Alleviating distressing intrusive memories in depression: a comparison between computerised cognitive bias modification and cognitive behavioural education.
Negative appraisals maintain intrusive memories and intrusion-distress in depression, but treatment is underdeveloped. This study compared the efficacy of computerised bias modification positive appraisal training (CBM) versus a therapist-delivered cognitive behavioural therapy session (CB-Education) that both aimed to target and alter negative appraisals of a negative intrusive autobiographical memory. Dysphoric participants (Mean BDI-II = 27.85; N = 60) completed baseline ratings of a negative intrusive memory, negative appraisals and the Impact of Event Scale, and were randomly allocated either one session of CBM, CB-Education, or a no intervention monitoring control condition (Control). Mood and intrusion symptoms were assessed at one week follow-up. For all groups, there were significant reductions over one week in mood (depression and anxiety), memory intrusiveness and negative appraisals. Groups differed in terms of intrusion-related distress, with the CB-Education group showing greatest reduction, followed by the CBM group. The study provides evidence for the link between maladaptive appraisals of intrusive memories and distress in depressed mood. Further, both a single session of CB-Education and (to a lesser degree) CBM are useful in reducing intrusion-related distress. This study may have been underpowered to detect differences and replication is needed with larger samples.


t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients.
Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.


Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor.
Metabolic flexibility of skeletal muscle, that is, the preference for fat oxidation (FOx) during fasting and for carbohydrate oxidation in response to insulin, is decreased during insulin resistance. The aim of this study was to test the hypothesis that the capacity of myotubes to oxidize fat in vitro reflects the donor's metabolic characteristics. Insulin sensitivity (IS) and metabolic flexibility of 16 healthy, young male subjects was determined by euglycemic hyperinsulinemic clamp. Muscle samples were obtained from vastus lateralis, cultured, and differentiated into myotubes. In human myotubes in vitro, we measured suppressibility (glucose suppression of FOx) and adaptability (an increase in FOx in the presence of high palmitate concentration). We termed these dynamic changes in FOx metabolic switching. In vivo, metabolic flexibility was positively correlated with IS and maximal oxygen uptake and inversely correlated with percent body fat. In vitro suppressibility was inversely correlated with IS and metabolic flexibility and positively correlated with body fat and fasting FFA levels. Adaptability was negatively associated with percent body fat and fasting insulin and positively correlated with IS and metabolic flexibility. The interindividual variability in metabolic phenotypes was preserved in human myotubes separated from their neuroendocrine environment, which supports the hypothesis that metabolic switching is an intrinsic property of skeletal muscle.


Automatic brain tissue segmentation in fetal MRI using convolutional neural networks.
MR images of fetuses allow clinicians to detect brain abnormalities in an early stage of development. The cornerstone of volumetric and morphologic analysis in fetal MRI is segmentation of the fetal brain into different tissue classes. Manual segmentation is cumbersome and time consuming, hence automatic segmentation could substantially simplify the procedure. However, automatic brain tissue segmentation in these scans is challenging owing to artifacts including intensity inhomogeneity, caused in particular by spontaneous fetal movements during the scan. Unlike methods that estimate the bias field to remove intensity inhomogeneity as a preprocessing step to segmentation, we propose to perform segmentation using a convolutional neural network that exploits images with synthetically introduced intensity inhomogeneity as data augmentation. The method first uses a CNN to extract the intracranial volume. Thereafter, another CNN with the same architecture is employed to segment the extracted volume into seven brain tissue classes: cerebellum, basal ganglia and thalami, ventricular cerebrospinal fluid, white matter, brain stem, cortical gray matter and extracerebral cerebrospinal fluid. To make the method applicable to slices showing intensity inhomogeneity artifacts, the training data was augmented by applying a combination of linear gradients with random offsets and orientations to image slices without artifacts. To evaluate the performance of the method, Dice coefficient (DC) and Mean surface distance (MSD) per tissue class were computed between automatic and manual expert annotations. When the training data was enriched by simulated intensity inhomogeneity artifacts, the average achieved DC over all tissue classes and images increased from 0.77 to 0.88, and MSD decreased from 0.78 mm to 0.37 mm. These results demonstrate that the proposed approach can potentially replace or complement preprocessing steps, such as bias field corrections, and thereby improve the segmentation performance.


Discordant phenotypes in fraternal twins having an identical mutation in exon ORF15 of the RPGR gene.
To report discordant phenotypes, resulting from the same mutation in exon ORF15 (GenBank AF286472) of the retinitis pigmentosa GTPase regulator gene (RPGR) (GenBank U57629), in 2 presumed dizygotic twin brothers with X-linked retinal disease. The 2 brothers underwent complete ophthalmic examination that included best-corrected visual acuity, slitlamp biomicroscopy, and detailed fundus examination. Visual field recording using Goldmann kinetic perimetry and a full-field electroretinogram were also obtained in both patients. Mutational screening was performed for RPGR because of an X-linked pattern of inheritance indicated by pedigree analysis. One brother had a phenotypic expression of cone-rod dystrophy, while the other exhibited X-linked retinitis pigmentosa. A 1-nucleotide deletion was identified in the 3' region of exon ORF15 of RPGR (ORF15 + 1339delA). An identical mutation in RPGR-ORF15 manifested distinct clinical phenotypes in individuals of the same family. Our data provide strong evidence in support of additional modifier genes that can produce diverse disease phenotypes in patients with RPGR mutations. The clinical observation of different retinal phenotypes in a family with the same mutation in exon ORF15 of RPGR implicates the potential importance of modifier genes for the phenotypic expression of this form of X-linked retinal disease.


Isolated limb perfusion with melphalan and TNF-alpha in the treatment of extremity sarcoma.
Isolated limb perfusion (ILP) with chemotherapy alone has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor necrosis factor-alpha (TNF-alpha) to this treatment approach contributed to a major step forward in the treatment of locally advanced extremity soft tissue sarcoma (STS). High response rates and limb salvage rates have been reported in multicenter trials, which combined ILP with TNF-alpha plus melphalan, which resulted in the approval of TNF-alpha for this indication in Europe in 1998. Subsequently a series of confirmatory single institution reports on the efficacy of the procedure have now been published. TNF-alpha has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in high-grade soft tissue sarcomas. This induction therapy thus allows for resection of tumor remnants some 3 months after ILP and thus avoidance of limb amputation. TNF-alpha-based ILP is a well-established treatment to avoid amputations. It represents an important example of tumor vascularity-modulating combination therapy and should be offered in large volume tertiary referral centers.


Designed synthesis of 3D covalent organic frameworks.
Three-dimensional covalent organic frameworks (3D COFs) were synthesized by targeting two nets based on triangular and tetrahedral nodes: ctn and bor. The respective 3D COFs were synthesized as crystalline solids by condensation reactions of tetrahedral tetra(4-dihydroxyborylphenyl) methane or tetra(4-dihydroxyborylphenyl)silane and by co-condensation of triangular 2,3,6,7,10,11-hexahydroxytriphenylene. Because these materials are entirely constructed from strong covalent bonds (C-C, C-O, C-B, and B-O), they have high thermal stabilities (400 degrees to 500 degrees C), and they also have high surface areas (3472 and 4210 square meters per gram for COF-102 and COF-103, respectively) and extremely low densities (0.17 grams per cubic centimeter).


Intravital microscopy of localized stem cell delivery using microbubbles and acoustic radiation force.
The use of stem cells for the repair of damaged cardiac tissue after a myocardial infarction holds great promise. However, a common finding in experimental studies is the low number of cells delivered at the area at risk. To improve the delivery, we are currently investigating a novel delivery platform in which stem cells are conjugated with targeted microbubbles, creating echogenic complexes dubbed StemBells. These StemBells vibrate in response to incoming ultrasound waves making them susceptible to acoustic radiation force. The acoustic force can then be employed to propel circulating StemBells from the centerline of the vessel to the wall, facilitating localized stem cell delivery. In this study, we investigate the feasibility of manipulating StemBells acoustically in vivo after injection using a chicken embryo model. Bare stem cells or unsaturated stem cells (<5 bubbles/cell) do not respond to ultrasound application (1 MHz, peak negative acoustical pressure P_ = 200 kPa, 10% duty cycle). However, stem cells which are fully saturated with targeted microbubbles (>30 bubbles/cell) can be propelled toward and arrested at the vessel wall. The mean translational velocities measured are 61 and 177 μm/s for P- = 200 and 450 kPa, respectively. This technique therefore offers potential for enhanced and well-controlled stem cell delivery for improved cardiac repair after a myocardial infarction.


