Surgical synovectomy combined with yttrium 90 in patients with recurrent joint synovitis.
Radiation synovectomy (RS) is one of many therapeutic options used for recurrent joint synovitis. Our aim was to analyze the effect of the surgical synovectomy combined with yttrium 90 ((90)Y) in the treatment for recurrent joint synovitis. A surgical combined RS procedure was used on 32 knees of 30 patients. They were divided into two groups. Group 1 consisted of 7 knees of 7 patients (5 women and 2 men) with a mean age of 40.7 years in whom RS was combined with the open synovectomy. Group 2 consisted of 25 knees of 23 patients (21 men and 2 women) with a mean age of 45.5 years in whom RS was combined with the arthroscopic synovectomy. Arthroscopic synovectomy or open surgery biopsy was carried out for all cases who diagnosed of having synovitis. A scintigraphic examination was conducted within 24 h after the RS procedure to investigate the systemic leakage of (90)Y in all patients. The outcome of treatment was assessed based on self-reporting using the visual analogue scale (VAS) of night pain, rest pain, activity pain, effusion, and satisfactory scores. The average follow-up period was 4.15 years. There was a significant difference between before and after treatment in terms of outcome parameters' VAS scores in both groups (p < 0.05). But there was no statistically significant difference between open and arthroscopic synovectomy groups in terms of outcome parameters (p > 0.05). Satisfactory outcome was excellent in 3 patients (42.8 %) in group 1 and 8 patients (32 %) in group 2. Surgical synovectomy with combined (90)Y could treat recurrent joint synovitis successfully. There was no statistically significant difference between open and arthroscopic synovectomy techniques combined with RS procedure.


Synthetical bone-like and biological hydroxyapatites: a comparative study of crystal structure and morphology.
Phase composition, crystal structure and morphology of biological hydroxyapatite (BHAp) extracted from human mandible bone, and carbonated hydroxyapatite (CHAp), synthesized by the chemical precipitation method, were studied by x-ray powder diffraction (XRD), Fourier transform infrared (FTIR) and Raman (R) spectroscopy techniques, combined with transmission electron microscopy (TEM). Structural and microstructural parameters were determined through Rietveld refinement of recorded XRD data, performed using the FullProf computing program, and TEM. Microstructural analysis shows anisotropic extension along the [00l] crystallographic direction (i.e. elongated crystallites shape) of both investigated samples. The average crystallite sizes of 10 and 8 nm were estimated for BHAp and CHAp, respectively. The FTIR and R spectroscopy studies show that carbonate ions substitute both phosphate and hydroxyl ions in the crystal structure of BHAp as well as in CHAp, indicating that both of them are mixed AB-type of CHAp. The thermal behaviour and carbonate content were analysed using thermogravimetric and differential thermal analysis. The carbonate content of about 1 wt.% and phase transition, at near 790 °C, from HAp to β-tricalcium phosphate were determined in both samples. The quality of synthesized CHAp powder, particularly, the particle size distribution and uniformity of morphology, was analysed by a particle size analyser based on laser diffraction and field emission scanning electron microscopy, respectively. These data were used to discuss similarity between natural and synthetic CHAp. Good correlation between the unit cell parameters, average crystallite size, morphology, carbonate content and crystallographic positions of carbonate ions in natural and synthetic HAp samples was found.


Cognitive distance, absorptive capacity and group rationality: a simulation study.
We report the results of a simulation study in which we explore the joint effect of group absorptive capacity (as the average individual rationality of the group members) and cognitive distance (as the distance between the most rational group member and the rest of the group) on the emergence of collective rationality in groups. We start from empirical results reported in the literature on group rationality as collective group level competence and use data on real-life groups of four and five to validate a mathematical model. We then use this mathematical model to predict group level scores from a variety of possible group configurations (varying both in cognitive distance and average individual rationality). Our results show that both group competence and cognitive distance are necessary conditions for emergent group rationality. Group configurations, in which the groups become more rational than the most rational group member, are groups scoring low on cognitive distance and scoring high on absorptive capacity.


Prediction of survival risks with adjusted gene expression through risk-gene networks.
Network-based analysis of biomedical data has been extensively studied over the last decades. As a successful application, gene networks have been used to illustrate interactions among genes and explain the associated phenotypes. However, the gene network approaches have not been actively applied for survival analysis, which is one of the main interests of biomedical research. In addition, a few previous studies using gene networks for survival analysis construct networks mainly from prior knowledge, such as pathways, regulations and gene sets, while the performance considerably depends on the selection of prior knowledge. In this paper, we propose a data-driven construction method for survival risk-gene networks as well as a survival risk prediction method using the network structure. The proposed method constructs risk-gene networks with survival-associated genes using penalized regression. Then, gene expression indices are hierarchically adjusted through the networks to reduce the variance intrinsic in datasets. By illustrating risk-gene structure, the proposed method is expected to provide an intuition for the relationship between genes and survival risks. The risk-gene network is applied to a low grade glioma dataset, and produces a hypothesis of the relationship between genetic biomarkers of low and high grade glioma. Moreover, with multiple datasets, we demonstrate that the proposed method shows superior prediction performance compared to other conventional methods. The R package of risk-gene networks is freely available in the web at http://cdal.korea.ac.kr/NetDA/. Supplementary data are available at Bioinformatics online.


Price and tax measures and illicit trade in the framework convention on tobacco control: what we know and what research is required.
Article 6 of the Framework Convention on Tobacco Control commits Parties to use tax and price policies to reduce tobacco use, whereas Article 15 commits Parties to implement measures to eliminate the illicit trade in tobacco products. This paper identifies research gaps/needs, especially in low- and middle-income countries, which, if adequately addressed, would help in implementing Articles 6 and 15. Based on a recent comprehensive review on the impact of tax and price on tobacco consumption and a summary of reviews and narratives about the illicit tobacco market, research gaps are identified. Countries have highly diverse research needs, depending on the stage of the tobacco epidemic, previous research and data availability, and making a ranking of research needs infeasible. Broad issues for further research are the following: (1) monitoring tobacco consumption, prices, and taxes, (2) assessing the effectiveness of the tax structure in generating revenue and reducing tobacco use, (3) strengthening the tax administration system in order to reduce tax evasion and tax avoidance, (4) improving our understanding of the political economy of tobacco tax policy, and (5) employing a multidisciplinary approach to assessing the magnitude of illicit tobacco trade. At a technical level, the case for increasing excise taxes to improve public health and increase government revenue is easily made, but the political and policy environment is often not supportive. In order to effectively impact policy, the required approach would typically make use of rigorous economic techniques, and be cognizant of the political economy of raising excise taxes.


Weight of the evidence on the human carcinogenicity of 2,4-D.
The phenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is widely used to control the growth of weeds and broadleaf plants. We convened a panel of 13 scientists to weigh the evidence on the human carcinogenicity of 2,4-D. The panel based its findings on a review of the toxicological and epidemiological literature on 2,4-D and related phenoxy herbicides. The toxicological data do not provide a strong basis for predicting that 2,4-D is a human carcinogen. Although a cause-effect relationship is far from being established, the epidemiological evidence for an association between exposure to 2,4-D and non-Hodgkin's lymphoma is suggestive and requires further investigation. There is little evidence of an association between use of 2,4-D and soft-tissue sarcoma or Hodgkin's disease, and no evidence of an association between 2,4-D use and any other form of cancer. Scientists on the panel were asked to categorize 2,4-D as a "known," "probable," "possible," or "unlikely" carcinogen or as a noncarcinogen in humans. The predominant opinion among the panel members was that the weight of the evidence indicates that it is possible that exposure to 2,4-D can cause cancer in humans, although not all of the panelists believed the possibility was equally likely: one thought the possibility was strong, leaning toward probable, and five thought the possibility was remote, leaning toward unlikely. Two panelists believed it unlikely that 2,4-D can cause cancer in humans.


Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by alpha-Ca2+/calmodulin-dependent protein kinase II.
Some forms of activity-dependent synaptic potentiation require the activation of postsynaptic Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Activation of CaMKII has been shown to phosphorylate the glutamate receptor 1 subunit of the AMPA receptor (AMPAR), thereby affecting some of the properties of the receptor. Here, a recombinant, constitutively active form of alphaCaMKII tagged with the fluorescent marker green fluorescent protein (GFP) [alphaCaMKII(1-290)-enhanced GFP (EGFP)] was expressed in CA1 pyramidal neurons from hippocampal slices. The changes in glutamatergic transmission onto these cells were analyzed. AMPA but not NMDA receptor-mediated EPSCs were specifically potentiated in infected compared with nearby noninfected neurons. This potentiation was associated with a reduction in the proportion of synapses devoid of AMPARs. In addition, expression of alphaCaMKII(1-290)-EGFP increased the quantal size of AMPAR-mediated responses. This effect reflected, at least in part, an increased unitary conductance of the channels underlying the EPSCs. These results reveal that several key features of long-term potentiation of hippocampal glutamatergic synapses are reproduced by the sole activity of alphaCaMKII.


Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.


