Implementation and effectiveness of integrated trauma and addiction treatment for incarcerated men.
A controlled trial of Seeking Safety (SS) and Male-Trauma Recovery Empowerment Model (M-TREM) examined implementation and effectiveness of integrated group therapy for comorbid post-traumatic stress disorder (PTSD) and substance use disorder (SUD) on PTSD and mental health symptoms plus self-esteem and efficacy for incarcerated men. The study sample (n=230) was male inmates 18 years or older who were primarily non-white, high school graduates or equivalents, had childhood trauma histories, committed violent crimes, had serious mental illnesses, and resided in a maximum security prison. Incarcerated men, who screened positive for PTSD and SUD, were assigned randomly (n=142) or by preference (n=88) to receive SS or M-TREM, with a waitlist group of (n=93). Manualized interventions were group-administered for 14 weeks. Primary outcomes were PTSD and other mental health symptoms. Secondary outcomes were self-esteem, coping, and self-efficacy. SUD outcomes cannot be measured in a correctional setting. Implementation feasibility was exhibited by the ability to recruit, screen, assign, and retain participants. Effectiveness findings depended on sample, design, and method for analysis. Using a waitlist control group and no follow-up period, we found no aggregate effect of treatment on PTSD symptoms, although, when disaggregated, M-TREM was found to improve PTSD severity and SS improved general mental health symptoms and psychological functioning. Using intent-to-treat and completer analyses, no significant differences were found in the relative performance between SS and M-TREM on primary or secondary outcomes. When longitudinal data were maximized and modeled in ways that reflect the hierarchical nature of the data, we found that SS and M-TREM performed better than no treatment on PTSD severity and secondary outcomes, and that treatment benefits endured. Findings cautiously support implementing either Seeking Safety or M-TREM to treat incarcerated men with co-morbid PTSD and addiction problems.


Dietary flexibility and intestinal plasticity in birds: a field and laboratory study.
The adaptive modulation hypothesis posits that the expression of digestive proteins should be modulated in response to intake of their respective substrates. A corollary of this hypothesis suggests that dietary flexibility and digestive plasticity should be correlated. We examined these two hypotheses in two granivorous Chilean birds (Zonotrichia capensis and Diuca diuca) that differ in dietary breadth. D. diuca is a strict granivore, whereas Z. capensis also eats insects. In field-caught birds, the activity of the intestinal dipeptidase aminopeptidase-N was positively correlated with intake of insects in Z. capensis but not in D. diuca. This is the first field documentation of modulation of intestinal enzymes by diet in birds. Intestinal maltase and sucrase activities were not correlated with seed (vs. insect) intake in either species. In the laboratory, captive birds of both species exhibited similar modulation of membrane-bound intestinal hydrolases when fed on synthetic diets of contrasting carbohydrate and protein composition. Maltase, sucrase, and aminopeptidase-N activities were significantly higher in birds fed on the carbohydrate-free than those on the carbohydrate-containing diet. Activities of the three enzymes were positively correlated. Therefore, this increase probably resulted from nonspecific increases of all enzymes resulting from intake of the carbohydrate-free diet. Principal components analysis separating the effect of diet on specific and on nonspecific modulation revealed that diet had a strong effect on nonspecific activity of intestinal enzymes in both Z. capensis and D. diuca. Diet also significantly affected aminopeptidase-N activities when the effect of diet on nonspecific modulation was removed. Birds fed on the carbohydrate-free, high-protein diet had significantly higher specific aminopeptidase-N activities than those fed on the carbohydrate-containing diet. Our results cast doubts on the notion that dietary flexibility and the plasticity of the gut's enzymes are necessarily correlated and on the general validity of the adaptive modulation hypothesis.


Community-Based Mind-Body Meditative Tai Chi Program and Its Effects on Improvement of Blood Pressure, Weight, Renal Function, Serum Lipoprotein, and Quality of Life in Chinese Adults With Hypertension.
Obesity, metabolic syndrome, dyslipidemia, and poor quality of life are common conditions associated with hypertension, and incidence of hypertension is age dependent. However, an effective program to prevent hypertension and to improve biomedical factors and quality of life has not been adequately examined or evaluated in Chinese older adults. This study aims to examine the effectiveness of a Tai Chi program to improve health status in participants with hypertension and its related risk factors such as dyslipidemia, hyperglycemia, and quality of life in older adults in China. A randomized study design was used. At the conclusion of the intervention, 266 patients remained in the study. Blood pressure and biomedical factors were measured according to the World Diabetes Association standard 2002. A standardized quality-of-life measure was used to measure health-related quality of life. It was found that a Tai Chi program to improve hypertension in older adults is effective in reducing blood pressure and body mass index, maintaining normal renal function, and improving physical health of health-related quality of life. It did not improve existing metabolic syndrome levels, lipid level (dyslipidemia) or fasting glucose level (hyperglycemia), to prevent further deterioration of the biomedical risk factors. In conclusion, Tai Chi is effective in managing a number of risk factors associated with hypertension in Chinese older adults. Future research should examine a combination of Tai Chi and nutritional intervention to further reduce the level of biomedical risks.


Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations.
Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of "universal" drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens.


Systematic review of the evidence on the effectiveness of sexual and reproductive health interventions in humanitarian crises.
This systematic review aims to evaluate evidence on the effectiveness of sexual and reproductive health (SRH) interventions delivered in humanitarian crises. Crisis affected low-income or middle-income countries. Crisis-affected populations in low-income or middle-income countries. Peer-reviewed and grey literature sources were systematically searched for relevant papers detailing interventions from 1 January 1980 until the search date on 30 April 2013. Data from included studies were then extracted, and the papers' quality evaluated using criteria based on modified STROBE and CONSORT checklists. Primary outcomes include, but are not limited to, changes in morbidity, mortality, sexually transmitted infection (STI) diagnosis or gender-based violence. Secondary outcomes include, but are not limited to, reported condom use or skilled attendance at birth. Primary outputs include, but are not limited to, condoms distributed or education courses taught. Of 7149 returned citations, 15 studies met the inclusion criteria. Only one randomised controlled trial was identified. The remaining observational studies were of moderate quality, demonstrating limited use of controls and inadequate attempts to address bias. Evidence of effectiveness was available for the following interventions: impregnated bed nets for pregnant women, subsidised refugee healthcare, female community health workers, and tiered community reproductive health services. The limited evidence base for SRH interventions highlights the need for improved research on the effectiveness of public health interventions in humanitarian crises. While interventions proven efficacious in stable settings are being used in humanitarian efforts, more evidence is required to demonstrate the effectiveness of delivering and scaling-up such interventions in humanitarian crises.


Synaptotagmin 2 Is the Fast Ca2+ Sensor at a Central Inhibitory Synapse.
GABAergic synapses in brain circuits generate inhibitory output signals with submillisecond latency and temporal precision. Whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Here, we examined the Ca2+ sensor of exocytosis at GABAergic basket cell (BC) to Purkinje cell (PC) synapses in cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2), whereas synaptotagmin 1 (Syt1) was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ∼10%, identifying Syt2 as the major Ca2+ sensor at BC-PC synapses. Differential adenovirus-mediated rescue revealed that Syt2 triggered release with shorter latency and higher temporal precision and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as release sensor at BC-PC synapses ensures fast and efficient feedforward inhibition in cerebellar microcircuits.


Biosensor technology: recent advances in threat agent detection and medicine.
Biosensors are of great significance because of their capability to resolve a potentially large number of analytical problems and challenges in very diverse areas such as defense, homeland security, agriculture and food safety, environmental monitoring, medicine, pharmacology, industry, etc. The expanding role of biosensing in society and a real-world environment has led to an exponential growth of the R&D efforts around the world. The world market for biosensor devices, according to Global Industry Analysts, Inc., is expected to reach $12 billion by 2015. Such expedient growth is driven by several factors including medical and health problems, such as a growing population with a high risk of diabetes and obesity, and the rising incidence of chronic diseases such as heart disease, stroke, cancer, chronic respiratory diseases, tuberculosis, etc.; significant problems with environmental monitoring; and of course serious challenges in security and military applications and agriculture/food safety. A review paper in the biosensor technology area may be structured based on (i) the principles of detection, such as the type of transducer platform, bioanalytical principles (affinity or kinetic), and biorecognition elements origin/properties (i.e. antibodies, enzymes, cells, aptamers, etc.), and (ii) the application area. This review follows the latter strategy and focuses on the applications. This allows discussion on how different sensing strategies are brought to bear on the same problem and highlights advantages/disadvantages of these sensing strategies. Given the broad range of biosensor related applications, several particularly relevant areas of application were selected for review: biological threat agents, chemical threat agents, and medicine.


