Mirtazapine: a newer antidepressant.
Mirtazapine is a newer antidepressant that exhibits both noradrenergic and serotonergic activity. It is at least as effective as the older antidepressants for treating mild to severe depression. Sedation is the most common side effect. Although agranulocytosis is the most serious side effect, it is rare (approximately one in 1,000) and usually reversible when the medication is stopped. Mirtazapine is relatively safe in overdose. Many clinicians consider mirtazapine a second-line or even third-line antidepressant to be used when older antidepressants are not tolerated or are ineffective. Physicians who are concerned about the risks of elevated lipid levels and agranulocytosis may choose to reserve mirtazapine as a third-line choice. It is particularly useful in patients who experience sexual side effects from other antidepressants. Mirtazapine is also a good choice in depressed patients with significant anxiety or insomnia. Although mirtazapine has been used successfully in Europe for a number of years, its place in the care of patients with depression in the United States has not yet been established.


Draft genome sequence analysis of a Pseudomonas putida W15Oct28 strain with antagonistic activity to Gram-positive and Pseudomonas sp. pathogens.
Pseudomonas putida is a member of the fluorescent pseudomonads known to produce the yellow-green fluorescent pyoverdine siderophore. P. putida W15Oct28, isolated from a stream in Brussels, was found to produce compound(s) with antimicrobial activity against the opportunistic pathogens Staphylococcus aureus, Pseudomonas aeruginosa, and the plant pathogen Pseudomonas syringae, an unusual characteristic for P. putida. The active compound production only occurred in media with low iron content and without organic nitrogen sources. Transposon mutants which lost their antimicrobial activity had the majority of insertions in genes involved in the biosynthesis of pyoverdine, although purified pyoverdine was not responsible for the antagonism. Separation of compounds present in culture supernatants revealed the presence of two fractions containing highly hydrophobic molecules active against P. aeruginosa. Analysis of the draft genome confirmed the presence of putisolvin biosynthesis genes and the corresponding lipopeptides were found to contribute to the antimicrobial activity. One cluster of ten genes was detected, comprising a NAD-dependent epimerase, an acetylornithine aminotransferase, an acyl CoA dehydrogenase, a short chain dehydrogenase, a fatty acid desaturase and three genes for a RND efflux pump. P. putida W15Oct28 genome also contains 56 genes encoding TonB-dependent receptors, conferring a high capacity to utilize pyoverdines from other pseudomonads. One unique feature of W15Oct28 is also the presence of different secretion systems including a full set of genes for type IV secretion, and several genes for type VI secretion and their VgrG effectors.


Capacity attributes of future urban water management regimes: projections from Australian sustainability practitioners.
Transitioning to more sustainable urban water management is widely accepted as an essential societal objective. While there has been significant progress in developing technical solutions to the challenges faced, numerous barriers remain at the regime level, indicating that further investigation into the regime is required. This paper reports on a social research project aimed at identifying capacity attributes of a more sustainable urban water management regime. Attributes were identified for the administrative and regulatory framework, inter- and intra-organisational and individual regime spheres. Over 125 urban water practitioners specialising in sustainability in Sydney and Melbourne were interviewed to identify the attributes of a more sustainable regime. The attributes reveal that a sustainable urban water management regime emphasises learning, diverse policy tools and institutional arrangements, together with interaction among stakeholders and professional disciplines. The interaction is characterised by respect, trust and mutual understanding. The sustainable regime attributes are compared to the traditional regime and reveal that while progress has been made towards a sustainable regime, additional improvement is required. Attributes identified across multiple regime spheres indicate potential focus areas for capacity building programs or reform efforts to more effectively enable regime change towards sustainable urban water management.


