The target selective neural response--similarity, ambiguity, and learning effects.
A network of frontal and parietal brain regions is commonly recruited during tasks that require the deliberate 'top-down' control of thought and action. Previously, using simple target detection, we have demonstrated that within this frontoparietal network, the right ventrolateral prefrontal cortex (VLPFC) in particular is sensitive to the presentation of target objects. Here, we use a range of target/non-target morphs to plot the target selective response within distinct frontoparietal sub-regions in greater detail. The increased resolution allows us to examine the extent to which different cognitive factors can predict the blood oxygenation level dependent (BOLD) response to targets. Our results reveal that both probability of positive identification (similarity to target) and proximity to the 50% decision boundary (ambiguity) are significant predictors of BOLD signal change, particularly in the right VLPFC. Furthermore, the profile of target related signal change is not static, with the degree of selectivity increasing as the task becomes familiar. These findings demonstrate that frontoparietal sub-regions are recruited under increased cognitive demand and that when recruited, they adapt, using both fast and slow mechanisms, to selectively respond to those items that are of the most relevance to current intentions.


Cleft palate is caused by CNS dysfunction in Gad1 and Viaat knockout mice.
Previous studies have shown that disruption of GABA signaling in mice via mutations in the Gad1, Gabrb3 or Viaat genes leads to the development of non-neural developmental defects such as cleft palate. Studies of the Gabrb3 and Gad1 mutant mice have suggested that GABA function could be required either in the central nervous system or in the palate itself for normal palatogenesis. To further examine the role of GABA signaling in palatogenesis we used three independent experimental approaches to test whether Gad1 or Viaat function is required in the fetal CNS for normal palate development. We used oral explant cultures to demonstrate that the Gad1 and Viaat mutant palates were able to undergo palatogenesis in culture, suggesting that there is no defect in the palate tissue itself in these mice. In a second series of experiments we found that the GABA(A) receptor agonist muscimol could rescue the cleft palate phenotype in Gad1 and Viaat mutant embryos. This suggested that normal multimeric GABA(A) receptors in the CNS were necessary for normal palatogenesis. In addition, we showed that CNS-specific inactivation of Gad1 was sufficient to disrupt palate development. Our results are consistent with a role for Gad1 and Viaat in the central nervous system for normal development of the palate. We suggest that the alterations in GABA signaling lead to non-neural defects such as cleft palate as a secondary effect due to alterations in or elimination of fetal movements.


Nitrogen-doped one-dimensional (1D) macroporous carbonaceous nanotube arrays and their application in electrocatalytic oxygen reduction reactions.
A nitrogen(N)-doped one-dimensional (1D) macroporous carbonaceous nanotube array was fabricated by using an anodic alumina oxide (AAO) template. The large diameter of the nanotubes (∼200 nm) could overcome the sluggish mass transfer phenomena in the common micro/mesoporous carbon-based electrodes. Combining the activation of the π electrons of the sp(2) carbon array by N-doping, the novel 1D macroporous carbonaceous nanotube array exhibited high performance for the oxygen reduction reaction (ORR).


Oral curcumin in elective abdominal aortic aneurysm repair: a multicentre randomized controlled trial.
Curcumin, a popular herbal supplement from the plant turmeric, has prevented ischemic reperfusion and toxin-induced injury in many animal studies and a single-centre randomized human trial. We sought to test whether perioperative oral curcumin (compared with placebo) affects the inflammatory response and risk of postrepair complications after elective abdominal aortic aneurysm repair in humans. We conducted a parallel-group, randomized, placebo-controlled trial of patients from 10 hospitals in Canada who were scheduled to undergo elective repair of an unruptured abdominal aortic aneurysm (November 2011 to November 2014). Patients in the treatment group received perioperative oral curcumin (2000-mg doses 8 times over 4 d). Patients, health care providers and local research staff were unaware of the treatment assignment. The primary outcomes were median concentrations of 4 bio markers indicating injury and inflammation (postoperative urine interleukin-18 and perioperative rise in serum creatinine, plasma N-terminal pro-B-type natriuretic peptide and plasma high-sensitivity C-reactive protein). Baseline characteristics were similar in the 2 groups (606 patients overall; median age 76 yr). More than 85% of patients in each group took more than 80% of their scheduled capsules. Neither curcumin nor placebo significantly affected any of the 4 biomarkers (p > 0.05 for all comparisons). Regarding the secondary outcomes, there was a higher risk of acute kidney injury with curcumin than with placebo (17% v. 10%, p = 0.01), but no between-group difference in the median length of hospital stay (5 v. 5 days, p > 0.9) or the risk of clinical events (9% v. 9%, p = 0.9). Curcumin had no beneficial effects when used in elective abdominal aortic aneurysm repair. These findings emphasize the importance of testing turmeric and curcumin before espousing their health benefits, as is currently done in the popular media. ClinicalTrials.gov, no. NCT01225094.


CRISPR-Cas9-mediated knockout of SPRY2 in human hepatocytes leads to increased glucose uptake and lipid droplet accumulation.
The prevalence of obesity and its comorbidities, including type 2 diabetes mellitus (T2DM), is dramatically increasing throughout the world; however, the underlying aetiology is incompletely understood. Genome-wide association studies (GWAS) have identified hundreds of genec susceptibility loci for obesity and T2DM, although the causal genes and mechanisms are largely unknown. SPRY2 is a candidate gene identified in GWAS of body fat percentage and T2DM, and has recently been linked to insulin production in pancreatic β-cells. In the present study, we aimed to further understand SPRY2 via functional characterisation in HepG2 cells, an in vitro model of human hepatocytes widely used to investigate T2DM and insulin resistance. CRISPR-Cas9 genome editing was used to target SPRY2 in HepG2 cells, and the functional consequences of SPRY2 knockout (KO) and overexpression subsequently assessed using glucose uptake and lipid droplet assays, measurement of protein kinase phosphorylation and RNA sequencing. The major functional consequence of SPRY2 KO was a significant increase in glucose uptake, along with elevated lipid droplet accumulation. These changes were attenuated, but not reversed, in cells overexpressing SPRY2. Phosphorylation of protein kinases across key signalling pathways (including Akt and mitogen activated protein kinases) was not altered after SPRY2 KO. Transcriptome profiling in SPRY2 KO and mock (control) cells revealed a number of differentially expressed genes related to cholesterol biosynthesis, cell cycle regulation and cellular signalling pathways. Phospholipase A2 group IIA (PLA2G2A) mRNA level was subsequently validated as significantly upregulated following SPRY2 KO, highlighting this as a potential mediator downstream of SPRY2. These findings suggest a role for SPRY2 in glucose and lipid metabolism in hepatocytes and contribute to clarifying the function of this gene in the context of metabolic diseases.


Quantum memristors.
Technology based on memristors, resistors with memory whose resistance depends on the history of the crossing charges, has lately enhanced the classical paradigm of computation with neuromorphic architectures. However, in contrast to the known quantized models of passive circuit elements, such as inductors, capacitors or resistors, the design and realization of a quantum memristor is still missing. Here, we introduce the concept of a quantum memristor as a quantum dissipative device, whose decoherence mechanism is controlled by a continuous-measurement feedback scheme, which accounts for the memory. Indeed, we provide numerical simulations showing that memory effects actually persist in the quantum regime. Our quantization method, specifically designed for superconducting circuits, may be extended to other quantum platforms, allowing for memristor-type constructions in different quantum technologies. The proposed quantum memristor is then a building block for neuromorphic quantum computation and quantum simulations of non-Markovian systems.


Determination of obesity associated gene variants related to TMEM18 through ultra-deep targeted re-sequencing in a case-control cohort for pediatric obesity.
Genome-wide association studies (GWAS) have revealed association of a locus approximately 25b downstream of the TMEM18 gene with body mass and obesity. We utilized targeted re-sequencing of the body mass associated locus in proximity of TMEM18 in a case-control population of severely obese children and adolescents from the Stockholm area. We expanded our study to include the TMEM18 gene itself, with the aim of identifying body mass associated genetic variants. Sequencing was performed on the SOLiD platform, on long-range PCR fragments generated through targeted amplification of the regions of interest. Candidate single nucleotide polymorphisms (SNPs) were validated by TaqMan genotyping. We were able to observe 131 SNPs across the re-sequenced regions. Chi squared tests comparing the allele frequencies between cases and controls revealed 57 SNPs as candidates for association with obesity. Validation and replication genotyping revealed robust associations for SNPs within the haplotype block region located downstream from the TMEM18 gene. This study provides a high resolution map of the genetic variation pattern in the TMEM18 gene, as well as the associated haplotype block, and further strengthens the association of variants within the proximal haplotype block with obesity and body mass.


Assessment of Bonding Effectiveness of Adhesive Materials to Tooth Structure using Bond Strength Test Methods: A Review of Literature.
The rapid developments in the field of adhesive dental materials have led to improvements in many aspects of clinical dentistry. Adhesive bond strength plays an important role in determining the clinical performance and longevity of dental restorations. Nevertheless, bond strength tests have never been well-standardized, although a number of important recommendations have been made. The aim of this paper is to critically review the validity of different bond strength testing methods for assessment of bonding effectiveness of adhesive materials to tooth structure and discuss factors that may affect bond strength measurement. Relevant literature published between 1983 and 2018 was collected and reviewed from the PubMed database and Google scholar resources. Results of the current bond testing methods should be used to compare materials tested under the same laboratory settings, but they shouldn't be used to make direct inferences on their clinical behaviour. Shear and micro-shear tests, result in non-uniform stress distribution, stress concentration at the substrate area, and predominantly tensile stresses rather than shear stresses. Micro-tensile bond tests provide many advantages over the shear tests, although these methods are technique sensitive and labour intensive. Bond strength testing methods should be well-standardized, but there are many factors that cannot be fully controlled which leads to variation and misinterpretation of the data about the bonding abilities of adhesives. New adhesive materials should be subjected to a combination of testing protocols to properly assess their bonding effectiveness.


