Thermoelectric and piezoelectric properties of the predicted AlxIn1-xN composites based on ab initio calculations.
Theoretical investigations of the thermoelectric and piezoelectric characteristics in the AlxIn1-xN system have been carried out based on a first principles approach in combination with the semi-classical Boltzmann transport concept and density functional perturbation theory. Based on our previous work, herein, the study specimens Al5InN6, Al6In2N8, Al4In2N6, Al3In3N6, Al2In4N6, and AlIn7N8 have been predicted to be stable phases. These novel phases intrinsically exhibit moderate positive Seebeck curves (199.1-284.6 μV K-1) and a ZT close to unity that varies marginally over a broad temperature range of 200-800 K, demonstrating the sign of good bipolar effect tolerance. Addition of heftier elements, such as In, results in lower thermal conductivity, which in turn generates a high power factor (0.019-0.345 W m-1 K-2) in these alloys. While hole doping enhances the peak Seebeck coefficient of each phase, the electrical conductivity has been greatly compromised, resulting in a lower power factor. These composites also exhibit large piezoelectric constants, in which their respective largest piezoelectric tensor is several orders higher than that of quartz. The decomposition process shows that In and N are the main contributors of the internal piezoelectric term. Overall results indicate that AlxIn1-xN show bright prospects in thermoelectric and piezoelectric applications.


Opposing effects of CD70 costimulation during acute and chronic lymphocytic choriomeningitis virus infection of mice.
T cell costimulation is important for T cell activation. The CD27/CD70 pathway contributes to effector and memory T cell development and is involved in T cell and B cell activation. CD27/CD70 is known for having opposing roles during different models of antigenic challenges. During primary T cell responses to influenza virus infection or during tumor challenges, CD27/CD70 costimulation has a positive role on T cell responses. However, during some chronic infections, constitutive triggering of this signaling pathway has a negative role on T cell responses. It is currently unclear what specific characteristic of an antigen determines the outcome of CD27/CD70 costimulation. We investigated the effect of a transient CD70 blockade during an acute or a chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Blockade of this pathway during acute LCMV infection (Armstrong strain) resulted in delayed T cell responses and decreased CD127 (interleukin-7 receptor α [IL-7Rα] chain) conversion. Upregulation of CD127 is an important event in T cell differentiation that heralds the passage of an effector T cell to a long-lived memory T cell. In contrast to the reduced CD8 T cell responses after CD70 blockade during acute infection, CD70 blockade during chronic LCMV infection resulted in increased CD8 T cell responses. Our data show the dual roles of this costimulatory pathway in acute versus persistent antigen challenge. Our findings suggest that antigen persistence may determine the effect of CD27/CD70 signaling on CD8 T cell responses. Tailored triggering or blockade of this costimulatory pathway may be important in vaccination regimens against acute or chronic pathogens.


Pleomorphic leiomyosarcoma of the soft parts: a reassessment by histology and immunohistochemistry of pleomorphic soft tissue sarcomas.
Histologically it is often difficult to differentiate malignant fibrous histiocytoma (MFH) from leiomyosarcoma. Sixty-three cases formerly diagnosed as pleomorphic soft tissue sarcomas were examined by immunohistochemistry. We identified three different types according to its positivity for the myogenic markers: A) positive cells with a fascicular pattern, 13 cases (26%); B) a small number of scattered positive cells, 29 cases (57%); C) negative for markers, 9 cases (17%). We reassessed 51 MFHs as follows: A type as pleomorphic leiomyosarcoma, B+C types as MFH. Pleomorphic leiomyosarcomas were also positive for collagen type IV around the compactly arranged individual tumor cells. An imunohistochemical analysis and detection of fascicular structures are thus considered to be necessary in order to distinguish between leiomyosarcoma and MFH.


The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study.
Although significant progress has been made in reducing malaria transmission globally in recent years, a large number of people remain at risk and hence the gains made are fragile. Funding lags well behind amounts needed to protect all those at risk and ongoing contributions from major donors, such as the President's Malaria Initiative (PMI), are vital to maintain progress and pursue further reductions in burden. We use a mathematical modelling approach to estimate the impact of PMI investments to date in reducing malaria burden and to explore the potential negative impact on malaria burden should a proposed 44% reduction in PMI funding occur. We combined an established mathematical model of Plasmodium falciparum transmission dynamics with epidemiological, intervention, and PMI-financing data to estimate the contribution PMI has made to malaria control via funding for long-lasting insecticide treated nets (LLINs), indoor residual spraying (IRS), and artemisinin combination therapies (ACTs). We estimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million) malaria cases and saved 940,049 (95% CrI: 545,228, 1.4 million) lives since 2005. If funding is maintained, PMI-funded interventions are estimated to avert a further 162 million (95% CrI: 116 million, 194 million) cases, saving a further 692,589 (95% CrI: 392,694, 955,653) lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166) per Disability Adjusted Life Year (DALY) averted, PMI-funded interventions are highly cost-effective. We also demonstrate the further impact of this investment by reducing caseloads on health systems. If a 44% reduction in PMI funding were to occur, we predict that this loss of direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million) cases and 290,649 (95% CrI: 167,208, 395,263) deaths between 2017 and 2020. We have not modelled indirect impacts of PMI funding (such as health systems strengthening) in this analysis. Our model estimates that PMI has played a significant role in reducing malaria cases and deaths since its inception. Reductions in funding to PMI could lead to large increases in the number of malaria cases and deaths, damaging global goals of malaria control and elimination.


Determining the price for pharmaceuticals in Germany: comparing a shortcut for IQWiG's efficiency frontier method with the price set by the manufacturer for ticagrelor.
Under the recently enacted pharmaceutical price and reimbursement regulation in Germany, manufacturers and payers negotiate an appropriate reimbursement price for new products. If one of the parties involved wishes so, a formal evaluation of costs and benefits will be conducted by the Institute for Quality and Efficiency in Health Care (IQWiG). IQWiG makes recommendations for a reimbursement price based on the 'efficiency frontier' in a therapeutic area. The analysis requires, when applicable, to calculate savings in other areas of the healthcare system (cost offsets) and healthcare costs during the years of life gained (i.e., downstream costs). A recent paper described the conditions under which calculation of downstream costs is not required. The purpose of this study is to use the drug ticagrelor as an example to demonstrate this shortcut for the efficiency frontier method. The analysis shows that applying the IQWiG approach would result in substantial savings.


Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3.
Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force perpetuating continued alcohol use/abuse. Although no animal model duplicates alcoholism, models for specific factors, like the withdrawal syndrome, are useful to identify potential determinants of liability in humans. We previously detected quantitative trait loci (QTLs) with large effects on predisposition to physical dependence and associated withdrawal following chronic or acute alcohol exposure to a large region of chromosome 1 in mice (Alcdp1 and Alcw1, respectively). Here, we provide the first confirmation of Alcw1 in a congenic strain, and, using interval-specific congenic strains, narrow its position to a minimal 1.1 Mb (maximal 1.7 Mb) interval syntenic with human chromosome 1q23.2-23.3. We also report the development of a small donor segment congenic that confirms capture of a gene(s) affecting physical dependence after chronic alcohol exposure within this small interval. This congenic will be invaluable for determining whether this interval harbors a gene(s) involved in additional alcohol responses for which QTLs have been detected on distal chromosome 1, including alcohol consumption, alcohol-conditioned aversion and -induced ataxia. The possibility that this QTL plays an important role in such diverse responses to alcohol makes it an important target. Moreover, human studies have identified markers on chromosome 1q associated with alcoholism, although this association is still suggestive and mapped to a large region. Thus, the fine mapping of this QTL and analyses of the genes within the QTL interval can inform developing models for genetic determinants of alcohol dependence in humans.


Safety of antithrombotic therapy in subjects with hereditary hemorrhagic telangiectasia: prospective data from a multidisciplinary working group.
Subjects with the rare autosomal dominant disease Hereditary Hemorrhagic Telangiectasia (HHT) may develop medical conditions that require antithrombotic therapy (AT). However, safety of AT is uncertain in these patients and the only data currently available derive from retrospective analyses of registries and/or databases. At the HHT Centre of the 'Fondazione Policlinico Universitario A. Gemelli IRCCS' (Rome, Italy), a prospective study is currently ongoing to evaluate the safety of AT in subjects affected by HHT. The study is enrolling subjects with a definite diagnosis of HHT who receive an AT prescription by one of the physicians of the HHT Centre. The primary outcome is the number of hemorrhagic events, distinguished in major, clinically relevant non-major (CRNM), and minor bleedings, according to the criteria of the International Society on Thrombosis and Hemostasis (ISTH). Another primary outcome is worsening of epistaxis upon initiation of AT, assessed using the internationally accepted Epistaxis Severity Score (ESS). Additional outcomes are changes in hemoglobin levels and changes in the need of blood transfusion after initiation of AT. Here, we present the results of an interim analysis, conducted on the 12 HHT subjects that have been enrolled so far. After a mean follow-up of 6.5 ± 0.8 months, no major bleedings, no CRNM bleedings, and no minor bleedings different from epistaxis were recorded. Worsening of epistaxis upon initiation of AT was documented only in one patient, but did not require discontinuation of AT. There were no significant changes in the mean ESS measured before and after initiation of AT. There were no significant changes in hemoglobin levels and need for blood transfusion after initiation of AT. Although preliminary, these are the first prospective data on the safety of AT in HHT patients. Our interim analysis suggests that, when prescribed by experienced physicians in a multidisciplinary setting, AT is well tolerated by HHT patients. More patients and a longer follow-up are needed to confirm these findings.


The Participation of People with Disabilities in the Workplace Across the Employment Cycle: Employer Concerns and Research Evidence.
Despite legislation on diversity in the workplace, people with disabilities still do not experience the same access to work opportunities as do their counterparts without disabilities. Many employers have been shown to harbor sincere yet ill-founded views about the work-related abilities of people with disabilities; these negative views are often a result of interrelated concerns that permeate the entire employment cycle. In this paper, we provide evidence-based responses to 11 specific concerns that employers have about people with disabilities, from pre-employment and entry experiences to the final dissolution of the employment relationship. At each stage of the employment cycle, we summarize and evaluate the relevant empirical evidence and provide recommendations for organizations committed to creating more effective, equitable, and inclusive workplaces for all individuals. We also suggest avenues for future research.