Synthesis, Molecular Packing, and Electrical Properties of New Regioisomeric n-type Semiconducting Molecules with Modification of Alkyl Substituents Position.
We design and synthesize a series of regioisomeric n-type small molecules, which have an identical diketopyrrolopyrrole (DPP) core and 2-(2,3-dihydro-3-oxo-1H-inden-1-ylidene)propanedinitrile (INCN) terminal groups with octyl substituents at different positions. The isomeric structures are confirmed by two-dimensional NMR spectroscopy based on the heteronuclear multiple-bond coupling method. Incorporation of the electron-deficient DPP and strongly electron-withdrawing INCN groups yields deep frontier molecular orbitals with n-type charge-transport properties in solution-processed organic field-effect transistors (OFETs). Interestingly, a minor change in the substitution position of the octyl side chains significantly influences the optoelectronic and morphological properties of the thin film. The polycrystalline morphology of the as-cast films is reorganized differently with thermal annealing depending on the octyl topology, significantly affecting the OFET performance. With thermal treatment at 200 °C, the kinked DPP(EH)-INCNO1 (EH = 2-ethylhexyl) structures transform into single crystalline-like structures, exhibiting a remarkably improved electron mobility up to ∼0.6 cm2V-1 s-1 compared with DPP(EH)-INCNO2 isomers. The more linear DPP(EH or HD)-INCNO2 (HD = 2-hexyldecyl) molecules become more crystalline with thermal treatments, but their polycrystalline packing structures with large grain boundaries are the main reason for their lower electron mobility. When the solubilizing alkyl substituents are selected, careful molecular design is needed, with consideration of both the solubility and intermolecular packing, for optimizing the optoelectronic properties.


Movement reveals scale dependence in habitat selection of a large ungulate.
Ecological processes operate across temporal and spatial scales. Anthropogenic disturbances impact these processes, but examinations of scale dependence in impacts are infrequent. Such examinations can provide important insight to wildlife-human interactions and guide management efforts to reduce impacts. We assessed spatiotemporal scale dependence in habitat selection of mule deer (Odocoileus hemionus) in the Piceance Basin of Colorado, USA, an area of ongoing natural gas development. We employed a newly developed animal movement method to assess habitat selection across scales defined using animal-centric spatiotemporal definitions ranging from the local (defined from five hour movements) to the broad (defined from weekly movements). We extended our analysis to examine variation in scale dependence between night and day and assess functional responses in habitat selection patterns relative to the density of anthropogenic features. Mule deer displayed scale invariance in the direction of their response to energy development features, avoiding well pads and the areas closest to roads at all scales, though with increasing strength of avoidance at coarser scales. Deer displayed scale-dependent responses to most other habitat features, including land cover type and habitat edges. Selection differed between night and day at the finest scales, but homogenized as scale increased. Deer displayed functional responses to development, with deer inhabiting the least developed ranges more strongly avoiding development relative to those with more development in their ranges. Energy development was a primary driver of habitat selection patterns in mule deer, structuring their behaviors across all scales examined. Stronger avoidance at coarser scales suggests that deer behaviorally mediated their interaction with development, but only to a degree. At higher development densities than seen in this area, such mediation may not be possible and thus maintenance of sufficient habitat with lower development densities will be a critical best management practice as development expands globally.


Isolation and sequence analysis of cDNA for rat carboxypeptidase E [EC 188.8.131.52], a neuropeptide processing enzyme.
Carboxypeptidase E (CPE) is the carboxypeptidase B-like enzyme associated with the biosynthesis of numerous peptide hormones and neurotransmitters. This enzyme has been previously purified to homogeneity from bovine tissues, and cDNA clones (non-full length) isolated from a bovine pituitary cDNA library. In the present study, cDNA encoding full-length rat CPE has been isolated and sequenced. Both the nucleotide and amino acid sequences of rat CPE show substantial homology with the bovine sequences. The bovine and rat nucleotide sequences are homologous within the entire coding region, as well as within several portions of the 3'-untranslated region. The predicted amino acid sequence of rat CPE is greater than 90% homologous with the bovine enzyme. Northern blot analyses indicate a single species of CPE mRNA approximately 2100 nucleotides in length to be present in many neural and endocrine tissues. High levels of CPE mRNA are present in rat hypothalamus, hippocampus, midbrain, striatum, and cerebral cortex; and moderate levels are present in the brain stem, cerebellum, heart, adrenal, and eye. Low levels are detected in testis and duodenum, but not in liver or thymus. This tissue-specific expression of CPE mRNA is consistent with the proposed role for this enzyme in the production of numerous peptide hormones and neurotransmitters.