Dynamic Metabolic Changes in the Human Thalamus at the Transition From Waking to Sleep - Insights From Simultaneous Functional MR Spectroscopy and Polysomnography.
An important contribution of the thalamus to the transition from wakefulness to sleep is a consistent finding in animal studies. In humans, only little is currently known about the specific role of the thalamus in regulating wake-sleep transitions. Although changes in thalamic blood flow and activity have been reported, the underlying molecular mechanisms have not been investigated. Knowledge about neurotransmitter changes at the wake-to-sleep transition would be indispensable for a better translation of basic animal research findings to humans. Here, we start to fill this important scientific gap. More specifically, we benefit from recent advances in magnetic resonance (MR) spectroscopy, which allow for the non-invasive, local-specific and high-quality detection of naturally occurring metabolite changes in the human brain. We demonstrate in nine young adults able to produce consolidated sleep in the MR spectroscopy scanner, a specific decrease in thalamic glutamate concentration from wakefulness to stage N2 sleep. The magnitude of this decrease was highly correlated with individual N2 sleep duration. When five participants of the original experiment were kept awake in a separate control condition, no decrease in thalamic glutamate levels occurred. The study highlights for the first time in humans that dynamic changes in distinct brain metabolites can be reliably detected at the transition from waking to sleep. The reported methodology to simultaneously acquire functional MR spectroscopy data and neurophysiological signals offers great potential for investigating the molecular mechanisms underlying the transition between and the maintenance of sleep and wake states in humans.


The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers.
MicroRNAs (miRNA/miR) are a class of small noncoding RNAs implicated in the pathogenesis of various malignancies. In the current study, using micro(RNA) arrays, we found a ubiquitous loss of miR-126 expression in colon cancer lines when compared to normal human colon epithelia. Reconstitution of miR-126 in colon cancer cells resulted in a significant growth reduction as evidenced in clonogenic assays. A search for miR-126 gene targets revealed p85beta, a regulatory subunit involved in stabilizing and propagating the phosphatidylinositol 3-kinase (PI3K) signal, as one of the potential substrates. Restoration of miR-126 in cancer cells induced a > or =3-fold reduction in p85beta protein levels, with no concomitant change in p85alpha, a gene that is functionally related to p85beta but not a supposed target of miR-126. Additionally, using reporter constructs, we show that the p85beta-3' untranslated region is directly targeted by miR-126. Furthermore, this miR-126 mediated reduction of p85beta was accompanied by a substantial reduction in phosphorylated AKT levels in the cancer cells, suggesting an impairment in PI3K signaling. Finally, in a panel of matched normal colon and primary colon tumors, each of the tumors demonstrated miR-126 down-regulation together with an increase in the p85beta protein level. Taken together, we propose that miR-126 regulates PI3K signaling partly by targeting p85beta, and that the loss of miR-126 may provide a selective growth advantage during colon carcinogenesis.


Getting the most out of living abroad: biculturalism and integrative complexity as key drivers of creative and professional success.
The current research investigated how patterns of home and host cultural identification can explain which individuals who have lived abroad achieve the greatest creative and professional success. We hypothesized that individuals who identified with both their home and host cultures (i.e., biculturals) would show enhanced creativity and professional success compared with individuals who identified with only a single culture (i.e., assimilated and separated individuals). Further, we expected that these effects would be driven by biculturals' greater levels of integrative complexity, an information processing capacity that involves considering and combining multiple perspectives. Two studies demonstrated that biculturals exhibited more fluency, flexibility, and novelty on a creative uses task (Study 1) and produced more innovations at work (Study 2) than did assimilated or separated individuals. Study 3 extended these findings to general professional outcomes: Bicultural professionals achieved higher promotion rates and more positive reputations compared with assimilated or separated individuals. Importantly, in all 3 studies, integrative complexity mediated the relationship between home/host identification and performance. Overall, the current results demonstrate who is most likely to achieve professional and creative success following experiences abroad and why.


Impact of the 1997 revised Centers for Disease Control criteria on case rates of legionellosis in Taiwan: review of 38 cases at a teaching hospital, 1998-2002.
In 1997, the United States Centers for Disease Control and Prevention (CDC) published revised case definitions for legionellosis which eliminated the previously used category of "probable case" based on a single indirect fluorescence antibody (IFA) titer. This study evaluated the influence of revision on the case rates of legionellosis in Taiwan. From 1988 to 2002, 4615 patients with pneumonia were tested for legionellosis in our hospital. The testing methods included IFA assay for serum specimens and direct fluorescence antibody (DFA) assay for sputum specimens. Using the revised criteria, Legionnaires' disease (LD) was diagnosed by DFA in 27 cases and by IFA in 11 cases. The most common underlying conditions were cigarette smoking (44.7%), chronic obstructive pulmonary disease (28.9%) and corticosteroid use (26.3%). The clinical features were nonspecific, including fever (73.7%), dyspnea (63.2%), cough (63.2%) and leukocytosis (63.2%). The overall mortality rate was 18.4%, and the directly LD-attributable mortality rate was 10.5%. Nasogastric tube insertion, endotracheal intubation, congestive heart failure before the onset of LD, inappropriate antimicrobial therapy, respiratory failure and absence of fever during the LD course were significantly associated with LD-attributable mortality. Older age (>70 years) was not associated with higher mortality (p=0.053). Using the revised diagnostic criteria in our series, the positive rate of case identification by IFA was 0.26%, while use of the previous case definitions resulted in a positive rate of 7.6% (including probable and definitive cases). Recognition that the original CDC criteria of IFA titer >1:256 or elevation of IFA titer <4-fold in paired sera could not adequately define an LD etiology has led to a dramatic lowering of case rates among studies after the criteria revision in Taiwan and elsewhere. Assays that are faster, more sensitive and less technician dependent are needed to diagnosis this disease.


Overview of lung cancer surgery in Ontario.
Surgery is the primary curative treatment for lung cancer and thus appropriate surgical resource allocation is critical. This study describes the distribution of lung cancer incidence and surgical care in Ontario, a Canadian province with universal health care, for the fiscal year of 2004. All new lung cancer cases in Ontario between April 1, 2003 and March 31, 2004 were identified in the Ontario Cancer Registry. Incidence rates and surgical procedures were compared by age, health region, neighborhood income, and community size. Lung cancer incidence was highest in lower income neighborhoods (90.2 cases of 100,000 vs 55.6 in the highest quintile, p < 0.001) and smaller communities (87.1 of 100,000 in communities less than 100,000 vs 56.3 of 100,000 in cities greater than 1.25 million, p < 0.001). Surgical interventions were most common in younger patients (47.4% aged 20 to 54 years versus 30.5% greater than 75 years, p < 0.001), and those in wealthier neighborhoods (43.4% in highest quintile versus 35.8% in the lowest, p < 0.001). Surgical procedures overall and specifically formal resections (20% in cities >1.25 million versus 18% in communities <100,000, p < 0.03) were more common in larger communities (43.4% versus 37.7%, p < 0.001). Pneumonectomy was more common in smaller communities (14.5% vs 9.9%, p = 0.048, whereas more lobar (53.8 vs 45.2%, p = 0.01) and sublobar resections (44.9% vs 31.7%, p < 0.0001) were more common in larger communities. Thoracic surgeons provided the majority of formal resections (51% to 57%) compared with general surgeons (17% to 21%). Lung cancer incidence and surgical care vary significantly by health region, income level, and community size. These disparities require further evaluation to meet the needs of patients with lung cancer.


Field cricket genome reveals the footprint of recent, abrupt adaptation in the wild.
Evolutionary adaptation is generally thought to occur through incremental mutational steps, but large mutational leaps can occur during its early stages. These are challenging to study in nature due to the difficulty of observing new genetic variants as they arise and spread, but characterizing their genomic dynamics is important for understanding factors favoring rapid adaptation. Here, we report genomic consequences of recent, adaptive song loss in a Hawaiian population of field crickets (Teleogryllus oceanicus). A discrete genetic variant, flatwing, appeared and spread approximately 15 years ago. Flatwing erases sound-producing veins on male wings. These silent flatwing males are protected from a lethal, eavesdropping parasitoid fly. We sequenced, assembled and annotated the cricket genome, produced a linkage map, and identified a flatwing quantitative trait locus covering a large region of the X chromosome. Gene expression profiling showed that flatwing is associated with extensive genome-wide effects on embryonic gene expression. We found that flatwing male crickets express feminized chemical pheromones. This male feminizing effect, on a different sexual signaling modality, is genetically associated with the flatwing genotype. Our findings suggest that the early stages of evolutionary adaptation to extreme pressures can be accompanied by greater genomic and phenotypic disruption than previously appreciated, and highlight how abrupt adaptation might involve suites of traits that arise through pleiotropy or genomic hitchhiking.


No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).
A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis.


Preparation of hierarchical mesoporous CaCO3 by a facile binary solvent approach as anticancer drug carrier for etoposide.
To develop a nontoxic system for targeting therapy, a new highly ordered hierarchical mesoporous calcium carbonate nanospheres (CCNSs) as small drug carriers has been synthesized by a mild and facile binary solvent approach under the normal temperature and pressure. The hierarchical structure by multistage self-assembled strategy was confirmed by TEM and SEM, and a possible formation process was proposed. Due to the large fraction of voids inside the nanospheres which provides space for physical absorption, the CCNSs can stably encapsulate the anticancer drug etoposide with the drug loading efficiency as high as 39.7 wt.%, and etoposide-loaded CCNS (ECCNS) nanoparticles can dispersed well in the cell culture. Besides, the drug release behavior investigated at three different pH values showed that the release of etoposide from CCNSs was pH-sensitive. MTT assay showed that compared with free etoposide, ECCNSs exhibited a higher cell inhibition ratio against SGC-7901 cells and also decreased the toxicity of etoposide to HEK 293 T cells. The CLSM image showed that ECCNSs exhibited a high efficiency of intracellular delivery, especially in nuclear invasion. The apoptosis test revealed that etoposide entrapped in CCNSs could enhance the delivery efficiencies of drug to achieve an improved inhibition effect on cell growth. These results clearly implied that the CCNSs are a promising drug delivery system for etoposide in cancer therapy.