Human monoclonal antibodies derived from memory B cells following live attenuated dengue virus vaccination or natural infection exhibit similar characteristics.
The immunopathogenesis of severe dengue is poorly understood, but there is concern that induction of cross-reactive nonneutralizing antibodies by infection or vaccination may increase the likelihood of severe disease during a subsequent infection. We generated a total of 63 new human monoclonal antibodies to compare the B-cell response of subjects who received the National Institutes of Health live attenuated dengue vaccine rDEN1Δ30 to that of subjects following symptomatic primary infection with DENV1. Both infection and vaccination induced serum neutralizing antibodies and DENV1-reactive peripheral blood B cells, but the magnitude of induction was lower in vaccinated individuals. Serotype cross-reactive weakly neutralizing antibodies dominated the response in both vaccinated and naturally infected subjects. Antigen specificities were very similar, with a slightly greater percentage of antibodies targeting E protein domain I/II than domain III. These data shed light on the similarity of human B-cell response to live attenuated DENV vaccine or natural infection.


Intake of fat, meat, and fiber in relation to risk of colon cancer in men.
Some evidence suggests that diets high in animal fat or red meat may increase the risk of colon cancer, whereas high intake of fiber or vegetables may be protective. Frequently, intake of red meat has been a stronger risk factor than total fat. Because data from prospective cohort studies are sparse, we examined fat, meat, fiber, and vegetable intake in relation to risk of colon cancer in a cohort of 47,949 U.S. male health professionals who were free of diagnosed cancer in 1986. At baseline, these men, 40 to 75 years of age, completed a validated food frequency questionnaire and provided detailed information on other lifestyle and health-related factors. Between 1986 and 1992, 205 new cases of colon cancer were diagnosed in these men. Intakes of total fat, saturated fat, and animal fat were not related to risk of colon cancer. However, an elevated risk of colon cancer was associated with red meat intake (relative risk, 1.71; 95% confidence interval, 1.15-2.55 between high and low quintiles; P = 0.005 for trend). Men who ate beef, pork, or lamb as a main dish five or more times per week had a relative risk of 3.57 (95% confidence interval, 1.58-8.06; P = 0.01 for trend) compared to men eating these foods less than once per month. The association with red meat was not confounded appreciably by other dietary factors, physical activity, body mass, alcohol intake, cigarette smoking, or aspirin use. Other sources of animal fat, including dairy products, poultry, and fish as well as vegetable fat, were slightly inversely related to risk of colon cancer. No clear association existed between fiber or vegetable intake and risk of colon cancer. These data support the hypothesis that intake of red meat is related to an elevated risk of colon cancer.


Modulation of T cell responses by IL-2 and IL-2 complexes.
Interleukin-2 (IL-2) is a cytokine centrally involved in the regulation of immune tolerance and activation by its effects on CD4+ T regulatory (Treg) cells and cytotoxic effector lymphocytes, respectively. Due to these properties IL-2 immunotherapy has been used, as low-dose IL-2, in the treatment of autoimmune and chronic-inflammatory disorders; conversely, at high doses, IL-2 has shown efficacy in a subset of patients with metastatic cancer. Recent advances have highlighted the possibility of using improved IL-2-based therapies, such IL-2-antibody complexes (IL-2 complexes), able to selectively and potently stimulate either Treg cells or cytotoxic effector cells. This article discusses the properties and clinical implications of IL-2 and IL-2 complexes.


Cytotoxic and antiproliferative effect of tepary bean lectins on C33-A, MCF-7, SKNSH, and SW480 cell lines.
For many years, several studies have been employing lectin from vegetables in order to prove its toxic effect on various cell lines. In this work, we analyzed the cytotoxic, antiproliferative, and post-incubatory effect of pure tepary bean lectins on four lines of malignant cells: C33-A; MCF-7; SKNSH, and SW480. The tests were carried out employing MTT and 3[H]-thymidine assays. The results showed that after 24 h of lectin exposure, the cells lines showed a dose-dependent cytotoxic effect, the effect being higher on MCF-7, while C33-A showed the highest resistance. Cell proliferation studies showed that the toxic effect induced by lectins is higher even when lectins are removed, and in fact, the inhibition of proliferation continues after 48 h. Due to the use of two techniques to analyze the cytotoxic and antiproliferative effect, differences were observed in the results, which can be explained by the fact that one technique is based on metabolic reactions, while the other is based on the 3[H]-thymidine incorporated in DNA by cells under division. These results allow concluding that lectins exert a cytotoxic effect after 24 h of exposure, exhibiting a dose-dependent effect. In some cases, the cytotoxic effect is higher even when the lectins are eliminated, however, in other cases, the cells showed a proliferative effect.


Gastrointestinal recall questionnaires compare poorly with prospective patient diaries for gastrointestinal symptoms: data from population and primary health centre samples.
Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome. Data are reported from a randomly selected general population sample (n=238) and also a primary healthcare centre (PHC) sample (n=503, 10 PHCs). All the patients completed the questionnaires, which included Rome III-qualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated. Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample. Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments.


Botulinum toxin B-induced mouse model of keratoconjunctivitis sicca.
To develop a mouse model of human chronic dry eye (keratoconjunctivitis sicca [KCS]). Under direct visualization with an operating microscope, CBA/J mice received a transconjunctival injection of saline or 1.25, 5, or 20 milliunits (mU) of botulinum toxin B (BTX-B) into the lacrimal gland. The mice were either left unstressed or were subjected to an air blower for 5 h/d, 5 d/wk in fixed temperature and humidity conditions. Tear production and corneal fluorescein staining were evaluated in all groups before injection and at several time points after. Tear production was measured with phenol red-impregnated cotton threads. Corneal fluorescein staining was photographed under cobalt blue light with a digital camera fitted with a macro lens. BTX-B-injected mice displayed significantly decreased tear production until the 4-week time point. Throughout all time points, the addition of environmental blower stress did not appear to alter tear production significantly. Linear regression models, used to evaluate the effects of various doses of BTX-B on tear production, showed that doses higher than 1.25 mU did not provide significantly different outcomes. After 3 days, saline-injected mice showed no corneal staining, whereas BTX-B-injected mice displayed various amounts of staining. At the early time point (day 3), there did not appear to be an additional effect of the blower on corneal fluorescein staining. However, at 1, 2, and 4 weeks, the blower stress appeared to increase the amount of corneal fluorescein staining at each BTX-B dose, although not significantly. Furthermore, at 8 to 10 weeks, in the BTX B-injected groups, corneas had persistent staining, even though tear production had already returned to normal levels. Histopathologic analyses revealed no inflammatory cell infiltration of the stroma or acini of the lacrimal glands and conjunctivae of both saline-injected and BTX-B-injected animals. Intralacrimal gland injection of BTX-B resulted in persistent corneal fluorescein staining within 3 days, and a significant decrease in aqueous tear production that persisted for 1 month. Intralacrimal gland injection of BTX-B suppressed lacrimation, thereby establishing a dry eye state. This animal model could be a useful tool for investigating the pathogenesis of the chronic condition KCS in humans.


Which part of a porcine stomach is suitable as an animal training model for gastric endoscopic submucosal dissection?
Training using an animal model is generally recommended before performing endoscopic submucosal dissection (ESD) in humans. This study aimed to clarify the suitability of an isolated porcine stomach as an animal training model for gastric ESD. Study 1: six experienced endoscopists performed ESDs of six simulated lesions located in six locations in an isolated porcine stomach (1, lower third [L]/ greater curvature [Gre]; 2, L/ anterior wall [Ant]; 3, L/ posterior wall [Post]; 4, upper third [U]/ Gre; 5, U/Ant; 6, U/Post). The procedure times (s/cm(2)) were compared among the different lesion locations. A questionnaire (scored 1 - 5) completed by the endoscopists was used to assess the difference in the difficulty compared to the human stomach of the three steps of the ESD procedure (injection, incision and dissection). Study 2: the thicknesses of the mucosal layers were histologically evaluated among the six locations in three porcine and two human stomachs. Study 1: the procedure speed was significantly slower at L/Gre and U/Gre in the porcine stomachs (P = 0.0004). The questionnaire responses revealed a tendency toward similarity between the lower regions of the human and porcine stomachs at L/Ant, L/Post, U/Ant and U/Post during the dissection step (P = 0.056). In contrast, the injection and incision steps at L/Gre in the porcine stomach were shown to differ in difficultly level (both P = 0.0006). Study 2: the mucosal layers in the porcine stomachs were significantly thicker than those in the human stomachs in the lower areas, especially L/Gre. The difficulty of ESD and the histological features of the porcine stomachs were coincident with those of the human stomachs at L/Ant, L/Post, U/Ant and U/Post. These parts of the porcine stomach may be suitable as animal training models for gastric ESD.


[Evaluation of coverage by family health teams for fatal stroke victims in Maringá, Paraná State, Brazil].
The work process in the Brazilian Family Health Program (FHP) allows teams to establish bonds, accept families, and take responsibility for the registered population and identify groups at risk. Monitoring allows problem surveying and evaluation of specific measures. Considering that a key objective of controlling arterial hypertension is to reduce stroke mortality, this study aimed to identify the coverage, follow-up, and quality of care for individuals in areas with the FHP who died of stroke, based on data from the family registries (Form A), follow-up (Form B), and patient records in primary health care units. The results showed low coverage, with 33.3% of registration on Form A, follow-up of 4.9% of deaths, and absence of any annotation on the care provided in most patient records (52.4%). Analysis of care in the group confirmed the fragmentation and disconnection between the different information systems. It is essential to encourage the use of available data and improve their recording in order to institutionalize evaluation practice and work organization from a health surveillance perspective.