Genetic variation in sperm production.
In boars, the primary determinant of daily sperm production is the number of Sertoli cells, which establishes testicular weight. The only breed comparison of foetal testicular development in boars contrasted two diverse breeds, White composite (WC, Landrace-Yorkshire) with Meishan, a Chinese breed that undergoes pubertal development at a young age and has small testicular size. During the prenatal period, the pattern of change in testicular development is similar in these two breeds with both having their greatest proportion of proliferating Sertoli cells at 90 days of gestation, and with WC boars possessing more Sertoli cells and greater mass of seminiferous tubules during the latter half of gestation. During the first month of life, Meishan boars accumulate Sertoli cells and mass of seminiferous tubules at a greater rate than WC boars, and Meishan boars undergo terminal differentiation of Sertoli cells at a younger age. Postpubertal boars, within each breed and crossbreds of the two breeds, with small testicular size have increased circulating concentrations of follicle-stimulating hormone. No direct breed comparisons of testicular development are apparent for postpubertal boars of other breeds. Accepting the limitations of data reported from different laboratories, Piau boars reach puberty at an older age and have a greater proportion of their testes occupied with seminiferous tubules than Meishan boars; both breeds have small testes. A gene or genes on the X chromosome code for small testicular size in Meishan crossbred boars; genetic determinants of testicular size and sperm production in other breeds remain to be identified.


Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNgamma and IL-4 are involved.
The suppressor of cytokine signaling-1 (SOCS1) is a potent negative regulator of various cytokines and it has been implicated in the regulation of immune responses. However, the role of SOCS1 in inflammatory bowel diseases (IBDs) has not been clarified. To determine the role of SOCS1 in colitis, we generated SOCS1/T-cell receptor alpha (TCRalpha) double knockout (DKO) mice. The depletion of interferon gamma (IFNgamma) and IL-4 was achieved by crossing the DKO mice with IFNgamma knockout (KO) mice and by the administration of anti-IL-4 antibody, respectively. The activation of cytokine-induced transcription factors was determined by Western blotting with phosphorylation-specific antibodies, and the induction of inflammatory factors was measured by reverse-transcription polymerase chain reaction. Much more severe colitis developed in 100% of the DKO mice within 9 weeks of age than in TCRalpha-KO mice. Although the proportion and the activation status of CD4(+) TCRalpha(-)beta(+) T cells in DKO mice were similar to those in TCRalpha-KO mice, signal transducer and activator of transcription 1, nuclear factor kappaB, and their target genes were hyperactivated in infiltrated mononuclear cells and colonic epithelial cells in DKO mice. Cytokine-depletion experiments showed that exacerbated colitis in the DKO mice was dependent on both IFNgamma and IL-4. SOCS1-deficient cells were hypersensitive to IFNgamma, IL-4, and lipopolysaccharides, depending on the target genes. SOCS1 plays an important role in preventing murine colitis by restricting the cytokine signals. SOCS1/TCRalpha DKO mice could be a useful model for investigating human IBD.