Differences in mechanisms of failure, intraoperative findings, and surgical characteristics between single- and multiple-revision ACL reconstructions: a MARS cohort study.
The factors that lead to patients failing multiple anterior cruciate ligament (ACL) reconstructions are not well understood. Multiple-revision ACL reconstruction will have different characteristics than first-time revision in terms of previous and current graft selection, mode of failure, chondral/meniscal injuries, and surgical charactieristics. Case-control study; Level of evidence, 3. A prospective multicenter ACL revision database was utilized for the time period from March 2006 to June 2011. Patients were divided into those who underwent a single-revision ACL reconstruction and those who underwent multiple-revision ACL reconstructions. The primary outcome variable was Marx activity level. Primary data analyses between the groups included a comparison of graft type, perceived mechanism of failure, associated injury (meniscus, ligament, and cartilage), reconstruction type, and tunnel position. Data were compared by analysis of variance with a post hoc Tukey test. A total of 1200 patients (58% men; median age, 26 years) were enrolled, with 1049 (87%) patients having a primary revision and 151 (13%) patients having a second or subsequent revision. Marx activity levels were significantly higher (9.77) in the primary-revision group than in those patients with multiple revisions (6.74). The most common cause of reruptures was a traumatic, noncontact ACL graft injury in 55% of primary-revision patients; 25% of patients had a nontraumatic, gradual-onset recurrent injury, and 11% had a traumatic, contact injury. In the multiple-revision group, a nontraumatic, gradual-onset injury was the most common cause of recurrence (47%), followed by traumatic noncontact (35%) and nontraumatic sudden onset (11%) (P < .01 between groups). Chondral injuries in the medial compartment were significantly more common in the multiple-revision group than in the single-revision group, as were chondral injuries in the patellofemoral compartment. Patients with multiple-revision ACL reconstructions had lower activity levels, were more likely to have chondral injuries in the medial and patellofemoral compartments, and had a high rate of a nontraumatic, recurrent injury of their graft.


Evaluation of a third-location decompression program for Canadian Forces members returning from Afghanistan.
Service members returning from combat can experience difficulty adapting to home life. To help ease this transition, the Canadian Forces provides a Third-location Decompression (TLD) program in Cyprus to members returning from deployment to Afghanistan. The 5-day program consists of individual free time, structured recreational activities, and educational programming. Its perceived value and impact were measured immediately afterward and 4 to 6 months later. Respondents overwhelmingly supported the TLD concept, with 95% agreeing that "some form of TLD is a good idea." Eighty-one percent of participants found the program valuable, and 83% recommended it for future deployments to Afghanistan. Perceived value persisted 4 to 6 months after return, and 74% felt that it helped to make reintegration easier for them. Canadian Forces members saw value in the TLD program, and most members believed that the program had its intended effect of making the reintegration process easier for them.


Intensity modulated irradiation of a thorax phantom: comparisons between measurements, Monte Carlo calculations and pencil beam calculations.
The present study investigates the application of compensators for the intensity modulated irradiation of a thorax phantom. Measurements are compared with Monte Carlo and standard pencil beam algorithm dose calculations. Compensators were manufactured to produce the intensity profiles that were generated from the scientific version of the KonRad IMRT treatment-planning system for a given treatment plan. The comparison of dose distributions calculated with a pencil beam algorithm, with the Monte Carlo code EGS4 and with measurements is presented. By measurements in a water phantom it is demonstrated that the method used to manufacture the compensators reproduces the intensity profiles in a suitable manner. Monte Carlo simulations in a water phantom show that the accelerator head model used for simulations is sufficient. No significant overestimations of dose values inside the target volume by the pencil beam algorithm are found in the thorax phantom. An overestimation of dose values in lung by the pencil beam algorithm is also not found. Expected dose calculation errors of the pencil beam algorithm are suppressed, because the dose to the low density region lung is reduced by the use of a non-coplanar beam arrangement and by intensity modulation.


Postprandial responses of incretin and pancreatic hormones in non-diabetic patients with end-stage renal disease.
Patients with end-stage renal disease (ESRD) have glucometabolic disturbances resulting in a high prevalence of prediabetes. The underlying pathophysiology remains unclear, but may prove important for the strategies employed to prevent progression to overt diabetes. Meal-induced release of the insulinotropic gut-derived incretin hormones and pancreatic hormones play a critical role in the maintenance of a normal postprandial glucose tolerance. We studied patients with ESRD and either normal (n = 10) or impaired (n = 10) glucose tolerance, and control subjects (n = 11). Plasma concentrations of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and paracetamol were measured repeatedly during a standardized 4-h liquid meal including 1.5 g paracetamol (added for evaluation of gastric emptying). Fasting glucose and postprandial glucose responses were comparable between groups (P > 0.082). Patients with ESRD exhibited higher fasting levels of GIP and glucagon compared with controls (P < 0.001). Baseline-corrected GLP-1 and glucagon responses were enhanced (P < 0.002), baseline-corrected insulin responses and insulin excursions were reduced (P < 0.035), and paracetamol excursions were delayed (P < 0.024) in patients with ESRD compared with controls. None of the variables differed between the two ESRD subgroups. Non-diabetic patients with ESRD were characterized by reduced postprandial insulin responses despite increased secretion of the insulinotropic incretin hormone GLP-1. Fasting levels and baseline-corrected responses of glucagon were elevated and gastric emptying was delayed in the ESRD patients. These perturbations seem to be caused by uraemia per se and may contribute to the disturbed glucose metabolism in ESRD patients.


Olfactory hallucinations in a population-based sample.
Olfactory hallucinations referring to olfactory perceptions in the absence of chemical stimuli, occur in non-clinical and clinical populations. Few studies have investigated their prevalence in the general population and little is known about factors triggering and maintaining them such as substance use, severe life events, and mood. We analyzed self-report data from 2500 community dwelling Norwegians, aged 18-96 years, for occurrence of olfactory hallucinations and co-occurring hallucinations in other modalities (auditory, visual, tactile). Analyses included age, sex, self-reported symptoms of depression and anxiety, mental health status, and experience of severe life-events. The results show that 4.2% (95% CI 3.5-5.1%) reported having experienced olfactory hallucinations, and 56% of individuals experiencing olfactory hallucinations also reported these in combination with hallucinations in other modalities. Prevalence varied significantly in terms of age and sex, in that olfactory hallucinations were most frequently reported by young individuals and females. Self-reported symptoms of anxiety and experience of stressful life events were significantly associated with olfactory hallucinations, suggesting that experiencing olfactory hallucinations may negatively affect functioning and may increase the likelihood of developing psychopathology. Findings underline the need to continue to examine olfactory hallucinations albeit with a more comprehensive assessment in order to increase knowledge on this experience.


MX2 mediates establishment of interferon response profile, regulates XAF1, and can sensitize melanoma cells to targeted therapy.
MX2 is an interferon inducible gene that is mostly known for its antiviral activity. We have previously demonstrated that MX2 is also associated with the tumorigenesis process in melanoma. However, it remains unknown which molecular mechanisms are regulated by MX2 in response to interferon signaling in this disease. Here, we report that MX2 is necessary for the establishment of an interferon-induced transcriptional profile partially through regulation of STAT1 phosphorylation and other interferon-related downstream factors, including proapoptotic tumor suppressor XAF1. MX2 and XAF1 expression tightly correlate in both cultured melanoma cell lines and in patient-derived primary and metastatic tumors, where they also are significantly related with survival. MX2 mediates IFN growth-inhibitory signals in both XAF1 dependent and independent ways and in a cell type and context-dependent manner. Higher MX2 expression renders melanoma cells more sensitive to targeted therapy drugs such as vemurafenib and trametinib; however, this effect is XAF1 independent. In summary, we uncovered a new mechanism in the complex regulation of interferon signaling in melanoma that can influence both survival and response to therapy.


Prenatal care utilization and the implementation of prophylaxis to prevent perinatal HIV-1 transmission.
To describe prenatal care utilization among women with HIV-1 in 4 US states, and to determine whether the adequacy of prenatal care utilization is associated with the implementation of prenatal, intrapartum, and postnatal HIV antiretroviral therapy (ARV). Three-hundred three women completed a prenatal interview. Prenatal, labor and delivery, and infant medical records were reviewed. Thirty-nine percent of women did not receive adequate prenatal care; nearly one quarter of women did not begin care within the recommended timeframe, and approximately one-fifth of women received fewer than the recommended number of prenatal care visits from the time of entry into care until delivery. Those classified as less than adequate in terms of receipt of recommended visits were at increased risk for not receiving ARV during the prenatal care period and during labor and delivery, and were more likely to have had an infant subsequently diagnosed with HIV infection. Although women with HIV require adequate prenatal care for their own health as well as to improve perinatal outcomes, many are at risk for not receiving this care. Lower adherence to prenatal care appointments is an important risk factor for not receiving full HIV prophylactic regimens.