Outcomes and prognostic factors after emergent carotid artery stenting for hyperacute stroke within 6 hours of symptom onset.
The optimal treatment for hyperacute stroke attributable to cervical internal carotid artery (C-ICA) occlusion remains controversial. This study sought to evaluate clinical outcomes and prognostic factors after carotid artery stenting (CAS) in patients with hyperacute stroke within 6 hours of onset. Forty-seven patients with hyperacute stroke attributable to atherosclerotic C-ICA occlusion underwent emergent CAS. Forty-two patients (89.4%) had tandem intracranial artery occlusion (TIO). When patients showed remnant M1 or proximal M2 occlusions after CAS, intracranial recanalization therapy was performed by using pharmacologic thrombolysis and mechanical thrombectomy with a Solitaire stent. Clinical and radiologic data were compared between patients with favorable (modified Rankin scale, 0-2) and unfavorable outcomes. Binary logistic regression analysis was used to find independent prognostic factors. Emergent CAS was successful in all but 1 patient. Seven (16.7%) of 42 patients with TIO did not need further treatment, because thrombolysis in cerebral ischemia ≥2b was achieved immediately after CAS. Of the 35 patients who underwent intracranial recanalization therapy for remnant TIO, thrombolysis in cerebral ischemia ≥2b was achieved in 71.4% (25 of 35). Twenty-six patients (55.3%) had favorable outcomes, and mortality was 6.4% at 3 months. Time from symptom onset to carotid recanalization was inversely and independently associated with a favorable outcome for all patients and for those with TIO (P < .05). In our patient group, emergent CAS for hyperacute stroke caused by atherosclerotic C-ICA occlusion seemed to be effective and safe. Time to carotid recanalization was inversely and independently associated with a favorable outcome.


Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians.
To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. Population based, cohort, data linkage study in Australia. COHORT MEMBERS: 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. 60,674 cancers were recorded, including 3150 in 680,211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.38 per 100,000 person years at risk, as of 31 December 2007. The average effective radiation dose per scan was estimated as 4.5 mSv. The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. Because the cancer excess was still continuing at the end of follow-up, the eventual lifetime risk from CT scans cannot yet be determined. Radiation doses from contemporary CT scans are likely to be lower than those in 1985-2005, but some increase in cancer risk is still likely from current scans. Future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.


[Effects of inhaled corticosteroids on bone age and growth in children with asthma].
Long-term inhaled corticosteroids are the preferred treatment for asthma, but their safety still controversial. The aim of the present study was to explore the effects of inhaled corticosteroids on bone age and growth in children with asthma. Seventy-three children with asthma received inhaled fluticasone treatment at a starting dosage of 250 μg/d for 3 months, when the dosage was reduced by a third. Three months later, the patients were treated with fluticasone at a dosage of 125 μg/d for 6 months. Bone age, heights and weights were measured before and one year of treatment. The increase in the heights, weights and RUS (radius, ulna and short finger bones) bone age of the children with asthma after one year of treatment was not significantly different from healthy children. There were no significant differences in body mass index (BMI) before and after one year of treatment, however the level of carpal bone age [-0.2(-0.6,0.8) years] was delayed after therapy compared to before treatment [-0.5(-1.0,0.6) years] (P<0.05). Treatment with inhaled corticosteroids for 1 year may suppress the level of carpal bone age, but the level of RUS bone age, heights, weights and BMI are not affected. It is necessary to monitor the growth of children with asthma who receive long-term inhaled corticosteroid treatment.


The Global Leadership Mentoring Community: building capacity across seven global regions.
The purpose of this paper is to report on the evaluation of the online Global Leadership Mentoring Community, a programme designed to build relationships across seven global regions and promote leadership development for emerging nurse leaders. There is a pressing need and opportunity for sustainable global leadership mentoring programmes. This programme of Sigma Theta Tau International (Sigma) brought mentors and mentees together from across the world to build leadership capacity, understand global leadership issues and build networks. Community coordinators purposively selected mentors from each of Sigma's seven Global Regions, and mentees were chosen through a process of snowball sampling. Mentors and mentees met monthly with quarterly group calls. The study followed a programme evaluation, outcomes-focused approach. All eleven pairs of mentors-mentees were invited to complete online surveys at the outset and end of programme capturing both quantitative and qualitative data. Quantitative data were analysed using descriptive statistics and for qualitative data, a thematic analysis. Quantitative data confirmed that all 22 participants gained from the experience. From qualitative analysis, themes emerged illustrating the scope of achievements: 1. facilitation of successful outcomes for both mentors and mentees, 2. challenges of global mentoring and 3. strategies for successful global mentoring. Participants reported that creating global leadership is a longitudinal process that needs sustained attention to effect change. This evaluation identified many strengths of the programme and recommended its continuation to help further development of global leaders, particularly through focusing more purposefully on policy issues. Empowerment of nurses globally through a Global Leadership Mentoring Community can improve leadership at all levels, thus emboldening their voices to influence nursing and health policy and ultimately improve patient care.


Benign prostatic enlargement is not associated with diabetes: a population-based study.
The association between diabetes and benign prostatic hyperplasia remains inconclusive. In this case-control study, we examined the association of diabetes with benign prostatic enlargement (BPE) using the Longitudinal Health Insurance Database 2000 in Taiwan. In total, 20 152 patients with BPE as cases and 20 152 age-matched patients without BPE were included as controls. Conditional logistic regression analyses were performed to calculate the odds ratio (OR) and corresponding 95% CI for having been previously diagnosed with diabetes between cases and controls. We found that of the 40 304 sampled patients, 9492 (23.6%) had a history of diabetes before the index date. This mean age for the sampled patients was 65.9 with a standard deviation of 12.0 years. A Chi-squared test revealed that there was a significant difference in the prevalence of prior diabetes between cases and controls (25.3% vs. 21.8%, p < 0.001). The conditional logistic regression found that the OR of prior diabetes for cases was 1.21 (95% CI = 1.15-1.27) compared with controls. However, after adjusting for geographic region, monthly income, urbanization level, hypertension, coronary heart disease (CHD), hyperlipidemia, tobacco use disorder, and obesity, the association between prior diabetes and BPE did not reach a statistically significant level (OR = 1.03, 95% CI = 0.98-1.08). In addition, it was noteworthy that hypertension (OR = 1.25, 95% CI = 1.20-1.31), CHD (OR = 1.40, 95% CI = 1.32-1.48), and hyperlipidemia (OR = 1.30, 95% CI = 1.24-1.36) were all significantly associated with BPE. We found that men with a diagnosis of diabetes were not significantly associated with BPE after adjusting for patient's sociodemographic characteristics and comorbidities.


Infectious Bronchitis Virus Nonstructural Protein 4 Alone Induces Membrane Pairing.
Positive-strand RNA viruses, such as coronaviruses, induce cellular membrane rearrangements during replication to form replication organelles allowing for efficient viral RNA synthesis. Infectious bronchitis virus (IBV), a pathogenic avian Gammacoronavirus of significant importance to the global poultry industry, has been shown to induce the formation of double membrane vesicles (DMVs), zippered endoplasmic reticulum (zER) and tethered vesicles, known as spherules. These membrane rearrangements are virally induced; however, it remains unclear which viral proteins are responsible. In this study, membrane rearrangements induced when expressing viral non-structural proteins (nsps) from two different strains of IBV were compared. Three non-structural transmembrane proteins, nsp3, nsp4, and nsp6, were expressed in cells singularly or in combination and the effects on cellular membranes investigated using electron microscopy and electron tomography. In contrast to previously studied coronaviruses, IBV nsp4 alone is necessary and sufficient to induce membrane pairing; however, expression of the transmembrane proteins together was not sufficient to fully recapitulate DMVs. This indicates that although nsp4 is able to singularly induce membrane pairing, further viral or host factors are required in order to fully assemble IBV replicative structures. This study highlights further differences in the mechanism of membrane rearrangements between members of the coronavirus family.


Hypothermic machine preservation in liver transplantation revisited: concepts and criteria in the new millennium.
To overcome the present shortage of liver donors by expansion of the existing donor pool and possibly lengthening of the storage time, hypothermic machine perfusion of the liver as a dynamic preservation method is revisited. The three most important aspects are defined to be the type of preservation solution, the characteristics of perfusion dynamics, and the oxygen supply. Reviewing hypothermic liver machine perfusion experiments, the University of Wisconsin machine preservation solution is the solution most used. It is also found that nothing conclusive can be said about the optimal perfusion characteristics, since either perfusion pressure or perfusion flow is reported. The best estimation is perfusion of the liver in a physiological manner, i.e. pulsatile arterial perfusion and continuous portal venous perfusion. The applied pressures could be chosen to be somewhat lower than physiological pressures to prevent possible endothelial cell damage. Oxygen supply is necessary to achieve optimal preservation of the liver. The minimal amount of partial oxygen pressure required is inversely related to the normalized flow. Incorporating these features in a system based on existing standard surgical and organ sharing procedures and which is able to work stand-alone for 24 h, weighing less than 23 kg, could successfully implement this technique into every day clinical practise.


Analysis of efficiently packaged defective interfering RNAs of murine coronavirus: localization of a possible RNA-packaging signal.
We have previously shown that most of the defective interfering (DI) RNA of mouse hepatitis virus (MHV) are not packaged into virions. We have now identified, after 21 serial undiluted passages of MHV, a small DI RNA, DIssF, which is efficiently packaged into virions. The DIssF RNA replicated at a high efficiency on its transfection into the helper virus-infected cells. The virus released from the transfected cells interfered strongly with mRNA synthesis and growth of helper virus. cDNA cloning and sequence analysis of DIssF RNA revealed that it is 3.6 kb and consists of sequences derived from five discontinuous regions of the genome of the nondefective virus. The first four regions (domains I to IV) from the 5' end are derived from gene 1, which presumably encodes the RNA polymerase of the nondefective virus. The entire domain I (859 nucleotides) and the first 750 nucleotides of domain II are also present in a previously characterized DI RNA, DIssE, which is not efficiently packaged into virions. Furthermore, the junction between these two domains is identical between the two DI RNAs. The remaining 77 nucleotides at the 3' end of domain II and all of domains III (655 nucleotides) and IV (770 nucleotides) are not present in DIssE RNA. These four domains are derived from gene 1. In contrast, the 3'-most domain (domain V, 447 nucleotides) is derived from the 3' end of the genomic RNA and is also present in DIssE. The comparison of primary sequences and packaging properties between DIsse and DIssF RNAs suggested that domains III and IV and part of the 3' end of domain II contain the packaging signal for MHV RNA. This conclusion was confirmed by inserting these DIssF-unique sequences into a DIssE cDNA construct; the in vitro-transcribed RNA from this hybrid construct was efficiently packaged into virion particles. DIssF RNA also contains an open reading frame, which begins from domain I and ends at the 5'-end 20 bases of domain III. In vitro translation of DIssF RNA and metabolic labeling of the virus-infected cells showed that this open reading frame is indeed translated into a 75-kDa protein. The structures of both DIssE and DIssF RNAs suggest that a protein-encoding capability is a common characteristic of MHV DI RNA.


Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry).
Unexplained cardiac arrest may be because of an inherited arrhythmia syndrome. The role of genetic testing in cardiac arrest survivors without a definite clinical phenotype is unclear. The CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) is a large registry of cardiac arrest survivors where initial assessment reveals normal coronary arteries, left ventricular function, and resting ECG. Of 375 cardiac arrest survivors in CASPER from 2006 to 2015, 174 underwent genetic testing. Patients were classified as phenotype-positive (n=72) or phenotype-negative (n=102). Genetic testing was performed at treating physicians' discretion in line with contemporary guidelines and availability. All genetic variants identified from original laboratory reports were reassessed by the investigators in line with modern criteria. Pathogenic variants were identified in 29 (17%) patients (60% channelopathy-associated and 40% cardiomyopathy-associated genes) and 70 variants of unknown significance were identified in 32 (18%) patients. Prior syncope (odds ratio, 4.0; 95% confidence interval, 1.6-9.7) and a family history of sudden death (odds ratio, 3.2; 95% confidence interval, 1.1-9.4) were independently associated with the presence of a pathogenic variant. In phenotype-negative patients, broad multiphenotype genetic testing led to higher yields (21% versus 8%; P=0.04) but was associated with more variants of unknown significance (55% versus 5%; P<0.01). Genetic testing identifies a pathogenic variant in a significant proportion of unexplained cardiac arrest survivors. Prior syncope and family history of sudden death are predictors of a positive genetic test. Both arrhythmia and cardiomyopathy genes are implicated. Broad, multiphenotype testing revealed the highest frequency of pathogenic variants in phenotype-negative patients. https://www.clinicaltrials.gov. Unique Identifier: NCT00292032.


Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood-brain barrier protection.
Ultra-early hematoma evacuation (< 4 hours) after intracerebral hemorrhage (ICH) may reduce mass effect and edema development and improve outcome. To test this hypothesis, the authors induced lobar hematomas in pigs. The authors infused 2.5 ml of blood into the frontal cerebral white matter in pigs weighing 8 to 10 kg. In the treatment group, clots were lysed with tissue plasminogen activator ([tPA], 0.3 mg) and aspirated at 3.5 hours after hematoma induction. Brains were frozen in situ at 24 hours post-ICH and hematomal and perihematomal edema volumes were determined on coronal sections by using computer-assisted morphometry. Hematoma evacuation rapidly reduced elevated cerebral tissue pressure from 12.2+/-1.3 to 2.8+/-0.8 mm Hg. At 24 hours, prior clot removal markedly reduced hematoma volumes (0.40+/-0.10 compared with 1.26+/-0.13 cm3, p < 0.005) and perihematomal edema volumes (0.28+/-0.05 compared with 1.46+/-0.24 cm3, p < 0.005), compared with unevacuated control lesions. Furthermore, no Evans blue dye staining of perihematomal edematous white matter was present in brains in which the hematomas had been evacuated, compared with untreated controls. Hematomas were quickly and easily aspirated after treatment with tPA, resulting in significant reductions in mass effect. Hematoma aspiration after fibrinolysis with tPA enabled removal of the bulk of the hematoma (> 70%), markedly reduced perihematomal edema, and prevented the development of vasogenic edema. These findings in a large-animal model of ICH provide support for clinical trials that include the use of fibrinolytic agents and ultra-early stereotactically guided clot aspiration for treating ICH.


Blood pressure reduction following accumulated physical activity in prehypertensive.
Accumulated moderate physical activity (PA) for 30 min in a day is the only recommended treatment of prehypertension. We investigated autonomic modulation as a possible mechanism for the decrease in blood pressure (BP) during the rest periods in each 10 min session of PA. We conducted a single-blind randomized multi-arm control trial on 40 prehypertensive (pre-HT) young male adults. Participants were randomly divided by using random number table into four groups. Control (no intervention); Group 1 (walking at 50% of predicted VO2 peak); Group 2 (walking at 60% of predicted VO2 peak); Group 3 (walking at 70% of predicted VO2 peak). BP, heart rate variability (HRV), and heart rate recovery 1 min (HRR 1 min) were measured at baseline and during the rest period after each session of 10 min over 30 min of accumulated physical activity (PAcumm). Significant diastolic BP (DBP) reduction (P < 0.001) was observed during the rest period after each session of PAcumm in intervention groups. An average reduction in DBP was more in pre-HT undertaking PAcumm at 70% of predicted VO2 Peak. Decrease in the mean value of low-frequency (LF) and LF/high-frequency ratio was observed following PAcumm in all intervention groups irrespective of the intensity of PA. No significant association of reduction of BP with HRV and HRR 1 s was observed. Reduction in BP was observed during the rest period after each 10 min session of PAcumm irrespective of the intensity of PA. Autonomic modulation does not seem to be the possible mechanism for the reduction in BP during the sessions.


Deletion-bias in DNA double-strand break repair differentially contributes to plant genome shrinkage.
In order to prevent genome instability, cells need to be protected by a number of repair mechanisms, including DNA double-strand break (DSB) repair. The extent to which DSB repair, biased towards deletions or insertions, contributes to evolutionary diversification of genome size is still under debate. We analyzed mutation spectra in Arabidopsis thaliana and in barley (Hordeum vulgare) by PacBio sequencing of three DSB-targeted loci each, uncovering repair via gene conversion, single strand annealing (SSA) or nonhomologous end-joining (NHEJ). Furthermore, phylogenomic comparisons between A. thaliana and two related species were used to detect naturally occurring deletions during Arabidopsis evolution. Arabidopsis thaliana revealed significantly more and larger deletions after DSB repair than barley, and barley displayed more and larger insertions. Arabidopsis displayed a clear net loss of DNA after DSB repair, mainly via SSA and NHEJ. Barley revealed a very weak net loss of DNA, apparently due to less active break-end resection and easier copying of template sequences into breaks. Comparative phylogenomics revealed several footprints of SSA in the A. thaliana genome. Quantitative assessment of DNA gain and loss through DSB repair processes suggests deletion-biased DSB repair causing ongoing genome shrinking in A. thaliana, whereas genome size in barley remains nearly constant.


Fetal Head and Neck Masses: MRI Prediction of Significant Morbidity.
The purpose of this study is to determine which MRI parameters of fetal head and neck masses predict high-morbidity neonatal outcomes, including ex utero intrapartum treatment (EXIT) procedure. This retrospective study (2004-2016) included parameters of polyhydramnios (based on largest vertical pocket), mass effect on the trachea, mass midline extension, and morphologic grade and size of masses. The morbid cohort included those requiring an EXIT procedure, difficult intubation at delivery, or lethal outcome. Predictive modeling with a multivariable logistic regression and ROC analysis was then performed. Of 36 fetuses, five were delivered by EXIT procedures, there was one neonatal death within 12 hours after delivery, and another neonate required multiple intubation attempts. The remaining 29 fetuses were delivered at outside institutions with no interventions or neonatal morbidity. The largest vertical pocket and mass effect on the trachea were selected as independent predictors by the logistic regression. The cross-validated ROC AUC was 0.951 (95% CI, 0.8795-1). The largest vertical pocket measurement and mass effect on the trachea were the most contributory MRI parameters that predicted significant morbidity in fetuses with masses of the face and neck, along with other significant parameters. These parameters predict significant morbid neonatal outcomes, including the need for EXIT procedures.