Conformational equilibria of the L-iduronate residue in non-sulphated di-, tetra- and hexa-saccharides and their alditols derived from dermatan sulphate.
The conformation of the L-iduronate residue in non-sulphated di-, tetra- and hexa-saccharides and their alditol derivatives derived from rooster comb dermatan sulphate was investigated by 400 MHz 1H-n.m.r. spectroscopy. The ratio of conformational isomers is obtained by the average spin-spin coupling constants of a mixture of nearly isoenergetic conformers (1C4, 4C1 and 2S0). The non-reducing terminal L-iduronate residue in the tetrasaccharides (I-H-I-H and I-H-G-H) and their alditols (I-H-I-H-ol and I-H-G-H-ol) is in equilibrium with three conformers (1C4, 30%; 4C1, 40%; 2S0, 30%) of nearly equal population. Whereas the internal L-iduronate residue in the tetrasaccharides (I-H-I-H and G-H-I-H) exists as an equilibrium mixture of 1C4 (54%) and 2S0 (42-44%) conformers, that of their alditols (I-H-I-H-ol and G-H-I-H-ol) is in equilibrium between 2S0 conformer (66%) and 1C4 conformer (28%). The conformational population for the internal L-iduronate residue 2I in the hexasaccharide (3I-H-2I-H-1I-H) is also calculated and compared with that for the L-iduronate residue in native dermatan sulphate, which was calculated on the basis of the spin-spin coupling constants reported by Gatti, Casu, Torri & Vercellotti [(1979) Carbohydr. Res. 68, c3-c7].


A generic camera model and calibration method for conventional, wide-angle, and fish-eye lenses.
Fish-eye lenses are convenient in such applications where a very wide angle of view is needed, but their use for measurement purposes has been limited by the lack of an accurate, generic, and easy-to-use calibration procedure. We hence propose a generic camera model, which is suitable for fish-eye lens cameras as well as for conventional and wide-angle lens cameras, and a calibration method for estimating the parameters of the model. The achieved level of calibration accuracy is comparable to the previously reported state-of-the-art.


Genome analysis of the marine bacterium Kiloniella laminariae and first insights into comparative genomics with related Kiloniella species.
Kiloniella laminariae is a true marine bacterium and the first member of the family and order, the Kiloniellaceae and Kiloniellales. K. laminariae LD81T (= DSM 19542T) was isolated from the marine macroalga Saccharina latissima and is a mesophilic, typical marine chemoheterotrophic aerobic bacterium with antifungal activity. Phylogenetic analysis of 16S rRNA gene sequence revealed the similarity of K. laminariae LD81T not only with three validly described species of the genus Kiloniella, but also with undescribed isolates and clone sequences from marine samples in the range of 93.6-96.7%. We report on the analysis of the draft genome of this alphaproteobacterium and describe some selected features. The 4.4 Mb genome has a G + C content of 51.4%, contains 4213 coding sequences including 51 RNA genes as well as 4162 protein-coding genes, and is a part of the Genomic Encyclopaedia of Bacteria and Archaea (GEBA) project. The genome provides insights into a number of metabolic properties, such as carbon and sulfur metabolism, and indicates the potential for denitrification and the biosynthesis of secondary metabolites. Comparative genome analysis was performed with K. laminariae LD81T and the animal-associated species Kiloniella majae M56.1T from a spider crab, Kiloniella spongiae MEBiC09566T from a sponge as well as Kiloniella litopenai P1-1 from a white shrimp, which all inhabit quite different marine habitats. The analysis revealed that the K. laminariae LD81T contains 1397 unique genes, more than twice the amount of the other species. Unique among others is a mixed PKS/NRPS biosynthetic gene cluster with similarity to the biosynthetic gene cluster responsible for the production of syringomycin.


DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway.
Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays. WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, P = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50 < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type ERBB2 model. The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.


The global coverage of prevalence data for mental disorders in children and adolescents.
Children and adolescents make up almost a quarter of the world's population with 85% living in low- and middle-income countries (LMICs). Globally, mental (and substance use) disorders are the leading cause of disability in young people; however, the representativeness or 'coverage' of the prevalence data is unknown. Coverage refers to the proportion of the target population (ages 5-17 years) represented by the available data. Prevalence data for conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), eating disorders (EDs), depression, and anxiety disorders were sourced from systematic reviews conducted for the Global Burden of Disease Study 2010 (GBD 2010) and 2013 (GBD 2013). For each study, the location proportion was multiplied by the age proportion to give study coverage. Location proportion was calculated by dividing the total study location population by the total study location population. Age proportion was calculated by dividing the population of the country aged within the age range of the study sample by the population of the country aged within the age range of the study sample. If a study only sampled one sex, study coverage was halved. Coverage across studies was then summed for each country to give coverage by country. This method was repeated at the region and global level, and separately for GBD 2013 and GBD 2010. Mean global coverage of prevalence data for mental disorders in ages 5-17 years was 6.7% (CD: 5.0%, ADHD: 5.5%, ASDs: 16.1%, EDs: 4.4%, depression: 6.2%, anxiety: 3.2%). Of 187 countries, 124 had no data for any disorder. Many LMICs were poorly represented in the available prevalence data, for example, no region in sub-Saharan Africa had more than 2% coverage for any disorder. While coverage increased between GBD 2010 and GBD 2013, this differed greatly between disorders and few new countries provided data. The global coverage of prevalence data for mental disorders in children and adolescents is limited. Practical methodology must be developed and epidemiological surveys funded to provide representative prevalence estimates so as to inform appropriate resource allocation and support policies that address mental health needs of children and adolescents.


Perceived Risk of Infection Linked to Changes in Comfort in Social Situations From Before to During the COVID-19 Pandemic.
Background: Social lives have significantly changed since social distancing measures have been implemented to prevent the spread of the coronavirus disease 2019 (COVID-19). This study aimed to investigate how our appraisal of social situations changed during the pandemic. Methods: In two online surveys, conducted in October 2019 and April 2020, 58 participants rated their personal level of comfort for sketches depicting social situations. Situations were separately categorized according to the risk of a possible COVID-19 infection and changes in ratings were analyzed by using a repeated measures ANOVA. Moreover, potential influencing factors on the change in ratings such as perceived infection risk and social factors like regular frequency and liking of social interactions were examined. Results: There was a significant interaction (p < 0.001) between time of measurement and risk category. Comfort ratings of depicted situations with low and medium infection risk were higher during the second compared to the first survey period. Ratings of high-risk situations did not change significantly, although there was a tendency toward lower ratings during the pandemic. Multiple regression analyses showed that perceived probability of short-term infection could explain variance in the change of ratings of social situations with low- and medium risk, but not perceived probability of long-term infection or social factors. Conclusion: The results suggest that the change of participant's appraisal of the social situations during the COVID-19 pandemic relates to perceived infection risk. Both, the risk associated with the specific scenario as well as the general belief of short-term infection risk were associated with change. This change predominantly manifested in greater thought of comfort during low and medium risk situations, which might give a sense of safety during the pandemic. The finding that high-risk social situations were not rated as uncomfortable as expected must be considered with regard to the young sample and may not be generalizable to other individuals. Further research is necessary to evaluate long-term effects on social interactions caused by global pandemics such as the COVID-19 pandemic.


Hormonal and subjective responses to intravenous meta-chlorophenylpiperazine in bulimia nervosa.
Several lines of evidence point to serotonergic abnormalities in patients with bulimia nervosa (BN). Our goal was to further examine central serotonergic function in bulimic patients using neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist meta-chlorophenylpiperazine (mCPP). Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to intravenous mCPP (0.1 mg/kg) and placebo in 16 patients with BN, free of medication, and 14 normal control subjects. Plasma prolactin and cortisol levels were used as neuroendocrine measures, whereas subjective responses were measured using a visual analog scale of 10 different mood states. Compared with controls, the BN group exhibited blunted prolactin and net cortisol responses following mCPP challenge. Subjective responses, while preliminary, also differed between groups on items related to anxiety, calmness, and altered self-awareness. Evidence of dysfunction at or downstream of central serotonergic receptors in BN confirms and extends findings of prior research.


Ensuring quality in AFRINEST and SATT: clinical standardization and monitoring.
Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials' results.


Identification of rat hepatocyte plasma membrane proteins using monoclonal antibodies.
We have localized and identified five rat hepatocyte plasma membrane proteins using hybridoma technology in combination with morphological and biochemical methods. Three different membrane preparations were used as immunogens: isolated hepatocytes, a preparation of plasma membrane sheets that contained all three recognizable surface domains of the intact hepatocyte (sinusoidal, lateral, and bile canalicular), and a glycoprotein subfraction of that plasma membrane preparation. We selected monoclonal IgGs that were hepatocyte specific and localized them using both immunofluorescence on 0.5-micron sections of frozen liver and immunoperoxidase at the ultrastructural level. One antigen (HA 4) was localized predominantly to the bile canalicular surface, whereas three (CE 9, HA 21, and HA 116) were localized predominantly to the lateral and sinusoidal surfaces. One antigen (HA 16) was present in all three domains. Only one antigen (HA 116) could be detected in intracellular structures both in the periphery of the cell and in the Golgi region. The antigens were all integral membrane proteins as judged by their stability to alkaline extraction and solubility in detergents. The apparent molecular weights of the antigens were established by immunoprecipitation and/or immunoblotting. In a related study (Bartles, J.R., L.T. Braiterman, and A.L. Hubbard, 1985, J. Cell. Biol., 100:1126-1138), we present biochemical confirmation of the domain-specific localizations for two of the antigens, HA 4 and CE 9, and demonstrate their suitability as endogenous domain markers for monitoring the separation of bile canalicular and sinusoidal lateral membrane on sucrose density gradients.