Chile's 2014 sugar-sweetened beverage tax and changes in prices and purchases of sugar-sweetened beverages: An observational study in an urban environment.
On October 1, 2014, the Chilean government modified its previous sugar-sweetened beverage (SSB) tax, increasing the tax rate from 13% to 18% on industrialized beverages with high levels of sugar (H-SSBs) (greater than 6.25 grams [g] sugar/100 milliliters [mL]) and decreasing the tax rate from 13% to 10% on industrialized beverages with low or no sugar (L-SSBs) (less than 6.25 g sugar/100 mL). This study examines changes in beverage prices and household beverage purchases following the implementation of the tax reform. We used longitudinal data collected between January 1, 2013, and December 31, 2015, from 2,000 households. We defined the pretax period as January 1, 2013, to September 30, 2014, and the posttax period as October 1, 2014, to December 31, 2015. We conducted a pre-post analysis for changes in prices and purchases, with the latter examined by volume and calories. We compared posttax changes in prices and purchases to a counterfactual, defined as what would have been expected in the posttax period based on pretax trends. All results are stated as comparisons to this counterfactual. We linked beverages at the bar code level to nutrition facts panel data collected by a team of Chilean nutritionists who categorized them by taxation level and beverage subcategory, which included carbonated and noncarbonated H-SSBs and concentrated, ready-to-drink L-SSBs and untaxed beverages. We reconstituted concentrated beverages and analyzed all beverages using as-consumed volumes and calories. Posttax monthly prices of H-SSBs increased, but these changes were small. Prices of carbonated H-SSBs increased by 2.0% (95% confidence interval [CI] 1.0%-3.0%), while those of noncarbonated H-SSBs increased by 3.9% (95% CI 1.6%-6.2%). Prices of L-SSB concentrates decreased after the tax by 6.7% (95% CI -8.2%--4.6%), and prices of ready-to-drink L-SSBs increased by 1.5% (95% CI 0.3%-2.7%). Households decreased monthly per capita purchases of H-SSBs by 3.4% by volume (95% CI -5.9%--0.9%) and 4.0% by calories (95% CI -6.3%--1.9%), and this change was greater among high socioeconomic status (SES) households. The volume of household purchases of L-SSBs increased 10.7% (95% CI 7.5%-13.9%), while that of untaxed beverage purchases decreased by 3.1% (95% CI -5.1%--1.1%). The main limitation of this study was that there was no control group, so we were unable to assess the causal impact of the tax. The modifications of Chile's SSB tax were small, and observed changes in prices and purchases of beverages after the tax were also small. Our results are consistent with previous evidence indicating that small increases in SSB taxes are unlikely to promote large enough changes in SSB purchases to reduce obesity and noncommunicable diseases (NCDs).


Efficacy of clinical methods to assess jawbone tissue prior to and during endosseous dental implant placement: a systematic literature review.
To evaluate the evidence for the diagnostic accuracy of clinical methods to assess bone density, quantity, or quality prior to and during dental implant placement. A PubMed literature search with specific indexing terms and a hand search were made. From the retrieved titles and abstracts, 3 reviewers selected publications on the basis of predetermined inclusion and exclusion criteria. Data were extracted from the selected publications using a protocol. Original studies were interpreted with the aid of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. The literature search yielded 145 titles and abstracts, of which 71 were selected and read in full text. Seven studies were judged relevant. In 1 study, no method was presented as the test method. In 6 studies, the results of the test method were compared to those of a reference method. However, only 1 study presented the results in terms of percentage of correct diagnoses. In that study, the use of periapical radiography together with reference images yielded correct assessment of the trabecular pattern of the mandible in 3 categories in 58% of the sites. The kappa index of interobserver agreement was 0.35 and intraobserver agreement was 0.67. Corresponding kappa values for 4 classes of bone quality presented by Lekholm and Zarb were 0.33 and 0.43, respectively. No study examined the accuracy of the method originally described by Lekholm and Zarb. The evidence for the efficacy of clinical methods to assess jawbone tissue prior to and during endosseous dental implant placement is sparse. This emphasizes the need for studies that incorporate accepted methodologic criteria for diagnostic efficacy.


Association between catechol-O-methyltrasferase Val108/158Met genotype and prefrontal hemodynamic response in schizophrenia.
"Imaging genetics" studies have shown that brain function by neuroimaging is a sensitive intermediate phenotype that bridges the gap between genes and psychiatric conditions. Although the evidence of association between functional val108/158met polymorphism of the catechol-O-methyltransferase gene (COMT) and increasing risk for developing schizophrenia from genetic association studies remains to be elucidated, one of the most topical findings from imaging genetics studies is the association between COMT genotype and prefrontal function in schizophrenia. The next important step in the translational approach is to establish a useful neuroimaging tool in clinical settings that is sensitive to COMT variation, so that the clinician could use the index to predict clinical response such as improvement in cognitive dysfunction by medication. Here, we investigated spatiotemporal characteristics of the association between prefrontal hemodynamic activation and the COMT genotype using a noninvasive neuroimaging technique, near-infrared spectroscopy (NIRS). Study participants included 45 patients with schizophrenia and 60 healthy controls matched for age and gender. Signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions from 52-channel NIRS and compared between two COMT genotype subgroups (Met carriers and Val/Val individuals) matched for age, gender, premorbid IQ, and task performance. The [oxy-Hb] increase in the Met carriers during the verbal fluency task was significantly greater than that in the Val/Val individuals in the frontopolar prefrontal cortex of patients with schizophrenia, although neither medication nor clinical symptoms differed significantly between the two subgroups. These differences were not found to be significant in healthy controls. These data suggest that the prefrontal NIRS signals can noninvasively detect the impact of COMT variation in patients with schizophrenia. NIRS may be a promising candidate translational approach in psychiatric neuroimaging.


A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma.
Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.


Non-injection drug use and Hepatitis C Virus: a systematic review.
This systematic review examined the evidence on the prevalence of the Hepatitis C Virus (HCV) in non-injecting drug users (NIDUs) who sniff, smoke or snort drugs such as heroin, cocaine, crack or methamphetamine. The search included studies published from January 1989 to January 2006. Twenty-eight eligible studies were identified and the prevalence of HCV in these NIDU populations ranged from 2.3 to 35.3%. There was substantial variation in study focus and in the quality of the NIDU data presented in the studies. The results of our systematic review suggested that there are important gaps in the research of HCV in NIDUs. We identified a problem of study focus; much of the research did not aim to study HCV in users of non-injection drugs. Instead, NIDUs were typically included as a secondary research concern, with a principal focus on the problem of transmission of HCV in IDU populations. Despite methodological issues, HCV prevalence in this population is much higher than in a non-drug using population, even though some IDUs might have inadvertently been included in the NIDU samples. These studies point to a real problem of HCV in NIDU populations, but the causal pathway to infection remains unclear.


A tale of two dairies.
Milk has always been susceptible to price fluctuations. Farmers are used to putting away money during good times to see themselves through lean times. Recently, however, the cycles have become more violent, with lows falling lower and highs rising not quite so high and the intervals between peaks and valleys shrinking. In 1970, when milk was bringing farmers the same amount that it is today, there were nearly 650,000 dairy farms in the United States. Now there are fewer than one tenth as many, only about 54,000. The largest 1 percent of dairy farms (a figure than includes only enormous factory farms with over 2,000 cows) produced nearly one quarter of the milk we consume. Recently, dairy farmers banded together to propose a radical solution to the dairy crisis. In order to survive, they concluded, American dairy farmers would have to join together to control the supply of milk, an approach along lines similar to the one taken in Canada.


Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.
Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the FFA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with type 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of beta-cell failure in obese individuals who are at risk for developing type 2 diabetes. They do not, however, seem to further deteriorate the beta-cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group.


Effect of a Modified Hospital Elder Life Program on Delirium and Length of Hospital Stay in Patients Undergoing Abdominal Surgery: A Cluster Randomized Clinical Trial.
Older patients undergoing abdominal surgery commonly experience preventable delirium, which extends their hospital length of stay (LOS). To examine whether a modified Hospital Elder Life Program (mHELP) reduces incident delirium and LOS in older patients undergoing abdominal surgery. This cluster randomized clinical trial of 577 eligible patients enrolled 377 older patients (≥65 years of age) undergoing gastrectomy, pancreaticoduodenectomy, and colectomy at a 2000-bed urban medical center in Taipei, Taiwan, from August 1, 2009, through October 31, 2012. Consecutive older patients scheduled for elective abdominal surgery with expected LOS longer than 6 days were enrolled, with a recruitment rate of 65.3%. Participants were cluster randomized by room to receive the mHELP or usual care. The intervention (implemented by an mHELP nurse) consisted of 3 protocols administered daily: orienting communication, oral and nutritional assistance, and early mobilization. Intervention group participants received all 3 mHELP protocols postoperatively, in addition to usual care, as soon as they arrived in the inpatient ward and until hospital discharge. Adherence to protocols was tracked daily. Presence of delirium was assessed daily by 2 trained nurses who were masked to intervention status by using the Confusion Assessment Method. Data on LOS were abstracted from the medical record. Of 577 eligible patients, 377 (65.3%) were enrolled and randomly assigned to the mHELP (n = 197; mean [SD] age, 74.3 [5.8] years; 111 [56.4%] male) or control (n = 180; mean [SD] age, 74.8 [6.0] years; 103 [57.2%] male) group. Postoperative delirium occurred in 13 of 196 (6.6%) mHELP participants vs 27 of 179 (15.1%) control individuals, representing a relative risk of 0.44 in the mHELP group (95% CI, 0.23-0.83; P = .008). Intervention group participants received the mHELP for a median of 7 days (interquartile range, 6-10 days) and had a shorter median LOS (12.0 days) than control participants (14.0 days) (P = .04). For older patients undergoing abdominal surgery who received the mHELP, the odds of delirium were reduced by 56% and LOS was reduced by 2 days. Our findings support using the mHELP to advance postoperative care for older patients undergoing major abdominal surgery. clinicaltrials.gov Identifier: NCT01045330.