Gut symbionts from distinct hosts exhibit genotoxic activity via divergent colibactin biosynthesis pathways.
Secondary metabolites produced by nonribosomal peptide synthetase (NRPS) or polyketide synthase (PKS) pathways are chemical mediators of microbial interactions in diverse environments. However, little is known about their distribution, evolution, and functional roles in bacterial symbionts associated with animals. A prominent example is colibactin, a largely unknown family of secondary metabolites produced by Escherichia coli via a hybrid NRPS-PKS biosynthetic pathway that inflicts DNA damage upon eukaryotic cells and contributes to colorectal cancer and tumor formation in the mammalian gut. Thus far, homologs of this pathway have only been found in closely related Enterobacteriaceae, while a divergent variant of this gene cluster was recently discovered in a marine alphaproteobacterial Pseudovibrio strain. Herein, we sequenced the genome of Frischella perrara PEB0191, a bacterial gut symbiont of honey bees and identified a homologous colibactin biosynthetic pathway related to those found in Enterobacteriaceae. We show that the colibactin genomic island (GI) has conserved gene synteny and biosynthetic module architecture across F. perrara, Enterobacteriaceae, and the Pseudovibrio strain. Comparative metabolomics analyses of F. perrara and E. coli further reveal that these two bacteria produce related colibactin pathway-dependent metabolites. Finally, we demonstrate that F. perrara, like E. coli, causes DNA damage in eukaryotic cells in vitro in a colibactin pathway-dependent manner. Together, these results support that divergent variants of the colibactin biosynthetic pathway are widely distributed among bacterial symbionts, producing related secondary metabolites and likely endowing its producer with functional capabilities important for diverse symbiotic associations.


Inhaler Technique in Asthma: How Does It Relate to Patients' Preferences and Attitudes Toward Their Inhalers?
Correct inhaler technique can increase medication efficacy, reducing both dose and side effects. Patient preference for inhaler device has not been fully explored, and we hypothesized that if patients have a preference and can choose their inhaler, they might be more likely to use it correctly. Our aim was to determine the preferences, attitudes, and perceptions of patients with asthma toward their inhalers, and to evaluate whether any of these factors were related to inhalation technique. Twenty-five patients with asthma (mean age 43.1 years) participated. Qualitative semi-structured interviews and quantitative patient satisfaction and preference questionnaires (PASAPQ) were used to explore patients' preferences, attitudes, and perceptions about their inhalers. Objective inhalation technique assessment was performed. Data were triangulated to identify characteristics that could indicate a relationship between inhaler technique, satisfaction, preference, and decision making. Themes from qualitative interviews were as follows: asthma inhalers and expectations; inhaler preference; characteristics of an ideal inhaler; perceived effectiveness of inhalers; and inhalers and patient decision making. PASAPQ scores indicated that all patients were at least "somewhat satisfied" with their inhalers, regardless of technique. Only 12% of inhalers were used correctly, despite pilot PASAPQ data suggesting that most patients were confident with their technique. The inhaler technique was unlikely to be related to satisfaction, perception of inhaler devices, or choice in device selection. Patients with correct inhaler technique were more aware of their asthma and expressed motivation to achieve optimal asthma control. The majority of the asthmatic patients did not use their inhaler(s) correctly, despite most having confidence in their technique. Patients attributed confidence in their inhaler technique to their belief that their inhaler was effective. Most patients had not been involved in decision making about which inhalation device to use. These findings highlight the lack of understanding of the important role of correct inhaler technique in asthma management.


