvenile worms, by a hormone produced by the brain and is lost when this hormonal activity becomes low at the time the worms undergo their sexual maturation. By characterizing posterior regeneration at the morphological and molecular levels in worms that have been decapitated, we show that the presence of the head is essential for multiple aspects of posterior regeneration, as well as for the subsequent production of new segments. We also show that methylfarnesoate, the molecule proposed to be the brain hormone, can partially rescue the posterior regeneration defects observed in decapitated worms. Our results are therefore consistent with a key role of brain hormonal activity in the control of regeneration and growth in P. dumerilii, and support the hypothesis of the involvement of methylfarnesoate in this control.


Prediction on the light-assisted exfoliation of multilayered arsenene by the photo-isomerization of azobenzene.
The exfoliation of gray arsenic into single- or few-layered arsenene is a challenge of utmost importance. We propose here that the conformational change in the photo-isomerization of azobenzene-based photochromes might be used to promote the exfoliation of multilayered arsenene. Our density functional theory calculations show that the trans-to-cis conformational change can lead to an increase of the adjacent interlayer distance of arsenene from 6.59 Å to 11.07 Å. Starting from the transition state, the azobenzene molecule can be isomerized into the more stable trans form based on further ab initio molecular dynamics simulations. Reactive molecular dynamics simulations also show that about a 5 Å interlayer distance change can be induced by the cis-to-trans photo-isomerization of an azobenzene-OC10H21 molecule. The computational results may inspire the experimental enthusiasm for light-driven synthesis of single or few-layered arsenene.


Measurement of skeletal related events in SEER-Medicare: a comparison of claims-based methods.
Skeletal related events (SREs) are common in men with metastatic prostate cancer (mPC). Various methods have been used to identify SREs from claims data. The objective of this study was to provide a framework for measuring SREs from claims and compare SRE prevalence and cumulative incidence estimates based on alternative approaches in men with mPC. Several claims-based approaches for identifying SREs were developed and applied to data for men aged [greater than or equal to] 66 years newly diagnosed with mPC between 2000 and 2009 in the SEER-Medicare datasets and followed through 2010 or until censoring. Post-diagnosis SREs were identified using claims that indicated spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (BS), or radiation (suggestive of bone palliative radiation, RAD). To measure SRE prevalence, two SRE definitions were created: 'base case' (most commonly used in the literature) and 'alternative' in which different claims were used to identify each type of SRE. To measure cumulative incidence, we used the 'base case' definition and applied three periods in which claims were clustered to episodes: 14-, 21-, and 28-day windows. Among 8997 mPC patients, 46 % experienced an SRE according to the 'base case' definition and 43 % patients experienced an SRE according to the 'alternative' definition. Varying the code definition from 'base case' to 'alternative' resulted in an 8 % increase in the overall SRE prevalence. Using the 21-day window, a total of 12,930 SRE episodes were observed during follow up. Varying the window length from 21 to 28 days resulted in an 8 % decrease in SRE cumulative incidence (RAD: 10 %, PF: 8 %, SCC: 6 %, BS: 0.2 %). SRE prevalence was affected by the codes used, with PF being most impacted. The overall SRE cumulative incidence was affected by the window length used, with RAD being most affected. These results underscore the importance of the baseline definitions used to study claims data when attempting to understand relevant clinical events such as SREs in the real world setting.