Mitochondria interaction networks show altered topological patterns in Parkinson's disease.
Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.


ADP and ATP activate distinct signaling pathways in human promonocytic U-937 cells differentiated with 1,25-dihydroxy-vitamin D3.
We investigated the effects of purinergic P2 agonists on cell adhesion, as well as the signaling pathways involved, in U-937 human promonocytic cells differentiated to a more mature monocytic phenotype with 1,25-(OH)2-vitamin D3. In cell adhesion studies, ATP was more potent than ADP, whereas ADP showed greater efficacy. The time course of the intracellular calcium concentration ([Ca2+]i) response to ATP was biphasic (a spike followed by a plateau), whereas ADP evoked a plateau after a time lag of several seconds. The spike [Ca2+]i response evoked by ATP was due to both myo-inositol-1,4,5-trisphosphate-induced Ca2+ mobilization and influx, whereas the ADP effect was Ca2+ influx dependent. Moreover, ADP and ATP activated distinct Ca2+ influx mechanisms, as shown by Mn2+ quenching of the fura-2 signal, which was slow and long-lasting for ADP but rapid for ATP. Treatment with phorbol dibutyrate shifted the EC50 of the [Ca2+]i spike response to the right and abolished the plateau response. Accordingly, phorbol dibutyrate inhibited the ADP-evoked response but only partly inhibited the ATP-evoked Ca2+ influx. cAMP-raising agents had no effect on the [Ca2+]i spike or on Ca2+ influx but delayed or transiently inhibited the plateau phase. The plateau response thus appears to be independent of the spike response, because it can be directly evoked by ADP and undergoes distinct regulation. This suggests that ADP and ATP activate U-937 cells through distinct signaling pathways, probably involving specific receptors.


Aggression and related behavioral traits: the impact of winning and losing and the role of hormones.
A suite of correlated behaviors reflecting between-individual consistency in behavior across multiple situations is termed a "behavioral syndrome." Researchers have suggested that a cause for the correlation between different behaviors might lie in the neuroendocrine system. In this study, we examined the relationships between aggressiveness (a fish's readiness to perform gill display to its mirror image) and each of boldness (the readiness to emerge from a shelter), exploratory tendency (the readiness to approach a novel shelter), and learning performance (the probability of entering the correct reservoir in a T-maze test) in a mangrove rivulus, Kryptolebias marmoratus. We explored the possibility that the relationships between them arise because these behaviors are all modulated by cortisol and testosterone. We also tested the stability of the relationships between these behaviors shortly after using a winning or losing experience to alter individuals' aggressiveness. The results were that aggressiveness correlated positively with boldness and the tendency to explore, and that these three behavioral traits were all positively correlated with pre-experience testosterone levels. Aggressiveness and boldness also positively correlated with pre-experience cortisol levels; exploratory tendency did not. The relationship between aggressiveness and boldness appeared to be stronger than that between either of them and exploratory tendency. These results suggest that testosterone and cortisol play important roles in mediating the correlations between these behavioral traits. Learning performance was not significantly correlated with the other behavioral traits or with levels of testosterone or cortisol. Recent experience in contests influenced individuals' aggressiveness, tendency to explore, and learning performance but not their boldness; individuals that received a winning experience were quicker to display to their mirror image and performed better in the learning task but were slower to approach a novel object than were individuals that lost. Contest experience did not, however, significantly influence the relationships between aggressiveness and any of boldness, exploratory tendency, or learning performance. The results show that the individual components of a suite of correlated behaviors can preserve a flexibility to respond differently to environmental stimuli.


Binding and Energetics of Electron Transfer between an Artificial Four-Helix Mn-Protein and Reaction Centers from Rhodobacter sphaeroides.
The ability of an artificial four-helix bundle Mn-protein, P1, to bind and transfer an electron to photosynthetic reaction centers from the purple bacterium Rhodobacter sphaeroides was characterized using optical spectroscopy. Upon illumination of reaction centers, an electron is transferred from P, the bacteriochlorophyll dimer, to QA, the primary electron acceptor. The P1 Mn-protein can bind to the reaction center and reduce the oxidized bacteriochlorophyll dimer, P+, with a dissociation constant of 1.2 μM at pH 9.4, comparable to the binding constant of c-type cytochromes. Amino acid substitutions of surface residues on the Mn-protein resulted in increases in the dissociation constant to 8.3 μM. The extent of reduction of P+ by the P1 Mn-protein was dependent on the P/P+ midpoint potential and the pH. Analysis of the free energy difference yielded a midpoint potential of approximately 635 mV at pH 9.4 for the Mn cofactor of the P1 Mn-protein, a value similar to those found for other Mn cofactors in proteins. The linear dependence of -56 mV/pH is consistent with one proton being released upon Mn oxidation, allowing the complex to maintain overall charge neutrality. These outcomes demonstrate the feasibility of designing four-helix bundles and other artificial metalloproteins to bind and transfer electrons to bacterial reaction centers and establish the usefulness of this system as a platform for designing sites to bind novel metal cofactors capable of performing complex oxidation-reduction reactions.


Partial nephrectomy for T3aN0M0 renal cell carcinoma: shall we step forward?
To evaluate the prognosis of non-metastatic T3a renal cell carcinoma (RCC) with partial nephrectomy (PN). We retrospectively evaluated 125 patients with non-metastatic T3a RCC. Patients undergoing PN and radical nephrectomy (RN) were strictly matched by clinic-pathologic characteristics. Log-rank test and Cox regression model were used for univariate and multivariate analysis. 18 pair patients were matched and the median follow-up was 35.5 (10-86) months. PN patients had a higher postoperative eGFR than RN patients (P=0.034). Cancer-specific survival (CSS) and recurrence-free survival (RFS) did not differ between two groups (P=0.305 and P=0.524). On multivariate analysis, CSS decreased with positive surgical margin and anemia (both P<0.01) and RFS decreased with Furhman grade, positive surgical margin, and anemia (all P<0.01). For patients with non-metastatic pT3a RCC, PN may be a possible option for similar oncology outcomes and better renal function.


Regulation of site-specific recombination by the C-terminus of lambda integrase.
Site-specific recombination catalyzed by bacteriophage lambda integrase (Int) is essential for establishment and termination of the viral lysogenic life cycle. Int is the archetype of the tyrosine recombinase family whose members are responsible for DNA rearrangement in prokaryotes, eukaryotes and viruses. The mechanism regulating catalytic activity during recombination is incompletely understood. Studies of tyrosine recombinases bound to their target substrates suggest that the C-termini of the proteins are involved in protein-protein contacts that control the timing of DNA cleavage events during recombination. We investigated an Int truncation mutant (W350) that possesses enhanced topoisomerase activity but greater than 100-fold reduced recombination activity. Alanine scanning mutagenesis of the C-terminus indicates that two mutants, W350A and I353A, cannot perform site-specific recombination although their DNA binding, cleavage and ligation activities are at wild-type levels. Two other mutants, R346A and R348A, are deficient solely in the ability to cleave DNA. To explain these results, we have constructed a homology-threaded model of the Int structure using a Cre crystal structure. We propose that residues R346 and R348 are involved in orientation of the catalytic tyrosine that cleaves DNA, whereas W350 and I353 control and make intermolecular contacts with other Int proteins in the higher order recombination structures known as intasomes. These results suggest that Int and the other tyrosine recombinases have evolved regulatory contacts that coordinate site-specific recombination at the C-terminus.


New classification system for ossification of the posterior longitudinal ligament using CT images.
Ossification of the posterior longitudinal ligament (OPLL) is most frequently seen in the cervical spine. The types of cervical OPLL are classified into continuous, mixed, segmental, and other based on plain lateral X-ray. Computed tomography (CT) imaging is often used in clinical practice for evaluating ossified lesions as it can detect their precise location, size, and shape. However, to date, no CT classification of OPLL lesions has been proposed. One hundred and forty-four patients diagnosed with cervical OPLL by plain radiograph were included in this study. Sagittal and axial CT images of the cervical spine were obtained. We propose three classification systems: A, B, and axial. Classification A comprises two lesion types: bridge and nonbridge. Classification B requires examiners to describe all vertebral and intervertebral levels where OPLL exits in the cervical spine. Axial classification comprises central and lateral lesions identified on axial CT images. Seven observers evaluated CT images using this classification system, and intra- and interrater reliability were examined. Averaged Fleiss' kappa coefficient of interrater agreement was 0.43 ± 0.26 among the seven observers, averaged intrarater reliability for the existence of OPLL was 72.4 ± 8.8% [95% confidence interval (CI) 67.5-76.8]. Fifty-four patients (37.5%) had the bridge type and 90 the nonbridge type according to Classification A; 102 (70.8%) had central and 42 (29.2%) lateral OPLL in the axial classification. Four representative cases defined according to the three classification types are reported here. Subcommittee members of the Investigation Committee on the Ossification of the Spinal Ligaments of the Japanese Ministry of Public Health and Welfare propose three new classification systems of cervical OPLL based on CT imaging: A, B, and axial.


Clinical ethnography in severe mental illness: a clinical method to tackle social determinants and structural racism in personalised care.
Ethnic inequalities in the experiences and outcomes of severe mental illness are well established. These include a higher incidence of severe mental illnesses (psychoses), adverse pathways into and through care, including crisis care, police and criminal justice systems involvement, and care under the powers of the Mental Health Act. The situation persists despite awareness and is driven by a mixture of the social determinants of poor health, societal disadvantage and structural racism, as well as conflictual interactions with care systems, which themselves are configured in ways that sustain or deepen these inequalities. Although training and education are often proposed, this is not shown to have sustained effects. Clinical processes (interviewing/assessment/formulation/intervention) need to address systemic influences and improve the cultural precision with which care is delivered, organised and commissioned. We discuss clinical ethnography and present evidence of its value in addressing systemic as well as individual care needs for diverse communities.