VALIDATE: Exploiting the synergy between complex intracellular pathogens to expedite vaccine research and development for tuberculosis, leishmaniasis, melioidosis and leprosy.
For several complex intracellular pathogens, we have an urgent need for effective vaccines and yet there are common barriers to vaccine development. These diseases, including tuberculosis, leishmaniasis, leprosy and melioidosis, cause a huge burden of disease and disproportionately affect low and middle income countries. They are therefore often neglected due to the marginalisation of affected populations and the poor predicted commercial return on investment. Barriers to vaccine development include an incomplete understanding of protective immunity and translation from the bench into clinical vaccine trials. The current linear approach to vaccine research and development for these pathogens, which involves basic research, vaccine design, and vaccine evaluation in preclinical challenge models and clinical trials, is inefficient for these complex intracellular pathogens. We have established a Global Challenges Research Fund Network for VAccine deveLopment for complex Intracellular neglecteD pAThogEns, "VALIDATE", where we aim to adopt a more flexible, integrated cross-pathogen approach to accelerate vaccine research and clinical development for these four pathogens, by cross-pathogen analyses, cross-discipline collaborations, and repeated integration of data from human and animal studies. This network provides a unique opportunity to bring together individuals working on four exemplar complex intracellular neglected pathogens ( M.tb, Leishmania spp., B. pseudomallei and M.leprae), which share a common lifestyle as pathogens of macrophages, induce similar end-stage pathologies and alter host immune and metabolic responses. The horizontal collaborations established throughout this network, together with the provision of a protected environment for early data sharing, will exploit these biological synergies. By interrogating mechanisms that lead from infection to disease, we will be able to develop common vaccine development strategies for these and other complex intracellular pathogens.


To Treat or Not to Treat?
Background and Purpose- The 2015 updated US Food and Drug Administration alteplase package insert altered several contraindications. We thus explored clinical factors influencing alteplase treatment decisions for patients with minor stroke. Methods- An expert panel selected 7 factors to build a series of survey vignettes: National Institutes of Health Stroke Scale (NIHSS), NIHSS area of primary deficit, baseline functional status, previous ischemic stroke, previous intracerebral hemorrhage, recent anticoagulation, and temporal pattern of symptoms in first hour of care. We used a fractional factorial design (150 vignettes) to provide unconfounded estimates of the effect of all 7 main factors, plus first-order interactions for NIHSS. Surveys were emailed to national organizations of neurologists, emergency physicians, and colleagues. Physicians were randomized to 1 of 10 sets of 15 vignettes, presented randomly. Physicians reported the subjective likelihood of giving alteplase on a 0 to 5 scale; scale categories were anchored to 6 probabilities from 0% to 100%. A conjoint statistical analysis was applied. Results- Responses from 194 US physicians yielded 156 with complete vignette data: 74% male, mean age 46, 80% neurologists. Treatment mean probabilities for individual vignettes ranged from 6% to 95%. Treatment probability increased from 24% for NIHSS score =1 to 41% for NIHSS score =5. The conjoint model accounted for 25% of total observed response variance. In contrast, a model accounting for all possible interactions accounted for 30% variance. Four of the 7 factors accounted jointly for 58% of total relative importance within the conjoint model: previous intracerebral hemorrhage (18%), recent anticoagulation (17%), NIHSS (13%), and previous ischemic stroke (10%). Conclusions- Four main variables jointly account for only a small fraction (<15%) of the total variance related to deciding to treat with intravenous alteplase, reflecting high variability and complexity. Future studies should consider other variables, including physician characteristics.


Endoscopic Surgery versus Minimal Puncture Drainage Surgery for Treatment of Supratentorial Intracerebral Hemorrhage.
To compare neuroendoscopy versus minimal puncture drainage for surgical treatment of supratentorial hypertensive intracerebral hemorrhage. A total of 108 cases involving supratentorial intracerebral hemorrhage were retrospectively analyzed. In 30 cases, endoscopic surgery was performed, while 78 cases involved puncture surgery. We compared hematoma clearance rate, postoperative rebleeding rate, incidence of postoperative complications, operation duration, and Glasgow coma score seven days after surgery. Clinical data such as early postoperative rehabilitation time, Glasgow outcome score three months after surgery, and intensive care unit (ICU) stay were also compared between the two groups. The results showed that endoscopic surgery was associated with a superior clinical therapeutic effect in hematoma clearance rates, GCS scores on postoperative day 7, the average ICU stay, early postoperative rehabilitation time and intracranial infection outcomes than minimal puncture drainage surgery for the treatment of supratentorial intracerebral hemorrhage (p < 0.05). Three months after surgery, the favorable prognosis rate in the endoscopic treatment group was significantly higher than that in the craniotomy group [83.3% (28/34) vs. 61.5% (31/51), respectively; ? < sup > 2 < /sup > =4.698, p=0.030]. In contrast, no significant differences in rebleeding, pulmonary infection, tracheotomy, secondary epilepsy, gastrointestinal hemorrhage, death in late postoperative period, or in baseline parameters were observed between the two groups (p > 0.05). Endoscopic surgery potentially represents a beneficial surgical procedure for treatment of supratentorial spontaneous intracerebral hemorrhage.


Synthesis and antifungal activity of novel oxazolidin-2-one-linked 1,2,3-triazole derivatives.
Novel oxazolidin-2-one-linked 1,2,3-triazole derivatives (4a-k) were synthesized by straightforward and versatile azide-enolate (3 + 2) cycloaddition. The series of compounds was screened for antifungal activity against four filamentous fungi as well as six yeast species of Candida spp. According to their efficiency and breadth of scope, they can be ordered as 4k > 4d > 4h > 4a, especially in relation to the activity displayed against Candida glabrata ATCC-34138, Trichosporon cutaneum ATCC-28592 and Mucor hiemalis ATCC-8690, i.e. compounds 4d, 4h and 4k showed excellent activity against C. glabrata (MIC 0.12, 0.25 and 0.12 μg mL-1, respectively), better than that of itraconazole (MIC 1 μg ml-1). The activity of compound 4d (MIC = 2 μg mL-1) was higher than that observed for the standard antifungal drug (MIC = 8 μg mL-1) against Trichosporon cutaneum, while compound 4k displayed an excellent antimycotic activity against Mucor hiemalis (MIC = 2 μg mL-1vs. 4 μg mL-1 for itraconazole). In addition, we describe herein a novel mild and eco-friendly synthetic protocol for obtaining β-ketosulfones (adducts to afford compounds 4a-k) from α-brominated carbonyls in an aqueous nanomicellar medium at room temperature.


Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline.
The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are risk-based, exposure-related clinical practice guidelines intended to promote earlier detection of and intervention for complications that may potentially arise as a result of treatment for pediatric malignancies. Developed through the collaborative efforts of the Children's Oncology Group Late Effects Committee, Nursing Discipline, and Patient Advocacy Committee, these guidelines represent a statement of consensus from a multidisciplinary panel of experts in the late effects of pediatric cancer treatment. The guidelines are both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of risk with the intensity of screening recommendations). They are intended for use beginning 2 or more years following the completion of cancer therapy; however, they are not intended to provide guidance for follow-up of the survivor's primary disease. A complementary set of patient education materials ("Health Links") was developed to enhance follow-up care and broaden the application of the guidelines. The information provided in these guidelines is important for health care providers in the fields of pediatrics, oncology, internal medicine, family practice, and gynecology, as well as subspecialists in many fields. Implementation of these guidelines is intended to increase awareness of potential late effects and to standardize and enhance follow-up care provided to survivors of pediatric cancer throughout the lifespan. The Guidelines, and related Health Links, can be downloaded in their entirety at www.survivorshipguidelines.org.


Activation of superficial dorsal horn neurons in the mouse by a PAR-2 agonist and 5-HT: potential role in itch.
Itch, an unpleasant sensation associated with the desire to scratch, is symptomatic of dermatologic and systemic disorders that often resist antihistamine treatment. Histamine-independent itch mediators include serotonin (5-HT) and agonists of the protease-activated receptor-2 (PAR-2). We used behavior, Fos immunohistochemistry, and electrophysiology to investigate if these mediators activate spinal dorsal horn neurons in a manner consistent with itch. Intradermal (i.d.) injection of the PAR-2 agonist SLIGRL-NH(2) in the rostral back evoked bouts of directed hindlimb scratches over 20-30 min. Hindpaw injection of SLIGRL-NH(2) produced Fos staining in superficial dorsal horn which was then targeted for single-unit recording. Small id microinjections of SLIGRL-NH(2) or 5-HT identified responsive single units in the superficial dorsal horn of mice anesthetized with pentobarbital. Thirty-eight units characterized as wide dynamic range, nociceptive specific, or mechanically insensitive exhibited significantly increased firing after i.d. SLIGRL-NH(2) for 9 min, to partial (25%) tachyphylaxis with repeated injection. A majority additionally responded to 5-HT (70%), mustard oil (79%), and capsaicin (71%). Seven units isolated with the 5-HT search stimulus exhibited significant and prolonged responses to 5-HT with tachyphylaxis to repeated injections. The majority also responded to SLIGRL-NH(2), mustard oil, and capsaicin. The prolonged responses of superficial dorsal horn neurons to SLIGRL-NH(2) and 5-HT suggest a role in signaling itch. However, their responsiveness to algogens is inconsistent with itch specificity. Alternatively, such neurons may signal itch, whereas noxious stimulus levels recruit these and a larger population of pruritogen-insensitive cells to signal pain which masks or occludes the itch signal.