Mechanism of the Class I KDPG aldolase.
In vivo, 2-keto-3-deoxy-6-phosphogluconate (KDPG) aldolase catalyzes the reversible, stereospecific retro-aldol cleavage of KDPG to pyruvate and D-glyceraldehyde-3-phosphate. The enzyme is a lysine-dependent (Class I) aldolase that functions through the intermediacy of a Schiff base. Here, we propose a mechanism for this enzyme based on crystallographic studies of wild-type and mutant aldolases. The three dimensional structure of KDPG aldolase from the thermophile Thermotoga maritima was determined to 1.9A. The structure is the standard alpha/beta barrel observed for all Class I aldolases. At the active site Lys we observe clear density for a pyruvate Schiff base. Density for a sulfate ion bound in a conserved cluster of residues close to the Schiff base is also observed. We have also determined the structure of a mutant of Escherichia coli KDPG aldolase in which the proposed general acid/base catalyst has been removed (E45N). One subunit of the trimer contains density suggesting a trapped pyruvate carbinolamine intermediate. All three subunits contain a phosphate ion bound in a location effectively identical to that of the sulfate ion bound in the T. maritima enzyme. The sulfate and phosphate ions experimentally locate the putative phosphate binding site of the aldolase and, together with the position of the bound pyruvate, facilitate construction of a model for the full-length KDPG substrate complex. The model requires only minimal positional adjustments of the experimentally determined covalent intermediate and bound anion to accommodate full-length substrate. The model identifies the key catalytic residues of the protein and suggests important roles for two observable water molecules. The first water molecule remains bound to the enzyme during the entire catalytic cycle, shuttling protons between the catalytic glutamate and the substrate. The second water molecule arises from dehydration of the carbinolamine and serves as the nucleophilic water during hydrolysis of the enzyme-product Schiff base. The second water molecule may also mediate the base-catalyzed enolization required to form the carbon nucleophile, again bridging to the catalytic glutamate. Many aspects of this mechanism are observed in other Class I aldolases and suggest a mechanistically and, perhaps, evolutionarily related family of aldolases distinct from the N-acetylneuraminate lyase (NAL) family.


Life cycle and population growth rate of Caenorhabditis elegans studied by a new method.
The free-living nematode Caenorhabditis elegans is the predominant model organism in biological research, being used by a huge number of laboratories worldwide. Many researchers have evaluated life-history traits of C. elegans in investigations covering quite different aspects such as ecotoxicology, inbreeding depression and heterosis, dietary restriction/supplement, mutations, and ageing. Such traits include juvenile growth rates, age at sexual maturity, adult body size, age-specific fecundity/mortality, total reproduction, mean and maximum lifespan, and intrinsic population growth rates. However, we found that in life-cycle experiments care is needed regarding protocol design. Here, we test a recently developed method that overcomes some problems associated with traditional cultivation techniques. In this fast and yet precise approach, single individuals are maintained within hanging drops of semi-fluid culture medium, allowing the simultaneous investigation of various life-history traits at any desired degree of accuracy. Here, the life cycles of wild-type C. elegans strains N2 (Bristol, UK) and MY6 (Münster, Germany) were compared at 20 degrees C with 5 x 10(9) Escherichia coli ml-1 as food source. High-resolution life tables and fecundity schedules of the two strains are presented. Though isolated 700 km and 60 years apart from each other, the two strains barely differed in life-cycle parameters. For strain N2 (n = 69), the intrinsic rate of natural increase (r m d(-1)), calculated according to the Lotka equation, was 1.375, the net reproductive rate (R 0) 291, the mean generation time (T) 90 h, and the minimum generation time (T min) 73.0 h. The corresponding values for strain MY6 (n = 72) were r m = 1.460, R0 = 289, T = 84 h, and T min = 67.3 h. Peak egg-laying rates in both strains exceeded 140 eggs d(-1). Juvenile and early adulthood mortality was negligible. Strain N2 lived, on average, for 16.7 d, while strain MY6 died 2 days earlier; however, differences in survivorship curves were statistically non-significant. We found no evidence that adaptation to the laboratory altered the life history traits of C. elegans strain N2. Our results, discussed in the light of earlier studies on C. elegans, demonstrate certain advantages of the hanging drop method in investigations of nematode life cycles. Assuming that its reproducibility is validated in further studies, the method will reduce the inter-laboratory variability of life-history estimates and may ultimately prove to be more convenient than the current standard methods used by C. elegans researchers.


Are obstetric outcomes affected by female genital mutilation?
Female genital mutilation (FGM) has been associated with adverse obstetric and neonatal outcomes, such as postpartum haemorrhage (PPH), perineal trauma, genital fistulae, obstructed labour and stillbirth. The prevalence of FGM has increased in the UK over the last decade. There are currently no studies available that have explored the obstetric impact of FGM in the UK. The aim of our study was to investigate the obstetric and neonatal outcomes of women with FGM when compared with the general population. We conducted a retrospective case-control study of consecutive pregnant women with FGM over a 5-year period between 1 January 2009 and 31 December 2013. Each woman with FGM was matched for age, ethnicity, parity and gestation with subsequent patients without FGM (control cohort) over the same 5-year period. Outcomes assessed were mode of delivery, duration of labour, estimated blood loss, analgaesia, perineal trauma and foetal outcomes. A total of 242 eligible women (121 FGM, 121 control) were identified for the study. There was a significant increase in the use of episiotomy in the FGM group (p = 0.009) and a significant increase in minor PPH in the control group during caesarean sections (p = 0.0001). There were no differences in all other obstetric and neonatal parameters. In our unit, FGM was not associated with an increased incidence of adverse obstetric and foetal morbidity or mortality.


ACTH-stimulated cortisol release from head kidney of rainbow trout is modulated by glucose concentration.
To assess the hypothesis that cortisol release in rainbow trout is modulated by glucose levels, we first evaluated cortisol release [basal and adrenocorticotropic hormone (ACTH)-regulated] by head kidney tissue superfused with medium reflecting hypoglycaemic, normoglycaemic or hyperglycaemic conditions. Next, cortisol release from head kidney fragments in static incubations was assessed in parallel with changes in parameters related to cortisol synthesis (mRNA abundance of StAR, P450scc, 3βHSD and 11βH) and the GK-mediated glucosensing mechanism (levels of glycogen and glucose, activities of GK, GSase and PK, and mRNA levels of GK, GLUT-2, Kir6.x-like and SUR-like). We then evaluated the effects of two inhibitors of glucose transport, cytochalasin B and phlorizin, on cortisol production and glucosensing mechanisms. The ACTH-induced release of cortisol proved to be modulated by glucose concentration such that increased release occurs under high glucose levels, and decreased ACTH-stimulated cortisol release occurs when glucose transport is inhibited by cytochalasin B. The release of cortisol can be associated with increased synthesis as enhanced mRNA abundance of genes related to cortisol synthesis was also noted in high glucose medium. Specific GK immunoreactivity in the cortisol-producing cells (not in chromaffin cells) further substantiates GK-mediated glucosensing in cortisol production. In contrast, no changes compatible with those of glucose levels and cortisol release/synthesis in the presence of ACTH were noted for any other putative glucosensor mechanisms based on LXR, SGLT-1 or Gnat3. These combined results are the first evidence for a mechanism in fish linking the synthesis and release of a non-pancreatic hormone like cortisol with circulating glucose levels. The relationship was evident for the regulated (ACTH-dependent) pathway and this suggests that under acute stress conditions glucose is important for the regulation of cortisol synthesis and release.


Radionuclide imaging.
Recent advances in nuclear cardiology have included the application of radionuclide imaging techniques to the detection of coronary artery disease. Exercise Thallium-201 myocardial imaging has proved a sensitive and specific test for the detection of significant coronary artery disease and allows differentiation between myocardial ischaemia and infarction. Other conditions affecting the myocardium may produce abnormal myocardial images but, with recognition of this and the variations seen in normal subjects, the diagnostic accuracy of Thallium-201 myocardial imaging compares favourably with exercise electrocardiography. The technique is particularly useful where the exercise electrocardiogram is non-diagnostic or equivocal. Preliminary results from application to screening asymptomatic subjects have been encouraging. Radionuclide ventriculography allows the assessment of global and regional left ventricular function. The development of new regional wall motion abnormalities during stress is a highly specific indicator of the presence of myocardial ischaemia, and combined with analysis of the left ventricular ejection fraction response to exercise provides a sensitive test for the detection of significant coronary artery disease. Probability theory allows consideration of the place of these techniques in the investigation of the individual with proven or suspected coronary artery disease.


Towards athermal organic-inorganic guided mode resonance filters.
We demonstrate guided-mode resonance filters featuring an amorphous TiO(2) layer fabricated by atomic layer deposition on a polymeric substrate. The thermal properties of such filters are studied in detail by taking into account both thermal expansion of the structure and thermo-optic coefficients of the materials. We show both theoretically and experimentally that these two effects partially compensate for each other, leading to nearly athermal devices. The wavelength shift of the resonance reflectance peak (< 1 nm) is a small fraction of the peak width (~11 nm) up to temperatures exceeding the room temperature by tens of degrees centigrade.


Plant growth-promoting traits of Pseudomonas geniculata isolated from chickpea nodules.
A bacterium, isolated from nodules of chickpea grown in alluvial soils of Haryana state of India, designated as IC-76 was characterized for in vitro plant growth-promoting (PGP) properties and further evaluated under greenhouse, on-station and on-farm field conditions for PGP activity in chickpea. The isolate IC-76 produced indole acetic acid, siderophore, hydrocyanic acid, cellulase, protease, and β-1,3-glucanase. When the bacterium was evaluated individually for their PGP potential in the greenhouse on chickpea and in combination with five Streptomyces sp. (strains CAI-24, CAI-121, CAI-127, KAI-32, and KAI-90; demonstrated earlier as biocontrol potential against Fusarium wilt disease in chickpea), the traits, including nodule number and weight, shoot, and root weight, pod number and weight, seed number and weight, available phosphorus and % organic carbon were found significantly, enhanced over un-inoculated control. In the on-station and on-farm field conditions, IC-76 significantly enhanced nodule number and weight, shoot, and root weight, stover and grain yield and total dry matter. In the rhizosphere (0-15 cm soil), the bacterium also significantly enhanced the total nitrogen, available phosphorus and % organic carbon. The sequence of 16S rDNA gene of the IC-76 was matched with Pseudomonas geniculata in BLAST analysis. This study demonstrates that IC-76 has the potential for PGP in chickpea.