Donepezil and rivastigmine in the treatment of Alzheimer's disease: a best-evidence synthesis of the published data on their efficacy and cost-effectiveness.
Various drugs have been approved for the treatment of Alzheimer's disease (AD) in the United States and Canada, including donepezil and rivastigmine, although questions remain as to their efficacy, effectiveness, and long-term benefits. The goal of this study was to conduct a best-evidence synthesis of data on the efficacy and cost-effectiveness of donepezil and rivastigmine in the treatment of AD. Relevant published randomized controlled trials (RCTs) and Phase IV open-label extension studies (excluding abstracts) were identified through searches of MEDLINE, HealthSTAR, and PsycINFO for the period January 1984 to October 2001. The bibliographies of retrieved articles were searched for additional publications. For inclusion in the best-evidence synthesis, clinical trials had to pass a blinded quality assessment (score > or =5 on the Jadad scale) and use National Institute of Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria. Economic studies were selected using National Health Service Centre for Reviews and Dissemination criteria for reporting critical summaries of economic evaluations. Nine RCTs of donepezil and 2 of rivastigmine were identified and met inclusion criteria for the best-evidence synthesis. Eight donepezil trials and both rivastigmine trials included patients with mild AD (Mini-Mental State Examination [MMSE] score, 15-27) or moderate AD (MMSE score, 8-14); 1 donepezil trial included patients with moderate or severe AD (MMSE score, 0-7). In the RCTs of donepezil, the mean decrease in scores on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was greater with active treatment than with placebo (lower scores indicate less cognitive deterioration). In the RCTs of rivastigmine, ADAS-cog scores decreased over the follow-up period with both active treatment and placebo; however, scores decreased more with active treatment. Three Phase IV studies of donepezil and I Phase IV study of rivastigmine were identified. Their results were consistent with those of the RCTs. Ten economic studies (7 donepezil, 3 rivastigmine) were identified and reviewed. In 4 of the donepezil studies and all 3 rivastigmine studies, use of the drug cost less than a no-drug strategy. The efficacy data indicate that both donepezil and rivastigmine can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild to moderate AD. Patients receiving active treatment will have more favorable ADAS-cog scores for at least 6 months, after which their scores will begin to converge with those of patients receiving placebo. Differences in methodology, types of direct or indirect costs included, and sources of cost data made it difficult to compare and synthesize findings of the economic studies; therefore, the cost-effectiveness data are inconclusive.


Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation.
Atopic dermatitis is a chronic inflammatory skin disorder characterized by defects in the epidermal barrier and keratinocyte differentiation. The expression of filaggrin, a protein thought to have a major role in the function of the epidermis, is downregulated. However, the impact of this deficiency on keratinocytes is not really known. This was investigated using lentivirus-mediated small-hairpin RNA interference in a three-dimensional reconstructed human epidermis (RHE) model, in the absence of other cell types than keratinocytes. Similar to what is known for atopic skin, the experimental filaggrin downregulation resulted in hypogranulosis, a disturbed corneocyte intracellular matrix, reduced amounts of natural moisturizing factor components, increased permeability and UV-B sensitivity of the RHE, and impaired keratinocyte differentiation at the messenger RNA and protein levels. In particular, the amounts of two filaggrin-related proteins and one protease involved in the degradation of filaggrin, bleomycin hydrolase, were lower. In addition, caspase-14 activation was reduced. These results demonstrate the importance of filaggrin for the stratum corneum properties/functions. They indicate that filaggrin downregulation in the epidermis of atopic patients, either acquired or innate, may be directly responsible for some of the disease-related alterations in the epidermal differentiation program and epidermal barrier function.


Binocular integration of pattern motion signals by MT neurons and by human observers.
Analysis of the movement of a complex visual stimulus is expressed in the responses of pattern-direction-selective neurons in area MT, which depend in turn on directionally selective inputs from area V1. How do MT neurons integrate their inputs? Pattern selectivity in MT breaks down when the gratings comprising a moving plaid are presented to non-overlapping regions of the (monocular) receptive field. Here we ask an analogous question, is pattern selectivity maintained when the component gratings are presented dichoptically to binocular MT neurons? We recorded from single units in area MT, measuring responses to monocular gratings and plaids, and to dichoptic plaids in which the components are presented separately to each eye. Neurons that are pattern selective when tested monocularly lose this selectivity when stimulated with dichoptic plaids. When human observers view these same stimuli, dichoptic plaids induce binocular rivalry. Yet motion signals from each eye can be integrated despite rivalry, revealing a dissociation of form and motion perception. These results reveal the role of monocular mechanisms in the computation of pattern motion in single neurons, and demonstrate that the perception of motion is not fully represented by the responses of individual MT neurons.