Statement on Exercise Testing in Cystic Fibrosis.
This statement summarizes the information available on specific exercise test protocols and outcome parameters used in patients with cystic fibrosis (CF) and provides expert consensus recommendations for protocol and performance of exercise tests and basic interpretation of results for clinicians. The conclusions were reached employing consensus meetings and a wide-band Delphi process. Although data on utility are currently limited, standardized exercise testing provides detailed information on physiological health, allows screening for exercise-related adverse reactions and enables exercise counselling. The Godfrey Cycle Ergometer Protocol with monitoring of oxygen saturation and ventilatory gas exchange is recommended for exercise testing in people 10 years and older. Cycle ergometry only with pulse oximetry using the Godfrey protocol or treadmill exercise with pulse oximetry - preferably with measurement of gas exchange - are second best options. Peak oxygen uptake, if assessed, and maximal work rate should be reported as the primary measure of exercise capacity. The final statement was reviewed by the European Cystic Fibrosis society and revised based on the comments received. The document was endorsed by the European Respiratory Society.


Understanding the interactions between sebum triglycerides and water: a molecular dynamics simulation study.
In recent years, sebum oil has been found to play a key role in the regulation of the hydration of the outermost layer of the skin, the stratum corneum. Understanding how a major component of the sebum oil, the triglyceride tri-cis-6-hexadecenoin (TG), interacts with water is an important step in gaining insight into the water regulation function of the sebum oil. Here we use molecular dynamics simulations to investigate the structural and interfacial properties of TG in bulk and at the air and water interface. Our model performs very well in reproducing experimental results, such as density, surface tensions and surface pressure area isotherms. We show that triglyceride molecules in the liquid phase assemble together, through the glycerol group, forming a single percolating network. TG-air interfaces orient the lipids with the interface enriched with the hydrophobic tails and the glycerol groups buried inside. When in contact with water, the TG molecules at the interface orient the glycerol group towards the water phase and adopt a characteristic trident conformation. Water is shown to penetrate the TG layer thanks to the interaction with the oxygen atoms of the TG molecules, which acts as a pathway for water diffusion. The activation energy for the passage of water is found to be ≈9.5kBT at 310 K, showing that the layer is permeable to water diffusion.


Pain Beliefs and Perceptions and Their Relationship with Coping Strategies, Stress, Anxiety, and Depression in Patients with Cancer.
The current study was conducted aiming at the investigation of pain beliefs and perceptions and their relationship with coping strategies, stress, anxiety, and depression in patients with cancer. Study design: This was a descriptive-correlational and cross-sectional study. Data collection tools - Demographic questionnaire, Pain Beliefs and Perceptions Inventory, Pain Coping Strategies Questionnaire (Rosenstiel and Keefe), and Depression, Anxiety, and Stress Scale were used in this study. The dataset was analyzed using descriptive and infreretial statistics that included the chi-square and one-way ANOVA with software SPSS v.16 analysis. Findings of the study indicated that the most common belief about pain in patients is pain permanence. In addition, the most commonly used strategies for coping pain in patients were praying/hoping (25.82 ± 7.86) and self-statements (22.3 ± 10.34). Results indicated that there is a significant difference between pain coping strategies and pain control (P = 0.02). No significant difference was observed between the pain beliefs and the coping strategies (P = 0.15). Depression and anxiety level of patients was estimated as moderate, and their stress was estimated as mild. It was specified that there is a significant difference between self-blame belief and depression of patients (P = 0.01). Understanding and identifying emotional-psychological variables in patients with chronic pains may provide a basis for implementing educational cognitive-behavioral programs for patients and the ground for increasing the ability to control the pain in nonpharmacological methods leading to promoting quality of life in these patients.


THISTLE: trial of hands-on Interprofessional simulation training for local emergencies: a research protocol for a stepped-wedge clustered randomised controlled trial.
Many adverse pregnancy outcomes in the UK could be prevented with better intrapartum care. Training for intrapartum emergencies has been widely recommended but there are conflicting data about their effectiveness. Observational studies have shown sustained local improvements in perinatal outcomes associated with the use of the PRactical Obstetric Multi-Professional Training - (PROMPT) training package. However this effect needs to be investigated in the context of randomised study design in settings other than enthusiastic early adopter single-centres. The main aim of this study is to determine the effectiveness of PROMPT to reduce the rate of term infants born with low APGAR scores. THISTLE (Trial of Hands-on Interprofessional Simulation Training for Local Emergencies) is a multi-centre stepped-wedge clustered randomised controlled superiority trial conducted across 12 large Maternity Units in Scotland. On the basis of prior observational findings all Units have been offered the intervention and have been randomly allocated in groups of four Units, to one of three intervention time periods, each six months apart. Teams of four multi-professional clinicians from each participating Unit attended a two-day PROMPT Train the Trainers (T3) programme prior to the start of their allocated intervention step. Following the T3 training, the teams commenced the implementation of local intrapartum emergency training in their own Units by the start of their allocated intervention period. Blinding has not been possible due to the nature of the intervention. The aim of the study is to follow up each Unit for at least 12-months after they have commenced their local courses. The primary outcome for the study is the proportion of Apgar scores <7 at 5 min for term vaginal or emergency caesarean section births (≥37 weeks) occurring in each of the study Units. These data will be extracted from the Information Services Division Scottish Morbidity Record 02, a national routine data collection on pregnancy and births. Mixed or marginal logistic regression will be employed for the main analysis. THISTLE is the first stepped wedge cluster randomised trial to evaluate the effectiveness of an intrapartum emergencies training programme. The results will inform training, trainers and policy going forward. ISRCTN11640515 (registered on 09/09/2013).


Inflammatory breast carcinoma: mammographic, ultrasonographic, clinical, and pathologic findings in 142 cases.
To determine and quantitate radiologic characteristics of inflammatory breast carcinoma and to report clinical and pathologic findings. A retrospective review of records of 2,733 women who received a diagnosis of breast carcinoma between January 1988 and May 2000 revealed 142 histologically proved inflammatory carcinomas. Analysis included history; findings at physical examination, mammography, and ultrasonography (US); and histologic type of inflammatory carcinoma. At physical examination, skin changes (n = 115, 81%) were the most common findings. A palpable mass was noted in 62% (n = 88), with axillary lymph node involvement in 68% (n = 96) of the carcinomas. Mammography revealed findings in carcinomas: skin thickening, 84% (n = 119); diffusely increased density, 37% (n = 53); trabecular thickening, 81% (n = 115); mass, 16% (n = 23); asymmetric focal density, 61% (n = 87); microcalcifications, 56% (n = 80); nipple retraction, 43% (n = 61); and axillary lymphadenopathy, 24% (n = 34). US showed changes in carcinomas: skin thickening, 96% (n = 136); parenchymal echogenicity changes, 73% (n = 104); dilated lymphatic channels, 68% (n = 96); solid mass, 80% (n = 114); pectoral muscle invasion, 10% (n = 14); focal areas of parenchymal acoustic shadowing, 37% (n = 52); and axillary lymphadenopathy, 73% (n = 104). Presence of isolated inflammatory signs is sufficient to suggest inflammatory breast carcinoma clinically. Inflammatory breast carcinoma has a mammographic pattern of inflammatory changes, such as skin thickening and stromal coarsening and/or diffusely increased breast density with or without an associated mass and/or malignant-type microcalcifications. US is helpful not only in depiction of masses masked by the edema pattern but also in demonstration of skin and pectoral muscle invasion and axillary involvement.


The association of PTSD with physical and mental health functioning and disability (VA Cooperative Study #569: the course and consequences of posttraumatic stress disorder in Vietnam-era veteran twins).
To assess the relationship of posttraumatic stress disorder (PTSD) with health functioning and disability in Vietnam-era Veterans. A cross-sectional study of functioning and disability in male Vietnam-era Veteran twins. PTSD was measured by the Composite International Diagnostic Interview; health functioning and disability were assessed using the Veterans RAND 36-Item Health Survey (VR-36) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). All data collection took place between 2010 and 2012. Average age of the 5,574 participating Veterans (2,102 Vietnam theater and 3,472 non-theater) was 61.0 years. Veterans with PTSD had poorer health functioning across all domains of VR-36 and increased disability for all subscales of WHODAS 2.0 (all p < .001) compared with Veterans without PTSD. Veterans with PTSD were in poorer overall health on the VR-36 physical composite summary (PCS) (effect size = 0.31 in theater and 0.47 in non-theater Veterans; p < .001 for both) and mental composite summary (MCS) (effect size = 0.99 in theater and 0.78 in non-theater Veterans; p < .001 for both) and had increased disability on the WHODAS 2.0 summary score (effect size = 1.02 in theater and 0.96 in non-theater Veterans; p < .001 for both). Combat exposure, independent of PTSD status, was associated with lower PCS and MCS scores and increased disability (all p < .05, for trend). Within-pair analyses in twins discordant for PTSD produced consistent findings. Vietnam-era Veterans with PTSD have diminished functioning and increased disability. The poor functional status of aging combat-exposed Veterans is of particular concern.