The Effect of Glycopyrrolate on the Incidence of Hypotension and Vasopressor Requirement During Spinal Anesthesia for Cesarean Delivery: A Meta-analysis.
The objective of this meta-analysis was to determine the efficacy of glycopyrrolate at reducing spinal hypotension during cesarean delivery. A literature search was performed to identify randomized controlled trials investigating the effect of glycopyrrolate on spinal-induced hypotension during cesarean delivery. Primary outcomes were intraoperative hypotension and vasopressor requirement (phenylephrine equivalents). Secondary outcomes included heart rate (HR), nausea and vomiting, dry mouth, and Apgar scores. Risk ratios (RRs), and mean differences (MDs) were calculated using random-effects modeling with 95% confidence intervals for primary outcomes and 99% confidence intervals for secondary outcomes. Five randomized controlled trials met our inclusion criteria. A total of 311 patients were included: 153 received glycopyrrolate and 158 placebo. The incidence of spinal-induced hypotension was no different with prophylactic glycopyrrolate compared to control (RR, 0.93 [0.71-1.21]; P = .59), but the total phenylephrine dose required was significantly reduced with glycopyrrolate (MD, -62.64 μg [-107.61 to -17.66 μg]; P = .006). The maximal HR achieved in the glycopyrrolate group was significantly higher compared to controls (MD, 15.85 bpm [5.40-26.31]; P < .0001); however, the incidence of bradycardia was not statistically different. The incidence of intraoperative nausea and vomiting was not different between groups; however, glycopyrrolate increased the risk of dry mouth (RR, 5.15 [1.82-14.57]; P < .0001). Apgar scores at 1 and 5 minutes did not differ between groups. Prophylactic glycopyrrolate does not reduce the incidence of spinal-induced hypotension but results in a modest reduction in vasopressor requirements while increasing maternal HR.


A cDNA microarray assessment of gene expression in the liver of rainbow trout (Oncorhynchus mykiss) in response to a handling and confinement stressor.
A purpose-designed microarray platform (Stressgenes, Phase 1) was utilised to investigate the changes in gene expression within the liver of rainbow trout during exposure to a prolonged period of confinement. Tissue and blood samples were collected from trout at intervals up to 648 h after transfer to a standardised confinement stressor, together with matched samples from undisturbed control fish. Plasma ACTH, cortisol, glucose and lactate were analysed to confirm that the neuroendocrine response to confinement was consistent with previous findings and to provide a phenotypic context to assist interpretation of gene expression data. Liver samples for suppression subtractive hybridisation (SSH) library construction were selected from within the experimental groups comprising "early" stress (2-48 h) and "late" stress (96-504 h). In order to reduce redundancy within the four SSH libraries and yield a higher number of unique clones an additional subtraction was carried out. After printing of the arrays a series of 55 hybridisations were executed to cover 6 time points. At 2 h, 6 h, 24 h, 168 h and 504 h 5 individual confined fish and 5 individual control fish were used with control fish only at 0 h. A preliminary list of 314 clones considered differentially regulated over the complete time course was generated by a combination of data analysis approaches and the most significant gene expression changes were found to occur during the 24 h to 168 h time period with a general approach to control levels by 504 h. Few changes in expression were apparent over the first 6 h. The list of genes whose expression was significantly altered comprised predominantly genes belonging to the biological process category (response to stimulus) and one cellular component category (extracellular region) and were dominated by so-called acute phase proteins. Analysis of the gene expression profile in liver tissue during confinement revealed a number of significant clusters. The major patterns comprised genes that were up-regulated at 24 h and beyond, the primary examples being haptoglobin, beta-fibrinogen and EST10729. Two representative genes from each of the six k-means clusters were validated by qPCR. Correlations between microarray and qPCR expression patterns were significant for most of the genes tested. qPCR analysis revealed that haptoglobin expression was up-regulated approximately 8-fold at 24 h and over 13-fold by 168 h.


Clinical practice guidelines for the management of non-specific low back pain in primary care: an updated overview.
The aim of this study was to provide an overview of the recommendations regarding the diagnosis and treatment contained in current clinical practice guidelines for patients with non-specific low back pain in primary care. We also aimed to examine how recommendations have changed since our last overview in 2010. The searches for clinical practice guidelines were performed for the period from 2008 to 2017 in electronic databases. Guidelines including information regarding either the diagnosis or treatment of non-specific low back pain, and targeted at a multidisciplinary audience in the primary care setting, were considered eligible. We extracted data regarding recommendations for diagnosis and treatment, and methods for development of guidelines. We identified 15 clinical practice guidelines for the management of low back pain in primary care. For diagnosis of patients with non-specific low back pain, the clinical practice guidelines recommend history taking and physical examination to identify red flags, neurological testing to identify radicular syndrome, use of imaging if serious pathology is suspected (but discourage routine use), and assessment of psychosocial factors. For treatment of patients with acute low back pain, the guidelines recommend reassurance on the favourable prognosis and advice on returning to normal activities, avoiding bed rest, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids for short periods. For treatment of patients with chronic low back pain, the guidelines recommend the use of NSAIDs and antidepressants, exercise therapy, and psychosocial interventions. In addition, referral to a specialist is recommended in case of suspicion of specific pathologies or radiculopathy or if there is no improvement after 4 weeks. While there were a few discrepancies across the current clinical practice guidelines, a substantial proportion of recommendations was consistently endorsed. In the current review, we identified some differences compared to the previous overview regarding the recommendations for assessment of psychosocial factors, the use of some medications (e.g., paracetamol) as well as an increasing amount of information regarding the types of exercise, mode of delivery, acupuncture, herbal medicines, and invasive treatments. These slides can be retrieved under Electronic Supplementary Material.


Determining the velocity required for skin perforation by fragment simulating projectiles: a systematic review.
Explosively propelled fragments are the most common cause of injury to soldiers on current operations. Researchers desire models to predict their injurious effects so as to refine methods of potential protection. Well validated physical and numerical models based on the penetration of standardised fragment simulating projectiles (FSPs) through muscle exist but not for skin, thereby reducing the utility of such models. A systematic review of the literature was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology to identify all open source information quantifying the effects of postmortem human subject (PMHS) and animal skin on the retardation of metallic projectiles. Projectile sectional density (mass over presented cross-sectional area) was compared with the velocity required for skin perforation or penetration, with regard to skin origin (animal vs PMHS), projectile shape (sphere vs cylinder) and skin backing (isolated skin vs that backed by muscle). 17 original experimental studies were identified, predominantly using skin from the thigh. No statistical difference in the velocity required for skin perforation with regard to skin origin or projectile shape was found. A greater velocity was required to perforate intact skin on a whole limb than isolated skin alone (p<0.05). An empirical relationship describing the velocity required to perforate skin by metallic FSPs of a range of sectional densities was generated. Skin has a significant effect on the retardation of FSPs, necessitating its incorporation in future injury models. Perforation algorithms based on animal and PMHS skin can be used interchangeably as well as spheres and cylinders of matching sectional density. Future numerical simulations for skin perforation must match the velocity for penetration and also require experimental determination of mechanical skin properties, such as tensile strength, strain and elasticity at high strain rates.


The p53 inactivators pifithrin-μ and pifithrin-α mitigate TBI-induced neuronal damage through regulation of oxidative stress, neuroinflammation, autophagy and mitophagy.
Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide. We investigated whether inhibition of p53 using pifithrin (PFT)-α or PFT-μ provides neuroprotective effects via p53 transcriptional dependent or -independent mechanisms, respectively. Sprague Dawley rats were subjected to controlled cortical impact TBI followed by the administration of PFTα or PFT-μ (2 mg/kg, i.v.) at 5 h after TBI. Brain contusion volume, as well as sensory and motor functions were evaluated at 24 h after TBI. TBI-induced impairments were mitigated by both PFT-α and PFT-μ. Fluoro-Jade C staining was used to label degenerating neurons within the TBI-induced cortical contusion region that, together with Annexin V positive neurons, were reduced by PFT-μ. Double immunofluorescence staining similarly demonstrated that PFT-μ significantly increased HO-1 positive neurons and mRNA expression in the cortical contusion region as well as decreased numbers of 4-hydroxynonenal (4HNE)-positive cells. Levels of mRNA encoding for p53, autophagy, mitophagy, anti-oxidant, anti-inflammatory related genes and proteins were measured by RT-qPCR and immunohistochemical staining, respectively. PFT-α, but not PFT-μ, significantly lowered p53 mRNA expression. Both PFT-α and PFT-μ lowered TBI-induced pro-inflammatory cytokines (IL-1β and IL-6) mRNA levels as well as TBI-induced autophagic marker localization (LC3 and p62). Finally, treatment with PFT-μ mitigated TBI-induced declines in mRNA levels of PINK-1 and SOD2. Our data suggest that both PFT-μ and PFT-α provide neuroprotective actions through regulation of oxidative stress, neuroinflammation, autophagy, and mitophagy mechanisms, and that PFT-μ, in particular, holds promise as a TBI treatment strategy.