Perceptions of physically active men with prostate cancer on the role of physical activity in maintaining their quality of life: possible influence of androgen deprivation therapy.
The primary aim of this study was to examine the perceptions of older men with prostate cancer regarding their quality of life and physical activity post-diagnosis, and the potential benefits and risks associated with being physically active. A secondary aim was to gain some preliminary insight into how these perceptions may differ as a function of androgen deprivation therapy (ADT). Two focus groups were conducted, consisting of six ADT and eight non-ADT men, respectively. The probe questions used assessed the link between quality of life and physical activity as well as the benefits and risks associated with physical activity. Data were transcribed verbatim and themes identified using a general inductive thematic approach. The primary themes identified were sexual health, 'plumbing' and non-urogenital side-effects, return to and increased levels of physical activity post-diagnosis, physical health/function and psychological benefits of physical activity as well as over-doing it and age-related risks of excessive physical activity. However, not all themes were present in both the ADT and the non-ADT sub-groups. These results further highlight the link between physical activity and quality of life in prostate cancer survivors and how they use physical activity as a part of their survivorship process. Of particular interest was how several men on ADT used resistance training to counteract ADT-related side-effects affecting their masculinity. As the evidence for physical activity for prostate cancer survivorship is increasing, cancer clinicians and service providers should consider ways to better assist these men, especially those on ADT become more active.


Recommended approaches to the scientific evaluation of ecotoxicological hazards and risks of endocrine-active substances.
A SETAC Pellston Workshop® "Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA)" was held in February 2016 in Pensacola, Florida, USA. The primary objective of the workshop was to provide advice, based on current scientific understanding, to regulators and policy makers; the aim being to make considered, informed decisions on whether to select an ecotoxicological hazard- or a risk-based approach for regulating a given endocrine-disrupting substance (EDS) under review. The workshop additionally considered recent developments in the identification of EDS. Case studies were undertaken on 6 endocrine-active substances (EAS-not necessarily proven EDS, but substances known to interact directly with the endocrine system) that are representative of a range of perturbations of the endocrine system and considered to be data rich in relevant information at multiple biological levels of organization for 1 or more ecologically relevant taxa. The substances selected were 17α-ethinylestradiol, perchlorate, propiconazole, 17β-trenbolone, tributyltin, and vinclozolin. The 6 case studies were not comprehensive safety evaluations but provided foundations for clarifying key issues and procedures that should be considered when assessing the ecotoxicological hazards and risks of EAS and EDS. The workshop also highlighted areas of scientific uncertainty, and made specific recommendations for research and methods-development to resolve some of the identified issues. The present paper provides broad guidance for scientists in regulatory authorities, industry, and academia on issues likely to arise during the ecotoxicological hazard and risk assessment of EAS and EDS. The primary conclusion of this paper, and of the SETAC Pellston Workshop on which it is based, is that if data on environmental exposure, effects on sensitive species and life-stages, delayed effects, and effects at low concentrations are robust, initiating environmental risk assessment of EDS is scientifically sound and sufficiently reliable and protective of the environment. In the absence of such data, assessment on the basis of hazard is scientifically justified until such time as relevant new information is available. Integr Environ Assess Manag 2017;13:267-279. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Live cell imaging of mouse intestinal organoids reveals heterogeneity in their oxygenation.
Intestinal organoids are widely applied in stem cell research, regenerative medicine, toxicology, pharmacology, and host-microbe interactions research. The variability of oxidative metabolism for stem and differentiated cell types constituting organoid is known to be important but so far it has not been studied in details. Here, we report the use of live cell microscopy of oxygen via the phosphorescence lifetime imaging microscopy (PLIM) method to address the oxygenation and variability of aerobic metabolism of individual organoids in the culture. Using the cell-penetrating phosphorescent O2-sensitive probe, we found inhomogeneous O2 distribution in live organoids, with areas of relatively high oxygenation (up to 73 μM in organoid compared to an average 40 μM O2) and trans-epithelial O2 microgradients (up to 0.6-0.83 μM/μm). We also demonstrated that intestinal organoid culture consists of units with different respiration activity and oxygenation (from 27 to 92 μM, equal to 2.8-9.7% O2), depending on age of the culture and drug treatment. Collectively, our results indicate that ignoring the metabolic heterogeneity of organoid culture can be critical for proper data interpretation. The live cell imaging PLIM method demonstrates a clear advantage of using individual organoids as separate experimental units rather than 'bulk' organoid cultures.


Local health department capacity for community engagement and its implications for disaster resilience.
Over the past decade, community engagement has become a central tenet of US federal doctrine on public health emergency preparedness. Little is known, however, about how the vision of a ready, aware, and involved populace has translated into local practice, or which conditions thus far have advanced community involvement in what is typically considered the province of government authorities and emergency professionals. In 2011-12, to help close that knowledge gap, investigators carried out semistructured qualitative interviews with practitioners (N=25) from 7 local health departments about which conditions have advanced or inhibited community engagement in public health emergency preparedness. Among the organizational factors identified as enabling local health departments' involvement of community residents and groups in emergency preparedness were a supportive agency leadership and culture, sufficient staffing and programmatic funding, interested and willing partners, and external triggers such as federal grants and disaster experiences that spotlighted the importance of community relationships to effective response. Facing budget and staff cuts, local health departments feel increasingly constrained in efforts to build trusted and lasting preparedness ties with community partners. At the same time, some progress in preparedness partnerships may be possible in the context of agency leadership, culture, and climate that affirms the value of collaboration with the community.


Cardiac effects of angiotensin antagonists in normotensive rats.
1. Angiotensin II (AII) antagonists, namely Sar1,Ile8-AII, Sar1,Ala8-AII and Sar1,Thr8-AII, were administered daily for 4 weeks to normotensive rats to study their effect on cardiac hypertrophy. 2. None of the antagonists altered blood pressure significantly but Sar1,Ile8-AII and Sar1,Ala8-AII produced a significant increase in heart weight, as compared with untreated age-matched control rats. Administration of Sar1,Thr8-AII did not produce cardiac hypertrophy. 3. A significant increase in catecholamine concentration was observed in the ventricles of rats treated with Sar1,Ile8-AII and Sar1,Ala8-AII but no change was found in the group treated with the Sar1,Thr8-AII analogue. The production of cardiac hypertrophy by Sar1,Ile8-AII was prevented by bilateral adrenalectomy, suggesting an important role for catecholamines in modulating cardiac hypertrophy.


Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea.
Obstructive sleep apnea (OSA) has been associated with cardiovascular disease (CVD), but whether OSA is an independent risk factor for CVD is controversial. The purpose of this study is to determine if patients with OSA have subclinical cardiovascular disease that is detectable by multi-modality cardiovascular imaging and whether these abnormalities improve after nasal continuous positive airway pressure (nCPAP). Of the 35 consecutive subjects with newly diagnosed moderate to severe OSA recruited from the Stanford Sleep Disorders Clinic, 20 patients were randomized to active vs. sham nCPAP. Active nCPAP was titrated to pressures that would prevent sleep disordered breathing based on inpatient polysomnography. OSA patients had baseline vascular function abnormalities including decreased myocardial perfusion reserve (MPR), brachial flow mediated dilation (FMD) and nitroglycerin-induced coronary vasodilation. Patients randomized to active nCPAP had improvement of MPR (1.5 ± 0.5 vs. 3.0 ± 1.3, p = 0.02) and brachial FMD (2.5% ± 5.7% vs. 9.0% ± 6.5%, p = 0.03) after treatment, but those randomized to sham nCPAP showed no significant improvement. There were no significant changes seen in chamber sizes, systolic and diastolic function, valvular function and coronary vasodilation to nitroglycerin. Patients with moderate to severe OSA had decreased MPR and brachial FMD that improved after 3 months of nCPAP. These findings suggest that relief of apnea in OSA may improve microvascular disease and endothelial dysfunction, which may prevent the development of overt cardiovascular disease. Further study in a larger patient population may be warranted.


Unifying dynamical and structural stability of equilibria.
We exhibit a fundamental relationship between measures of dynamical and structural stability of linear dynamical systems-e.g. linearized models in the vicinity of equilibria. We show that dynamical stability, quantified via the response to external perturbations (i.e. perturbation of dynamical variables), coincides with the minimal internal perturbation (i.e. perturbations of interactions between variables) able to render the system unstable. First, by reformulating a result of control theory, we explain that harmonic external perturbations reflect the spectral sensitivity of the Jacobian matrix at the equilibrium, with respect to constant changes of its coefficients. However, for this equivalence to hold, imaginary changes of the Jacobian's coefficients have to be allowed. The connection with dynamical stability is thus lost for real dynamical systems. We show that this issue can be avoided, thus recovering the fundamental link between dynamical and structural stability, by considering stochastic noise as external and internal perturbations. More precisely, we demonstrate that a linear system's response to white-noise perturbations directly reflects the intensity of internal white-noise disturbance that it can accommodate before becoming stochastically unstable.