Measuring conceptual health knowledge in the context of oral health literacy: preliminary results.
Health literacy encompasses several abilities including word recognition, reading comprehension, communication skills, and conceptual knowledge. To date, conceptual knowledge has not been included in oral health literacy research. This study assesses the validity and reliability of a new instrument and describes conceptual oral health knowledge among a sample of low-income adults. One hundred Baltimore adults were administered the Rapid Estimate of Adult Literacy in Medicine (REALM), Short Test of Functional Health Literacy in Adults (Short-TOFHLA), and a new survey of conceptual oral health knowledge. Respondents were also asked about sociodemographics, dental health, and utilization. Psychometric analysis was used to identify a subset of oral health knowledge questions from the new survey instrument. The resulting Comprehensive Measure of Oral Health Knowledge (CMOHK) was categorized into three levels of knowledge (poor, fair, good). Nearly one-third of Baltimore adults exhibited the lowest level. CMOHK scores were significantly associated with age, education level, and word recognition (REALM). CMOHK scores were not associated with reading comprehension (Short-TOFHLA) or dental care visits. Instrument reliability was good (Cronbach alpha = 0.74). This preliminary study yielded a new measure of oral health conceptual knowledge, available for use in future oral health literacy studies. The author presents a conceptual framework of oral health literacy that separates health literacy into four unique components and places decision-making at the center. Future studies are needed to determine whether this framework is supported by empirical data and leads to improvements in oral health and reductions in health disparities.


Electrically tunable liquid crystal waveguide attenuators.
The attenuator for the wavelength at 1550 nm is fabricated by using the capillary effect to infiltrate liquid crystal (LC) E7 into hollow waveguides (HWGs) on silicon substrate with SiO2 cladding layer. The length of the waveguide is 0.4 cm. The device can be operated with relatively low driving voltage below 5 V(pp) with the distance between two electrodes to be 9 μm. The light attenuation of the device can be over 30 dB. The performance of the device is independent of the polarization states of the input light.


[99mTc]-labelled interleukin-8 as a diagnostic tool compared to [18F]FDG and CT in an experimental porcine osteomyelitis model.
Osteomyelitis (OM) is an important cause of morbidity and sometimes mortality in children and adults. Long-term complications can be reduced when treatment is initiated in an early phase. The diagnostic gold standard is microbial examination of a biopsy and current non-invasive imaging methods are not always optimal. [111In]-leukocyte scintigraphy is recommended for peripheral OM, but is time-consuming and not recommended in children. [18F]FDG PET/CT is recommended for vertebral OM in adults, but has the disadvantage of false positive findings and a relatively high radiation exposure; the latter is a problem in children. [99mTc]-based tracers are consequently preferred in children. We, therefore, aimed to find a [99mTc]-marked tracer with high specificity and sensitivity for early detection of OM. Suppurating inflammatory lesions like OM caused by Staphylococcus aureus (S. aureus) will attract large numbers of neutrophils and macrophages. A preliminary study has shown that [99m Tc]-labelled IL8 may be a possible candidate for imaging of peripheral OM. We investigated [99mTc]IL8 scintigraphy in a juvenile pig model of peripheral OM and compared it with [18F]FDG PET/CT. The pigs were experimentally inoculated with S. aureus to induce OM and scanned one week later. We also examined leukocyte count, serum CRP and IL8, as well as performed histopathological and microbiological investigations. [ 99m Tc]IL8 was easily and relatively quickly prepared and was shown to be suitable for visualization of OM lesions in peripheral bones detecting 70% compared to a 100% sensitivity of [18F]FDG PET/CT. [ 99m Tc]IL8 is a promising candidate for detection of OM in peripheral bones in children.


Position of the American Dietetic Association: Nutrition intervention in the treatment of anorexia nervosa, bulimia nervosa, and other eating disorders.
It is the position of the American Dietetic Association that nutrition intervention, including nutritional counseling, by a registered dietitian (RD) is an essential component of the team treatment of patients with anorexia nervosa, bulimia nervosa, and other eating disorders during assessment and treatment across the continuum of care. Diagnostic criteria for eating disorders provide important guidelines for identification and treatment. However, it is thought that a continuum of disordered eating may exist that ranges from persistent dieting to subthreshold conditions and then to defined eating disorders, which include anorexia nervosa, bulimia nervosa, and binge eating disorder. Understanding the complexities of eating disorders, such as influencing factors, comorbid illness, medical and psychological complications, and boundary issues, is critical in the effective treatment of eating disorders. The nature of eating disorders requires a collaborative approach by an interdisciplinary team of psychological, nutritional, and medical specialists. The RD is an integral member of the treatment team and is uniquely qualified to provide medical nutrition therapy for the normalization of eating patterns and nutritional status. RDs provide nutritional counseling, recognize clinical signs related to eating disorders, and assist with medical monitoring while cognizant of psychotherapy and pharmacotherapy that are cornerstones of eating disorder treatment. Specialized resources are available for RDs to advance their level of expertise in the field of eating disorders. Further efforts with evidenced-based research must continue for improved treatment outcomes related to eating disorders along with identification of effective primary and secondary interventions.


Sprint-Specific Training in Youth: Backward Running vs. Forward Running Training on Speed and Power Measures in Adolescent Male Athletes.
Uthoff, A, Oliver, J, Cronin, J, Harrison, C, and Winwood, P. Sprint-specific training in youth: Backward running vs. forward running training on speed and power measures in adolescent male athletes. J Strength Cond Res 34(4): 1113-1122, 2020-This study compared the effects of 2 sprint-specific training programs against the natural development of speed, power, and stiffness in a group of adolescent male athletes. Forty-three male adolescents (aged 13-15 years) were randomly assigned to 1 of 2 training groups; backward running training (BRT = 26), or forward running training (FRT = 17). A physical education class (n = 24) of similar age constituted a control (CON) group. Both training groups performed running sessions matched for distance and intensity biweekly for 8 weeks. Parametric and magnitude-based inferences were used to analyze within group (pre-post measures) and between group (gain scores) for 10-m, 10- to 20-m, and 20-m sprint times, vertical countermovement jump (CMJ) height, and vertical leg stiffness. Both running groups significantly improved (p ≤ 0.05) in all performance tests from pre-training to post-training, with effect sizes ranging from -1.25 to 0.63. When the groups were compared, the BRT and FRT groups improved significantly (p ≤ 0.01) on all sprint performances and stiffness relative to the CON group. The BRT group demonstrated favorable effects for 10-m and 20-m sprint performances (effect size [ES] = -0.47 and -0.26, respectively) and CMJ height (ES = 0.51) compared with the FRT group. These results demonstrate that forward and backward sprint-specific training programs enhance speed and power measures more than natural development in adolescent male athletes. Furthermore, the greater training responses in sprint performance and CMJ ability indicate that BRT is a useful tool for improving concentric strength and power and may be classified as a sprint-specific training method.


Adolescent thriving: the role of sparks, relationships, and empowerment.
Although most social science research on adolescence emphasizes risks and challenges, an emergent field of study focuses on adolescent thriving. The current study extends this line of inquiry by examining the additive power of identifying and nurturing young people's "sparks," giving them "voice," and providing the relationships and opportunities that reinforce and nourish thriving. A national sample of 1,817 adolescents, all age 15 (49% female), and including 56% white, 17% Hispanic/Latino, and 17% African-American adolescents, completed an online survey that investigated their deep passions or interests (their "sparks"), the opportunities and relationships they have to support pursuing those sparks, and how empowered they feel to make civic contributions (their "voice"). Results consistently supported the hypothesis that linking one's spark with a sense of voice and supportive opportunities and relationships strengthens concurrent outcomes, particularly those reflecting prosociality, during a key developmental transition period. The three developmental strengths also predicted most outcomes to a greater degree than did demographics. However, less than 10 percent of 15-year-olds reported experiencing high levels of all three strengths. The results demonstrate the value of focusing on thriving in adolescence, both to reframe our understanding of this age group and to highlight the urgency of providing adolescents the opportunities and relationships they need to thrive.


New trends in coffee diterpenes research from technological to health aspects.
The coffee oil is rich in diterpenes, mainly cafestol and kahweol, which are predominantly present in the esterified form with different fatty acids. Despite their beneficial effects including anti-angiogenic and anti-carcinogenic properties, they have been also associated with negative consequences such as elevation of blood cholesterol. Considering the coffee, it is an important human beverage with biological effects, including potentially health benefits or risks. Therefore, it may have important public health implications due to its widespread massive consumption, with major incidence in the varieties Arabica and Robusta. According to literatures, cafestol (182-1308 mg/100 g), kahweol (0-1265 mg/100 g) and 16-O-methycafestol (0-223 mg/100 g) are the main diterpenes in green and roasted coffee beans. Nevertheless, the coffee species, genetic background, and technological parameters like roasting and brewing have a clear effect on coffee diterpene content. Besides that, bibliographic data indicated that limited studies have specifically addressed the recent analytical techniques used for determination of this class of compounds, being HPLC and GC the most common approaches. For these reasons, this review aimed to actualize the occurrence and the profile of diterpenes in coffee matrices, focusing on the effect of species, roasting and brewing and on the other hand, introduce the current state on knowledge regarding coffee diterpenes determination which are nowadays highly regarded and widely used. In general, since diterpenes exhibit different health effects depending on their consumption dosage, several parameters needs to be carefully analyzed and considered when comparing the results.