Insights from Operando and Identical Location (IL) Techniques on the Activation of Electrocatalysts for the Conversion of CO₂: A Mini-Review.
In this mini-review we compare two prototypical metal foam electrocatalysts applied to the transformation of CO₂ into value-added products (e.g. alcohols on Cu foams and formate on Bi foams). A substantial improvement in the catalyst performance is typically achieved through thermal annealing of the as-deposited foam materials, followed by the electro-reduction of the pre-formed oxidic precursors prior or during the actual CO₂ electrolysis. Utilizing highly insightful and sensitive complementary operando analytical techniques (XAS, XRD, and Raman spectroscopy) we demonstrate that this catalyst pre-activation process is entirely accomplished in case of the oxidized Cu foams prior to the formation of hydrocarbons and alcohols from the CO₂. The actually active catalyst is therefore the metallic Cu derived from the precursor by means of oxide electro-reduction. Conversely, in their oxidic form, the Cu-based foam catalysts are inactive towards the CO₂ reduction reaction (denoted ec-CO₂ RR). Oxidized Bi foams can be regarded as an excellent counter example to the above-mentioned Cu case as both metallic and the thermally derived oxidic Bi foams are highly active towards ec-CO₂ RR (formate production). Indeed, operando Raman spectroscopy reveals that CO₂ electrolysis occurs upon its embedment into the oxidic Bi₂O₃ foam precursor, which itself undergoes partial transformation into an active sub-carbonate phase. The potential-dependent transition of sub-carbonates/oxides into the corresponding metallic Bi foam dictates the characteristic changes of the ec-CO₂ RR pathway. Identical location (IL) microscopic inspection of the catalyst materials, e.g. by means of scanning electron microscopy, demonstrates substantial morphological alterations on the nm length scale on the material surface as consequence of the sub-carbonate formation and the potential-driven oxide reduction into the metallic Bi foam. The foam morphology on a mesoscopic length scale (macroporosity) remains, by contrast, fully unaffected by these phase transitions.


Xenotransplantation: a bioethical evaluation.
Allograft shortage is a formidable obstacle in organ transplantation. Xenotransplantation, the interspecies transplantation of cells, tissues, and organs, or ex vivo interspecies exchange between cells, tissues, and organs is a frequently suggested alternative to this allograft shortage. As xenotransplantation steadily improves into a viable allotransplantation alternative, several bioethical considerations coalesce. Such considerations include the Helsinki declaration's guarantee of patients' rights to privacy; political red tape that may select for undermined socioeconomic groups as the first recipients of xenografts; industry incentives in xenotransplantation investments; conflicts of interest when a clinician supervises a patient as a research subject; the psychosocial impact of transplantation on the xenograft recipient, and the rights of animals. This review illuminates these issues through a conglomeration of expert opinion and relevant experimental studies.


Influence of CO2 and Temperature on Metabolism and Development of Helicoverpa armigera (Noctuidae: Lepidoptera).
Climate change will have a major bearing on survival and development of insects as a result of increase in CO2 and temperature. Therefore, we studied the direct effects of CO2 and temperature on larval development and metabolism in cotton bollworm, Helicoverpa armigera (Hübner). The larvae were reared under a range of CO2 (350, 550, and 750 ppm) and temperature (15, 25, 35, and 45°C) regimes on artificial diet. Elevated CO2 negatively affected the larval survival, larval weight, larval period, pupation, and adult emergence, but showed a positive effect on pupal weight, pupal period, and fecundity. Increase in temperature exhibited a negative effect on larval survival, larval period, pupal weights, and pupal period, but a positive effect on larval growth. Pupation and adult emergence were optimum at 25°C. Elevated CO2 and temperature increased food consumption and metabolism of larvae by enhancing the activity of midgut proteases, carbohydrases (amylase and cellulase), and mitochondrial enzymes and therefore may cause more damage to crop production. Elevated CO2 and global warming will affect insect growth and development, which will change the interactions between the insect pests and their crop hosts. Therefore, there is need to gain an understanding of these interactions to develop strategies for mitigating the effects of climate change.


Characterization of defect levels in semi-insulating 6H-SiC by means of photoinduced transient spectroscopy and modulated photocurrent technique.
Parameters of electrically active defect centres in vanadium-doped 6H silicon carbide (6H-SiC:V) were investigated by means of the photoinduced transient spectroscopy (PITS) and modulated photocurrent (MPC) method. After a short description of the two techniques, experimental results are presented and briefly compared. Our aim is mainly to understand and explain these experimental results. In particular, in the PITS technique a shallow level seems to be at the origin of negative photoconductivity. Besides, in the same temperature range hole and electron levels can be detected at the same time. Finally, the detection of a given level seems to depend on the photon flux used to perform the PITS experiment. As far as the MPC experiment is concerned, it has put into evidence a very efficient shallow level. A numerical calculation was developed to simulate both experiments in order to understand the experimental results. By means of this simulation, we have explained all the phenomena observed experimentally in each technique and we propose a simple model for the distribution of electrically active defect centres in 6H-SiC:V crystals.


A Multistudy Cross-Sectional and Experimental Examination Into the Interactive Effects of Moral Identity and Moral Disengagement on Doping.
Moral identity and moral disengagement have been linked with doping likelihood. However, experiments testing the temporal direction of these relationships are absent. The authors conducted one cross-sectional and two experimental studies investigating the conjunctive effects of moral identity and moral disengagement on doping likelihood (or intention). Dispositional moral identity was inversely (marginally), and doping moral disengagement, positively, associated with doping intention (Study 1). Manipulating situations to amplify opportunities for moral disengagement increased doping likelihood via anticipated guilt (Study 2). Moreover, dispositional moral identity (Study 2) and inducing moral identity (Study 3) were linked with lower doping likelihood and attenuated the relationship between doping moral disengagement and doping likelihood. However, the suppressing effect of moral identity on doping likelihood was overridden when opportunities for moral disengagement were amplified. These findings support multifaceted antidoping efforts, which include simultaneously enhancing athlete moral identity and personal responsibility alongside reducing social opportunities for moral disengagement.


Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor.
Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor). Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. HIF-1alpha and HIF-2alpha immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA. Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration. 17/56 Ewing's tumours were HIF-1alpha-positive, 15 HIF-2alpha-positive and 10 positive for HIF-1alpha and HIF-2alpha. Expression of HIF-1alpha and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1alpha and HIF-2alpha in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2alpha in Ewing's. Downstream transcription was HIF-1alpha-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by >or= 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration. Co-localisation of HIF-1alpha and necrosis in Ewing's sarcoma suggests a role for hypoxia and/or hypoglycaemia in in vivo induction of HIF. In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing's and osteosarcoma, driving effects on proliferation and apoptosis. These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas.


Interactions between diphtheria toxin entry and anion transport in Vero cells. II. Inhibition of anion antiport by diphtheria toxin.
When cells with surface-bound diphtheria toxin were exposed to pH 4.5, the toxin became shielded against lactoperoxidase-catalyzed radioiodination, indicating that the toxin was inserted into the membrane. Cells thus treated had strongly reduced ability to take up 36Cl-, 35SO4(2-), and [14C]SCN-. The reduction of chloride uptake was strongest at neutral pH, whereas that of sulfate was strongest at acidic pH. Lineweaver-Burk plots indicated that the toxin treatment reduced the Jmax but not the Km for the anions. The toxin also inhibited the NaCl-stimulated efflux of 35SO4(2-), indicating that the toxin inhibits the antiporter. No inhibition was found when toxin-treated cells were not exposed to low pH, whereas exposure to pH 4.5 for 20 s induced close to maximal inhibition. Half-maximal inhibition was obtained after exposure to pH 5.4. The concentration of diphtheria toxin required to obtain maximal inhibition (0.3 micrograms/ml) was sufficient to ensure close to maximal toxin binding to the cells. Even in ATP-depleted cells and in the absence of permeant anions, low pH induced inhibition of anion antiport in toxin-treated Vero cells. There was no measurable inhibition of anion antiport in cells with little or no ability to bind the toxin.


Neuropathology of older persons without cognitive impairment from two community-based studies.
To examine the relation of National Institute on Aging-Reagan (NIA-Reagan) neuropathologic criteria of Alzheimer disease (AD) to level of cognitive function in persons without dementia or mild cognitive impairment (MCI). More than 2,000 persons without dementia participating in the Religious Orders Study or the Memory and Aging Project agreed to annual detailed clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains, including episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. A total of 134 persons without cognitive impairment died and underwent brain autopsy and postmortem assessment for AD pathology using NIA-Reagan neuropathologic criteria for AD, cerebral infarctions, and Lewy bodies. Linear regression was used to examine the relation of AD pathology to level of cognitive function proximate to death. Two (1.5%) persons met NIA-Reagan criteria for high likelihood AD, and 48 (35.8%) met criteria for intermediate likelihood; 29 (21.6%) had cerebral infarctions, and 18 (13.4%) had Lewy bodies. The mean Mini-Mental State Examination score proximate to death was 28.2 for those meeting high or intermediate likelihood AD by NIA-Reagan criteria and 28.4 for those not meeting criteria. In linear regression models adjusted for age, sex, and education, persons meeting criteria for intermediate or high likelihood AD scored about a quarter standard unit lower on tests of episodic memory (p = 0.01). There were no significant differences in any other cognitive domain. Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.