Might limiting liquid nicotine concentration result in more toxic electronic cigarette aerosols?
Some jurisdictions have instituted limits on electronic cigarette (ECIG) liquid nicotine concentration, in an effort to control ECIG nicotine yield, and others are considering following suit. Because ECIG nicotine yield is proportional to the product of liquid nicotine concentration (milligram per millilitre) and device power (watts) regulations that limit liquid nicotine concentration may drive users to adopt higher wattage devices to obtain a desired nicotine yield. In this study we investigated, under various hypothetical regulatory limits on ECIG liquid nicotine concentration, a scenario in which a user of a common ECIG device (SMOK TF-N2) seeks to obtain in 15 puffs the nicotine emissions equivalent to one combustible cigarette (ie, 1.8 mg). We measured total aerosol and carbonyl compound (CC) yields in 15 puffs as a function of power (15-80 W) while all else was held constant. The estimated nicotine concentration needed to achieve combustible cigarette-like nicotine yield at each power level was then computed based on the measured liquid consumption. We found that for a constant nicotine yield of 1.8 mg, reducing the liquid nicotine concentration resulted in greater amount of liquid aerosolised (p<0.01) and greater CC emissions (p<0.05). Thus, if users seek a given nicotine yield, regulatory limits on nicotine concentration may have the unintended consequence of increasing exposure to aerosol and respiratory toxicants. This outcome demonstrates that attempting to control ECIG nicotine yield by regulating one factor at a time may have unintended health effects and highlights the need to consider multiple factors and outcomes simultaneously when designing regulations.


[Role of continuous EEG monitoring in the diagnosis of pediatric epilepsy].
The diagnosis of epilepsy is basically clinical, but it frequently raises the differential diagnosis with non-epileptic events. The development of continuous EEG monitoring (CEEGM) in the past decades has allowed a better diagnosis of epileptic patients of all ages. In this paper we review the data available in the literature about the efficacy of the different modalities of CEEGM in the diagnosis of pediatric epilepsy, emphasizing our personal experience. In our studies the ambulatory CEEGM supplemented with video allowed to answer the question that prompted its request in 80% of patients diagnosed with epilepsy and in 83% of those with the suspected diagnosis of epilepsy. With ambulatory computer-assisted CEEGM those figures were 88% and 89%, respectively, and with inpatient video-CEEGM they were 82% and 51%, respectively. The latter is crucial in the evaluation of epilepsy patients who are candidates for surgical treatment. Inpatient video-CEEGM is also very important in the management of patients with acute encephalopathies admitted to the Intensive Care Units. Both, ambulatory or inpatient CEEGM, are very useful in the differential diagnosis of clinical epileptic versus non-epileptic events, as well as in the confirmation of the type of epilepsy or epileptic syndrome. The development of technological advances and new EEG modalities in the future will help to continue to consider electroencephalography as a very important technique in the study of brain function in patients with acute or chronic encephalopathies.


Comparative cost assessment of the Kato-Katz and FLOTAC techniques for soil-transmitted helminth diagnosis in epidemiological surveys.
The Kato-Katz technique is widely used for the diagnosis of soil-transmitted helminthiasis in epidemiological surveys and is believed to be an inexpensive method. The FLOTAC technique shows a higher sensitivity for the diagnosis of light-intensity soil-transmitted helminth infections but is reported to be more complex and expensive. We assessed the costs related to the collection, processing and microscopic examination of stool samples using the Kato-Katz and FLOTAC techniques in an epidemiological survey carried out in Zanzibar, Tanzania. We measured the time for the collection of a single stool specimen in the field, transfer to a laboratory, preparation and microscopic examination using standard protocols for the Kato-Katz and FLOTAC techniques. Salaries of health workers, life expectancy and asset costs of materials, and infrastructure costs were determined. The average cost for a single or duplicate Kato-Katz thick smears and the FLOTAC dual or double technique were calculated. The average time needed to collect a stool specimen and perform a single or duplicate Kato-Katz thick smears or the FLOTAC dual or double technique was 20 min and 34 sec (20:34 min), 27:21 min, 28:14 min and 36:44 min, respectively. The total costs for a single and duplicate Kato-Katz thick smears were US$ 1.73 and US$ 2.06, respectively, and for the FLOTAC double and dual technique US$ 2.35 and US$ 2.83, respectively. Salaries impacted most on the total costs of either method. The time and cost for soil-transmitted helminth diagnosis using either the Kato-Katz or FLOTAC method in epidemiological surveys are considerable. Our results can help to guide healthcare decision makers and scientists in budget planning and funding for epidemiological surveys, anthelminthic drug efficacy trials and monitoring of control interventions.


Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma.
The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc(®) (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007-2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WR(neutron)). When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates.


Urinary neutrophil gelatinase-associated lipocalin accurately detects acute allograft rejection among other causes of acute kidney injury in renal allograft recipients.
Urinary neutrophil gelatinase-associated lipocalin (NGAL) has emerged an early marker protein, predicative of acute kidney injury (AKI) in various clinical settings. Here, we demonstrate urinary NGAL to allow for differential diagnosis of AKI, accurately discriminating acute allograft rejection from other causes of AKI in renal allograft recipients. Urinary NGAL was assessed in spot urine of 182 outpatient renal allograft recipients on maintenance immunosuppression. Samples were blinded and NGAL concentrations determined by enzyme-linked immunosorbent assay. Patient data were classed according to standard criteria into stable allograft function or AKI, and according to underlying pathology into acute allograft rejection or AKI of other cause. Of the 182 patients investigated, 44 (24.2%) presented with AKI and 9 (4.9%) were diagnosed with acute allograft rejection. In 138 patients with stable allograft function, median urinary NGAL concentration was 7.8 ng/mL (interquartile range, 3.7-17.4 ng/mL). In acute allograft rejection, urinary NGAL concentration was 339 ng/mL (165-499 ng/mL), and in AKI of other cause was 59.1 ng/mL (33.1-136 ng/mL). With a cut-off at 100 ng/mL, urinary NGAL accurately predicted acute rejection as underlying pathology of AKI in our cohort (area under the curve-receiver operating characteristic 0.98, sensitivity 1.0, specificity 0.93). This concept was confirmed in an independent clinical setting in allograft recipients referred to our hospital with AKI. Urinary NGAL, at respective cut-off, accurately discriminates acute allograft rejection from other causes of AKI in follow-up after kidney transplantation. As a readily available parameter, urinary NGAL may guide differential diagnosis and initial therapy in allograft recipients with AKI.


Diagnostic accuracy of range of motion measurements in early symptomatic hip and/or knee osteoarthritis.
To examine the diagnostic accuracy of hip internal rotation, hip flexion, and knee flexion measurements for the presence of osteophytosis and joint space narrowing (JSN) in early symptomatic osteoarthritis (OA). The baseline data for 598 participants of the Cohort Hip & Cohort Knee study were used. Participants underwent a standardized physical and radiographic examination. The active range of motion (ROM) was assessed using a goniometer. The ROM cutoff with the highest discriminative ability for radiographic features of OA was defined by maximizing the sum of the sensitivity and specificity. Several diagnostic measures were calculated to establish the diagnostic accuracy of ROM measurements for the presence of radiographic features. In patients with hip symptoms, hip internal rotation <24° and flexion <114° were found to be the cutoffs with the highest discriminative ability to distinguish between patients with and without radiographic features. In patients with knee symptoms, knee flexion <132° was the cutoff with the highest discriminative ability. The American College of Rheumatology (ACR) criterion of hip internal rotation <15° increased the probability of the presence of osteophytosis or JSN from 25% to 58%. The diagnostic accuracy of hip and knee flexion measurements was low. To reduce the number of patients that are not identified by the ACR criterion of hip internal rotation <15°, it is recommended to change the cutoff to internal rotation <24° in patients with early symptomatic OA. Individual hip and knee flexion measurements seem to be of little diagnostic value in early symptomatic OA.


Biochemical and immunological characterization of a recombinantly-produced antifungal cysteine proteinase inhibitor from green kiwifruit (Actinidia deliciosa).
Plant proteinase inhibitors are considered important defense molecules against insect and pathogen attack. The cysteine proteinase inhibitor (CPI) from green kiwifruit (Actinidia deliciosa) belongs to the cystatin family and shows potent antifungal activity (in vitro and in vivo). However, the low abundance of this molecule in fruit (6μg/g of fresh fruit) seems to limit further investigations on the interaction between phytocystatin and photopathogenic fungi. In this paper the cDNA of the kiwi CPI was expressed in Escherichia coli. Fifteen N-terminal amino acids were identified by Edman degradation, and 77% of the rCPI primary structure was confirmed by mass fingerprint. The structural homology of recombinant CPI (rCPI) to its natural counterpart has been clearly demonstrated in immunological assays (immunoblot and ELISA inhibition). Biological activity of rCPI was demonstrated in inhibition assay with cysteine proteinase papain (EC50 2.78nM). In addition, rCPI reveals antifungal properties toward pathogenic fungi (Alternaria radicina and Botrytis cinerea), which designates it as an interesting model protein for the exploration of plant phytocystatins - pathogen interactions. Understanding the molecular mechanisms of natural plant resistance could lead to the development of ecologically safe fungicides for controlling post-harvest diseases and maintaining food quality.