Self-Myofascial Release: No Improvement of Functional Outcomes in 'Tight' Hamstrings.
Self-myofascial release (SMR) is a common exercise and therapeutic modality shown to induce acute improvements in joint range of motion (ROM) and recovery; however, no long-term studies have been conducted. Static stretching (SS) is the most common method used to increase joint ROM and decrease muscle stiffness. It was hypothesized that SMR paired with SS (SMR+SS) compared with SS alone over a 4-wk intervention would yield greater improvement in knee-extension ROM and hamstring stiffness. 19 men (22 ± 3 y) with bilateral reduced hamstring ROM had each of their legs randomly assigned to either an SMR+SS or an SS-only group. The intervention consisted of 4 repetitions of SS each for 45 s or the identical amount of SS preceded by 4 repetitions of SMR each for 60 s and was performed on the respective leg twice daily for 4 wk. Passive ROM, hamstring stiffness, rate of torque development (RTD), and maximum voluntary contraction (MVC) were assessed pre- and postintervention. Passive ROM (P < .001), RTD, and MVC (P < .05) all increased after the intervention. Hamstring stiffness toward end-ROM was reduced postintervention (P = .02). There were no differences between the intervention groups for any variable. The addition of SMR to SS did not enhance the efficacy of SS alone. SS increases joint ROM through a combination of decreased muscle stiffness and increased stretch tolerance.


Can widespread hypersensitivity in carpal tunnel syndrome be substantiated if neck and arm pain are absent?
Recent studies demonstrated that patients with carpal tunnel syndrome (CTS) have signs of thermal and mechanical hyperalgesia in extra-median territories suggesting an involvement of central pain mechanisms. As previous studies included patients with shoulder/arm symptoms or neck pain, a potential influence of these coexisting disorders cannot be excluded. This study therefore evaluated whether widespread sensory changes (hypoesthesia or hyperalgesia) are present in patients with unilateral CTS in the absence of coexisting disorders. Twenty-six patients with unilateral CTS with symptoms localised to their hand and 26 healthy controls participated in the study. A comprehensive quantitative sensory testing (QST) protocol including thermal and mechanical detection and pain thresholds was performed over the hands (median, ulnar and radial innervation area), lateral elbows, neck and tibialis anterior muscle. Patients with CTS demonstrated thermal and mechanical hypoesthesia in the hand but not at distant sites. Thermal or mechanical hyperalgesia was not identified at any location with traditional QST threshold testing. However, patients with CTS rated the pain during thermal pain testing significantly higher than healthy participants. This was especially apparent for heat pain ratings which were elevated not only in the affected hand but also in the neck and tibialis anterior muscle. In conclusion, CTS alone in the absence of coexisting neck and arm pain does not account for sensory changes outside the affected hand as determined by traditional QST threshold testing. Elevated pain ratings may however be an early indication of central pain mechanisms.


The GLEaMviz computational tool, a publicly available software to explore realistic epidemic spreading scenarios at the global scale.
Computational models play an increasingly important role in the assessment and control of public health crises, as demonstrated during the 2009 H1N1 influenza pandemic. Much research has been done in recent years in the development of sophisticated data-driven models for realistic computer-based simulations of infectious disease spreading. However, only a few computational tools are presently available for assessing scenarios, predicting epidemic evolutions, and managing health emergencies that can benefit a broad audience of users including policy makers and health institutions. We present "GLEaMviz", a publicly available software system that simulates the spread of emerging human-to-human infectious diseases across the world. The GLEaMviz tool comprises three components: the client application, the proxy middleware, and the simulation engine. The latter two components constitute the GLEaMviz server. The simulation engine leverages on the Global Epidemic and Mobility (GLEaM) framework, a stochastic computational scheme that integrates worldwide high-resolution demographic and mobility data to simulate disease spread on the global scale. The GLEaMviz design aims at maximizing flexibility in defining the disease compartmental model and configuring the simulation scenario; it allows the user to set a variety of parameters including: compartment-specific features, transition values, and environmental effects. The output is a dynamic map and a corresponding set of charts that quantitatively describe the geo-temporal evolution of the disease. The software is designed as a client-server system. The multi-platform client, which can be installed on the user's local machine, is used to set up simulations that will be executed on the server, thus avoiding specific requirements for large computational capabilities on the user side. The user-friendly graphical interface of the GLEaMviz tool, along with its high level of detail and the realism of its embedded modeling approach, opens up the platform to simulate realistic epidemic scenarios. These features make the GLEaMviz computational tool a convenient teaching/training tool as well as a first step toward the development of a computational tool aimed at facilitating the use and exploitation of computational models for the policy making and scenario analysis of infectious disease outbreaks.


Effects of circadian misalignment on sleep in mice.
Circadian rhythms and sleep-wake history determine sleep duration and intensity, and influence subsequent waking. Previous studies have shown that T cycles - light-dark (LD) cycles differing from 24 h - lead to acute changes in the daily amount and distribution of waking and sleep. However, little is known about the long-term effects of T cycles. Here we performed continuous 10 day recording of electroencephalography (EEG), locomotor activity and core body temperature in C57BL/6 mice under a T20 cycle, to investigate spontaneous sleep and waking at baseline compared with when the circadian clock was misaligned and then re-aligned with respect to the external LD cycle. We found that the rhythmic distribution of sleep was abolished during misalignment, while the time course of EEG slow wave activity (1-4 Hz) was inverted compared to baseline. Although the typical light-dark distribution of NREM sleep was re-instated when animals were re-aligned, slow wave activity during NREM sleep showed an atypical increase in the dark phase, suggesting a long-term effect of T cycles on sleep intensity. Our data show that circadian misalignment results in previously uncharacterised long-term effects on sleep, which may have important consequences for behaviour.


Tom70 is essential for PINK1 import into mitochondria.
PTEN induced kinase 1 (PINK1) is a serine/threonine kinase in the outer membrane of mitochondria (OMM), and known as a responsible gene of Parkinson's disease (PD). The precursor of PINK1 is synthesized in the cytosol and then imported into the mitochondria via the translocase of the OMM (TOM) complex. However, a large part of PINK1 import mechanism remains unclear. In this study, we examined using cell-free system the mechanism by which PINK1 is targeted to and assembled into mitochondria. Surprisingly, the main component of the import channel, Tom40 was not necessary for PINK1 import. Furthermore, we revealed that the import receptor Tom70 is essential for PINK1 import. In addition, we observed that although PINK1 has predicted mitochondrial targeting signal, it was not processed by the mitochondrial processing peptidase. Thus, our results suggest that PINK1 is imported into mitochondria by a unique pathway that is independent of the TOM core complex but crucially depends on the import receptor Tom70.


Randomised controlled trial of a self-guided online fatigue intervention in multiple sclerosis.
Fatigue is a major disabling symptom in many chronic diseases including multiple sclerosis (MS), but treatment options are limited.Here, we tested the effectiveness of a self-guided , interactive, online fatigue management programme (ELEVIDA) based on principles of cognitive behavioural therapy (CBT) and related psychotherapeutic approaches (eg, mindfulness) for reducing fatigue in MS. Patients with MS and self-reported fatigue were recruited via the website of the German MS Society and assigned via an automated randomisation generator (1:1, no blocking or stratification) to a 12-week online intervention (ELEVIDA, n=139, 82% female, mean age 40.8, median patient determined disease steps (PDDS) 3.0) or a waitlist control group (n=136, 79% female, mean age 41.9, median PDDS 3.0). The primary outcome was the Chalder Fatigue Scale. Outcomes were assessed at baseline, at week 12 (postintervention) and at follow-up (week 24). Compared with the control group, significantly greater reductions in Chalder Fatigue Scale scores were seen in the ELEVIDA group at week 12 (primary endpoint, intention-to-treat analysis: between-group mean difference 2.74 points; 95% CI 1.16 to 4.32; p=0.0007; effect size d=0.53), with effects sustained at week 24 (intention-to-treat analysis: between-group mean difference 2.19 points; 95% CI 0.57 to 3.82; p=0.0080). Our trial provides evidence for the effectiveness of a self-guided , internet-based intervention to reduce fatigue in MS. Interventions such as ELEVIDA may be a suitable low barrier, cost-effective treatment option for MS fatigue. ISRCTN registry (number ISRCTN25692173).


Acute pancreatitis in patients with pancreatic cancer: Timing of surgery and survival duration.
Acute pancreatitis (AP) is a rare manifestation of pancreatic cancer (PC). The relationship between AP and PC remains less distinct.From January 2009 to November 2015, 47consecutive patients with PC who presented with AP were reviewed for this study. Clinical features, clinicopathologic variables, postoperative complications, and follow-up evaluations of patients were documented in detail from our database. In order to identify cutoff threshold time for surgery, receiver operating curve (ROC) was built according to patients with or without postoperative complications. Cumulative rate of survival was calculated by using the Kaplan-Meier method. The study was conducted in accordance with the principles of the Declaration of Helsinki and the guidelines of West China Hospital.This study included 35 men (74.5%) and 12 women (25.5%) (mean age: 52 years), with a median follow-up of 40 months. AP was clinically mild in 45 (95.7%) and severe in 2 (4.3%). The diagnosis of PC was delayed by 2 to 660 days (median 101 days). Thirty-nine (83.0%) cases underwent surgery. Eight (17.0%) cases performed biopsies only. Of 39 patients, radical surgery was performed in 32 (82.1%) cases and palliative in 7 (19.9%) cases. Two (8.0%) patients were needed for vascular resection and reconstruction. Postoperative complications occurred in 12 (30.8%) patients. About 24.5 days was the best cutoff point, with an area under curve (AUC) of 0.727 (P = 0.025, 95% confidence interval: 0.555-0.8999). The survival rate of patients at 1 year was 23.4%. The median survival in patients with vascular resection and reconstruction was 18 months, compared with 10 months in patients without vascular resection (P = 0.042). For the primary stage (T), Tix was identified in 3 patients, the survival of whom were 5, 28, 50 months, respectively. And 2 of them were still alive at the follow-up period.The severity of AP was mainly mild. Surgical intervention after 24.5 days may benefit for reducing postoperative complications. Patients with vascular resection and reconstruction, thus achieving tumor-free margins, had a long-time survival.