A Wireless Electro-Optic Headstage With a 0.13- μm CMOS Custom Integrated DWT Neural Signal Decoder for Closed-Loop Optogenetics.
We present a wireless electro-optic headstage that uses a 0.13- μm CMOS custom integrated circuit (IC) implementing a digital neural decoder (ND-IC) for enabling real-time closed-loop (CL) optogenetics. The ND-IC processes the neural activity data using three digital cores: 1) the detector core detects and extracts the action potential (AP) of individual neurons by using an adaptive threshold; 2) the data compression core compresses the detected AP by using an efficient Symmlet-2 discrete wavelet transform (DWT) processor for decreasing the amount of data to be transmitted by the low-power wireless link; and 3) the classification core sorts the compressed AP into separated clusters on the fly according to their wave shapes. The ND-IC encompasses several innovations: 1) the compression core decreases the complexity from O(n 2) to O(n · log(n)) compared to the previous solutions, while using two times less memory, thanks to the use of a new coefficient sorting tree; and 2) the AP classification core reuses both the compressed DWT coefficients to perform implicit dimensionality reduction, which allows for performing intensive signal processing on-chip, while increasing power and hardware efficiency. This core also reuses the signal standard deviation already computed by the AP detector core as threshold for performing automatic AP sorting. The headstage also introduces innovations by enabling a new wireless CL scheme between the neural data acquisition module and the optical stimulator. Our CL scheme uses the AP sorting and timing information produced by the ND-IC for detecting complex firing patterns within the brain. The headstage is also smaller (1.13 cm 3), lighter (3.0 g with a 40 mAh battery) and less invasive than the previous solutions, while providing a measured autonomy of 2h40, with the ND-IC. The whole system and the ND-IC are first validated in vivo in the LD thalamus of a Long-Evans rat, and then in freely-moving CL experiments involving a mouse virally expressing ChR2-mCherry in inhibitory neurons of the prelimbic cortex, and the results show that our system works well within an in vivo experimental setting with a freely moving mouse.


Randomized Trial of Studer Pouch versus T-Pouch Orthotopic Ileal Neobladder in Patients with Bladder Cancer.
The need to prevent reflux in the construction of an orthotopic ileal neobladder is controversial. We designed the USC-STAR trial to determine whether the T-pouch neobladder that included an antireflux mechanism was superior to the Studer pouch in patients with bladder cancer undergoing radical cystectomy. This single center, randomized, controlled trial recruited patients with clinically nonmetastatic bladder cancer scheduled to undergo radical cystectomy with neobladder. Eligible patients were randomly assigned to undergo T-pouch or Studer ileal orthotopic neobladder. Treatment assignment was not masked. The primary end point was change in renal function from baseline to 3 years. The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation was used to calculate the estimated glomerular filtration rate. Between February 2002 and November 2009, 237 patients were randomly assigned to T-pouch ileal orthotopic neobladder and 247 to Studer ileal orthotopic neobladder. Baseline characteristics did not differ between the groups. Between baseline and 3 years the estimated glomerular filtration rate decreased by 6.4 ml/minute/1.73 m(2) in the Studer group and 6.6 ml/minute/1.73 m(2) in the T-pouch group (p=0.35). Multivariable analysis showed that type of ileal orthotopic neobladder was not independently associated with 3-year renal function (p=0.63). However, baseline estimated glomerular filtration rate, age and urinary tract obstruction were independently associated with 3-year decline in renal function. Cumulative risk of urinary tract infection and overall late complications were not different between the groups, but the T-pouch was associated with an increased risk of secondary diversion related surgeries. T-pouch ileal orthotopic neobladder with an antireflux mechanism did not prevent a moderate reduction in renal function observed at 3 years compared to the Studer pouch, but did result in an increase in diversion related secondary surgical procedures.


Tumor control probability modeling for stereotactic body radiation therapy of early-stage lung cancer using multiple bio-physical models.
This work is to analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ2) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. The fits to the clinic data yield consistent results of large α/β ratios of about 20Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1Gy physical dose at isocenters per fraction (⩽5 fractions) to achieve the optimal TCP when compared to the T1 tumors. In conclusion, this systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/β ratios of about 20Gy. The six models predict that a BED (calculated with α/β of 20) of 90Gy is sufficient to achieve TCP⩾95%. Among the models considered, the regrowth model leads to a better fit to the clinical data.