Partial reconstruction of the microvillus core bundle: characterization of villin as a Ca++-dependent, actin-bundling/depolymerizing protein.
The brush border, isolated from chicken intestine epithelial cells, contains the 95,000 relative molecular mass (M(r)) polypeptide, villin. This report describes the purification and characterization of villin as a Ca(++)-dependent, actin bundling/depolymerizing protein. Then 100,000 g supernatant from a Ca(++) extract of isolated brush borders is composed of three polypeptides of 95,000 (villin), 68,000 (fimbrin), and 42,000 M(r) (actin). Villin, following purification from this extract by differential ammonium sulfate precipitation and ion-exchange chromatography, was mixed with skeletal muscle F-actin. Electron microscopy of negatively stained preparations of these villin-actin mixtures showed that filament bundles were present. This viscosity, sedimentability, and ultrastructural morphology of filament bundles are dependent on the villin:actin molar ratio, the pH, and the free Ca(++) concentration in solution. At low free Ca(++) (less than 10(-6) M), the amount of protein in bundles, when measured by sedimentation, increased as the villin: actin molar ratio increased and reached a plateau at approximately a 4:10 ratio. This behavior correlates with the conversion of single actin filaments into filament bundles as detected in the electron microscope. At high free Ca(++) (more than 10(-6) M), there was a decrease in the apparent viscosity in the villin-actin mixtures to a level measured for the buffer. Furthermore, these Ca(++) effects were correlated with the loss of protein sedimented, the disappearance of filament bundles, and the appearance of short fragments of filaments. Bundle formation is also pH-sensitive, being favored at mildly acidic pH. A decrease in the pH from 7.6 to 6.6 results in an increase in sedimentable protein and also a transformation of loosly associated actin filaments into compact actin bundles. These results are consistent with the suggestions that villin is a bundling protein in the microvillus and is responsible for the Ca(++)-sensitive disassembly of the microvillar cytoskeleton. Thus villin may function in the cytoplasm as a major cytoskeletal element regulating microvillar shape.


Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies.
Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4-6, 6-8 and 8-10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.


Perfectionism and Effort-Related Cardiac Activity: Do Perfectionists Try Harder?
Do perfectionists try harder? Previous research on perfectionism and effort has used self-report items and task performance as indicators of effort. The current study investigated whether individual differences in perfectionism predicted effort-related cardiac activity during a mental effort task. Based on past research that suggests adaptive perfectionism is associated with higher effort, it was hypothesized that self-oriented perfectionism (SOP) would predict increased effort on the task. One hundred and eleven college students completed the Multidimensional Perfectionism Scale (MPS) and a self-paced parity task in which they received a small cash reward (3 cents) for each correct response. Impedance cardiography was used to assess autonomic reactivity, and regression models tested whether SOP and socially prescribed perfectionism (SPP) explained autonomic reactivity. Overall, participants showed both sympathetic (faster pre-ejection period; PEP) and parasympathetic activation (elevated high-frequency heart rate variability; HRV) during the task, reflecting higher effort and engagement. Contrary to predictions, individual differences in perfectionism did not moderate cardiac reactivity. These findings draw attention to the importance of assessing physiological components of effort and motivation directly rather than inferring them from task performance or self-reported effort.


Primary antiphospholipid syndrome: a 5-year transesophageal echocardiographic followup study.
To study valvular abnormalities in patients with primary antiphospholipid syndrome (APS) assessed by transesophageal echocardiography (TEE). This was a 5-year followup study. Between 1995 and 1997, 29 consecutive patients with primary APS were studied by TEE. Twenty-four patients were evaluated in our institution and 5 were referred from elsewhere. Four patients had died, 12 patients had the 5-year followup TEE, and 8 failed to report for the study. In the first TEE, valve lesions were found in 17 patients (70.8%), myocardial infarction in 5 cases (29.4%), pulmonary hypertension in 4 (23.5%), and a calcified thrombus in the right atrium in one patient. Five-year followup TEE was performed in 12 patients. Valve lesions were unchanged in 3 cases, and in one of them a new apical akinesis of the left ventricle appeared. New valve lesions were detected in 3 patients. In 6 patients, the valve lesions had progressed and in 2, abnormalities of ventricular wall motion had appeared. In this highly selected population of patients with primary APS, the predominant cardiac lesion was a noninfective valve lesion. Oral anticoagulant treatment and aspirin proved ineffective in terms of valvular lesion regression. Altogether, myocardial infarction occurred in 9 (37.5%) patients. All had coronary angiography and coronary arteries were normal in 6.


Calmodulin-dependent protein kinase II, and not protein kinase C, is sufficient for triggering cell-cycle resumption in mammalian eggs.
Mouse eggs arrest at metaphase II following ovulation and are only triggered to complete meiosis when fertilized. Sperm break the cell-cycle arrest by a long-lasting series of Ca2+ spikes that lead to an activation of the anaphase-promoting complex/cyclosome. The signal transduction pathway is not fully resolved but both protein kinase C (PKC) and calmodulin-dependent protein kinase II (CamKII) activities increase at fertilization and previous pharmacological studies have implicated both in cell-cycle resumption. We have used a combination of pharmacological inhibitors and constitutively active cRNA constructs of PKCalpha and CamKIIalpha microinjected into mouse eggs to show that it is CamKII and not PKC that is the sufficient trigger for cell-cycle resumption from metaphase II arrest. Constitutively active PKC constructs had no effect on the resumption of meiosis but caused an immediate and persistent elevation in intracellular Ca2+ when store-operated Ca2+ entry was stimulated. With respect to resumption of meiosis, the effects of constitutively active CamKII on eggs were the same as sperm. Eggs underwent second polar body extrusion and pronucleus formation with normal timings; while both securin and cyclin B1 destruction, visualised by coupling to fluorescent protein tags, were complete by the time of polar body extrusion. Induction of a spindle checkpoint by overexpression of Mad2 or by spindle poisons blocked CamKII-induced resumption of meiosis, but the Ca2+ chelator BAPTA did not. Furthermore direct measurement of Ca2+ levels showed that CamKII did not induce exit from metaphase II arrest by raising Ca2+. Therefore, we conclude that PKCs may play an important role in maintaining Ca2+ spiking at fertilization by promoting store-operated Ca2+ entry, while CamKII transduces cell-cycle resumption, and lies downstream of sperm-induced Ca2+ release but upstream of a spindle checkpoint. These data, combined with the knowledge that CamKII activity increase at fertilization, suggest that mouse eggs undergo cell-cycle resumption through stimulation of CamKII.


Single-step adhesives are permeable membranes.
This study tested the hypotheses that micro-tensile bond strengths of all currently available single-step adhesives to dentine are adversely affected by delayed activation of a light-cured composite, and that such a phenomenon only occurs in the presence of water from the substrate side of the bonded interface. In experiment I, a control three-step adhesive (All-Bond 2, Bisco) and six single-step adhesives (One-Up Bond F, Tokuyama; Etch&Prime 3.0, Degussa; Xeno CF Bond, Sankin; AQ Bond, Sun Medical; Reactmer Bond, Shofu and Prompt L-Pop, 3M ESPE) were bonded to sound, hydrated dentine. A microfilled composite was placed over the cured adhesive and was either light-activated immediately, or after leaving the composite in the dark for 20 min. In experiment II, three single-step adhesives (Etch&Prime 3.0, Xeno CF Bond and AQ Bond) were similarly bonded to completely dehydrated dentine using the same delayed light-activation protocol. In experiment III, a piece of processed composite was used as the bonding substrate for the same three single-step adhesives. The microfilled composite was applied to the cured adhesives using the same immediate and delayed light-activation protocols. Bonded specimens were sectioned for micro-tensile bond strength evaluation. Fractographic analysis of the specimens was performed using SEM. Stained, undemineralised sections of unstressed, bonded specimens were also examined by TEM. When bonded to hydrated dentine, delayed light-activation had no effect on the control three-step adhesive, but significantly lowered the bond strengths of all the single-step adhesives (p < 0.05). This adverse effect of delayed light-activation was not observed in the three single-step adhesives that were bonded to either dehydrated dentine or processed composite. Morphological manifestations of delayed light-activation of composite in the hydrated dentine bonding substrate were exclusively located along the composite-adhesive interface, and were present as large voids, resin globules and honeycomb structures that formed partitions around a myriad of small blisters along the fractured interfaces. These features resembled the 'overwet phenomenon' that was previously reported along the dentine-adhesive interfaces of some acetone-based three-step adhesives. The cured adhesive layer in single-step adhesives may act as semi-permeable membranes that allow water diffusion from the bonded hydrated dentine to the intermixed zone between the adhesive and the uncured composite. Osmotic blistering of water droplets along the surface of the cured adhesive layer and emulsion polymerisation of immiscible resin components probably account for the compromised bond strength in single-step adhesives after delayed activation of light-cured composites.