Redevelopment and Examination of the Psychometric Properties of the Chinese Version of the Last 7-Day Sedentary Behaviour Questionnaire (SIT-Q-7d-Chi) in Hong Kong Older Adults.
(1) Background: This study examined the psychometric properties of the Chinese version of the Last 7-Day Sedentary Behaviour Questionnaire (SIT-Q-7d-Chi) in Hong Kong older adults; (2) Methods: Study 1 assessed the questionnaire's test-retest reliability, and Study 2 examined its validity. Place the question addressed in a broad context and highlight the purpose of the study; (3) Results: In Study 1, 84 older adults (aged 60-90) completed the SIT-Q-7d-Chi twice over a 2-week interval, and in Study 2, 38 older adults (i) completed the SIT-Q-7d-Chi and the Sedentary Behaviour Questionnaire for Older Adults (SBQOA) and (ii) wore a waist-mounted accelerometer for 7 consecutive days. In Study 1, the SIT-Q-7d-Chi's test-retest reliability (ICC = 0.91-0.99) was satisfactory, and adequate internal consistency was found for most domains of the SIT-Q-7d-Chi (Cronbach's alpha value being 0.7 or above). Study 2's results showed that the SIT-Q-7d-Chi results were significantly correlated with the SBQOA results, but not with the accelerometer results; (4) Conclusions: This study revealed the prevalence of sedentary behavior among Hong Kong's senior citizens, which can be used as a reference to plan or evaluate a future sedentary behavior intervention for older persons, including identifying the content and intensity of activities.


The effectiveness of intermittent pneumatic compression in long-term therapy of lymphedema of lower limbs.
The manual lymphatic drainage in lymphedema has proved to be successful; however, this method cannot be applied to millions of patients around the world. The only solution is to offer inexpensive, easily accessible mechanical devices for pneumatic compression (IPC). These devices should be designed on parameters of edema fluid hydromechanics. Recent data point to high pressures and long time of compression. To validate the effects of 3 years daily high pressure, long inflation time IPC therapy in terms of decrease of limb circumference/volume, tissue elasticity, histological changes, and incidental complications. A group of 18 patients with unilateral leg lymphedema stage II to IV was treated for a period of 3 years using an 8-chamber sleeve, sequential inflation of chambers to 100-120 mmHg for 50 sec (total 400 sec). Limb circumference and tissue tonicity were measured at monthly intervals. Correlation between decrease in calf and thigh circumference and increase in elasticity was done. The treatment revealed durable permanent decrease of limb circumference and increased elasticity of tissues. The improvement was most expressed in the calf above the ankle and mid-calf. No complications as thigh ring or chronic genital edema were observed. There was no direct correlation between the decrease in limb circumference and increase in elasticity, most likely due to different mass of fibrous tissue. IPC takes over the permanently missing function of the obliterated lymphatics by squeezing edema tissue fluid to the regions with normal lymphatic drainage. The limb circumference is decreased or at least does not further increase, elasticity of tissue is increased and maintained. No complications in limb tissues were observed. The long-term, high pressure IPC, long inflation timed therapy can be safely be recommended to patients with lower limb lymphedema.


Kin-biased distribution in brown trout: an effect of redd location or kin recognition?
A wide range of animals have been reported to show kin-biased behaviours, such as reduced aggressiveness and increased food sharing among relatives. However, less is known about whether wild animals also associate with relatives under natural conditions, which is a prerequisite to facilitate kin-biased behaviours and hence kin selection. We tested, by means of microsatellite polymorphism, correlations between pair-wise relatedness and pair-wise metric distance in wild brown trout (Salmo trutta L.) under natural conditions in two streams. Our data show that young-of-the-year as well as older trout found close together also had a higher genetic relatedness in one of the two streams, whereas no relationship was found in the other stream. Very few half and full siblings were found in the second stream and under these conditions it is unlikely that kin-biased behaviours will receive positive selection. We discuss the underlying mechanisms for the observed structure and we specifically address the issue of whether the grouping of related individuals could reflect dispersal from the same spawning redds, or if it reflects active association with relatives, possibly conferring kin-selected advantages.


On Mellitella stokesii and Amphipholis geminata (Echinodermata), from an intertidal flat in the upper Gulf of Nicoya estuary, Pacific, Costa Rica.
Information on changes over time in the biodiversity and ecology of tropical systems is of increasing importance against the background of local, regional, and global dynamics. This study aimed to contribute with long-term data on the abundance fluctuations of two species of echinoderms from a tropical tidal flat. From February 1984 to December 1986, March 1985 to April 1987, and July 1994 to September 1996 (total: 76 dates), core samples (17.7 cm2, 15 cm deep) were collected at low tide at a mud-sand flat in the mid upper Gulf of Nicoya estuary, Costa Rica, as part of a survey of the benthic community. Among more than 100 taxa, the burrowing brittle star, Amphipholis geminata, and the sand dollar, Mellitella stokesii, consistently appeared in the samples over the study period. A total of 63 M. stokesii and 149 A. geminata were collected. The 43 sand dollars found during 1984-1985, give an approximate density of 35 ind./m2, which is within the range reported for this species. M. stokesii was almost absent from 1994 to 1996, while A. geminata had its peak of abundance at the end of 1995. Low abundances of the sand dollar during the rainy seasons (May-November) and slight increments in dry seasons (December-April) cores, also agrees with a report from the region. A. geminata also presented an irregular pattern of abundance, with slight increases at the end of the rainy seasons or during the dry seasons, when higher salinities are more suitable for echinoderms. The patchy spatial distribution of both species makes difficult the detection of patterns with a corer. Nevertheless, this information is unique due to its extensive time coverage and provides a baseline for future surveys designed specifically for the study of tropical intertidal estuarine echinoderms.


Tumor allograft rejection is mainly mediated by CD8+ cytotoxic T lymphocytes stimulated with class I alloantigens in cooperation with CD4+ helper T cells recognizing class II alloantigens.
Presence of the three major pathways (self-Ia restricted, allo-K/D restricted, and allo-Ia restricted pathways) in generating class I-restricted CTL has been reported. The present study was conducted in order to clarify which of the three is the main pathway in mediating tumor allograft rejection. One million EL-4 tumor cells derived from C57BL/6 (B6;H-2b) were inoculated into the various strains of mice that were genetically different from B6. Class I (K/D) Ag-disparate but IA Ag-matched B6.C-H-2bm1 (bm1;Kbm1, IAb, IE-, Db) mice or B10.A (5R) (5R; b, b, k, d) mice could not reject 1 x 10(6) EL-4 tumor cells in spite of the strong generation of CTL against the B6 Ag, suggesting the inability of the self-Ia restricted pathway and the allo-K/D restricted pathway in rejecting tumor allografts. The strains of mice being capable of rejecting EL-4 tumor were disparate from B6 mice in both class I and class II (IA) Ag, suggesting the importance of the allo-Ia restricted pathway in rejecting tumor allografts. To generate CTL against Kb Ag via the allo-Ia restricted pathway in the bm1 mice, 2 x 10(7) B6.H-2bm12 (bm12; b, bm12, -, b) spleen cells were injected into the bm1 mice as a supplementary source of allogeneic APC that possibly raise CTL through CD4+ Th cells of bm1 origin. These bm1 mice became capable of rejecting 1 x 10(6) EL-4 tumor cells. The same was observed in the combination of bm12----B10.A (5R) (b, b, k, d) mice. To further elucidate the role of the class II restricted CD4+ Th cells, anti-CD4 antibody was repeatedly i.v. administered into the C3H/He (C3H; H-2k) or the DBA/2 (DBA; H-2d) mice on days 0, 1, and 4. Injection of anti-CD4 antibody led 1 x 10(6) EL-4 tumor cells to grow and kill the C3H and DBA mice. These results suggest that the main effector CTL pathway involved in tumor allograft rejection is allo-Ia restricted pathway where CD8+ precursor CTL were stimulated by the class II-restricted CD4+ Th cells.


Efficient simulation of SPECT down-scatter including photon interactions with crystal and lead.
A major image degrading factor in simultaneous Dual Isotope (DI) SPECT or simultaneous Emission-Transmission (ECT-TCT) imaging, is the detection of photons emitted by the higher energy isotope in the energy window used for imaging the lower energy isotope. In Tc-99m/Tl-201 DI-SPECT typically tens of percents of the total detected down-scatter is caused by lead x rays. In Tc-99m/Gd-153 ECT-TCT, a comparable fraction of the down-scatter originates from Tc-99m photons which only partly deposit their energy in the detector crystal (i.e., due to crystal interactions). Efficient simulation methods which model down-scatter can be used to optimize DI-SPECT or ECT-TCT imaging acquisition or reconstruction protocols. In this paper we adapt a previously proposed efficient down-scatter simulation method, to include the interactions of photons with the detector crystal and collimator lead. To this end, point spread function tables including crystal and lead interactions are precalculated. Subsequently, photons are traced through the patient body until their last scatter position, and the precalculated responses are used to project the photons onto the detector plane, while photon attenuation in the patient is taken into account. The approach is evaluated by comparing simulated Tc-99m down-scatter projections with measured projections. Incorporation of photon interaction with crystal and lead leads to significantly improved accuracy of the shape of down-scatter responses, while differences in total counts between simulated and measured projections typically decrease from tens of percents to a couple of percents. Calculating 60 down-scatter projections of an extended distribution on a 64 x 64 x 64 grid takes about three minutes on a PC with two 1.2 GHz processors. We conclude that accurate and efficient simulation of down-scatter is now possible including the major effects of the nonuniform mass density of the patient as well as photon interactions with the crystal and collimator lead.