Quantitative metric for assessment of pancreatic ductal adenocarcinoma treatment response in T1-weighted gadolinium-enhanced magnetic resonance imaging.
We theoretically derived a new quantitative metric reflecting the product of T1 signal intensity and contrast media concentration (T1C) using first principles for the signal provided by the gradient echo sequence. This metric can be used with conventional gadolinium contrast-enhanced magnetic resonance imaging (CE-MRI) exams. We used this metric to test our hypothesis that gadolinium enhancement changes with pancreatic ductal adenocarcinoma (PDA) treatment response, and that this metric may differentiate responders from non-responders. Out of 264 initially identified patients, a final total of 35 patients with PDA were included in a retrospective study of responders (n=24) and non-responders (n=11), which used changes in cancer antigen 19-9 (CA 19-9) and tumor size as reference standards. T1C was computed for the pancreatic mass in the arterial, portal venous, and delayed phases in pre-treatment and post-treatment MRIs. Changes in measurements and correlations with treatment response were assessed by repeated measures analysis of variance and paired t-tests. In the treatment responder group, T1C significantly increased in the arterial, portal venous, and delayed phases (P=7.57e-5, P=3.25e-4, P=1.75e-4). In the non-responder group, T1C did not significantly change in any phase (P>0.58). Post-treatment T1C significantly differed between responders and non-responders (P=0.044) by repeated measures analysis of variance. T1C significantly increases in all phases of CE-MRI in responders to treatment, but does not change in non-responders. T1C correlates with treatment response, can be computed from clinical MRI exams, and may be useful as an additional metric to stratify patients undergoing treatment.


Evaluation of lipid peroxidation level in corn dried distillers grains with solubles.
Lipid peroxidation in feed can negatively affect animal health, growth performance, and meat quality. The objective of this study was to determine the lipid peroxidation level in corn dried distillers grains with solubles (DDGS) samples from 31 U.S. ethanol plants and compare results with a corn sample obtained from a corn processing plant. Lipids from each sample were extracted with hexane and analyzed for peroxide value (PV) and thiobarbituric acid reactive substances (TBARS). Peroxide values of DDGS samples ranged from 4.2 to 84.1 milliequivalents (meq)/kg oil (CV = 97.5%). The greatest PV among DDGS samples was 27 times greater than that of the corn sample (3.1 meq/kg oil). The TBARS values for DDGS samples ranged from 1.0 to 5.2 ng malondialdehyde (MDA) equivalents/mg oil (CV = 43.6%). The DDGS sample with the greatest TBARS value was 25 times greater than that of the corn sample (0.2 ng MDA equivalents/mg oil). Color of DDGS samples was measured by Minolta L*, a*, and b*, corresponding to the degree of lightness, redness, and yellowness, respectively. Correlations between PV, TBARS, and color were determined. Values of PV and TBARS were correlated positively (r = 0.81; P < 0.001). Both TBARS and PV were correlated negatively with L* (r = -0.73; P < 0.001, and r = -0.63; P < 0.001, respectively) and b* (r = -0.67; P < 0.001, and r = -0.57; P < 0.001, respectively), which suggests that darker and less yellow-colored DDGS samples were more likely to have a greater lipid peroxidation level, as measured by TBARS and PV, compared with lighter or more yellow-colored DDGS samples. However, a* was not correlated with either PV (P = 0.97) or TBARS (P = 0.66). These results indicate that color can be a preliminary indicator of lipid peroxidation level in DDGS, but a more reliable assessment of peroxidation level is achieved by measuring PV and TBARS.