Estimating the proportion of pneumonia attributable to pneumococcus in Kenyan adults: latent class analysis.
Community-acquired pneumonia is a common cause of hospitalization among African adults, and Streptococcus pneumoniae is assumed to be a frequent cause. Pneumococcal conjugate vaccine is currently being introduced into childhood immunization programs in Africa. The case for adult vaccination is dependent on the contribution of the pneumococcus to the hospital pneumonia burden. Pneumococcal diagnosis is complex because there is no gold standard, and culture methods are invalidated by antibiotic use. We used latent class analysis to estimate the proportion of pneumonia episodes caused by pneumococcus. Furthermore, we extended this methodology to evaluate the effect of antimicrobial treatment on test accuracies and the prevalence of the disease. The study combined data from 5 validation studies of pneumococcal diagnostic tests performed on 281 Kenyan adults with pneumonia. The proportion of pneumonia episodes attributable to pneumococcus was 0.46 (95% confidence interval = 0.36-0.57). Failure to account for the effect of antimicrobial exposure underestimates this proportion as 0.32. A history of antibiotic exposure was a poor predictor of antimicrobial activity in patients' urine. Blood culture sensitivity for pneumococcus was estimated at 0.24 among patients with antibiotic exposure, and 0.75 among those without. The large contribution of pneumococcus to adult pneumonia provides a strong case for the investigation of pneumococcal vaccines in African adults.


Isolation of nanomolar scFvs of non-human primate origin, cross-neutralizing botulinum neurotoxins A1 and A2 by targeting their heavy chain.
Botulism is a naturally occurring disease, mainly caused by the ingestion of food contaminated by the botulinum neurotoxins (BoNTs). Botulinum neurotoxins are the most lethal. They are classified among the six major biological warfare agents by the Centers for Disease Control. BoNTs act on the cholinergic motoneurons, where they cleave proteins implicated in acetylcholine vesicle exocytosis. This exocytosis inhibition induces a flaccid paralysis progressively affecting all the muscles and generally engendering a respiratory distress. BoNTs are also utilized in medicine, mainly for the treatment of neuromuscular disorders, preventing large scale vaccination. Botulism specific treatment requires injections of antitoxins, usually of equine origin and thus poorly tolerated. Therefore, development of human or human-like neutralizing antibodies is of a major interest, and it is the subject of the European framework project called "AntiBotABE". In this study, starting from a macaque immunized with the recombinant heavy chain of BoNT/A1 (BoNT/A1-HC), an immune antibody phage-display library was generated and antibody fragments (single chain Fragment variable) with nanomolar affinity were isolated and further characterized. The neutralization capacities of these scFvs were analyzed in the mouse phrenic nerve-hemidiaphragm assay. After a three-round panning, 24 antibody fragments with affinity better than 10 nM were isolated. Three of them neutralized BoNT/A1 efficiently and two cross-neutralized BoNT/A1 and BoNT/A2 subtypes in the mouse phrenic nerve-hemidiaphragm assay. These are the first monoclonal human-like antibodies cross-neutralizing both BoNT/A1 and BoNT/A2. The antibody A1HC38 was selected for further development, and could be clinically developed for the prophylaxis and treatment of botulism.


Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons.
Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function.SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction.


Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE.
Peptide receptor radionuclide therapy (PRRT) is a promising treatment for patients with neuroendocrine tumors, giving rise to improved survival. Dosimetric calculations in relation to PRRT have been concentrated to normal organ dosimetry in order to limit side effects. However, the relation between the absorbed dose to the tumor and treatment response has so far not been established. Better knowledge in this respect may improve the understanding of treatment effects, allow for improved selection of those patients who are expected to benefit from PRRT, and avoid unnecessary treatments. The aim of the present work was to evaluate the dose-response relationship for pancreatic neuroendocrine tumors treated with PRRT using (177)Lu-DOTATATE. Tumor-absorbed dose calculations were performed for 24 lesions in 24 patients with metastasized pancreatic neuroendocrine tumors treated with repeated cycles of (177)Lu-DOTATATE at 8-wk intervals. The absorbed dose calculations relied on sequential SPECT/CT imaging at 24, 96, and 168 h after infusion of (177)Lu-DOTATATE. The unit density sphere model from OLINDA was used for absorbed dose calculations. The absorbed doses were corrected for partial-volume effect based on phantom measurements. On the basis of these results, only tumors larger than 2.2 cm in diameter at any time during the treatment were included for analysis. To further decrease the effect of partial-volume effect, a subgroup of tumors (>4.0 cm) was analyzed separately. Tumor response was evaluated by CT using Response Evaluation Criteria In Solid Tumors. Tumor-absorbed doses until best response ranged approximately from 10 to 340 Gy. A 2-parameter sigmoid fit was fitted to the data, and a significant correlation between the absorbed dose and tumor reduction was found, with a Pearson correlation coefficient (R(2)) of 0.64 for tumors larger than 2.2 cm and 0.91 for the subgroup of tumors larger than 4.0 cm. The largest tumor reduction was 57% after a total absorbed dose of 170 Gy. The results imply a significant correlation between absorbed dose and tumor reduction. However, further studies are necessary to address the large variations in response for similar absorbed doses.


The basal keratin network of stratified squamous epithelia: defining K15 function in the absence of K14.
Keratin 5 and keratin 14 have been touted as the hallmarks of the basal keratin networks of all stratified squamous epithelia. Absence of K14 gives rise to epidermolysis bullosa simplex, a human blistering skin disorder involving cytolysis in the basal layer of epidermis. To address the puzzling question of why this disease is primarily manifested in skin rather than other stratified squamous epithelia, we ablated the K14 gene in mice and examined various tissues expressing this gene. We show that a key factor is the presence of another keratin, K15, which was hitherto unappreciated as a basal cell component. We show that the levels of K15 relative to K14 vary dramatically among stratified squamous epithelial tissues, and with neonatal development. In the absence of K14, K15 makes a bona fide, but ultrastructurally distinct, keratin filament network with K5. In the epidermis of neonatal mutant mice, K15 levels are low and do not compensate for the loss of K14. In contrast, the esophagus is unaffected in the neonatal mutant mice, but does appear to be fragile in the adult. Parallel to this phenomenon is that esophageal K14 is expressed at extremely low levels in the neonate, but rises in postnatal development. Finally, despite previous conclusions that the formation of suprabasal keratin filaments might depend upon K5/K14, we find that a wide variety of suprabasal networks composed of different keratins can form in the absence of K14 in the basal layer.


Canine Gouging: A Taboo Resurfacing in Migrant Urban Population.
Cosmopolitan cities have become a pool of migrants from different parts of the world, who carry their cultural beliefs and superstitions with them around the globe. Canine gouging is a kind of infant oral mutilation (IOM) which is widely practiced among rural population of Africa where the primary tooth bud of the deciduous canine is enucleated. The belief is that the life threatening illnesses in children like vomiting, diarrhoea, and fevers are caused by worms which infest on tooth buds. This case report is of a 15-year-old Somalian born boy, who presented at the dental institute with intermittent pain in his lower right permanent canine which was associated with a discharging intra oral buccal sinus. The tooth was endodontically treated and then restored with composite. General dental practitioners need to be vigilant when encountered with tooth presenting unusual morphology, unilateral missing tooth, and shift in the midline due to early loss of deciduous/permanent canines. Identification of any such dental mutilation practice will need further counselling of the individual and family members. It is the duty of every dental professional to educate and safeguard the oral and dental health of general public.


Modeling possible cooling-water intake system impacts on Ohio River fish populations.
To assess the possible impacts caused by cooling-water intake system entrainment and impingement losses, populations of six target fish species near power plants on the Ohio River were modeled. A Leslie matrix model was constructed to allow an evaluation of bluegill, freshwater drum, emerald shiner, gizzard shad, sauger, and white bass populations within five river pools. Site-specific information on fish abundance and length-frequency distribution was obtained from long-term Ohio River Ecological Research Program and Ohio River Sanitation Commission (ORSANCO) electrofishing monitoring programs. Entrainment and impingement data were obtained from 316(b) demonstrations previously completed at eight Ohio River power plants. The model was first run under a scenario representative of current conditions, which included fish losses due to entrainment and impingement. The model was then rerun with these losses added back into the populations, representative of what would happen if all entrainment and impingement losses were eliminated. The model was run to represent a 50-year time period, which is a typical life span for an Ohio River coal-fired power plant. Percent changes between populations modeled with and without entrainment and impingement losses in each pool were compared to the mean interannual coefficient of variation (CV), a measure of normal fish population variability. In 6 of the 22 scenarios of fish species and river pools that were evaluated (6 species x 5 river pools, minus 8 species/river pool combinations that could not be evaluated due to insufficient fish data), the projected fish population change was greater than the expected variability of the existing fish population, indicating a possible adverse environmental impact. Given the number of other variables affecting fish populations and the conservative modeling approach, which assumed 100% mortality for all entrained fish and eggs, it was concluded that the likelihood of impact was by no means assured, even in these six cases. It was concluded that in most cases, current entrainment and impingement losses at six Ohio River power plants have little or no effect at the population level.