Persistent infections and immunity in cystic fibrosis.
Cystic fibrosis (CF) is the most common autosomal recessive lethal disease in the Caucasian population. Chronic respiratory infections with Pseudomonas aeruginosa, neutrophil-dominated airway inflammation and progressive lung damage are the major causes of morbidity and mortality in CF. Two persistent infection phenotypes expressed by this bacterium are biofilm and mucoidy. Biofilm, also called the microcolony mode of growth is the surface-associated adherent bacterial community, while mucoidy refers to a phenotype conducive to copious amounts of mucoid exopolysaccharide (MEP)/alginate that provides a matrix for mature biofilms conferring resistance to host defenses and antibiotics. Recent completion of the whole genomic sequence of the standard reference strain P. aeruginosa PAO1 has led to discoveries that many clinical isolates of this species possess unique genomic sequences (genomic islands) due to horizontal gene transfer. We propose this type of genetic exchange may play an important role in causing intrinsic genomic diversity of this organism. Therefore, the diversity, as revealed through profiles of restriction fragment length polymorphism (RFLP), may be linked to an array of novel and unexplored pathogenic mechanisms in P. aeruginosa. CF mouse models, while displaying many clinical similarities to human CF, have yet to demonstrate a chronic pulmonary disease phenotype. This review is intended to provide an overview of P. aeruginosa persistent infection phenotypes (biofilm and mucoidy) and an aerosol infection mouse model for CF. Genomic diversity of P. aeruginosa and its implications in the pathogenesis in CF will also be discussed.


Transdiagnostic Cognitive Behavioral Therapy Versus Treatment as Usual in Adult Patients With Emotional Disorders in the Primary Care Setting (PsicAP Study): Protocol for a Randomized Controlled Trial.
Demand for primary care (PC) services in Spain exceeds available resources. Part of this strong demand is due to the high prevalence of emotional disorders (EDs)-anxiety, depression, and somatic symptom disorders-and related comorbidities such as pain or chronic illnesses. EDs are often under- or misdiagnosed by general practitioners (GPs) and, consequently, treatment is frequently inadequate. We aim to compare the short- and long-term effectiveness of group-delivered transdiagnostic cognitive behavioral therapy (TD-CBT) versus treatment as usual (TAU) in the treatment of EDs in the PC setting in Spain. We also aim to compare the effect of these treatments on disability, quality of life, cognitive-emotional factors, and treatment satisfaction. Here we present the study design of a two-arm, single-blind, randomized controlled trial (N=1126) to compare TAU to TD-CBT for EDs. TAU will consist primarily of pharmacological treatment and practical advice from the GP while TD-CBT will be administered in seven 90-minute group sessions held over a period ranging from 12 to 14 weeks. Psychological assessments are carried out at baseline (ie, pretreatment); posttreatment; and at 3-, 6-, and 12-month follow-up. The study is conducted in approximately 26 PC centers from the National Health System in Spain. This study was initiated in December 2013 and will remain open to new participants until recruitment and follow-up has been completed. We expect all posttreatment evaluations to be completed by December 2017, and follow-up will end in December 2018. We expect the TD-CBT group to have better results compared to TAU on all posttreatment measures and that this improvement will be maintained during follow-up. This project could serve as a model for use in other areas or services of the National Health System in Spain and even in other countries. International Standard Randomized Controlled Trial Number (ISRCTN): 58437086; http://www.isrctn.com/ISRCTN58437086 (Archived by WebCite at http://www.webcitation.org/6mbYjQSn3).


Toward Regeneration of the Heart: Bioengineering Strategies for Immunomodulation.
Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF development. Two newly emerging fields of biomedical research, immunomodulatory therapies and cardiac bioengineering, provide potential options to target the causative mechanisms underlying HF development. Combining these two fields to develop biomaterials for delivery of immunomodulatory bioactive molecules holds great promise for HF therapy. Specifically, minimally invasive delivery of injectable hydrogels, loaded with bioactive factors with angiogenic, proliferative, anti-apoptotic and immunomodulatory functions, is a promising route for influencing the cascade of immune events post-MI, preventing adverse left ventricular remodeling, and offering protection from early inflammation to fibrosis. Here we provide an updated overview on the main injectable hydrogel systems and bioactive factors that have been tested in animal models with promising results and discuss the challenges to be addressed for accelerating the development of these novel therapeutic strategies.


Demography and mating system shape the genome-wide impact of purifying selection in Arabis alpina.
Plant mating systems have profound effects on levels and structuring of genetic variation and can affect the impact of natural selection. Although theory predicts that intermediate outcrossing rates may allow plants to prevent accumulation of deleterious alleles, few studies have empirically tested this prediction using genomic data. Here, we study the effect of mating system on purifying selection by conducting population-genomic analyses on whole-genome resequencing data from 38 European individuals of the arctic-alpine crucifer Arabis alpina We find that outcrossing and mixed-mating populations maintain genetic diversity at similar levels, whereas highly self-fertilizing Scandinavian A. alpina show a strong reduction in genetic diversity, most likely as a result of a postglacial colonization bottleneck. We further find evidence for accumulation of genetic load in highly self-fertilizing populations, whereas the genome-wide impact of purifying selection does not differ greatly between mixed-mating and outcrossing populations. Our results demonstrate that intermediate levels of outcrossing may allow efficient selection against harmful alleles, whereas demographic effects can be important for relaxed purifying selection in highly selfing populations. Thus, mating system and demography shape the impact of purifying selection on genomic variation in A. alpina These results are important for an improved understanding of the evolutionary consequences of mating system variation and the maintenance of mixed-mating strategies.


An R2R3 MYB transcription factor determines red petal colour in an Actinidia (kiwifruit) hybrid population.
Red colour in kiwifruit results from the presence of anthocyanin pigments. Their expression, however, is complex, and varies among genotypes, species, tissues and environments. An understanding of the biosynthesis, physiology and genetics of the anthocyanins involved, and the control of their expression in different tissues, is required. A complex, the MBW complex, consisting of R2R3-MYB and bHLH transcription factors together with a WD-repeat protein, activates anthocyanin 3-O-galactosyltransferase (F3GT1) to produce anthocyanins. We examined the expression and genetic control of anthocyanins in flowers of Actinidia hybrid families segregating for red and white petal colour. Four inter-related backcross families between Actinidia chinensis Planch. var. chinensis and Actinidia eriantha Benth. were identified that segregated 1:1 for red or white petal colour. Flower pigments consisted of five known anthocyanins (two delphinidin-based and three cyanidin-based) and three unknowns. Intensity and hue differed in red petals from pale pink to deep magenta, and while intensity of colour increased with total concentration of anthocyanin, no association was found between any particular anthocyanin data and hue. Real time qPCR demonstrated that an R2R3 MYB, MYB110a, was expressed at significant levels in red-petalled progeny, but not in individuals with white petals.A microsatellite marker was developed that identified alleles that segregated with red petal colour, but not with ovary, stamen filament, or fruit flesh colour in these families. The marker mapped to chromosome 10 in Actinidia.The white petal phenotype was complemented by syringing Agrobacterium tumefaciens carrying Actinidia 35S::MYB110a into the petal tissue. Red pigments developed in white petals both with, and without, co-transformation with Actinidia bHLH partners. MYB110a was shown to directly activate Actinidia F3GT1 in transient assays. The transcription factor, MYB110a, regulates anthocyanin production in petals in this hybrid population, but not in other flower tissues or mature fruit. The identification of delphinidin-based anthocyanins in these flowers provides candidates for colour enhancement in novel fruits.


Acute effects of device-guided slow breathing on sympathetic nerve activity and baroreflex sensitivity in posttraumatic stress disorder.
Patients with posttraumatic stress disorder (PTSD) have elevated sympathetic nervous system reactivity and impaired sympathetic and cardiovagal baroreflex sensitivity (BRS). Device-guided slow breathing (DGB) has been shown to lower blood pressure (BP) and sympathetic activity in other patient populations. We hypothesized that DGB acutely lowers BP, heart rate (HR), and improves BRS in PTSD. In 23 prehypertensive veterans with PTSD, we measured continuous BP, ECG, and muscle sympathetic nerve activity (MSNA) at rest and during 15 min of DGB at 5 breaths/min ( n = 13) or identical sham device breathing at normal rates of 14 breaths/min (sham; n = 10). Sympathetic and cardiovagal BRS was quantified using pharmacological manipulation of BP via the modified Oxford technique at baseline and during the last 5 min of DGB or sham. There was a significant reduction in systolic BP (by -9 ± 2 mmHg, P < 0.001), diastolic BP (by -3 ± 1 mmHg, P = 0.019), mean arterial pressure (by -4 ± 1 mmHg, P = 0.002), and MSNA burst frequency (by -7.8 ± 2.1 bursts/min, P = 0.004) with DGB but no significant change in HR ( P > 0.05). Within the sham group, there was no significant change in diastolic BP, mean arterial pressure, HR, or MSNA burst frequency, but there was a small but significant decrease in systolic BP ( P = 0.034) and MSNA burst incidence ( P = 0.033). Sympathetic BRS increased significantly in the DGB group (-1.08 ± 0.25 to -2.29 ± 0.24 bursts·100 heart beats-1·mmHg-1, P = 0.014) but decreased in the sham group (-1.58 ± 0.34 to -0.82 ± 0.28 bursts·100 heart beats-1·mmHg-1, P = 0.025) (time × device, P = 0.001). There was no significant difference in the change in cardiovagal BRS between the groups (time × device, P = 0.496). DGB acutely lowers BP and MSNA and improves sympathetic but not cardiovagal BRS in prehypertensive veterans with PTSD. NEW & NOTEWORTHY Posttraumatic stress disorder is characterized by augmented sympathetic reactivity, impaired baroreflex sensitivity, and an increased risk for developing hypertension and cardiovascular disease. This is the first study to examine the potential beneficial effects of device-guided slow breathing on hemodynamics, sympathetic activity, and arterial baroreflex sensitivity in prehypertensive veterans with posttraumatic stress disorder.