A Feasibility Study of Single-inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional Lung Ventilation in Humans.
The objective of this study was to assess the feasibility of single-inhalation xenon-enhanced computed tomography (XeCT) to provide clinically practical, high-resolution pulmonary ventilation imaging to clinics with access to only a single-energy computed tomography scanner, and to reduce the subject's overall exposure to xenon by utilizing a higher (70%) concentration for a much shorter time than has been employed in prior studies. We conducted an institutional review board-approved prospective feasibility study of XeCT for 15 patients undergoing thoracic radiotherapy. For XeCT, we acquired two breath-hold single-energy computed tomography images of the entire lung with a single inhalation each of 100% oxygen and a mixture of 70% xenon and 30% oxygen, respectively. A video biofeedback system for coached patient breathing was used to achieve reproducible breath holds. We assessed the technical success of XeCT acquisition and side effects. We then used deformable image registration to align the breath-hold images with each other to accurately subtract them, producing a map of lung xenon distribution. Additionally, we acquired ventilation single-photon emission computed tomography-computed tomography (V-SPECT-CT) images for 11 of the 15 patients. For a comparative analysis, we partitioned each lung into 12 sectors, calculated the xenon concentration from the Hounsfield unit enhancement in each sector, and then correlated this with the corresponding V-SPECT-CT counts. XeCT scans were tolerated well overall, with a mild (grade 1) dizziness as the only side effect in 5 of the 15 patients. Technical failures in five patients occurred because of inaccurate breathing synchronization with xenon gas delivery, leaving seven patients analyzable for XeCT and single-photon emission computed tomography correlation. Sector-wise correlations were strong (Spearman coefficient >0.75, Pearson coefficient >0.65, P value <.002) for two patients for whom ventilation deficits were visibly pronounced in both scans. Correlations were nonsignificant for the remaining five who had more homogeneous XeCT ventilation maps, as well as strong V-SPECT-CT imaging artifacts attributable to airway deposition of the aerosolized imaging agent. Qualitatively, XeCT demonstrated higher resolution and no central airway deposition artifacts compared to V-SPECT-CT. In this pilot study, single-breath XeCT ventilation imaging was generally feasible for patients undergoing thoracic radiotherapy, using an imaging protocol that is clinically practical and potentially widely available. In the future, the xenon delivery failures can be addressed by straightforward technical improvements to the patient biofeedback coaching system.


Informed consent and moral integrity.
Informed consent is required for any medical procedure although the situations in which it is given are beset by uncertainties and indeterminacies. These make medicolegal scrutiny of such situations very difficult. Although some people find the decision in the Sidaway case incomprehensible because of its continuing regard for a 'professional practice standard' in informed consent, I will argue that an important fact in many cases is the moral integrity of the doctor concerned and the pattern of his practice. This may provide the only morally principled and legally accessible evidence enabling a correct decision to be made in a difficult case. Although the epistemological significance of a professional practice standard is thereby defended the 'prudent patient standard' for what counts as consent is left intact.


New drugs for the treatment of non-Hodgkin lymphomas.
Non-Hodgkin lymphomas (NHL) are diverse diseases either of mature B-cell or T-cell derivation. Despite being generally chemosensitive diseases, the last decade has focused on developing more targeted agents based on improved insights of underlying biology. The hope is that more targeted and biologically rational treatments will improve both the efficacy and toxicity profile of standard approaches, with the ultimate goal of improving clinical outcomes. Among the newest agents to be approved are inhibitors of B-cell receptor (BCR) and PI3K signaling; however, a number of other classes of agents such as selective inhibitors of nuclear export (SINE), inhibitors of immune regulation such as PD1 inhibitors, and small molecule inhibitors of apoptosis are on the horizon. In addition, growing clinical evidence supports continued and new applications for immunomodulatory agents, proteasome inhibitors and histone deacetylase inhibitors. Altogether, this is an exciting time for NHL, with a number of promising agents and early clinical data. The key path forward will be to better apply these new agents in a personalized way, which will hopefully constitute the next generation of trials.