A Novel, Tumor-Induced Osteoclastogenesis Pathway Insensitive to Denosumab but Interfered by Cannabidiol.
Bone metabolism is strictly regulated, and impaired regulation caused by hormonal imbalances induces systemic bone loss. Local bone loss caused by tumor invasion into bone is suggested to be induced by the generation of cytokines, which affect bone metabolism, by tumor cells. The major cause of systemic and local bone losses is excess bone resorption by osteoclasts, which differentiate from macrophages by receptor activator of nuclear factor kappa-B ligand (RANKL) or tumor necrosis factor-alpha (TNF-α). We previously found a novel pathway for tumor-induced osteoclastogenesis targeting osteoclast precursor cells (OPCs). Tumor-induced osteoclastogenesis was resistant to RANKL and TNF-α inhibitors. In the present study, we confirmed that exosomes derived from oral squamous cell carcinoma (OSCC) cells induced osteoclasts from OPCs. We also showed that the depletion of exosomes from culture supernatants of OSCC cells partially interfered with osteoclastogenesis, and cannabidiol, an innoxious cannabinoid without psychotropic effects, almost completely suppressed tumor-induced osteoclastogenesis. Osteoclastogenesis and its interference by cannabidiol were independent of the expression of nuclear factor of T cell c1 (NFATc1). These results show that osteoclastogenesis induced by OSCC cells targeting OPCs is a novel osteoclastogenic pathway independent of NFATc1 expression that is partially caused by tumor-derived exosomes and suppressed by cannabidiol.


Phone and Video-Based Modalities of Central Blinded Adjudication of Modified Rankin Scores in an Endovascular Stroke Trial.
The standard outcome measure in stroke research is modified Rankin scale (mRS) evaluated by local blinded investigators. We aimed to assess feasibility and reliability of 2 central adjudication methods of mRS in the setting of a randomized endovascular stroke trial. This is a secondary analysis derived from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) trial cohort. Primary outcome was distribution of mRS at 90 days. Local evaluation was done by certified investigators masked to treatment assignment using structured face-to-face interviews. In addition, central assessment was performed by 2 independent raters via structured phone interview (n=120) and via video recordings of the face-to-face interviews with local investigators (n=106). Interrater agreement was evaluated using kappa and discordance statistics. Sensitivity analyses for the primary end point using different adjudication approaches were performed. Correlation between mRS obtained with each modality and 24-hour follow-up infarct volumes was studied. Using local evaluation as the reference, higher agreement rates were noted with central video than with central phone evaluations (kw 0.92 [0.88-0.96] versus 0.77 [0.72-0.83]). Discrepancies in mRS scoring between local and central raters (phone- and video-based) were similar in both treatment allocation arms. Sensitivity analyses showed benefit of endovascular treatment irrespective of adjudication method, but higher odds ratios were observed with local evaluations. Final infarct volume was similarly correlated with mRS across all 3 evaluation modalities. Central adjudication of mRS is feasible, reducing interrater variability and avoiding potential problems related to lack of blinding. Our findings may have implications in the planning of future randomized acute stroke trials, especially in those including nonpharmacological interventions. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.


Molecular genetic characterization of alternatively spliced CD44 transcripts in human stomach carcinoma.
CD44 is a member of cell surface glycoproteins which are involved in cell-matrix adhesion and tumor metastasis. Certain types of tumors express complex CD44 isoforms generated by alternative splicing of 2v-10v exons, and their expression appears to promote metastasis of tumor cells. Using a nested RT-PCR, we analyzed expression of CD44 variants in 26 stomach carcinoma, 21 matched normal tissues, and 2 carcinoma cell lines. We observed frequent and complex patterns of CD44 variant expression in tumor tissues. While exons 6v and 7v expression was detected in most normal and tumor tissues, exon 9v was most rarely detected. Exon 5v showed a significantly frequent expression in carcinoma, suggesting that its expression might contribute to the malignant progression. While exon 9v was frequently observed in diffuse-type tumors, the other 8 variant exons including 6v showed more frequent expression in intestinal-type tumors. Exons 9v and 10v were predominantly expressed in advanced tumor tissues and exon 8v was expressed more frequently in tumors of lymph node metastasis. We believe that series with a longer follow-up now need to be tested to clarify the association between CD44 splice variant expression and distant metastasis or long-term prognosis.


Lung transcriptional unresponsiveness and loss of early influenza virus control in infected neonates is prevented by intranasal Lactobacillus rhamnosus GG.
Respiratory viral infections contribute substantially to global infant losses and disproportionately affect preterm neonates. Using our previously established neonatal murine model of influenza infection, we demonstrate that three-day old mice are exceptionally sensitive to influenza virus infection and exhibit high mortality and viral load. Intranasal pre- and post-treatment of neonatal mice with Lactobacillus rhamnosus GG (LGG), an immune modulator in respiratory viral infection of adult mice and human preterm neonates, considerably improves neonatal mice survival after influenza virus infection. We determine that both live and heat-killed intranasal LGG are equally efficacious in protection of neonates. Early in influenza infection, neonatal transcriptional responses in the lung are delayed compared to adults. These responses increase by 24 hours post-infection, demonstrating a delay in the kinetics of the neonatal anti-viral response. LGG pretreatment improves immune gene transcriptional responses during early infection and specifically upregulates type I IFN pathways. This is critical for protection, as neonatal mice intranasally pre-treated with IFNβ before influenza virus infection are also protected. Using transgenic mice, we demonstrate that the protective effect of LGG is mediated through a MyD88-dependent mechanism, specifically via TLR4. LGG can improve both early control of virus and transcriptional responsiveness and could serve as a simple and safe intervention to protect neonates.


TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal.
Transforming growth factor-beta (TGFbeta) family members regulate many developmental and pathological events through Smad transcriptional modulators. How nuclear accumulation of Smad is coupled to the transcriptional machinery is poorly understood. Here we demonstrate that in response to TGFbeta stimulation the transcriptional regulator TAZ binds heteromeric Smad2/3-4 complexes and is recruited to TGFbeta response elements. In human embryonic stem cells TAZ is required to maintain self-renewal markers and loss of TAZ leads to inhibition of TGFbeta signalling and differentiation into a neuroectoderm lineage. In the absence of TAZ, Smad2/3-4 complexes fail to accumulate in the nucleus and activate transcription. Furthermore, TAZ, which itself engages in shuttling, dominantly controls Smad nucleocytoplasmic localization and can be retained in the nucleus by transcriptional co-factors such as ARC105, a component of the Mediator complex. TAZ thus defines a hierarchical system regulating Smad nuclear accumulation and coupling to the transcriptional machinery.


Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind, controlled trial.
Seventy-five patients with acute hepatic decompensation superimposed on chronic alcoholic cirrhosis were prospectively randomized for a blinded trial of the treatment of hepatic encephalopathy. The control group received 4 g of enteral neomycin daily along with 25% dextrose by a central venous catheter. The experimental group received a placebo resembling neomycin and isocaloric dextrose plus a modified amino acid mixture enriched with branched-chain amino acids to 36% and deficient in aromatic amino acids and methionine. Thirty patients in the F080 group and 29 in the control group completed the trial. The group receiving the modified amino acid mixture demonstrated a statistically significant improvement in encephalopathy as compared to the neomycin group, while maintaining nitrogen equilibrium. Survival and discharge from the hospital were statistically greater in the group treated with the modified amino acid solution and hypertonic dextrose. Treatment of hepatic encephalopathy in the presence of hepatic decompensation with an amino acid solution formulated for its treatment seems to produce faster, more complete recovery with improved capacity for nutritional support.


Pursuing the active species in an aluminium-based Lewis acid system for catalytic Diels-Alder cycloadditions.
Several Al-based complexes supported by a bis(imino)aryl NCN pincer ligand have been prepared. Systematic structural and experimental evidence identified a cationic species, supported by a THF molecule, as the best Lewis acid precatalyst for a range of Diels-Alder cycloadditions. This highlighted the importance of fully isolating and characterizing the active species in any catalytic process especially when Lewis acids are used due to the presence of hidden Brønsted acids (HBAs). Finally, the control experiments conducted in order to eliminate HBA activity that involve a bulky pyridine base should be performed with caution as the corresponding protonated pyridinium salt could also serve as a proton source.


Insights into the molecular mechanism of mitochondrial toxicity by AIDS drugs.
Several of the nucleoside analogs used in the treatment of AIDS exhibit a delayed clinical toxicity limiting their usefulness. The toxicity of nucleoside analogs may be related to their effects on the human mitochondrial DNA polymerase (Pol gamma), the polymerase responsible for mitochondrial DNA replication. Among the AIDS drugs approved by the FDA for clinical use, two are modified cytosine analogs, Zalcitabine (2',3'-dideoxycytidine (ddC)) and Lamivudine (beta-d-(+)-2',3'-dideoxy-3'-thiacytidine ((-)3TC])). (-)3TC is the only analog containing an unnatural l(-) nucleoside configuration and is well tolerated by patients even after long term administration. In cell culture (-)3TC is less toxic than its d(+) isomer, (+)3TC, containing the natural nucleoside configuration, and both are considerably less toxic than ddC. We have investigated the mechanistic basis for the differential toxicity of these three cytosine analogs by comparing the effects of dideoxy-CTP), (+)3TC-triphosphate (TP), and (-)3TC-TP on the polymerase and exonuclease activities of recombinant human Pol gamma. This analysis reveals that Pol gamma incorporates (-)3TC-triphosphate 16-fold less efficiently than the corresponding (+)isomer and 1140-fold less efficiently than dideoxy-CTP, showing a good correlation between incorporation rate and toxicity. The rates of excision of the incorporated analogs from the chain-terminated 3'-end of the DNA primer by the 3'-5'-exonuclease activity of Pol gamma were similar (0.01 s(-)1) for both 3TC analogs. In marked contrast, the rate of exonuclease removal of a ddC chain-terminated DNA occurs at least 2 orders of magnitude slower, suggesting that the failure of the exonuclease to remove ddC may play a major role in its greater toxicity. This study demonstrates that direct analysis of the mitochondrial DNA polymerase structure/function relationships may provide valuable insights leading to the design of less toxic inhibitors.