Physician age and outcomes in elderly patients in hospital in the US: observational study.
Objectives To investigate whether outcomes of patients who were admitted to hospital differ between those treated by younger and older physicians.Design Observational study.Setting US acute care hospitals.Participants 20% random sample of Medicare fee-for-service beneficiaries aged ≥65 admitted to hospital with a medical condition in 2011-14 and treated by hospitalist physicians to whom they were assigned based on scheduled work shifts. To assess the generalizability of findings, analyses also included patients treated by general internists including both hospitalists and non-hospitalists.Main outcome measures 30 day mortality and readmissions and costs of care. Results 736 537 admissions managed by 18 854 hospitalist physicians (median age 41) were included. Patients' characteristics were similar across physician ages. After adjustment for characteristics of patients and physicians and hospital fixed effects (effectively comparing physicians within the same hospital), patients' adjusted 30 day mortality rates were 10.8% for physicians aged <40 (95% confidence interval 10.7% to 10.9%), 11.1% for physicians aged 40-49 (11.0% to 11.3%), 11.3% for physicians aged 50-59 (11.1% to 11.5%), and 12.1% for physicians aged ≥60 (11.6% to 12.5%). Among physicians with a high volume of patients, however, there was no association between physician age and patient mortality. Readmissions did not vary with physician age, while costs of care were slightly higher among older physicians. Similar patterns were observed among general internists and in several sensitivity analyses.Conclusions Within the same hospital, patients treated by older physicians had higher mortality than patients cared for by younger physicians, except those physicians treating high volumes of patients.


High handaxe symmetry at the beginning of the European Acheulian: The data from la Noira (France) in context.
In the last few decades, new discoveries have pushed the beginning of the biface-rich European Acheulian from 500 thousand years (ka) ago back to at least 700 ka, and possibly to 1 million years (Ma) ago. It remains, however, unclear to date if handaxes arrived in Europe as a fully developed technology or if they evolved locally from core-and-flake industries. This issue is also linked with another long-standing debate on the existence and behavioral, cognitive, and social meaning of a possibly chronological trend for increased handaxe symmetry throughout the Lower Paleolithic. The newly discovered sites can provide a link between the much older Acheulian in Africa and the Levant and the well-known assemblages from the later European Acheulian, enabling a rigorous testing of these hypotheses using modern morphometric methods. Here we use the Continuous Symmetry Measure (CSM) method to quantify handaxe symmetry at la Noira, a newly excavated site in central France, which features two archaeological levels, respectively ca. 700 ka and 500 ka old. In order to provide a context for the new data, we use a large aggregate from the well-known 500 ka old site of Boxgrove, England. We show that handaxes from the oldest layer at la Noira, although on average less symmetric than both those from the younger layers at the same site and than those from Boxgrove, are nevertheless much more symmetric than other early Acheulian specimens evaluated using the CSM method. We also correlate trends in symmetry to degree of reduction, demonstrating that raw material availability and discard patterns may affect observed symmetry values. We conclude that it is likely that, by the time the Acheulian arrived in Europe, its makers were, from a cognitive and motor-control point of view, already capable of producing the symmetric variant of this technology.


Speaker-listener neural coupling underlies successful communication.
Verbal communication is a joint activity; however, speech production and comprehension have primarily been analyzed as independent processes within the boundaries of individual brains. Here, we applied fMRI to record brain activity from both speakers and listeners during natural verbal communication. We used the speaker's spatiotemporal brain activity to model listeners' brain activity and found that the speaker's activity is spatially and temporally coupled with the listener's activity. This coupling vanishes when participants fail to communicate. Moreover, though on average the listener's brain activity mirrors the speaker's activity with a delay, we also find areas that exhibit predictive anticipatory responses. We connected the extent of neural coupling to a quantitative measure of story comprehension and find that the greater the anticipatory speaker-listener coupling, the greater the understanding. We argue that the observed alignment of production- and comprehension-based processes serves as a mechanism by which brains convey information.


Compliance in schizophrenia spectrum disorders: the role of clinical pharmacist.
The inability of patients with psychiatric illness to achieve full compliance with treatment during the postdischarge period is a major problem. In this study, our aim was to evaluate whether drug education provided by a clinical pharmacist during discharging period has an effect on compliance. Forty adult patients diagnosed with psychotic disorders were included. A number of scales were used to evaluate the severity of illness, medication adverse effects and compliance. At time of discharge, it was emphasized to patients by a clinical pharmacist that medication compliance was important to prevent exacerbation or hospitalization. Six to eight weeks after discharge, patients were invited to be reevaluated using the same scales as those applied during hospitalization. There was a statistically significant increase in compliance after drug education (P < 0.001). A decrease in the baseline compliance score was associated with an increase in the total number of hospitalizations and the number of psychotropic drugs used. When the risk factors that may affect compliance were evaluated, akathisia was found to have the highest impact on compliance (P = 0.012). It is necessary to take advantage of counseling on medication use and to develop strategies in order to improve compliance in psychiatry.


Audiogram configurations among older adults: prevalence and relation to self-reported hearing problems.
There are only a few population-based epidemiological studies on audiogram configurations among adults. The aim of this study was to investigate the prevalence of different audiogram configurations among older adults. In addition, audiogram configurations among subjects reporting hearing problems were examined. Cross-sectional, population-based, unscreened epidemiological study among older adults. The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. The most prevalent audiogram configuration among men was high-frequency steeply sloping (65.3% left ear, 51.2% right ear) and among women, high-frequency gently sloping (33.0% left ear, 31.5% right ear). There were significantly more flat configurations among women than among men. Unclassified audiograms were common especially among women (17.5%). Subjects reporting hearing difficulties, difficulties in following conversation in noise, or tinnitus, more often had a high-frequency steeply sloping configuration than those not reporting. High-frequency sloping audiogram configurations were common among older adults, and a high-frequency steeply sloping configuration was common among those reporting hearing problems.


Poverty-related and neglected diseases - an economic and epidemiological analysis of poverty relatedness and neglect in research and development.
Economic growth in low- and middle-income countries (LMIC) has raised interest in how disease burden patterns are related to economic development. Meanwhile, poverty-related diseases are considered to be neglected in terms of research and development (R&D). Developing intuitive and meaningful metrics to measure how different diseases are related to poverty and neglected in the current R&D system. We measured how diseases are related to economic development with the income relation factor (IRF), defined by the ratio of disability-adjusted life-years (DALYs) per 100,000 inhabitants in LMIC versus that in high-income countries. We calculated the IRF for 291 diseases and injuries and 67 risk factors included in the Global Burden of Disease Study 2010. We measured neglect in R&D with the neglect factor (NF), defined by the ratio of disease burden in DALYs (as percentage of the total global disease burden) and R&D expenditure (as percentage of total global health-related R&D expenditure) for 26 diseases. The disease burden varies considerably with the level of economic development, shown by the IRF (median: 1.38; interquartile range (IQR): 0.79-6.3). Comparison of IRFs from 1990 to 2010 highlights general patterns of the global epidemiological transition. The 26 poverty-related diseases included in our analysis of neglect in R&D are responsible for 13.8% of the global disease burden, but receive only 1.34% of global health-related R&D expenditure. Within this group, the NF varies considerably (median: 19; IQR: 6-52). The IRF is an intuitive and meaningful metric to highlight shifts in global disease burden patterns. A large shortfall exists in global R&D spending for poverty-related and neglected diseases, with strong variations between diseases.


Sodium fluoride induces changes on proteoglycans synthesized by avian osteoblasts in culture.
The results reported here show that sodium fluoride (NaF) at low concentration (up to 10 microM) increased four times the proliferation rate of avian osteoblasts in culture. Also NaF increases, in a concentration dependent manner, 10 times the alkaline phosphatase activity. However, NaF decreased the incorporation of 35S-sulfate into proteoglycans (PGs) synthesized by osteoblasts (60-65%). Also, we observed that PGs synthesized in the presence of NaF (50 microM) exhibited a higher sensitivity to chondroitinase ABC than PGs synthesized by osteoblasts in the absence of NaF, suggesting an increase in the chondroitin sulfate moieties associated with the core protein of PGs. The modification of glycosaminoglycan (GAG) chains composition was evidenced also by change in the mean charge density of the PGs observed by ion exchange chromatography. Since the ratio of 35SO4/3H-glucosamine incorporated into PGs was similar in the presence and in the absence of NaF (8.2 and 7, respectively), it is not possible to explain differences in mean charge density by changes in the sulfation extent of PGs. No differences were observed in the hydrodynamic size of PG synthesized in the presence of NaF, nor in the hydrodynamic size of the GAG chains. According to these results, we speculate that the stimulatory effect of fluoride on bone mineralization may be mediated, in part, by the changes in the rate of synthesis or in the structural characteristics of bone PGs. The changes produced by fluoride in PGs suggest that these molecules play an inhibitory role in the bone mineralization process.


[New aspects of guidelines for treatment of chronic heart failure (JCS 2010)].
The Japanese Circulation Society (JCS) first published guidelines for the treatment of chronic heart failure (CHF) in 2000 and published revised guidelines in 2005. A great deal of progress has been made in the development of both pharmacologic and nonpharmacologic treatment for CHF in the world. In addition, various data from Japanese clinical trials have been accumulated since first publication. Accordingly, JCS determined to reassess and update guidelines in 2010. Experts in the subject are selected from 13 Japanese organizations including JCS. The guideline recommendations are based on the data from clinical trials and are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches for the diagnosis and management of CHF. The guideline recommendations regarding as cardiac resynchronization therapy (CRT), cardiac rehabilitation, and waon therapy are newly added. Moreover, the effect of gender differences is taken into account in the pharmacologic treatment. Guidelines will be updated with advances in future.