A High Throughput, 384-Well, Semi-Automated, Hepatocyte Intrinsic Clearance Assay for Screening New Molecular Entities in Drug Discovery.
A high throughput, semi-automated clearance screening assay in hepatocytes was developed allowing a scientist to generate data for 96 compounds in one week. The 384-well format assay utilizes a Thermo Multidrop Combi and an optimized LC-MS/MS method. The previously reported LCMS/ MS method reduced the analytical run time by 3-fold, down to 1.2 min injection-to-injection. The Multidrop was able to deliver hepatocytes to 384-well plates with minimal viability loss. Comparison of results from the new 384-well and historical 24-well assays yielded a correlation of 0.95. In addition, results obtained for 25 marketed drugs with various metabolism pathways had a correlation of 0.75 when compared with literature values. Precision was maintained in the new format as 8 compounds tested in ≥39 independent experiments had coefficients of variation ≤21%. The ability to predict in vivo clearances using the new stability assay format was also investigated using 22 marketed drugs and 26 AbbVie compounds. Correction of intrinsic clearance values with binding to hepatocytes (in vitro data) and plasma (in vivo data) resulted in a higher in vitro to in vivo correlation when comparing 22 marketed compounds in human (0.80 vs 0.35) and 26 AbbVie Discovery compounds in rat (0.56 vs 0.17), demonstrating the importance of correcting for binding in clearance studies. This newly developed high throughput, semi-automated clearance assay allows for rapid screening of Discovery compounds to enable Structure Activity Relationship (SAR) analysis based on high quality hepatocyte stability data in sufficient quantity and quality to drive the next round of compound synthesis.


Psychometric validation of a patient-reported measure of physical functioning in sporadic inclusion body myositis.
To assess self-reported physical functioning in patients with sporadic inclusion body myositis (sIBM), the sIBM Physical Functioning Assessment (sIFA) was developed. This research establishes the validity, reliability, and responsiveness of the sIFA in patients with sIBM. Data from 3 small, noninterventional, observational studies were analyzed. Several measures of physical function were included to assess validity. Reliability (Cronbach alpha, test-retest intraclass correlations), construct validity (correlations, analyses of variance), and responsiveness (effect size estimates) were evaluated. Cronbach alphas (range = 0.86-0.91) and test-retest reliability (0.91) were highly satisfactory. Correlations with other measures provided evidence of convergent validity. sIBM patients able to walk without assistive devices scored significantly better on the sIFA (means = 36.0-47.05) than those who required power mobility or wheelchairs (means = 54.9-71.5), demonstrating the discriminating ability of the sIFA. Effect size estimates of responsiveness suggested mild functional progression. Psychometric analyses of the sIFA demonstrate satisfactory reliability, validity, and responsiveness. Muscle Nerve 54: 658-665, 2016.


Emergency department visits for ambulatory care sensitive conditions.
To describe emergency department visits for ambulatory care sensitive conditions. Exploratory, descriptive, ecological, quantitative study. From January 2015 to December 2016, was accessed the database with information of visits performed in an emergency department located in the region of Campo Limpo, municipality of São Paulo. A 99% confidence interval was considered for the incidence of visits with identification of ambulatory care sensitive conditions, and a margin of error of 0.4%. The analyzes were performed with use of the statistical package SPSS. We found 434,883 visits, of which 17.1% were due to ambulatory care sensitive conditions, mostly of women and children up to 4 years of age. The reason for most visits were ear, nose and throat infections (45.4%). There was a higher chance of visits for the indicator in chronic patients (p<0.001). This study demonstrated the emergency department ambulatory care sensitive conditions visits that may indicate poor access to primary care.


Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies.
Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25-hydroxy-vitamin D (25[OH]-vitamin D) levels for potential cardiovascular health benefits remain unclear. We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65 994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30-1.77) for total CVD, 1.42 (95% confidence interval, 1.19-1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21-1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ≈60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00-1.06) per 25-nmol/L decrement in 25(OH)-vitamin D. This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations.


Concurrent Radiosurgery and Immune Checkpoint Inhibition: Improving Regional Intracranial Control for Patients With Metastatic Melanoma.
The anti-CTLA-4 and antiprogrammed cell death-1 (PD-1) therapies have significantly improved survival of patients with metastatic melanoma. However, there is limited data regarding the interaction between immunotherapy (IT) and stereotactic radiosurgery (SRS) in patients with brain metastasis, particularly how combination therapy may affect toxicity and intracranial tumor control. We retrospectively reviewed 26 patients with metastatic melanoma who received immune check point inhibitors and SRS for brain metastasis from 2011 to 2017. We evaluated lesions receiving SRS concurrently (within 30 days) and sequentially with IT. Overall survival (OS), local control (LC), and regional progression free survival (RPFS) were determined. In total, 26 patients and 90 lesions were treated using pembrolizumab, nivolumab and/or ipilimumab, sequentially, or concurrently with SRS. Median follow-up was 18.9 months (range, 4.9 to 62.3 mo). Median overall survival was 26.1 months. There were 3 local failures, but no significant difference between the 2 groups. Following concurrent SRS and immunotherapy, patients had a significantly longer period of intracranial progression free survival than those treated with nonconcurrent therapy, 19 months versus 3.4 months (P<0.0001). No grade 4-5 toxicities were observed. Patients with melanoma metastatic to brain treated with SRS and immune checkpoint inhibitors had favorable median survival of 26.1 months compared with historical controls. Patients receiving immunotherapy within 30 days of SRS had significantly improved regional intracranial progression free survival compared with patients receiving sequential therapy. Our findings suggest synergy between checkpoint inhibitor immunotherapy and radiosurgery. Further studies are needed to confirm these findings.


Cannabinoids: A New Perspective on Epileptogenesis and Seizure Treatment in Early Life in Basic and Clinical Studies.
Neural hyperexcitability in the event of damage during early life, such as hyperthermia, hypoxia, traumatic brain injury, status epilepticus, or a pre-existing neuroinflammatory condition, can promote the process of epileptogenesis, which is defined as the sequence of events that converts a normal circuit into a hyperexcitable circuit and represents the time that occurs between the damaging event and the development of spontaneous seizure activity or the establishment of epilepsy. Epilepsy is the most common neurological disease in the world, characterized by the presence of seizures recurring without apparent provocation. Cannabidiol (CBD), a phytocannabinoid derived from the subspecies Cannabis sativa (CS), is the most studied active ingredient and is currently studied as a therapeutic strategy: it is an anticonvulsant mainly used in children with catastrophic epileptic syndromes and has also been reported to have anti-inflammatory and antioxidant effects, supporting it as a therapeutic strategy with neuroprotective potential. However, the mechanisms by which CBD exerts these effects are not entirely known, and the few studies on acute and chronic models in immature animals have provided contradictory results. Thus, it is difficult to evaluate the therapeutic profile of CBD, as well as the involvement of the endocannabinoid system in epileptogenesis in the immature brain. Therefore, this review focuses on the collection of scientific data in animal models, as well as information from clinical studies on the effects of cannabinoids on epileptogenesis and their anticonvulsant and adverse effects in early life.


Lost in Time: Temporal Monitoring Elicits Clinical Decrements in Sustained Attention Post-Stroke.
Mental fatigue, 'brain fog', and difficulties maintaining engagement are commonly reported issues in a range of neurological and psychiatric conditions. Traditional sustained attention tasks commonly measure this capacity as the ability to detect target stimuli based on sensory features in the auditory or visual domains. However, with this approach, discrete target stimuli may exogenously capture attention to aid detection, thereby masking deficits in the ability to endogenously sustain attention over time. To address this, we developed the Continuous Temporal Expectancy Task (CTET) where individuals continuously monitor a stream of patterned stimuli alternating at a fixed temporal interval (690 ms) and detect an infrequently occurring target stimulus defined by a prolonged temporal duration (1020 ms or longer). As such, sensory properties of target and non-target stimuli are perceptually identical and differ only in temporal duration. Using the CTET, we assessed stroke survivors with unilateral right hemisphere damage (N = 14), a cohort in which sustained attention deficits have been extensively reported. Stroke survivors had overall lower target detection accuracy compared with neurologically healthy age-matched older controls (N = 18). Critically, stroke survivors performance was characterised by significantly steeper within-block performance decrements, which occurred within short temporal windows (˜3 ½ min), and were restored by the break periods between blocks. These findings suggest that continuous temporal monitoring taxes sustained attention processes to capture clinical deficits in this capacity over time, and outline a precise measure of the endogenous processes hypothesised to underpin sustained attention deficits following right hemisphere stroke.