Geometry of behavioral spaces: A computational approach to analysis and understanding of agent based models and agent behaviors.
Systems with non-linear dynamics frequently exhibit emergent system behavior, which is important to find and specify rigorously to understand the nature of the modeled phenomena. Through this analysis, it is possible to characterize phenomena such as how systems assemble or dissipate and what behaviors lead to specific final system configurations. Agent Based Modeling (ABM) is one of the modeling techniques used to study the interaction dynamics between a system's agents and its environment. Although the methodology of ABM construction is well understood and practiced, there are no computational, statistically rigorous, comprehensive tools to evaluate an ABM's execution. Often, a human has to observe an ABM's execution in order to analyze how the ABM functions, identify the emergent processes in the agent's behavior, or study a parameter's effect on the system-wide behavior. This paper introduces a new statistically based framework to automatically analyze agents' behavior, identify common system-wide patterns, and record the probability of agents changing their behavior from one pattern of behavior to another. We use network based techniques to analyze the landscape of common behaviors in an ABM's execution. Finally, we test the proposed framework with a series of experiments featuring increasingly emergent behavior. The proposed framework will allow computational comparison of ABM executions, exploration of a model's parameter configuration space, and identification of the behavioral building blocks in a model's dynamics.


Clinical and Molecular Features of Late Onset Huntington Disease in a Peruvian Cohort.
Late onset cases of Huntington disease (HD), with onset ≥60 years, account for up to 20% of HD cases worldwide. Clinical features include mild motor dysfunction with slow progression and cognitive impairment, frequent absence of family history and low number of CAG repeats. The clinical and molecular features of late onset HD is still understudied in Latin America. To describe the clinical and molecular characteristics of late onset HD in a Peruvian cohort. An observational study was carried out by reviewing the HD registry at the Neurogenetics Research Center-INCN from 2000 to 2014. Genotyping of HTT gene …was confirmed using standard PCR and PAGE in accordance to protocols previously established. Thirty-one late onset HD cases from 27 pedigrees were identified (9.42% of total HD cases, n = 329), 51.61% were male. Mean age at onset was 64.1 ± 4.2 and CAG repeats mean was 42.5 ± 2.5. We did not find significant correlation between age at onset and CAG repeats. 33.3% of cases were traced back to Cañete valley. Twenty-two cases had a positive family history, 14 of them with paternal transmission. Choreic movements and cognitive impairment were the main existing manifestations reported in this cohort, with lower frequency of psychiatric disturbances. This report of late onset HD affected individuals shows a mild phenotype expression of the disease, associated with low range of CAG repeats and up to 30% of cases with absence of clear family history. Cañete valley remains the region with more cases.


Depressive effect of coughing on spinal monosynaptic reflexes in conscious man.
1. The relationship between coughing and spinal monosynaptic reflexes (SMR) in extensors and flexors was investigated in eight healthy subjects by using the Hoffmann technique. Coughing exerted major depression (81% in extensor and 83% in flexor SMR). This depressant effect began simultaneously with the first cough and lasted through the coughing phase. Complete recovery to initial values occurred an average of 40 s thereafter. 2. In comparison, mental tasks induced only a slight decrease in SMR amplitude. In contrast, the Mueller and Valsalva manoeuvres induced facilitation. 3. During coughing, large variations in extensor amplitudes were observed that were coupled with the ventilatory cycle. Slight facilitation was observed during inspiration, but expiration induced pronounced depression, occurring 0.20 s after the beginning of the expiratory period. Experiments performed during baseline breathing failed to show any change throughout inspiratory or expiratory phases. 4. Chemical stimulation of irritant receptors (inhalation of citric acid) produced no specific modification of extensor responses compared with the effect of placebo inhalation (distilled water). 5. These data suggest that coughing exerts a major depressant effect on motor activity via a loop that possibly includes cardiopulmonary receptors and inhibitory supraspinal descending pathways.


Moving on in life after intensive care--partners' experience of group communication.
Partners have a burdensome time during and after their partners' intensive care period. They may appear to be coping well outwardly but inside feel vulnerable and lost. Evaluated interventions for partners on this aspect are limited. The aim of this study was to describe the experience of participating in group communication with other partners of former intensive care patients. The study has a descriptive intervention-based design where group communication for partners of former, surviving intensive care unit (ICU) patients was evaluated. A strategic selection was made of adult partners to former adult intensive care patients (n = 15), 5 men and 10 women, aged 37-89 years. Two group communication sessions lasting 2 h were held at monthly intervals with three to five partners. The partners later wrote, in a notebook, about their feelings of participating in group communications. To deepen the understanding of the impact of the sessions, six of the partners were interviewed. Content analysis was used to analyse the notebooks and the interviews. Three categories were identified: (1) Emotional impact, the partners felt togetherness and experienced worries and gratitude, (2) Confirmation, consciousness through insight and reflection and (3) The meeting design, group constellation and recommendation to participate in group communication. Partners of an intensive care patient are on a journey, constantly trying to adapt to the new situation and find new strategies to ever-changing circumstances. Group communications contributed to togetherness and confirmation. To share experiences with others is one way for partners to be able to move forward in life. Group communication with other patients' partners eases the process of going through the burden of being a partner to an intensive care patient. Group communications needs to be further developed and evaluated to obtain consensus and evidence for the best practice.


The evolution of prolonged life after reproduction.
Why females of some species cease ovulation before the end of their natural lifespan is a longstanding evolutionary puzzle. For many species in captivity, post-reproductive life is simply an epiphenomenon of lengthened lifespan. Yet in natural populations of humans as well as some cetaceans and insects, reproductive senescence occurs much faster than somatic aging and females exhibit prolonged post-reproductive lifespans (PRLSs). Determining the mechanisms and functions that underpin PRLSs has proved a significant challenge. Here we bring together both classic and modern hypotheses proposed to explain PRLSs and discuss their application to both human and nonhuman animals. By taking an integrative and broad taxonomic approach we highlight the need to consider multiple interacting explanations for the evolution of PRLSs.


Visual abnormalities associated with high-energy microwave exposure.
A 44-year-old man was accidentally exposed to high-energy microwave irradiation. After resolution of facial erythema and iritis, he noted a foreign body sensation and blurring of vision. Ophthalmoscopic examination showed bilateral, small hard drusen. Ancillary tests were consistent with abnormal cone function. Electroretinogram testing revealed a marked decrease in the flicker electroretinogram. Results of D15 and Farnsworth Munsel Hue 100 color tests were abnormal. Two years later, the patient's visual acuity was stable at 20/25 in both eyes; however, results of flicker electroretinogram test remain markedly decreased.


Gain and loss of subcutaneous and abdominal fat depot mass from late pregnancy to 100 days in milk in German Holsteins.
This research paper addresses the hypothesis that in times of negative energy balance around parturition in dairy cattle, lipids stored in adipocytes are mobilised in a more intensive manner out of the abdominal depots than out of the subcutaneous adipose tissues. Furthermore, the impact of niacin supplementation and energy density of the ration on adipose tissue mass gain and loss was assessed. Absolute masses of subcutaneous (SCAT), retroperitoneal (RPAT), omental (OMAT), mesenterial (MAT) and abdominal adipose tissue as a whole (AAT) were estimated by ultrasonography at -42, 3, 21 and 100 DIM. Absolute and relative daily gain during dry period (-42 to 3 DIM) and loss in fresh cow period (3 to 21 DIM) and early lactation period (22 to 100 DIM) were calculated. Feeding regime neither by niacin nor by energy density exerted any effect on adipose tissue masses. The AAT was always bigger than SCAT, but RPAT, OMAT and MAT did not differ amongst each other. All depot masses showed similar patterns with an increase during dry period and a decrease after calving. In fresh cow period AAT absolutely and relatively lost more mass than SCAT. This confirms that AAT is more intensively mobilised than SCAT during that time span. Further absolute daily gain during dry period was strongly negatively correlated with absolute daily loss during fresh cow period. This underlines the impact of individual body condition on adipose mobilisation in periparturient dairy cows. According to these results, it has to be taken into account that the largest amount of fat mobilised in the fresh cow period origins from AAT. This might impact the pattern of adipose derived metabolites and metabolic effectors interacting in physiological and deregulated adaptation to negative energy balance.


A Window Into the Bright Side of Psychology: Interview With Mihaly Csikszentmihalyi.
Mihaly Csikszentmihalyi is one of the most eminent psychologists of the modern era. His ideas, such as flow, or the systems model of creativity, have inspired numerous studies, theoretical analyses as well as pedagogic and psychological interventions. Alongside Martin Seligman, he founded positive psychology and continues to work to promote it. In this interview, he shares the stories behind his scientific interests, sources of scientific ideas and the process of promoting the concepts he had written about. He also shares his thoughts about academic work performance.


The remarkable convergence of skull shape in crocodilians and toothed whales.
The striking resemblance of long-snouted aquatic mammals and reptiles has long been considered an example of morphological convergence, yet the true cause of this similarity remains untested. We addressed this deficit through three-dimensional morphometric analysis of the full diversity of crocodilian and toothed whale (Odontoceti) skull shapes. Our focus on biomechanically important aspects of shape allowed us to overcome difficulties involved in comparing mammals and reptiles, which have fundamental differences in the number and position of skull bones. We examined whether diet, habitat and prey size correlated with skull shape using phylogenetically informed statistical procedures. Crocodilians and toothed whales have a similar range of skull shapes, varying from extremely short and broad to extremely elongate. This spectrum of shapes represented more of the total variation in our dataset than between phylogenetic groups. The most elongate species (river dolphins and gharials) are extremely convergent in skull shape, clustering outside of the range of the other taxa. Our results suggest the remarkable convergence between long-snouted river dolphins and gharials is driven by diet rather than physical factors intrinsic to riverine environments. Despite diverging approximately 288 million years ago, crocodilians and odontocetes have evolved a remarkably similar morphological solution to feeding on similar prey.