Observed Handwashing with Soap Practices Among Cholera Patients and Accompanying Household Members in a Hospital Setting (CHoBI7 Trial).
Household members of cholera patients are at a 100 times higher risk of cholera than the general population. Despite this risk, there are only a handful of studies that have investigated the handwashing practices among hospitalized diarrhea patients and their accompanying household members. To investigate handwashing practices in a hospital setting among this high-risk population, 444 hours of structured observation was conducted in a hospital in Dhaka, Bangladesh, among 148 cholera patients and their household members. Handwashing with soap practices were observed at the following key events: after toileting, after cleaning the anus of a child, after removing child feces, during food preparation, before eating, and before feeding. Spot-checks were also conducted to observe the presence of soap at bathroom areas. Overall, 4% (4/103) of key events involved handwashing with soap among cholera patients and household members during the structured observation period. This was 3% (1/37) among cholera patients and 5% (3/66) for household members. For toileting events, observed handwashing with soap was 7% (3/46) overall, 7% (1/14) for cholera patients, and 6% (2/32) for household members. For food-related events, overall observed handwashing with soap was 2% (2/93 overall), and 0% (0/34) and 3% (2/59) for cholera patients and household members, respectively. Soap was observed at only 7% (4/55) of handwashing stations used by patients and household members during spot-checks. Observed handwashing with soap at key times among patients and accompanying household members was very low. These findings highlight the urgent need for interventions to target this high-risk population.


Tunable modulational instability sidebands via parametric resonance in periodically tapered optical fibers.
We analyze the modulation instability induced by periodic variations of group velocity dispersion and nonlinearity in optical fibers, which may be interpreted as an analogue of the well-known parametric resonance in mechanics. We derive accurate analytical estimates of resonant detuning, maximum gain and instability margins, significantly improving on previous literature on the subject. We also design a periodically tapered photonic crystal fiber, in order to achieve narrow instability sidebands at a detuning of 35 THz, above the Raman maximum gain peak of fused silica. The wide tunability of the resonant peaks by variations of the tapering period and depth will allow to implement sources of correlated photon pairs which are far-detuned from the input pump wavelength, with important applications in quantum optics.


Smoking and mental health nurses: a survey of clinical staff in a psychiatric hospital.
There is a lack of evidence on the prevalence of smoking among mental health nurses, and the beliefs and attitudes they hold about smoking at work. This paper describes results from a cross-sectional survey of clinical staff working in a UK specialist charitable-status psychiatric hospital and focuses on the responses of registered mental health nurses. Questionnaires specifically developed for this study were sent to all 1371 clinical employees. Completed questionnaires were returned by 167 of 429 (38.9%) registered nurses (RNs), 300 of 842 (35.6%) nursing assistants (NAs), and 123 of 200 (61.5%) other health professionals (OHPs). Twenty-nine (17.4%) RNs, 93 (31%) NAs and eight (6.5%) OHPs reported themselves as current smokers. Differences in response to attitudinal questions between groups could not be attributed to age. RN smokers were significantly more likely than RN non-smokers to state that staff should be allowed to smoke with patients, and to report therapeutic value for patients in this activity. RN smokers were less likely than RN non-smokers to report that patients should be encouraged to stop smoking. RNs were significantly more likely than OHPs to report therapeutic value for patients in smoking with staff, even after controlling for the possible confounding effect of smoking status. Implications of the survey are discussed in the context of the international literature, including the disproportionately high smoking prevalence among patients living in psychiatric institutions and current guidelines to move towards no 'smoking allowed' areas for staff working in them.


Topical bupivacaine compared to bupivacaine infiltration for post-tonsillectomy pain relief in children: a prospective randomized controlled clinical study.
The objective of this study is to compare the topical administration of bupivacaine hydrochloride, saline and bupivacaine hydrochloride infiltration on post-tonsillectomy pain in children. Sixty children undergoing tonsillectomy were enrolled in the study. Patients were randomized into three groups using sealed envelopes. Group 1 (n = 20) received topical 0.5 % bupivacaine hydrochloride, group 2 (n = 20) received topical 0.9 % NaCl (saline), and group 3 (n = 20) received 0.5 % bupivacaine hydrochloride infiltrated around each tonsil. Pain was evaluated using McGrath's face scale. Pain scores in topical bupivacaine hydrochloride group was significantly lesser than the topical saline group at 5th, 13th, 17th and 21st hours, until the 6th day (p < 0.017). Moreover, pain scores of topical bupivacaine hydrochloride group was superior to bupivacaine hydrochloride infiltration group at 5th, 13th, 17th hours and 2nd, 3rd, 4th and 5th day (p < 0.017). There were significantly lesser morbidities in topical bupivacaine hydrochloride than saline group in 1st and 4th day (p < 0.017). Topical administration of bupivacaine hydrochloride proved to provide more efficient pain control than bupivacaine hydrochloride infiltration.


Using 10,000 Fragment Ions to Inform Scoring in Native Top-down Proteomics.
Protein fragmentation is a critical component of top-down proteomics, enabling gene-specific protein identification and full proteoform characterization. The factors that influence protein fragmentation include precursor charge, structure, and primary sequence, which have been explored extensively for collision-induced dissociation (CID). Recently, noticeable differences in CID-based fragmentation were reported for native versus denatured proteins, motivating the need for scoring metrics that are tailored specifically to native top-down mass spectrometry (nTDMS). To this end, position and intensity were tracked for 10,252 fragment ions produced by higher-energy collisional dissociation (HCD) of 159 native monomers and 70 complexes. We used published structural data to explore the relationship between fragmentation and protein topology and revealed that fragmentation events occur at a large range of relative residue solvent accessibility. Additionally, our analysis found that fragment ions at sites with an N-terminal aspartic acid or a C-terminal proline make up on average 40 and 27%, respectively, of the total matched fragment ion intensity in nTDMS. Percent intensity contributed by each amino acid was determined and converted into weights to (1) update the previously published C-score and (2) construct a native Fragmentation Propensity Score. Both scoring systems showed an improvement in protein identification or characterization in comparison to traditional methods and overall increased confidence in results with fewer matched fragment ions but with high probability nTDMS fragmentation patterns. Given the rise of nTDMS as a tool for structural mass spectrometry, we forward these scoring metrics as new methods to enhance analysis of nTDMS data.


Identification of protein kinase C activation as a novel mechanism for RGS2 protein upregulation through phenotypic screening of natural product extracts.
Biochemical high-throughput screening is widely used in drug discovery, using a variety of small molecule libraries. However, broader screening strategies may be more beneficial to identify novel biologic mechanisms. In the current study we used a β-galactosidase complementation method to screen a selection of microbial-derived pre-fractionated natural product extracts for those that increase regulator of G protein signaling 2 (RGS2) protein levels. RGS2 is a member of a large family of proteins that all regulate signaling through G protein-coupled receptors (GPCRs) by accelerating GTPase activity on active Gα as well as through other mechanisms. RGS2(-/-) mice are hypertensive, show increased anxiety, and are prone to heart failure. RGS2 has a very short protein half-life due to rapid proteasomal degradation, and we propose that enhancement of RGS2 protein levels could be a beneficial therapeutic strategy. Bioassay-guided fractionation of one of the hit strains yielded a pure compound, Indolactam V, a known protein kinase C (PKC) activator, which selectively increased RGS2 protein levels in a time- and concentration-dependent manner. Similar results were obtained with phorbol 12-myristate 13-acetate as well as activation of the Gq-coupled muscarinic M3 receptor. The effect on RGS2 protein levels was blocked by the nonselective PKC inhibitor Gö6983 (3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione), the PKCβ-selective inhibitor Ruboxastaurin, as well as small interfering RNA-mediated knockdown of PKCβ. Indolactam V-mediated increases in RGS2 protein levels also had functional effects on GPCR signaling. This study provides important proof-of-concept for our screening strategy and could define a negative feedback mechanism in Gq/Phospholipase C signaling through RGS2 protein upregulation.


Management of hyperglycemia in a hospitalized patient with diabetes mellitus and cardiovascular disease.
Hyperglycemia in patients with and without known diabetes is a common finding in patients hospitalized with cardiovascular disease, and is associated with poor outcomes. Investigators have been examining the role of insulin to treat patients with acute myocardial infarction since the 1960's. Until the 1990's most studies evaluated fixed doses of glucose-insulin-potassium (GIK) infusions. The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial, published in 1995, evaluated the role of adjustable-dose insulin infusion to lower blood glucose. Its promising results spurred further interest and a number of trials evaluating the use of insulin to lower blood glucose in hospitalized patients - many of which included patients with cardiovascular disease - have been conducted over the last two decades with conflicting results. This manuscript reviews the epidemiology and pathophysiology of hyperglycemia in hospitalized patients, summarizes the evidence for benefits and harms of using insulin to treat hyperglycemic patients hospitalized with cardiovascular disease, and offers some practical management considerations.