Divergence of trends in US and UK aggregate exergy efficiencies 1960-2010.
National exergy efficiency analysis relates the quality of primary energy inputs to an economy with end useful work in sectoral energy uses such as transport, heat and electrical devices. This approach has been used by a range of authors to explore insights to macroscale energy systems and linkages with economic growth. However, these analyses use a variety of calculation methods with sometimes coarse assumptions, inhibiting comparisons. Therefore, building on previous studies, this paper first contributes toward a common useful work accounting framework, by developing more refined methodological techniques for electricity end use and transport exergy efficiencies. Second, to test this more consistent and granular approach, these advances are applied to the US and UK for 1960 to 2010. The results reveal divergent aggregate exergy efficiencies: US efficiency remains stable at around 11%, while UK efficiency rises from 9% to 15%. The US efficiency stagnation is due to "efficiency dilution", where structural shifts to lower efficiency consumption (e.g., air-conditioning) outweigh device-level efficiency gains. The results demonstrate this is an important area of research, with consequent implications for national energy efficiency policies.


The role of hypoxia in mental development and in the treatment of mental disorders: a review.
The purpose of this review is to trace the trends in studying and applying hypoxia in the field of mental problems. A literature review was conducted using the PubMed database, with a time-frame extending to October 2010. According to the neurodevelopmental model of mental disorders, abnormalities in brain development during pre- and perinatal life lead to psychotic manifestation in adolescence or young adulthood. Studies show that hypoxia plays an important role in almost any risk factor related to brain development in early life: pre-eclampsia, infection/inflammation, hypoxia/ischemia, preterm birth, and asphyxia at birth. The cited data show trends in using hypoxia, especially in the form of intermittent hypoxic training, for the treatment and prevention of mental disorders, and trends in using it for increasing mental capacity in animals.


Congruence between urban adolescent and caregiver responses to questions about the adolescent's asthma.
In clinical and research settings, it is increasingly acknowledged that adolescents may be better positioned than their caregivers to provide information in regard to their own health status, including information related to asthma. Very little is known, however, about the congruence between adolescent and caregiver responses to questions about asthma beyond reports of symptoms. We analyzed data for 215 urban, primarily African-American adolescent-caregiver pairs. Adolescents and caregiver reports concerning the adolescent's asthma-related medical history were moderately correlated and not found to differ at the aggregate level. Correlations between adolescent and caregiver reports of the adolescent's asthma symptoms and functional status were weak, although these differences deteriorated at the aggregate level. Adolescent-caregiver reports of symptoms and functioning were more likely to be in agreement if the adolescent was older, if school personnel were unaware of the child's asthma, and if the adolescent's asthma was classified as mild intermittent. For questions concerning the frequency of hospitalizations, emergency department visits, and physician visits, moderate correlations between adolescent and caregiver responses were noted, although with some differences at the aggregate level. Findings suggest that, when adolescents and their caregivers are asked about the adolescent's asthma in clinical and research settings, the extent to which the two perspectives are likely to agree depends on the type of information sought. Clinicians and researchers may obtain more accurate information if questions about symptoms and functional status are directed toward adolescents.


Improving swallowing outcomes in patients with head and neck cancer using a theory-based pretreatment swallowing intervention package: protocol for a randomised feasibility study.
The incidence of head and neck cancer (HNC) in the UK is rising, with an average of 31 people diagnosed daily. Patients affected by HNC suffer significant short-term and long-term post-treatment morbidity as a result of dysphagia, which affects daily functioning and quality of life (QOL). Pretreatment swallowing exercises may provide additional benefit over standard rehabilitation in managing dysphagia after primary HNC treatments, but uncertainty about their effectiveness persists. This study was preceded by an intervention development phase to produce an optimised swallowing intervention package (SIP). The aim of the current study is to assess the feasibility of this new intervention and research processes within a National Health Service (NHS) setting. A two-arm non-blinded randomised controlled feasibility study will be carried out at one tertiary referral NHS centre providing specialist services in HNC. Patients newly diagnosed with stage III and IV disease undergoing planned surgery and/or chemoradiation treatments will be eligible. The SIP will be delivered pre treatment, and a range of swallowing-related and QOL measures will be collected at baseline, 1, 3 and 6 months post-treatment. Outcomes will test the feasibility of a future randomised controlled trial (RCT), detailing rate of recruitment and patient acceptance to participation and randomisation. Salient information relating to protocol implementation will be collated and study material such as the case report form will be tested. A range of candidate outcome measures will be examined for suitability in a larger RCT. Ethical approval was obtained from an NHS Research Ethics Committee. Findings will be published open access in a peer-reviewed journal, and presented at relevant conferences and research meetings. ISRCTN40215425; Pre-results.


A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection.
Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322 .).


The Evolution of Champion Cross-Country-Skier Training: From Lumberjacks to Professional Athletes.
Competitive cross-country (XC) skiing has traditions extending back to the mid-19th century and was included as a men's event in the first Winter Games in 1924. Since then, tremendous improvements in equipment, track preparation, and knowledge about training have prompted greater increases in XC-skiing speeds than in any other Olympic sport. In response, this commentary focuses on how the training of successful XC skiers has evolved, with interviews and training data from surviving Norwegian world and Olympic XC champions as primary sources. Before 1970, most male champion XC skiers were lumberjacks who ran or skied long distances to and from felling areas while working long days in the woods. In addition, they trained as much as possible, with increased intensity during the autumn, while less work but more ski-specific training and competitions were done during the winter. Until the 1970s, few XC skiers were women, whom coaches believed tolerated less training than men did. Today's XC skiers are less physically active, but the influence of both science and the systematic approaches of former athletes and coaches have gradually taught XC skiers to adopt smarter, more goal-oriented training practices. Although the very high VO2max of world-class XC skiers has remained the same since the 1960s, new events in modern XC skiing have additionally required superior upper-body power, high-speed techniques, and tactical flexibility. These elements also emerge in the training of today's best skiers; women's physiological capacities and training routines especially seem to have improved dramatically.


Difference in the risk of depressive symptoms associated with physical activity in persons with diabetes: Across age, gender, and race/ethnicity.
To investigate the link between depressive symptoms and physical activity (PA) by examining their association across genders, age, and race/ethnicity. Data of the cross-sectional study were from the 2011 and 2015 Behavioral Risk Factor Surveillance System. The Patient Health Questionnaire-8, a well-validated instrument to measure depressive symptoms was used. PA was categorized as active, moderately active, and inactive. A generalized linear model specified with a Poisson distribution and log link was performed to investigate the association between depressive symptoms and PA across population characteristics. No significant association between PA and depressive symptoms between genders and across racial/ethnic groups was found. Persons aged 65 years or older showed a significantly lower risk of depressive symptoms than those below 45 years when physically active (Adjusted Prevalence Ratio (APR) 0.36, 95% CI = 0.16-0.82) and moderately active (APR 0.39, 95% CI = 0.16-0.98). The study included only leisure-time PA. Well-designed surveys that reflect a wider scope of PA are needed to strengthen the analysis. Compared to younger adults, older adults may gain further health benefits in reducing the risk of depressive symptoms by being physically active. Similar health benefits may be gained from PA between genders and between racial/ethnic groups. The different association between PA and depressive symptoms provides practical implications for the effective management of depressive symptoms in persons with diabetes.


Polymorphism of the p38β gene in patients with colorectal cancer.
The p38 mitogen-activated protein kinase (MAPK) signaling pathways have been proposed to participate in the pathological process of cancer by affecting inflammation, proliferation, metastasis and cell survival. A single nucleotide polymorphism (SNP; rs2235356, -1628A→G) in the promoter region of the p38β gene has been proposed as a genetic modifier for colorectal cancer (CRC) in a Chinese population. The present study evaluated the susceptibility of patients possessing this SNP to CRC, in addition to determining its association with clinical parameters in Swedish patients with CRC. Using the LightSNiP genotyping assay, this SNP was screened in 389 patients with CRC and 517 control subjects. No significant difference in the genotype distribution or in the allelic frequencies was identified between the two groups nor was any association identified with the clinical parameters. These findings indicate that the -1628A→G polymorphism of the p38β gene is not significantly associated with a susceptibility to CRC in a Swedish population.


Functional response of U.S. grasslands to the early 21st-century drought.
Grasslands across the United States play a key role in regional livelihood and national food security. Yet, it is still unclear how this important resource will respond to the prolonged warm droughts and more intense rainfall events predicted with climate change. The early 21st-century drought in the southwestern United States resulted in hydroclimatic conditions that are similar to those expected with future climate change. We investigated the impact of the early 21st-century drought on aboveground net primary production (ANPP) of six desert and plains grasslands dominated by C4 (warm season) grasses in terms of significant deviations between observed and expected ANPP. In desert grasslands, drought-induced grass mortality led to shifts in the functional response to annual total precipitation (P(T)), and in some cases, new species assemblages occurred that included invasive species. In contrast, the ANPP in plains grasslands exhibited a strong linear function of the current-year P(T) and the previous-year ANPP, despite prolonged warm drought. We used these results to disentangle the impacts of interannual total precipitation, intra-annual precipitation patterns, and grassland abundance on ANPP, and thus generalize the functional response of C4 grasslands to predicted climate change. This will allow managers to plan for predictable shifts in resources associated with climate change related to fire risk, loss of forage, and ecosystem services.