Ovarian vein thrombosis: incidence of recurrent venous thromboembolism and survival.
For patients with ovarian vein thrombosis (OVT), neither the rate of recurrence nor the expected survival are well established. Clarification of these natural history data would aid in defining the optimal management. We studied all female patients with OVT seen at the Mayo Clinic between 1990 and 2006. Survival, recurrent venous thrombosis rates, and prothrombotic factors were compared to a randomly selected group of 114 female patients with lower extremity venous thrombosis (DVT). Patients with OVT (n = 35; mean age 44.8 +/- 17.9 years) were significantly more likely to be under hormonal stimulation (48%), have an underlying malignancy (34%), experienced recent pelvic infection (23%) or undergone recent surgery (20%), compared to DVT patients. During a mean follow-up period of 34.6 +/- 44.3 months, three patients suffered three recurrent venous thrombi (event rate: three per 100 patient years of follow-up). This recurrence rate was comparable to patients with lower extremity DVT (2.2 per 100 patient years). Recurrent thrombosis involved the contralateral ovarian vein, left renal vein, and inferior vena cava. The five-year mortality rate for OVT patients was 43% compared to 20% for DVT patients (p = 0.08). All OVT deaths were cancer related. Survival was greater in OVT patients without cancer compared to those with active cancer (p < 0.0001). In conclusion, venous thromboembolism recurrence rates are low and comparable to lower extremity DVT. Therefore general treatment guidelines for lower extremity DVT may be applicable. Poor survival rates in OVT are principally governed by the presence of malignancy.


Seasonality and predictability shape temporal species diversity.
Temporal environmental fluctuations, such as seasonality, exert strong controls on biodiversity. While the effects of seasonality are well known, the predictability of fluctuations across years may influence seasonality in ways that are less well understood. The ability of a habitat to support unique, non-nested assemblages of species at different times of the year should depend on both seasonality (occurrence of events at specific periods of the year) and predictability (the reliability of event recurrence) of characteristic ecological conditions. Drawing on tools from wavelet analysis and information theory, we developed a framework for quantifying both seasonality and predictability of habitats, and applied this using global long-term rainfall data. Our analysis predicted that temporal beta diversity should be maximized in highly predictable and highly seasonal climates, and that low degrees of seasonality, predictability, or both would lower diversity in characteristic ways. Using stream invertebrate communities as a case study, we demonstrated that temporal species diversity, as exhibited by community turnover, was determined by a balance between temporal environmental variability (seasonality) and the reliability of this variability (predictability). Communities in highly seasonal mediterranean environments exhibited strong oscillations in community structure, with turnover from one unique community type to another across seasons, whereas communities in aseasonal New Zealand environments fluctuated randomly. Understanding the influence of seasonal and other temporal scales of environmental oscillations on diversity is not complete without a clear understanding of their predictability, and our framework provides tools for examining these trends at a variety of temporal scales, seasonal and beyond. Given the uncertainty of future climates, seasonality and predictability are critical considerations for both basic science and management of ecosystems (e.g., dam operations, bioassessment) spanning gradients of climatic variability.


Magnetic resonance imaging features of equine nigropallidal encephalomalacia.
Magnetic resonance imaging (MR) was used to make a diagnosis of equine nigropallidal encephalomalacia in a horse. Equine nigropallidal encephalomalacia is a neurodegenerative disease that has many characteristics with Parkinson-like diseases in humans. Historically, horses were euthanized based on clinical signs and exposure to the toxic weed, yellow star thistle (Centaurea solstitialis). Previously, the disease has only been confirmed on necropsy. MR imaging can provide accurate and sensitive visualization of typical lesions seen in the brain of horses affected with equine nigropallidal encephalomalacia. Lesions were seen on T1-weighted, T2-weighted and proton density images. There was no contrast enhancement following Gd-DTPA administration. Lesions seen on MR were confirmed at necropsy. Using MR to confirm a diagnosis of equine nigropallidal encephalomalacia will prevent unnecessary suffering of horses and expense to owners that would otherwise incur, while further diagnostics are performed.


Evaluation of Clinical Outcomes of Osseointegrated Dental Implantation of Fibula Free Flaps for Mandibular Reconstruction.
Dental implantation has been used for oral rehabilitation to improve cosmesis and function. We aim to evaluate the clinical outcomes and success rates of primary and secondary dental implant placement in vascularized fibula bone grafts used for segmental mandibulectomy defects. A retrospective review was performed between November 2005 and July 2014 on all patients undergoing both fibula free tissue reconstruction of mandibular defects and endosseous dental implantation at an academic tertiary care referral hospital. Either primary (n = 20) or secondary (n = 26) dental implantation of the fibula was performed. Timing of implantation, location of implants, history of tobacco, alcohol, and radiation, reason for mandibulectomy, and outcomes related to these parameters. Forty-six patients (31 males, 15 females; mean age, 58.0 years) underwent dental implantation to the fibula graft. A total of 227 implants were placed, with a mean of 5 implants per patient (range, 2-7). Of these, 44 were placed into native mandible and 183 into fibula flap. Twenty patients underwent primary implantation and received 96 implants, while 26 patients underwent secondary implantation and received 131 implants. There were no flap failures and 22 implant-related complications in 16 patients (implant failure, n = 10; granulation or soft-tissue overgrowth, n = 6; exposed bone around implant, n = 6). An implant failure occurred in 10 patients (22%) resulting in removal of 15 implants. Nine of these patients underwent successful dental rehabilitation, 5 without further implantation, and 4 with replaced implants. One patient was not rehabilitated secondary to failed implantation. Therefore, there was a 93% overall implant survival rate (n = 212) and 98% overall implant-supported prosthesis success rate (n = 45) at a mean follow-up of 22 months. There was no difference in implant survival between primary (94%) (n = 90) and secondary (93%) (n = 122) implantation. Neither a history of preimplant or postimplant radiation exposure nor the diagnosis of osteoradionecrosis affected implant survival. Osseointegrated dental implantation is a relatively safe procedure with few complications. Vascularized fibula grafts are a suitable method of mandibular reconstruction and are amenable to successful primary and secondary endosseous implantation. 4.


Characterization of Leaf Rust Resistance in Hard Red Spring Wheat Cultivars.
Leaf rust, caused by Puccinia triticina Eriks., is the most common disease of wheat (Triticum aestivum L.) in the United States and worldwide. The objective of this study was to characterize seedling and adult plant leaf rust resistance in hard red spring wheat cultivars grown in Minnesota, North Dakota, and South Dakota, and postulate the identity of the seedling leaf rust resistance genes in the cultivars. Twenty-six cultivars, near-isogenic lines of Thatcher wheat that differ for single leaf rust resistance genes, and three wheat cultivars with known leaf rust resistance genes, were tested with 11 different isolates of leaf rust collected from the United States and Canada. The leaf rust infection types produced on seedling plants of the cultivars in greenhouse tests were compared with the infection types produced by the same isolates on the Thatcher near-isogenic lines to postulate which seedling leaf rust resistance genes were present. Seedling leaf rust resistance genes Lr1, Lr2a, Lr10, Lr16, Lr21, and Lr24 were postulated to be present in spring wheat cultivars. Seedling genes Lr3, Lr14a, and Lr23 likely were present in some cultivars but could not be clearly identified in this study. Most of the cultivars had some level of adult plant leaf rust resistance, most likely due to Lr34. Cultivars that had seedling resistance genes Lr1, Lr2a, Lr10, or Lr16 had poor to intermediate levels of leaf rust resistance in field plots. Cultivars with combinations of seedling resistance genes Lr16 and Lr24 with additional adult plant resistance were highly resistant to leaf rust.


Characterizing Antimicrobial Resistant Escherichia coli and Associated Risk Factors in a Cross-Sectional Study of Pig Farms in Great Britain.
Combatting antimicrobial resistant (AMR) using a One-Health approach is essential as various bacteria, including Escherichia coli, a common bacteria, are becoming increasingly resistant and livestock may be a reservoir. The AMR gene content of 492 E. coli, isolated from 56 pig farms across Great Britain in 2014-2015, and purified on antibiotic selective and non-selective plates, was determined using whole genome sequencing (WGS). The E. coli were phylogenetically diverse harboring a variety of AMR profiles with widespread resistance to "old" antibiotics; isolates harbored up to seven plasmid Inc-types. None showed concurrent resistance to third-generation cephalosporins, fluoroquinolones and clinically relevant aminoglycosides, although ∼3% harbored AMR genes to both the former two. Transferable resistance to carbapenem and colistin were absent, and six of 117 E. coli STs belonged to major types associated with human disease. Prevalence of genotypically MDR E. coli, gathered from non-selective media was 46.9% and that of extended-spectrum-beta-lactamase E. coli was low (∼4% from non-selective). Approximately 72.6% of E. coli from ciprofloxacin plates and only 8.5% from the other plates harbored fluoroquinolone resistance due to topoisomerase mutations; the majority were MDR. In fact, multivariable analysis confirmed E. coli purified from CIP enrichment plates were more likely to be MDR, and suggested MDR isolates were also more probable from farms with high antibiotic usage, specialist finisher farms, and farms emptying their manure pits only after each batch. Additionally, farms from the South East were more likely to have MDR E. coli, whereas farms in Yorkshire and the Humber were less likely. Future investigations will determine whether suggested improvements such as better biosecurity or lower antimicrobial use decreases MDR E. coli on pig farms. Although this study focuses on pig farms, we believe the methodology and findings can be applied more widely to help livestock farmers in the United Kingdom and elsewhere to tackle AMR.