The association of vitamin D use with hypercalcemia and hyperphosphatemia in hemodialysis patients: a case-crossover study.
Elevated levels of phosphorus (P) and calcium (Ca) have been shown in observational studies to be associated with an increased risk of adverse clinical outcomes including mortality. Vitamin D sterols have been shown to increase the risk of hypercalcemia and hyperphosphatemia in clinical trials. We sought to explore these risks in real-world clinical practice. We employed a case-crossover design, which eliminates confounding by non-time-varying patient characteristics by comparing, within each patient, vitamin D doses before the event with those at an earlier period. Using this method, we estimated the risk of hypercalcemic (Ca ≥ 11 g/dL) and hyperphosphatemic (P ≥ 8 g/dL) events for patients at different dose quartiles of vitamin D relative to patients not on a vitamin D sterol. There was a dose-dependent association between vitamin D dose quartile and risk of hypercalcemia or hyperphosphatemia. In adjusted analyses, each increase in vitamin D quartile was associated with a multiple of hypercalcemia risk between 1.7 and 19 times compared with those not on vitamin D and a multiple of hyperphosphatemia risk between 1.8 and 4. Use of vitamin D sterols is associated with an increased risk of hypercalcemic and hyperphosphatemic events in real-world clinical practice. Other potential predictors of these events, such as phosphate binder use and dialysate Ca levels, were not examined in this analysis.


Effects of obesity on the biomechanics of walking at different speeds.
Walking is a recommended form of exercise for the treatment of obesity, but walking may be a critical source of biomechanical loads that link obesity and musculoskeletal pathology, particularly knee osteoarthritis. We hypothesized that compared with normal-weight adults 1) obese adults would have greater absolute ground-reaction forces (GRF) during walking, but their GRF would be reduced at slower walking speeds; and 2) obese adults would have greater sagittal-plane absolute leg-joint moments at a given walking speed, but these moments would be reduced at slower walking speeds. We measured GRF and recorded sagittal-plane kinematics of 20 adults (10 obese and 10 normal weight) as they walked on a level, force-measuring treadmill at six speeds (0.5-1.75 m.s(-1)). We calculated sagittal-plane net muscle moments at the hip, knee, and ankle. Compared with their normal-weight peers, obese adults had much greater absolute GRF (N), stance-phase sagittal-plane net muscle moments (N.m) and step width (m). Greater sagittal-plane knee moments in the obese subjects suggest that they walked with greater knee-joint loads than normal-weight adults. Walking slower reduced GRF and net muscle moments and may be a risk-lowering strategy for obese adults who wish to walk for exercise. When obese subjects walked at 1.0 versus 1.5 m.s(-1), peak sagittal-plane knee moments were 45% less. Obese subjects walking at approximately 1.1 m.s(-1) would have the same absolute peak sagittal-plane knee net muscle moment as normal-weight subjects when they walk at their typical preferred speed of 1.4 m.s(-1).


A comparison of 5-year administration of cyproterone acetate or leuprolide acetate in combination with estradiol in transwomen.
The impact of different combinations of long-term gender-affirming hormone therapy (GAHT) in transwomen (TW) is largely unknown. To assess the effects of 5-year administration of cyproterone acetate (CPA) or leuprolide acetate (Leu) plus transdermal or oral estradiol (E). Cohort study based on prospectively collected data. Fifty TW received 50 mg CPA daily orally (n = 25; CPA+E group) or 3.75 mg Leu i.m. monthly (n = 25; Leu+E group) with 1 or 2 mg E daily for 5 years. Reproductive hormones, biochemical and anthropometric parameters, body composition and bone mineral density (BMD) were assessed. LH, FSH and total testosterone levels were similarly and significantly suppressed in both groups. Prolactin increased only in the CPA+E group (P = 0.002). Fasting insulin resistance and glucose progressively increased in the CPA+E group only (treatment × time effect P = 0.002 and P = 0.043, respectively). Total cholesterol increased more in the Leu+E group than in the CPA+E group and HDL-cholesterol decreased in the CPA+E group (time × treatment interaction effect, P = 0.007). Lumbar and total body BMD increased in both groups after 3 years. No serious adverse events were recorded. Both regimens were effective in suppression of T production. CPA+E worsened the metabolic profile with a slight increase in PRL levels. All subjects presented an increase in BMD regardless of treatment. These preliminary data could have clinical implications in the choice of GAHT, in particular for those TW not requiring gender-affirming surgery.


The radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation.
Recent accumulating evidence suggests that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. Here, we show that a Toll-like receptor (TLR) protein, radioprotective 105 (RP105)/myeloid differentiation protein (MD)-1 complex, contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance. An HFD dramatically increased RP105 mRNA and protein expression in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. RP105 mRNA expression also was significantly increased in the visceral adipose tissue of obese human subjects relative to nonobese subjects. The RP105/MD-1 complex was expressed by most adipose tissue macrophages (ATMs). An HFD increased RP105/MD-1 expression on the M1 subset of ATMs that accumulate in eWAT. Macrophages also acquired this characteristic in coculture with 3T3-L1 adipocytes. RP105 knockout (KO) and MD-1 KO mice had less HFD-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance compared with wild-type (WT) and TLR4 KO mice. Finally, the saturated fatty acids, palmitic and stearic acids, are endogenous ligands for TLR4, but they did not activate RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling and may represent a novel therapeutic target for obesity-associated metabolic disorders.


Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.
Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165-76. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.


Maximal response plateau to methacholine as a reliable index for reducing inhaled budesonide in moderate asthma.
Although some studies suggest that asthma deteriorates after reducing inhaled steroids, results of long-term studies indicate that this might not be true for all patients. The aim of this study was to determine the utility of the detection of a plateau on the concentration-response curves to inhaled methacholine as a marker for safely reducing the dose of inhaled budesonide in asthmatic patients who are well-controlled with a moderately high dose of this inhaled steroid. A total of 46 patients with moderate asthma, well-controlled for at least 6 months by treatment with 800 microg budesonide daily, were included in the study. Subjects were treated for a 2-week run-in period with their usual dose of budesonide. At the end of the run-in, all subjects were challenged with methacholine (0.095-200 mg x mL(-1)). Plateau responses, median effective concentration values, slopes and provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) values were measured. For the subsequent 12 weeks, patients were treated in an open design with budesonide at a reduced dose (200 microg once daily), and were asked to record their peak expiratory flow (PEF) in the morning and in the evening. In addition, asthma symptoms and use of rescue terbutaline were recorded in diaries. Plateaus were present in 24 patients, whereas 22 subjects showed concentration-response curves without evidence of a plateau. Ten patients in the nonplateau group deteriorated after reducing inhaled budesonide, compared to one patient in the plateau group (p = 0.002). In the nonplateau group, FEV1 decreased from a baseline value of 3.28+/-0.19 L to 2.94+/-0.20 L at week 12 (p<0.0001). Likewise, morning PEF decreased from 419+/-19 L x min(-1) at baseline to 394+/-19 L x min(-1) at week 12 (p = 0.02). By contrast, these variables remained unchanged in the plateau group. In conclusion, in asthmatic patients, well-controlled with a moderately high dose of budesonide, the detection of a plateau on the concentration-response curve to inhaled methacholine may be used as a marker for safely reducing the corticosteroid dose.


The increase in theta/beta ratio on resting-state EEG in boys with attention-deficit/hyperactivity disorder is mediated by slow alpha peak frequency.
Attention-deficit/hyperactivity disorder (ADHD) was found to be characterized by a deviant pattern of electrocortical activity during resting state, particularly increased theta and decreased beta activity. The first objective of the present study is to confirm whether individuals with slow alpha peak frequency contribute to the finding of increased theta activity in ADHD. The second objective is to explore the relation between resting-state brain oscillations and specific cognitive functions. From 49 boys with ADHD and 49 healthy control boys, resting-state EEG during eyes open and eyes closed was recorded, and a variety of cognitive tasks were administered. Theta and beta power and theta/beta ratio were calculated using both fixed frequency bands and individualized frequency bands. As expected, theta/beta ratio, calculated using fixed frequency bands, was significantly higher in ADHD children than control children. However, this group effect was not significant when theta/beta ratio was assessed using individualized frequency bands. No consistent relation was found between resting-state brain oscillations and cognition. The present results suggest that previous findings of increased theta/beta ratio in ADHD may reflect individuals with slow alpha peak frequencies in addition to individuals with true increased theta activity. Therefore, the often reported theta/beta ratio in ADHD can be considered a non-specific measure combining several distinct neurophysiological subgroups such as frontal theta and slowed alpha peak frequencies. Future research should elucidate the functional role of resting-state brain oscillations by investigating neurophysiological subgroups, which may have a clearer relation to cognitive functions than single frequency bands.