A Mild Chest Trauma in an Infant who Developed Severe Pulmonary Hemorrhage.
Chest trauma, an important cause of morbidity and mortality, is the second most common cause of death in children under four years of age. Due to the different anatomy and physiology of the respiratory system in childhood, the injuries and consequences of chest trauma are also dissimilar. A seven-month-old male infant presented to the emergency clinic with cyanosis and respiratory distress. His medical history revealed that he had been found trapped behind his bed in a cyanotic state two hours earlier. Although physical examination revealed no signs of trauma, respiratory distress and hemorrhagic secretions indicated pulmonary hemorrhage or contusion. This preliminary diagnosis was confirmed by thoracic tomography. There was complete recovery following 48-hour oxygen and medical treatment. Even after mild injuries, the fact that severe pulmonary hemorrhages and contusions may develop without a trace of trauma should be kept in mind.


Three-dimensional surface and ultrasound imaging for daily IGRT of prostate cancer.
Image guided radiotherapy (IGRT) is an essential pre-requisite for delivering high precision radiotherapy. We compared daily variation detected by two non-ionizing imaging modalities (surface imaging and trans-abdominal ultrasound, US) to verify prostate patient setup and internal organ variations. Forty patients with organ confined prostate cancer and candidates to curative radiotherapy were enrolled in this prospective study. At each treatment session, after laser alignment, all patients received imaging by a 3D-surface and a 3D-US system. The shifts along the three directions (anterior-posterior AP, cranial-caudal CC, and later-lateral LL) were measured in terms of systematic and random errors. Then, we performed statistical analysis on the differences and the possible correlations between the two modalities. For both IGRT modalities, surface imaging and US, 1318 acquisitions were collected. According with Shapiro Wilk test, the positioning error distributions were not Gaussian for both modalities. The differences between the systematic errors detected by the two modalities were statistically significant only in LL direction (p < 0.05), while the differences between the random errors were not statistically significant in any directions. The 95% confidence interval of the residual errors obtained by subtracting the random errors detected with surface images to those detected with US was included in the range from -7 mm to 7 mm corresponding to the minimum PTV margin adopted in AP direction in our clinical routine. From our data, it emerges that setup misalignments measured by surface imaging can be predictive of US displacements after the adjustment for systematic errors. Moreover, surface imaging can detect setup errors predictive of registration errors measured by US. This data suggest that the two IGRT modalities could be considered as complementary to each other and could represent a daily "low-cost" and non-invasive IGRT modality in prostate cancer patients.


Implementation of a new program of gestational diabetes screening and management in Morocco: a qualitative exploration of health workers' perceptions.
Gestational diabetes mellitus (GDM) is associated with an increased risk for a future type 2 diabetes mellitus in women and their children. As linkage between maternal health and non-communicable diseases, antenatal care plays a key role in the primary and secondary prevention of GDM associated adverse outcomes. While implementing a locally adapted GDM screening and management approach through antenatal care services at the primary level of care, we assessed its acceptability by the implementing health care providers. As part of a larger implementation effectiveness study assessing a decentralized gestational diabetes screening and management approach in the prefecture of Marrakech and the rural district of Al Haouz in Morocco, we conducted four focus group discussions with 29 primary health care providers and seven in-depth interviews with national and regional key informants. After transcription of data, we thematically analyzed the data using a combined deductive and inductive approach. The intervention of screening and managing women with gestational diabetes added value to existing antenatal care services but presented an additional workload for first line health care providers. An existing lack of knowledge about gestational diabetes in the community and among private health care physicians required of public providers to spend more time on counselling women. Nurses had to adapt recommendations on diet to the socio-economic context of patients. Despite the additional task, especially nurses and midwives felt motivated by their gained capacity to detect and manage gestational diabetes, and to take decisions on treatment and follow-up. Detection and initial management of gestational diabetes is an acceptable strategy to extend the antenatal care service offer in Morocco and to facilitate service access for affected pregnant women. Despite its additional workload, gestational diabetes management can contribute to the professional motivation of primary level health care providers. clinicaltrials.gov; NCT02979756.


A Bayesian analysis of gene flow from crops to their wild relatives: cultivated (Lactuca sativa L.) and prickly lettuce (L. serriola L.) and the recent expansion of L. serriola in Europe.
Interspecific gene flow can lead to the formation of hybrid populations that have a competitive advantage over the parental populations, even for hybrids from a cross between crops and wild relatives. Wild prickly lettuce (Lactuca serriola) has recently expanded in Europe and hybridization with the related crop species (cultivated lettuce, L. sativa) has been hypothesized as one of the mechanisms behind this expansion. In a basically selfing species, such as lettuce, assessing hybridization in natural populations may not be straightforward. Therefore, we analysed a uniquely large data set of plants genotyped with SSR (simple sequence repeat) markers with two programs for Bayesian population genetic analysis, STRUCTURE and NewHybrids. The data set comprised 7738 plants, including a complete genebank collection, which provided a wide coverage of cultivated germplasm and a fair coverage of wild accessions, and a set of wild populations recently sampled across Europe. STRUCTURE analysis inferred the occurrence of hybrids at a level of 7% across Europe. NewHybrids indicated these hybrids to be advanced selfed generations of a hybridization event or of one backcross after such an event, which is according to expectations for a basically selfing species. These advanced selfed generations could not be detected effectively with crop-specific alleles. In the northern part of Europe, where the expansion of L. serriola took place, the fewest putative hybrids were found. Therefore, we conclude that other mechanisms than crop/wild gene flow, such as an increase in disturbed habitats and/or climate warming, are more likely explanations for this expansion.


Role for membrane and secreted insulin-like growth factor-binding protein-2 in the regulation of insulin-like growth factor action in lung tumors.
The insulin-like growth factors (IGFs) have been implicated in the autocrine and/or paracrine growth of a number of tumor types, including lung tumors. Importantly, insulin-like growth factor-binding proteins (IGFBPs), which both enhance and inhibit the physiological and biological actions of the IGFs, have been shown to be secreted in vitro by a wide range of tumors. In particular, IGFBP-2 is frequently produced by human tumor cells, suggesting that this protein may be an important determinant of IGF action in tumors. In the present study, we investigated IGFBP-2 effects in lung tumor cells by examining the influence of IGFBP-2 on IGF-receptor interaction and the biological actions of IGF-I and IGF-II. Affinity cross-linking studies demonstrated expression of type-I and type-II IGF receptors on small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells and the presence of abundant membrane-associated IGFBP in SCLC cells but not in NSCLC cells. An antiserum specific for IGFBP-2 was used in immunoprecipitation and immunoblotting studies which demonstrated that the membrane-associated IGFBP identified by affinity cross-linking in SCLC cells is IGFBP-2. In NSCLC cells, both IGF-I and IGF-II bound predominantly to IGF-I receptors, whereas in SCLC cells binding was principally to surface-associated IGFBP-2. SCLC cells failed to respond to IGF-I and -II stimulation in a DNA synthesis assay. For NSCLC cells, IGF-II was a more potent stimulator of DNA synthesis than IGF-I. Soluble IGFBP-2 inhibited the binding of radiolabeled IGF-I and -II to both SCLC and NSCLC cells in a concentration-dependent manner and inhibited IGF-stimulated DNA synthesis in NSCLC cells. These observations indicate that both soluble and membrane-associated IGFBP-2 compete with IGF receptors for ligand binding and, thus, are likely to be important determinants of IGF responsiveness. The findings of the present study also indicate that the type-I receptor on NSCLC cells contains a high-affinity binding site for IGF-II which presumably mediates the biological effects of IGF-II in these cells, thereby implicating IGF-II in the autocrine/paracrine growth of NSCLC.