Diesel exhaust particles up-regulate interleukin-17A expression via ROS/NF-κB in airway epithelium.
IL-17A is implicated in many aspects of pathogenesis of severe asthma, including inducing neutrophilic inflammation, airway hyperresponsiveness, steroid insensitivity and airway remodeling. Diesel exhaust particles (DEP) emission from vehicles has been shown to expand Th17 cells to increase IL-17A release that contributes to DEP-mediated exacerbation of asthma severity. It is not known whether non-immune cells in airways may also release IL-17A in response to DEP exposure. In this study, We found IL-17A expression was upregulated in the epithelium of severe allergic asthma patients from high road traffic pollution areas compared to those in low. Furthermore, we found DEP concentration-dependently increased IL-17A synthesis and release by 122.3 ± 15.72% and 235.5 ± 18.37%, respectively in primary bronchial epithelial cells (PBEC), accompanied with increased ROS production. Pretreatment of ROS scavenger (NAC) significantly inhibited DEP-induced IL-17A mRNA expression. DEP-induced IκBα degradation can be inhibited by NAC. We also found DEP increased p65 and RelB subunits expression, and pretreatment of NF-κB inhibitor (SN50) also inhibited DEP-induced IL-17A expression. We further found DEP increased NF-κB subunit RelB recruitment to IL-17A promoter in PBEC and airway tissue of severe allergic asthma patients from high road traffic pollution areas. These results indicate DEP stimulates IL-17A expression in airway epithelium through ROS/NF-κB pathway, and provide a possible link between traffic pollution exposure and IL-17A-related responses in severe allergic asthma patients.


Differences in membrane acyl phospholipid composition between an endothermic mammal and an ectothermic reptile are not limited to any phospholipid class.
This study examined questions concerning differences in the acyl composition of membrane phospholipids that have been linked to the faster rates of metabolic processes in endotherms versus ectotherms. In liver, kidney, heart and brain of the ectothermic reptile, Trachydosaurus rugosus, and the endothermic mammal, Rattus norvegicus, previous findings of fewer unsaturates but a greater unsaturation index (UI) in membranes of the mammal versus those of the reptile were confirmed. Moreover, the study showed that the distribution of phospholipid head-group classes was similar in the same tissues of the reptile and mammal and that the differences in acyl composition were present in all phospholipid classes analysed, suggesting a role for the physical over the chemical properties of membranes in determining the faster rates of metabolic processes in endotherms. The most common phosphatidylcholine (PC) molecules present in all tissues (except brain) of the reptile were 16:0/18:1, 16:0/18:2, 18:0/18:2, 18:1/18:1 and 18:1/18:2, whereas arachidonic acid (20:4), containing PCs 16:0/20:4, 18:0/20:4, were the common molecules in the mammal. The most abundant phosphatidylethanolamines (PE) used in the tissue of the reptile were 18:0/18:2, 18:0/20:4, 18:1/18:1, 18:1/18:2 and 18:1/20:4, compared to 16:0/18:2, 16:0/20:4, 16:0/22:6, 18:0/20:4, 18:0/22:6 and 18:1/20:4 in the mammal. UI differences were primarily due to arachidonic acid found in both PC and PEs, whereas docosahexaenoic acid (22:6) was a lesser contributor mainly within PEs and essentially absent in the kidney. The phospholipid composition of brain was more similar in the reptile and mammal compared to those of other tissues.


Association between use of pre-hospital ECG and 30-day mortality: A large cohort study of patients experiencing chest pain.
In the assessment of patients with chest pain, there is support for the use of pre-hospital ECG in the literature and in the care guidelines. Using propensity score methods, we aim to examine whether the mere acquisition of a pre-hospital ECG among patients with chest pain affects the outcome (30-day mortality). The association between pre-hospital ECG and 30-day mortality was studied in the overall cohort (n=13151), as well as in the one-to-one matched cohort with 2524 patients not examined with pre-hospital ECG and 2524 patients examined with pre-hospital ECG. In the overall cohort, 21% (n=2809) did not undergo an ECG tracing in the pre-hospital setting. Among those who had pain during transport, 14% (n=1159) did not undergo a pre-hospital ECG while 32% (n=1135) of those who did not have pain underwent an ECG tracing. In the overall cohort, the OR for 30-day mortality in patients who had a pre-hospital ECG, as compared with those who did not, was 0.63 (95% CI 0.05-0.79; p<0.001). In the matched cohort, the OR was 0.65 (95% CI 0.49-0.85; p<0.001). Using the propensity score, in the overall cohort, the corresponding HR was 0.65 (95% CI 0.58-0.74). Using propensity score methods, we provide real-world data demonstrating that the adjusted risk of death was considerably lower among the cases in whoma pre-hospital ECG was used. The PH-ECG is underused among patients with chest discomfort and the mere acquisition of a pre-hospital ECG may reduce mortality.


Genetic CFL: Hyperparameter Optimization in Clustered Federated Learning.
Federated learning (FL) is a distributed model for deep learning that integrates client-server architecture, edge computing, and real-time intelligence. FL has the capability of revolutionizing machine learning (ML) but lacks in the practicality of implementation due to technological limitations, communication overhead, non-IID (independent and identically distributed) data, and privacy concerns. Training a ML model over heterogeneous non-IID data highly degrades the convergence rate and performance. The existing traditional and clustered FL algorithms exhibit two main limitations, including inefficient client training and static hyperparameter utilization. To overcome these limitations, we propose a novel hybrid algorithm, namely, genetic clustered FL (Genetic CFL), that clusters edge devices based on the training hyperparameters and genetically modifies the parameters clusterwise. Then, we introduce an algorithm that drastically increases the individual cluster accuracy by integrating the density-based clustering and genetic hyperparameter optimization. The results are bench-marked using MNIST handwritten digit dataset and the CIFAR-10 dataset. The proposed genetic CFL shows significant improvements and works well with realistic cases of non-IID and ambiguous data. An accuracy of 99.79% is observed in the MNIST dataset and 76.88% in CIFAR-10 dataset with only 10 training rounds.


Entry of Epidemic Keratoconjunctivitis-Associated Human Adenovirus Type 37 in Human Corneal Epithelial Cells.
Ocular infection by human adenovirus species D type 37 (HAdV-D37) causes epidemic keratoconjunctivitis, a severe, hyperacute condition. The corneal component of epidemic keratoconjunctivitis begins upon infection of corneal epithelium, and the mechanism of viral entry dictates subsequent proinflammatory gene expression. Therefore, it is important to understand the specific pathways of adenoviral entry in these cells. Transmission electron microscopy of primary and tert-immortalized human corneal epithelial cells infected with HAdV-D37 was performed to identify the means of viral entry. Confocal microscopy was used to determine intracellular trafficking. The results of targeted small interfering RNA and specific chemical inhibitors were analyzed by quantitative PCR, and Western blot. By transmission electron microscopy, HAdV-D37 was seen to enter by both clathrin-coated pits and macropinocytosis; however, entry was both pH and dynamin 2 independent. Small interfering RNA against clathrin, AP2A1, and lysosome-associated membrane protein 1, but not early endosome antigen 1, decreased early viral gene expression. Ethyl-isopropyl amiloride, which blocks micropinocytosis, did not affect HAdV-D37 entry, but IPA, an inhibitor of p21-activated kinase, and important to actin polymerization, decreased viral entry in a dose-dependent manner. HAdV-D37 enters human corneal epithelial cells by a noncanonical clathrin-mediated pathway involving lysosome-associated membrane protein 1 and PAK1, independent of pH, dynamin, and early endosome antigen 1. We showed earlier that HAdV-D37 enters human keratocytes through caveolae. Therefore, epidemic keratoconjunctivitis-associated viruses enter different corneal cell types via disparate pathways, which could account for a relative paucity of proinflammatory gene expression upon infection of corneal epithelial cells compared with keratocytes, as seen in prior studies.


Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways.
Tetrahyrobiopterin (BH4) is a required cofactor for the synthesis of nitric oxide by endothelial nitric-oxide synthase (eNOS), and BH4 bioavailability within the endothelium is a critical factor in regulating the balance between NO and superoxide production by eNOS (eNOS coupling). BH4 levels are determined by the activity of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in de novo BH4 biosynthesis. However, BH4 levels may also be influenced by oxidation, forming 7,8-dihydrobiopterin (BH2), which promotes eNOS uncoupling. Conversely, dihydrofolate reductase (DHFR) can regenerate BH4 from BH2, but the functional importance of DHFR in maintaining eNOS coupling remains unclear. We investigated the role of DHFR in regulating BH4 versus BH2 levels in endothelial cells and in cell lines expressing eNOS combined with tet-regulated GTPCH expression in order to compare the effects of low or high levels of de novo BH4 biosynthesis. Pharmacological inhibition of DHFR activity by methotrexate or genetic knockdown of DHFR protein by RNA interference reduced intracellular BH4 and increased BH2 levels resulting in enzymatic uncoupling of eNOS, as indicated by increased eNOS-dependent superoxide but reduced NO production. In contrast to the decreased BH4:BH2 ratio induced by DHFR knockdown, GTPCH knockdown greatly reduced total biopterin levels but with no change in BH4:BH2 ratio. In cells expressing eNOS with low biopterin levels, DHFR inhibition or knockdown further diminished the BH4:BH2 ratio and exacerbated eNOS uncoupling. Taken together, these data reveal a key role for DHFR in eNOS coupling by maintaining the BH4:BH2 ratio, particularly in conditions of low total biopterin availability.


The impact of negative-pressure wound therapy with instillation on wounds requiring operative debridement: Pilot randomised, controlled trial.
Presence of bacteria in wounds can delay healing. Addition of a regularly instilled topical solution over the wound during negative-pressure wound therapy (NPWT) may reduce bioburden levels compared with standard NPWT alone. We performed a prospective, randomised, multi-centre, post-market trial to compare effects of NPWT with instillation and dwell of polyhexamethylene biguanide solution vs NPWT without instillation therapy in wounds requiring operative debridement. Results showed a significantly greater mean decrease in total bacterial counts from time of initial surgical debridement to first dressing change in NPWT plus instillation (n = 69) subjects compared with standard NPWT (n = 63) subjects (-0.18 vs 0.6 log10 CFU/g, respectively). There was no significant difference between the groups in the primary endpoint of required inpatient operating room debridements after initial debridement. Time to readiness for wound closure/coverage, proportion of wounds closed, and incidence of wound complications were similar. NPWT subjects had 3.1 times the risk of re-hospitalisation compared with NPWT plus instillation subjects. This study provides a basis for exploring research options to understand the impact of NPWT with instillation on wound healing.