Allogeneic lymphocyte stimulation in rabbits: induction of a low MW inhibitor for trypsin and for a concurrently induced alpha-macroglobulin-proteinase complex.
We have shown previously that the i.v. inoculation of allogeneic lymph node cells in rabbits induces the appearance in the serum of an alpha M-serine proteinase complex which behaves in an Ig-turnover assay as any polyclonal B-cell activator (PBA), and that this PBA activity is due to the enzyme. Here, we show that the allogeneic stimulation also induces the appearance in the low molecular weight fraction of the serum (1000-110,000 MW) of an inhibitor which blocks the PBA activity of the complex without affecting the PBA activity of LPS or dextran sulphate. The inhibitor blocked the ability of the enzyme associated with alpha M to degrade Chromozym TRY, a low MW trypsin substrate. The inhibitor also blocked the enzymatic activity of trypsin for large as well as for low MW substrates. Thus, allogeneic stimulation in vivo results in the production, not only of an alpha M-proteinase complex, but also of an inhibitor for this proteinase as well as for trypsin. The appearance of the inhibitor, along with the alpha M-serine proteinase complex as a result of allogeneic stimulation in rabbits, is of interest since a similar alpha M-serine proteinase complex and inhibitor may appear in the serum of patients with rheumatoid arthritis.


Collaborative care for patients with bipolar disorder: randomised controlled trial.
A substantial number of people with bipolar disorder show a suboptimal response to treatment. To study the effectiveness of a collaborative care programme on symptoms and medication adherence in patients with bipolar disorder, compared with care as usual. A two-armed, cluster randomised clinical trial was carried out in 16 out-patient mental health clinics in The Netherlands, in which 138 patients were randomised. Patient outcomes included duration and severity of symptoms and medication adherence, and were measured at baseline, 6 months and 12 months. Collaborative care comprised contracting, psychoeducation, problem-solving treatment, systematic relapse prevention and monitoring of outcomes. Mental health nurses functioned as care managers in this programme. The trial was registered with The Netherlands Trial Registry (NTR2600). Collaborative care had a significant and clinically relevant effect on number of months with depressive symptoms, both at 6 months (z = -2.6, P = 0.01, d = 0.5) and at 12 months (z = -3.1, P = 0.002, d = 0.7), as well as on severity of depressive symptoms at 12 months (z = -2.9, P = 0.004, d = 0.4). There was no effect on symptoms of mania or on treatment adherence. When compared with treatment as usual, collaborative care substantially reduced the time participants with bipolar disorder experienced depressive symptoms. Also, depressive symptom severity decreased significantly. As persistent depressive symptoms are difficult to treat and contribute to both disability and impaired quality of life in bipolar disorder, collaborative care may be an important form of treatment for people with this disorder.


Charge-Transfer-Driven Nonplanar Adsorption of F4TCNQ Molecules on Epitaxial Graphene.
π-conjugated organic molecules tend to adsorb in a planar configuration on graphene irrespective of their charge state. In contrast, here we demonstrate charging-induced strong structural relaxation of tetrafluorotetracyanoquinodimethane (F4TCNQ) on epitaxial graphene on Ir(111) (G/Ir(111)). The work function modulation over the graphene moiré unit cell causes site-selective charging of F4TCNQ. Upon charging, the molecule anchors to the face-centered cubic sites of the G/Ir(111) moiré through one or two cyano groups. The reaction is reversible and can be triggered on a single molecule by moving it between different adsorption sites. We introduce a model taking into account the trade-off between tilt-induced charging and reduced van der Waals interactions, which provides a general framework for understanding charging-induced structural relaxation on weakly interacting substrates. In addition, we argue that the partial sp3 rehybridization of the underlying graphene and the possible bonding mechanism between the cyano groups and the graphene substrate are also relevant for the complete understanding of the experiments. These results provide insight into molecular charging on graphene, and they are directly relevant for potential device applications where the use of molecules has been suggested for doping and band structure engineering.


Evaluation of NuStatr, a Novel Nonimpregnated Hemostatic Dressing, Compared With Combat Gauze in Severe Traumatic Porcine Hemorrhage Model.
Uncontrolled hemorrhage remains one of the most challenging problems facing emergency medical professionals and a leading cause of traumatic death in both battlefield and civilian environments. Survival is determined by the ability to rapidly control hemorrhage. Several commercially available topical adjunct agents have been shown to be effective in controlling hemorrhage, and one, Combat Gauze (CG), is used regularly on the battlefield and for civilian applications. However, recent literature reviews have concluded that no ideal topical agent exists for all injuries and scenarios. The authors compared a novel nonimpregnated dressing composed of cellulose and silica, NuStat (NS), to CG in a lethal hemorrhagic groin injury. These dressings were selected for their commercial availability and design intended for control of massive hemorrhage. A complex penetrating femoral artery groin injury was made using a 5.5mm vascular punch followed by 45 seconds of uncontrolled hemorrhage in 15 swine. The hemostatic dressings were randomized using a random sequence generator and then assigned to the animals. Three minutes of manual pressure was applied with each agent after the free bleed. Hextend bolus (500 mL) was subsequently rapidly infused using a standard pressure bag along with the addition of maintenance fluids to maintain blood pressure. Hemodynamic parameters were recorded every 10 minutes and additionally at critical time points defined in the protocol. Primary end points included immediate hemostasis upon release of manual pressure (T0), hemostasis at 60 minutes, and rebleeding during the 60-minute observation period. NS was statistically superior to CG in a 5.5 mm traumatic hemorrhage model at T0 for immediate hemostasis (p=.0475), duration of application time (p=.0093), use of resuscitative fluids (p=.0042) and additional blood loss after application (p=.0385). NS and CG were statistically equivalent for hemostasis at 60 minutes, rebleeding during the study, and the additional secondary metrics, although the trend indicated that in a larger sample size, NS could prove statistical superiority in selected categories. In this porcine model of uncontrolled hemorrhage, NS improved immediate hemorrhage control, stability, and use of fluid in a 60-minute severe porcine hemorrhage model. In this study, NS demonstrated equivalence to CG at achieving long-term hemostasis and the prevention of rebleed after application. NS was shown to be an efficacious choice for hemorrhage control in combat and civilian emergency medical service environments.


Alteration of adaptive behaviors of progeny after maternal mobile phone exposure.
Exposure of pregnant women to radiofrequency (RF) devices raises questions on their possible health consequences for their progeny. We examined the hazard threshold of gestational RF on the progeny's glial homeostasis, sensory-motor gating, emotionality, and novelty seeking and tested whether maternal immune activation would increase RF toxicity. Pregnant dams were daily restrained with loop antennas adjoining the abdomen (fetus body specific absorption rates (SAR): 0, 0.7, or 2.6 W/kg) and received three lipopolysaccharide (LPS) intra-peritoneal injections (0 or 80 μg/kg). Scores in the prepulse startle inhibition, fear conditioning, open field, and elevated plus maze were assessed at adolescence and adulthood. Glial fibrillary acidic protein (GFAP) and interleukines-1β (ILs) were quantified. LPS induced a SAR-dependent reduction of the prepulse startle inhibition in adults. Activity in the open field was reduced at 2.6 W/kg at adolescence. GFAP and ILs, emotional memory, and anxiety-related behaviors were not modified. These data support the hypothesis that maternal immune activation increased the developmental RF exposure-induced long-term neurobiological impairments. These data support the fact that fetuses who receive combined environmental exposures with RF need special attention for protection.


Inhaled corticosteroids for asthma: common clinical quandaries.
This narrative review provides evidence-based explanations to some of the common clinical concerns regarding inhaled corticosteroids. Inhaled corticosteroids are the treatment of choice for a newly diagnosed asthmatic patient. Better results are obtained when treatment is initiated as soon as the diagnosis is made. Asthma control can be achieved and maintained in most patients with a low or moderate dose of inhaled corticosteroid administered in two daily doses. Longer duration of treatment provides more sustained benefits than treatment that is intermittent and for short periods of time. The clinical benefits can be observed within 24 hours of commencing treatment and may be more pronounced in patients with an eosinophilic bronchitis. Inhaled corticosteroids provide additional benefit when used in conjunction with prednisone in acute severe asthma. Low doses do not have clinically deleterious side effects on the bones, growth, eye, or hypothalamo-pituitary-adrenal-axis. However, they do not normalize lung function and prevent structural changes in the airway wall in all asthmatic patients.


Republished: recent advances in autoimmune pancreatitis: type 1 and type 2.
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.


Synthesis of fluorophosphate nucleotide analogues and their characterization as tools for ¹⁹F NMR studies.
To broaden the scope of existing methods based on (19)F nucleotide labeling, we developed a new method for the synthesis of fluorophosphate (oligo)nucleotide analogues containing an O to F substitution at the terminal position of the (oligo)phosphate moiety and evaluated them as tools for (19)F NMR studies. Using three efficient and comprehensive synthetic approaches based on phosphorimidazolide chemistry and tetra-n-butylammonium fluoride, fluoromonophosphate, or fluorophosphate imidazolide as fluorine sources, we prepared over 30 fluorophosphate-containing nucleotides, varying in nucleobase type (A, G, C, U, m(7)G), phosphate chain length (from mono to tetra), and presence of additional phosphate modifications (thio, borano, imido, methylene). Using fluorophosphate imidazolide as fluorophosphorylating reagent for 5'-phosphorylated oligos we also synthesized oligonucleotide 5'-(2-fluorodiphosphates), which are potentially useful as (19)F NMR hybridization probes. The compounds were characterized by (19)F NMR and evaluated as (19)F NMR molecular probes. We found that fluorophosphate nucleotide analogues can be used to monitor activity of enzymes with various specificities and metal ion requirements, including human DcpS enzyme, a therapeutic target for spinal muscular atrophy. The compounds can also serve as reporter ligands for protein binding studies, as exemplified by studying interaction of fluorophosphate mRNA cap analogues with eukaryotic translation initiation factor (eIF4E).