TW-01, a piperazinedione-derived compound, inhibits Ras-mediated cell proliferation and angioplasty-induced vascular restenosis.
Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the pathogenesis of atherosclerosis and restenosis. This study investigated piperazinedione derived compound TW-01-mediated inhibitory effects on VSMC proliferation and intimal hyperplasia. Cell proliferation was determined using [(3)H]-thymidine incorporation and MTT assay; cell cycle distribution was measured using flow cytometry; proteins and mRNA expression were determined using western blotting and RT-PCR analyses; DNA binding activity of nuclear factor-κB (NF-κB), as measured using enzyme-linked immunosorbent assays (ELISA); in vivo effects of TW-01 were determined using balloon angioplasty in the rat. TW-01 significantly inhibited cell proliferation. At the concentrations used, no cytotoxic effects were observed. Three predominant signaling pathways were inhibited by TW-01: (a) extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) activation and its downstream effectors of c-fos, c-jun, and c-myc; (b) DNA binding activity of nuclear factor-κB (NF-κB); and, (c) Akt/protein kinase B (PKB) and cell cycle progression. Furthermore, TW-01 also inhibited Ras activation, a shared upstream event of each of these signaling cascades. In vascular injury studies, oral administration of TW-01 significantly suppressed intimal hyperplasia induced by balloon angioplasty. The present study suggests that TW-01 might be a potential candidate for atherosclerosis treatment.


Reducing excess readmissions: promising effect of hospital readmissions reduction program in US hospitals.
To evaluate the financial penalty effect of the Hospital Readmissions Reduction Program (HRRP) on 30-day inpatient readmissions for pneumonia (PN), acute myocardial infarction (AMI) and heart failure (HF) among hospitals identified as having excess readmissions. Short-term, acute care hospitals in the USA. Secondary data analysis of publicly available HRRP Supplemental Data to examine the effect of HRRP on reducing excess hospital readmissions by utilizing repeated-measures analysis of variance models. A total of 3395 nonfederal, short-term acute care hospitals under the Inpatient Prospective Payment System that are subject to the HRRP program and that reported discharges data for PN, AMI and HF for the calculation of readmission ratios for the fiscal years 2013, 2014 and 2015. Implementation of the HRRP in October 2012 by the Centers for Medicare and Medicaid Services (CMS) to reduce Medicare payments to hospitals with excess readmissions. Thirty-day hospital readmission ratios for PN, AMI and HF. There was a significant decrease in excess readmissions for PN, AMI and HF between FY 2013 and FY 2015. The reduction in excess readmission ratios was 0.035 for PN (P < 0.001), 0.082 for AMI (P < 0.001) and 0.034 for HF (P < 0.001). The effect of HRRP on excess readmissions was greater for small hospitals, public hospitals and hospitals located in rural areas. HRRP to reduce payments to hospitals with excess readmissions had a significant effect on the inpatient readmissions for PN, AMI and HF in US Hospitals.


Frequency of breast cancer subtypes among African American women in the AMBER consortium.
Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression. Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%). Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.


A Contextual Comparison of Risk Behaviors Among Older Adult Drug Users and Harm Reduction in Suburban Versus Inner-City Social Environments.
Recent epidemiological data show that older adults comprise a growing age group of drug users and new AIDS cases in the United States. Prevention and intervention studies show that risk behaviors leading to HIV infection are increasing among older users, particularly among the socially vulnerable. Yet older adults remain an under-researched population of drug users and little is known about their risk behaviors. Our aim is to address this gap in knowledge on older users by comparing contextual factors that influence risk behaviors and harm reduction strategies practiced by older drug users living in different communities. This study is based on ethnographic fieldwork in suburban and inner-city neighborhoods in a large metropolitan area in the southeastern USA. Interviewers conducted face-to-face, in-depth, life-history interviews with 69 older adults (age 45 and older) who used heroin, cocaine, and/or methamphetamine. Findings show that while risk behaviors were similar among older adult drug users living in suburban and inner-city environments, the provision of harm reduction education and paraphernalia varied widely. The results show the need for the expansion of harm reduction services focused on older adult drug users who are homeless, uninsured, or socially isolated. This application-oriented research will inform healthcare and treatment providers and generate new directions for future collaborative harm reduction services aimed to decrease the spread of HIV and other infectious diseases associated with drug use.


Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population.
HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case-control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690.


Influence of Final Apical Width on Smear Layer Removal Efficacy of Xp Endo Finisher and Endodontic Needle: An Ex Vivo Study.
Chemical disinfection along with mechanical instrumentation, is required to achieve debridement, especially in apical third of root canal. Thus, this study aimed to compare the influence of final apical width on the smear layer removal efficacy of XP Endo Finisher and Endodontic Needle, in mandibular premolars. 40 single-rooted mandibular premolars were included in the study, prepared using K3 XF rotary files (SybronEndo, Orange, CA). The samples were equally divided into 4 groups: Group 1: Master apical file 30/0.06 taper, final irrigation with endodontic needle (30G Max I probe, Dentsply International, York PA); Group 2: Master apical file 40/0.06 taper, final irrigation with endodontic needle; Group 3: Master apical file 30/0.06 taper, final irrigation with XP-Endo Finisher (FKG Dentaire, La Chaux-de-Fonds, Switzerland); Group 4: Master apical file 40/0.06 taper, final irrigation with XP-Endo Finisher. Smear layer and debris scores were given using SEM. Group 3 and 4 performed significantly better than group 1 & 2 (P<0.05). No significant difference was observed in Group 1&2 (P>0.05); and Group 3&4 (P>0.05). Significantly higher scores were observed in the apical third, as compared to other sections of the root canal, in all the 4 groups. Increase in the final apical width did not significantly improve root canal cleanliness for both XP Endo Finisher and endodontic needle. However, XP endo finisher proved to be significantly better than the endodontic needle.


Identifying residual speech sound disorders in bilingual children: a Japanese-english case study.
To describe (a) the assessment of residual speech sound disorders (SSDs) in bilinguals by distinguishing speech patterns associated with second language acquisition from patterns associated with misarticulations and (b) how assessment of domains such as speech motor control and phonological awareness can provide a more complete understanding of SSDs in bilinguals. A review of Japanese phonology is provided to offer a context for understanding the transfer of Japanese to English productions. A case study of an 11-year-old is presented, demonstrating parallel speech assessments in English and Japanese. Speech motor and phonological awareness tasks were conducted in both languages. Several patterns were observed in the participant's English that could be plausibly explained by the influence of Japanese phonology. However, errors indicating a residual SSD were observed in both Japanese and English. A speech motor assessment suggested possible speech motor control problems, and phonological awareness was judged to be within the typical range of performance in both languages. Understanding the phonological characteristics of the native language can help clinicians recognize speech patterns in the second language associated with transfer. Once these differences are understood, patterns associated with a residual SSD can be identified. Supplementing a relational speech analysis with measures of speech motor control and phonological awareness can provide a more comprehensive understanding of a client's strengths and needs.


Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism.
Perforin-2 (PFN2, MPEG1) is a pore-forming protein that acts as a first line of defense in the mammalian immune system, rapidly killing engulfed microbes within the phagolysosome in macrophages. PFN2 self-assembles into hexadecameric pre-pore rings that transition upon acidification into pores damaging target cell membranes. Here, using high-speed atomic force microscopy (HS-AFM) imaging and line-scanning and molecular dynamics simulation, we elucidate PFN2 pre-pore to pore transition pathways and dynamics. Upon acidification, the pre-pore rings (pre-pore-I) display frequent, 1.8 s-1, ring-opening dynamics that eventually, 0.2 s-1, initiate transition into an intermediate, short-lived, ~75 ms, pre-pore-II state, inducing a clockwise pre-pore-I to pre-pore-II propagation. Concomitantly, the first pre-pore-II subunit, undergoes a major conformational change to the pore state that propagates also clockwise at a rate ~15 s-1. Thus, the pre-pore to pore transition is a clockwise hand-over-hand mechanism that is accomplished within ~1.3 s. Our findings suggest a clockwise mechanism of membrane insertion that with variations may be general for the MACPF/CDC superfamily.


Divalent cations enhance fluoride binding to Streptococcus mutans and Streptococcus sanguinis cells and subsequently inhibit bacterial acid production.
One preventive effect of topical fluoride application is derived from the fact that fluoride can inhibit bacterial acid production. Furthermore, divalent cations such as Ca(2+) and Mg(2+) increase the binding of fluoride to bacterial cells. These findings suggest that exposure of oral bacteria to fluoride in the presence of divalent cations increases fluoride binding to bacterial cells and subsequently enhances fluoride-induced inhibition of bacterial acid production. This study investigated the effects of fluoride exposure (0-20,000 ppm F) in the presence of Ca(2+) or Mg(2+) prior to glucose challenge on pH fall ability by bacterial sugar fermentation, as well as fluoride binding to bacterial cells by exposure to fluoride, and fluoride release from bacterial cells during bacterial sugar fermentation, using caries-related bacteria, Streptococcus mutans and Streptococcus sanguinis. The pH fall by both streptococci was inhibited by exposure to over 250 ppm F in the presence of Ca(2+) (p < 0.01), whereas in the presence of Mg(2+), the pH fall by S. mutans and S. sanguinis was inhibited after exposure to over 250 and 950 ppm F, respectively (p < 0.05). The amounts of fluoride binding to and released from streptococcal cells increased with the concentration of fluoride the cells were exposed to in the presence of Mg(2+), but were high enough even after 250 ppm F exposure in the presence of Ca(2+). The enhanced inhibition of acid production in the presence of divalent cations is probably due to the improved efficiency of fluoride binding to bacterial cells being improved via these divalent cations.