Sonographically guided puncture of the pancreas: incidence of complications, and risk factors.
Data yielded by transabdominal ultrasound-guided puncture techniques are valuable for determining the malignancy of inoperable mass lesions of the pancreas. In this study we analyzed the incidence of complications and the risk factors. A total of 430 punctures of the pancreas were performed for 281 patients. Risk factors were prospectively assessed and complications were recorded. All punctures were sonographically guided. The 281 patients underwent a total of 351 puncture procedures including 430 punctures and 901 passes. The maximum diameter of the pancreatic mass lesion was documented; the mean diameter was 48.3 ± 29.1 mm. 75.8 % of punctures were performed with a needle diameter of 0.7-0.95 mm, and 23.0 % of punctures were performed as cutting biopsies producing a tissue sample 1.2 or 1.6 mm in diameter. In 77.8 % of punctures, one puncture was performed, and in 21.9 %, two punctures were performed. Three punctures were performed for one patient (0.3 %) only. The incidence of major complications was 0.3 %. None of the assessed risk factors was associated with an elevated incidence of complications. Our findings demonstrate the safety of transabdominal percutaneous puncture of the pancreas but do not enable conclusions to be drawn with regard to individual risk factors.


[Physical trauma and fibromyalgia--is there a true association?].
A total of 25-50% of fibromyalgia patients (FM) report the occurrence of physical trauma that preceded the onset of their symptoms by several weeks to several months. Yet, there is still no agreement among experts as to whether physical trauma can cause FM. The severity of the injury varies, but is usually milder than that seen in patients with post-traumatic stress syndrome. Road accidents, and, in particular, whiplash injuries, or accumulated injury inherent in some occupations have been described as causes of fibromyalgia. The only two prospective studies that assessed the incidence of fibromyalgia syndrome following accidents, such as whiplash injuries, were conducted by Israeli researchers and they reported opposite results. Possible mechanisms for the development of the syndrome following trauma have not been elucidated sufficiently to date. Stressful conditions are also known to contribute to the appearance of the syndrome. In most likelihood, there is no significant difference between idiopathic fibromyalgia and post traumatic fibromyalgia in terms of clinical course, symptom severity and prognosis, although some investigators have reported a worse prognosis in post-traumatic cases. In Israel, there is an increase in the number of suits filed against private insurance companies and the National Insurance system for post-traumatic fibromyalgia. According to the literature, it is probable that the number of cases that involve malingering or secondary gain is low. The ongoing controversy among medical experts as to whether there is an association between FS and physical trauma has made it very difficult, in the absence of guidelines and objective tools, for the legal and administrative systems to deal with this difficult issue.


Closed-loop glucose control in young people with type 1 diabetes during and after unannounced physical activity: a randomised controlled crossover trial.
Hypoglycaemia during and after exercise remains a challenge. The present study evaluated the safety and efficacy of closed-loop insulin delivery during unannounced (to the closed-loop algorithm) afternoon physical activity and during the following night in young people with type 1 diabetes. A randomised, two-arm, open-label, in-hospital, crossover clinical trial was performed at a single site in Slovenia. The order was randomly determined using an automated web-based programme with randomly permuted blocks of four. Allocation assignment was not masked. Children and adolescents with type 1 diabetes who were experienced insulin pump users were eligible for the trial. During four separate in-hospital visits, the participants performed two unannounced exercise protocols: moderate intensity (55% of [Formula: see text]) and moderate intensity with integrated high-intensity sprints (55/80% of [Formula: see text]), using the same study device either for closed-loop or open-loop insulin delivery. We investigated glycaemic control during the exercise period and the following night. The closed-loop insulin delivery was applied from 15:00 h on the day of the exercise to 13:00 h on the following day. Between 20 January and 16 June 2016, 20 eligible participants (9 female, mean age 14.2 ± 2.0 years, HbA1c 7.7 ± 0.6% [60.0 ± 6.6 mmol/mol]) were included in the trial and performed all trial-mandated activities. The median proportion of time spent in hypoglycaemia below 3.3 mmol/l was 0.00% for both treatment modalities (p = 0.7910). Use of the closed-loop insulin delivery system increased the proportion of time spent within the target glucose range of 3.9-10 mmol/l when compared with open-loop delivery: 84.1% (interquartile range 70.0-85.5) vs 68.7% (59.0-77.7), respectively (p = 0.0057), over the entire study period. This was achieved with significantly less insulin delivered via the closed-loop (p = 0.0123). Closed-loop insulin delivery was safe both during and after unannounced exercise protocols in the in-hospital environment, maintaining glucose values mostly within the target range without an increased risk of hypoglycaemia. Clinicaltrials.gov NCT02657083 FUNDING: University Medical Centre Ljubljana, Slovenian National Research Agency, and ISPAD Research Fellowship.


Tuning the sound speed in macroporous polymers with a hard or soft matrix.
In this paper, we investigate the factors affecting the sound speed in air-filled macroporous polymer materials at ultrasound frequencies. Due to the presence of large proportion of gas, these porous materials present high compressibility and, as a consequence, low sound speed which may fall down to values as low as 40 m s-1. Using an emulsion-templating method, we synthesize macroporous samples with similar porous structures but with three different matrices, i.e. a hard poly(styrene-divinylbenzene (DVB)) matrix, a soft epoxy-modified polydimethylsiloxane (PDMS) matrix and a very soft polyaddition PDMS matrix. We characterize the matrix mechanical properties by measuring both the bulk modulus K0 and the shear modulus G0. Next, we compare the sound speed measured in porous samples with porosity varying from 0 to 50%. We show that, in agreement with theoretical predictions, the sound speed is mainly controlled by two parameters, the porosity value and the K0/G0 ratio of the polymer matrix. These parameters may be used to control the sound propagation in porous polymers, which opens the way to the realization of gradient-index materials.


Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer.
Previous epidemiologic observations consistently suggest that suppression of ovulation, tubal ligation, and hysterectomy reduce the risk of ovarian cancer and that perineal talc use increases the risk. We examined these and other risk factors in the context of a new hypothesis: that inflammation may play a role in ovarian cancer risk. Ovulation entails ovarian epithelial inflammation; talc, endometriosis, cysts, and hyperthyroidism may be associated with inflammatory responses of the ovarian epithelium; gynecologic surgery may preclude irritants from reaching the ovaries via ascension from the lower genital tract. We evaluated these risk factors in a population-based case-control study. Cases 20-69 years of age with a recent diagnosis of epithelial ovarian cancer (767) were compared with community controls (1,367). We found that a number of reproductive and contraceptive factors that suppress ovulation, including gravidity, breast feeding, and oral contraception, reduced the risk of ovarian cancer. Environmental factors and medical conditions that increased risk included talc use, endometriosis, ovarian cysts, and hyperthyroidism. Gynecologic surgery including hysterectomy and tubal ligation were protective. Tubal ligation afforded a risk reduction even 20 or more years after the surgery. The spectrum of associations provides support for the hypothesis that inflammation may mediate ovarian cancer risk.


Do split-side rails present an increased risk to patient safety?
Concerns have been raised about the safety of split-side bed rails for patients in the UK. To investigate whether split-side rails were more likely to be associated with entrapment and injury of patients than other bed rail types. To establish whether there was a difference in the site of injury caused by different bed rail types and whether the outcome of the injury (death versus survival) varied by bedrail type. A search of the USA Food and Drug Administration MAUDE database was carried out. The reports were screened using rigorous inclusion/exclusion criteria and then coded for rail type, incident outcome, and area of body involved. Split-side rail incidents only accounted for 5% of the reports and were more likely to involve the chest or pelvis. Although the biggest overall risk by rail type cannot be determined from these data, the severity of the outcome changed with the equipment type. Incidents involving half rails were more likely to be associated with head, neck, or face entrapments and were also more likely than other bed rail types to result in death. Split-side rail entrapments were not a common occurrence. However, our findings suggest that bed rails are associated with some level of risk of entrapment that potentially could result in death. Healthcare providers should therefore ensure that they follow the guidelines for risk assessment and rail use from the MHRA and other professional bodies so that the cultural norm in the UK continues to be "opt in", where no bed rails are used unless indicated by a documented clinical assessment.


Review of Scientific Evidence of Medicinal Convoy Plants in Traditional Persian Medicine.
One concept used in traditional Persian medicine (TPM) for multidrug therapy is that of the convoy drug (Mobadregh). According to TPM texts, convoy drugs are substances (or drugs), which facilitate the access of drugs or foods to the whole body or to specific organs. This study reviewed some convoy drugs presented in TPM, their biological effects, and their probable interactions with main drugs, considering the increased absorption through inhibition of P-glycoprotein (P-gp) efflux function, bioavailability-enhancing effects, and decreased metabolism of the main drug using electronic databases including PubMed, Scopus, ScienceDirect, and Google Scholar in November and December, 2013. Recent studies have proven the beneficial effects of Crocus sativus L. (saffron) and camphor on the heart and brain, the cerebral therapeutic effects of Asarum europaeum (hazelwort), the hepatoprotective effects of Cichorium intybus (chicory), and Apium graveolens (celery) seeds, and the diuretic effects of Cinnamomum zeylanicum (cinnamon), and Cucumis melo (melon) seeds. The effects of vinegar in targeting the liver and brain have also been demonstrated. An evaluation of the results demonstrated that the suggested convoy drugs, including Piper nigrum (black pepper), Piper longum (long pepper), red wine, Camellia sinensis (tea), hazelwort, Mentha longifolia (pennyroyal), Anethum graveolens (dill), Foeniculum vulgare (fennel), cinnamon, and Sassafras albidum (sassafras) can increase the bioavailability of coadministered drugs by inhibition of P-gp or cytochrome P450s (CYP450s) or both of them. This evidence could be a good basis for the use of these agents as convoys in TPM.