Assessment of the progress of the back-pain patient 1981 Volvo Award in Clinical Science.
Fifteen subjective variables reflecting the severity of back pain, the circumstances exacerbating symptoms, and the impact of the problem on life style were scored on Visual Analogue Scales. It was possible to combine the results from these assessments to provide a global subjective index. Repeated measurements by the same observer showed a high degree of reproducibility, but when performed by separate observers discrepancies arose in certain questions. By improving certain questions and standardizing their presentation to the patient, a considerable improvement in the correlation of results between observers was obtained. Objective assessments of spinal motion and straight leg raising and a global objective index showed a high degree of intraobserver reproducibility. This technique was applied to a study of relief of back pain by lumbar corsets when it was found that there was significantly greater relief of back pain by a corset with a lumbar support than one without a spinal support. We conclude that the emphasis in assessing the progress of the back-pain patient must be on the subjective parameters, and the technique developed offers a useful method for reliably assessing patients and following their progress.


Crayfish plague affects juvenile survival and adult behaviour of invasive signal crayfish.
The spread of invasive, non-native species is a key threat to biodiversity. Parasites can play a significant role by influencing their invasive host's survival or behaviour, which can subsequently alter invasion dynamics. The North American signal crayfish (Pacifastacus leniusculus) is a known carrier of Aphanomyces astaci, an oomycete pathogen that is the causative agent of crayfish plague and fatal to European crayfish species, whereas North American species are considered to be largely resistant. There is some evidence, however, that North American species, can also succumb to crayfish plague, though how A. astaci affects such 'reservoir hosts' is rarely considered. Here, we tested the impact of A. astaci infection on signal crayfish, by assessing juvenile survival and adult behaviour following exposure to A. astaci zoospores. Juvenile signal crayfish suffered high mortality 4-weeks post-hatching, but not as older juveniles. Furthermore, adult signal crayfish with high-infection levels displayed altered behaviours, being less likely to leave the water, explore terrestrial areas and exhibit escape responses. Overall, we reveal that A. astaci infection affects signal crayfish to a much greater extent than previously considered, which may not only have direct consequences for invasions, but could substantially affect commercially harvested signal crayfish stocks worldwide.


Postoperative Delirium, Learning, and Anesthetic Neurotoxicity: Some Perspectives and Directions.
Evidence of anesthetic neurotoxicity is unequivocal when studied in animal models. These findings have translated poorly to the clinical domain when equated to postoperative delirium (POD) in adults and postoperative cognitive dysfunction (POCD) in either children or the elderly. In this perspective, we examine various reasons for the differences between animal modeling of neurotoxicity and the clinical situation of POD and POCD and make suggestions as to potential directions for ongoing research. We hypothesize that the animal anesthetic neurotoxicity models are limited, in part, due to failed scaling correction of physiological time. We posit that important insights into POCD in children and adults may be gleaned from studies in adults examining alterations in perioperative management designed to limit POD. In this way, POD may be more useful as the proxy for POCD rather than neuronal dropout or behavioral abnormalities that have been used in animal models but which may not be proxies for the human condition. We argue that it is time to move beyond animal models of neurotoxicity to directly examine these problems in well-conducted clinical trials with comprehensive preoperative neuropsychometric and psychiatric testing, high fidelity intraoperative monitoring of physiological parameters during the anesthetic course and postoperative assessment of subthreshold and full classification of POD. In this manner, we can "model ourselves" to better understand these important and poorly understood conditions.


Empowering local communities to make lifestyle changes: is the Health Mela a potential solution?
Health Melas are community-led public health events held in the North West of England that provide health information and free health checks. This descriptive observational study evaluates whether Health Melas are able to identify undiagnosed cardiovascular disease (CVD) risk factors in hard-to-reach communities and encourage individuals to make lifestyle changes. Attendees ≥18 years at three separate Health Melas in 2016-2017 were invited to participate in screening and counselling for CVD risk factors as part of a Health MOT. Information was collected about demographics, CVD risk factors, blood pressure, total cholesterol, blood sugar and attendees' feedback. QRISK2 scoring system was used to estimate CVD risk. 375 attendees completed a questionnaire. The highest proportion (36.9%) of attendees were from areas of the lowest Index of Health Deprivation and Disability quintile; 38.8% were of South Asian ethnicity. Of the attendees who were eligible for a free National Health Service Health Check, 9.1% had received one. Overall, 57.5% of all attendees had a QRISK2 score ≥10% (of whom 56.9% were not on statins), 92.2% of attendees believed the Health Mela will help them to make lifestyle changes, 98.2% said they had improved their understanding of their health, and 99.6% thought the Health Mela was useful. 73.6% of those who had received a previous Health MOT reported making lifestyle changes. There was a positive correlation between South Asian ethnicity and QRISK2 score. This study suggests the Health Melas successfully involve South Asian populations and people from a lower Index of Health Deprivation and Disability. Attendees felt the events were useful, improved understanding of their health needs and encouraged them to make lifestyle changes. High rates of modifiable CVD risk factors were newly identified and a high proportion of attendees were found to be at intermediate to high risk of CVD.


Impact of social media interventions and tools among informal caregivers of critically ill patients after patient admission to the intensive care unit: A scoping review.
The use of social media in healthcare continues to evolve. The purpose of this scoping review was to summarize existing research on the impact of social media interventions and tools among informal caregivers of critically ill patients after patient admission to the intensive care unit (ICU). This review followed established scoping review methods, including an extensive a priori-defined search strategy implemented in the MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane CENTRAL Register of Controlled Trials databases to July 10, 2020. Primary research studies reporting on the use of social media by informal caregivers for critically ill patients were included. We identified 400 unique citations and thirty-one studies met the inclusion criteria. Nine were interventional trials-four randomized controlled trials (RCTs)-and a majority (n = 14) were conducted (i.e., data collected) between 2013 to 2015. Communication platforms (e.g., Text Messaging, Web Camera) were the most commonly used social media tool (n = 17), followed by social networking sites (e.g., Facebook, Instagram) (n = 6), and content communities (e.g., YouTube, SlideShare) (n = 5). Nine studies' primary objective was caregiver satisfaction, followed by self-care (n = 6), and health literacy (n = 5). Nearly every study reported an outcome on usage feasibility (e.g., user attitudes, preferences, demographics) (n = 30), and twenty-three studies reported an outcome related to patient and caregiver satisfaction. Among the studies that assessed statistical significance (n = 18), 12 reported statistically significant positive effects of social media use. Overall, 16 of the 31 studies reported positive conclusions (e.g., increased knowledge, satisfaction, involvement) regarding the use of social media among informal caregivers for critically ill patients. Social media has potential benefits for caregivers of the critically ill. More robust and clinically relevant studies are required to identify effective social media strategies used among caregivers for the critically ill.


Alternative synthetic approaches for metal-organic frameworks: transformation from solid matters.
Developing economic and sustainable synthetic strategies for metal-organic frameworks (MOFs) is imperative for promoting MOF materials into large scale industrial use. Very recently, an alternative strategy for MOF synthesis by using solvent-insoluble "solid matters" as cation reservoirs and/or templates has been developed to accomplish this goal, in which the solid matters often refer to metals, metal oxides, hydroxides, carbonates, and so forth, but excluding the soluble metal salts which have been prevailingly used in MOF synthesis. Although most of the pioneering activities in this field have just started in the past 5 years, remarkable achievements have been made covering the synthesis, functionalization, positioning, and applications. A great number of MOFs in powder form, thin-films, or membranes, have been prepared through such solid-to-MOF transformations. This field is rapidly developing and expanding, and the number of related scientific publications has strikingly increased over the last few years. The aim of this review is to summarise the latest developments, highlight the present state-of-the-art, and also provide an overview for future research directions.


Use of a climatic rule and fuzzy sets to model geographic distribution of climatic risk for European canker (Neonectria galligena) of apple.
A rule-based model was developed to assess climatic risk of European canker (Neonectria galligena), which is a major disease of apple in some temperate zones. A descriptive rule was derived from published observations on climatic conditions favorable for European canker development. Fuzzy set theory was used to evaluate the descriptive rule quantitatively. The amount and frequency of rainfall and the average number of hours between 11 and 16°C/day were used as input variables whose values were matched with terms in the rule, e.g., 'high' or 'low'. The degree of a term, e.g., the state of being high or low, to a given input value was determined using a membership function that converts an input value to a number between 0 and 1. The rule was evaluated by combining the degree of the terms associated with monthly climate data. Monthly risk index values derived using the rule were combined for pairs of consecutive months over 12 months. The annual risk of European canker development was represented by the maximum risk index value for 2 months combined. The membership function parameters were adjusted iteratively to achieve a specified level of risk at Talca (Chile), Loughgall (Northern Ireland), East Malling (UK), and Sebastopol (USA), where European canker risk was known. The rule-based model was validated with data collected from Canada, Ecuador, Denmark, Germany, Norway, Poland, Sweden, the Netherlands, New Zealand, and the Pacific Northwest (USA), where European canker has been reported to occur. In these validation areas, the model's risk prediction agreed with reports of disease occurrence. The rule-based model also predicted high risk areas more reliably than the climate matching model, CLIMEX, which relies on correlations between the spatial distribution of a species and climatic conditions. The combination of a climatic rule and fuzzy sets could be used for other applications where prediction of the geographic distribution of organisms is required for climatic risk assessment.