Shifting research culture to address the mismatch between where trials recruit and where populations with the most disease live: a qualitative study.
Research participation is beneficial to patients, clinicians and healthcare services. There is currently poor alignment between UK clinical research activity and local prevalence of disease. The National Institute of Health Research is keen to encourage chief investigators (CIs) to base their research activity in areas of high patient need, to support equity, efficiency and capacity building. We explored how CIs choose sites for their trials and suggest ways to encourage them to recruit from areas with the heaviest burden of disease. Qualitative, semi-structured telephone interviews with a purposive sample of 30 CIs of ongoing or recently completed multi-centre trials, all of which were funded by the UK National Institute of Health Research. CIs want to deliver world-class trials to time and budget. Approaching newer, less research-active sites appears risky, potentially compromising trial success. CIs fear that funders may close the trial if recruitment (or retention) is low, with potential damage to their research reputation. We consider what might support a shift in CI behaviour. The availability of 'heat maps' showing the disparity between disease prevalence and current research activity will help to inform site selection. Embedded qualitative research during trial set up and early, appropriate patient and public involvement and engagement can provide useful insights for a more nuanced and inclusive approach to recruitment. Public sector funders could request more granularity in recruitment reports and incentivise research activity in areas of greater patient need. Accounts from the few CIs who had 'broken the mould' suggest that nurturing new sites can be very successful in terms of efficient recruitment and retention. While improvements in equity and capacity building certainly matter to CIs, most are primarily motivated by their commitment to delivering successful trials. Highlighting the benefits to trial delivery is therefore likely to be the best way to encourage CIs to focus their research activity in areas of greatest need.


Evaluating lifestyle and health-related characteristics of older adults with co-occurring depressive symptoms and cardiometabolic abnormalities.
Comorbid depression and cardiometabolic abnormalities might represent an important subgroup of depression. The aim of the present study was to evaluate lifestyle and health-related characteristics of individuals with both depressive symptoms and cardiometabolic abnormalities. Data were from the English Longitudinal Study of Ageing. The sample was comprised of 5365 adults aged 50-80 years. High depressive symptoms were based on the eight-item Center for Epidemiologic Studies - Depression scale. Cardiometabolic abnormalities were defined as having ≥3 cardiometabolic risk factors (hypertension, impaired glycemic control, systemic inflammation, low high-density lipoprotein cholesterol, hypertriglyceridemia, and central obesity). Four groups were created based on Center for Epidemiologic Studies - Depression scores and cardiometabolic abnormalities: those with (i) comorbid depressive symptoms and cardiometabolic abnormalities (DCM); (ii) depressive symptoms only (DnoCM); (iii) cardiometabolic abnormalities only; and (iv) neither depressive symptoms nor cardiometabolic abnormalities. Lifestyle and health-related characteristics of the four groups were compared using chi-square tests. A modified Poisson regression analysis was performed to compare the DCM and the DnoCM groups with respect to lifestyle and health-related characteristics. Those in the DCM group were significantly less physically active (p = 0.003), had poorer self-rated health (p < 0.001), had lower income (p = 0.001), and were more likely to be retired (p < 0.001) than those in the DnoCM group. The pattern of results remained after controlling for other lifestyle and health-related factors. These results provide support for a cardiometabolic subgroup of depression that is associated with physical inactivity, poorer self-rated health, lower income, and retirement. Copyright © 2015 John Wiley & Sons, Ltd.


Parasitic infections in live freshwater tropical fishes imported to Korea.
We examined 15 species of ornamental tropical fishes originating from Southeast Asia to determine the cause of losses among 8 fish farms in Korea. A total of 351 individuals belonging to 5 different families (1 species of Characidae, 6 of Cichlidae, 3 of Cyprinidae, 1 of Heleostomatidae, and 4 of Poecilidae) were collected for the purpose of detecting metazoan and protozoan parasites. Parasites were fixed and stained using routine methods, and identified. We found 3 ciliates, 2 monogeneans, 1 nematode, and 1 copepod from 7 host species. Of these, Ichthyophthirius multifiliis was the most common parasite in our study, and together with Trichodina sp., caused mass mortality of Sumatra barb Puntius tetrazona at 1 farm. We also found Camallanus cotti and Tetrahymena corlissi from guppies Poecilia reticulata, both for the first time in Korea. Farmers consider these 2 pathogens to be the most serious ones in Korea. Gussevia asota from oscar Astronotus ocellatus, and Gyrodactylus bullatarudis from platy Xiphophorus maculatus were also found in Korea for the first time. We believe that appropriate quarantine practices for tropical ornamental fishes should be introduced because the failure to require and implement quarantines has already resulted in the accidental introduction of exotic parasites to fish farms, and because these parasites can cause further economic losses if they become established in the wild.


Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours.
The implementation of personalised medicine in childhood cancers has been limited by a lack of clinically validated multi-target sequencing approaches specific for paediatric solid tumours. In order to support innovative clinical trials in high-risk patients with unmet need, we have developed a clinically relevant targeted sequencing panel spanning 311 kb and comprising 78 genes involved in childhood cancers. A total of 132 samples were used for the validation of the panel, including Horizon Discovery cell blends (n=4), cell lines (n=15), formalin-fixed paraffin embedded (FFPE, n=83) and fresh frozen tissue (FF, n=30) patient samples. Cell blends containing known single nucleotide variants (SNVs, n=528) and small insertion-deletions (indels n=108) were used to define panel sensitivities of ≥98% for SNVs and ≥83% for indels [95% CI] and panel specificity of ≥98% [95% CI] for SNVs. FFPE samples performed comparably to FF samples (n=15 paired). Of 95 well-characterised genetic abnormalities in 33 clinical specimens and 13 cell lines (including SNVs, indels, amplifications, rearrangements and chromosome losses), 94 (98.9%) were detected by our approach. We have validated a robust and practical methodology to guide clinical management of children with solid tumours based on their molecular profiles. Our work demonstrates the value of targeted gene sequencing in the development of precision medicine strategies in paediatric oncology.


Comparing the Pathway to Success in European Countries Competing in the Swimming World Championships.
Purpose: This study aimed to compare the performance progression model of the European countries that participated in the World Championships (WCs) from 2006 to 2017. Data from all championships were compared between the top five (1-5) and the next five (6-10) countries on the medal table. The study also identifies the ages of peak performance in senior swimmers, the annual ratio of progression and the effect of junior performance on senior success by these groups of countries. We hypothesized that: (1) countries with swimmers achieving better performances at the Junior WCs would also be higher in the medal ranking at the Senior WCs and (2) a higher annual performance progression in their swimmers increases the chances of countries being ranked in the top 5 at the Senior World Championships. Methods: Participant's data from all Junior and Senior WCs between 2006 and 2017 were obtained from FINA. The final, filtered database included 629 swimmers after removing those participating only in the Junior WCs and selecting swimmers from the top 10 countries. One-way ANOVA, F test, and decision tree methods were used to examine differences between the top (1-5) and the next best (6-10) countries on the medal table for first participation age, annual progress, and best-time in junior and senior championships. Results: There was no difference (p = 0.492 and p = 0.97) between 1-5 and 6-10 ranked countries for best senior time and annual progression, respectively. Countries ranked in the top 5 at the Senior WCs had swimmers with faster times at the Junior WCs (p > 0.001). Decision tree analysis found that best-time at the Junior WC had the greatest explanatory capacity (94%). Conclusion: European countries with swimmers who perform best at the Junior WCs are also likely to be in the top 5 countries that win medals at the Senior WCs.


Evidence-based guidelines for empirical therapy of neutropenic fever in Korea.
Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3-5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers.


Context-dependent spindle pole focusing.
The formation of a robust, bi-polar spindle apparatus, capable of accurate chromosome segregation, is a complex process requiring the co-ordinated nucleation, sorting, stabilization and organization of microtubules (MTs). Work over the last 25 years has identified protein complexes that act as functional modules to nucleate spindle MTs at distinct cellular sites such as centrosomes, kinetochores, chromatin and pre-existing MTs themselves. There is clear evidence that the extent to which these different MT nucleating pathways contribute to spindle mass both during mitosis and meiosis differs not only between organisms, but also in different cell types within an organism. This plasticity contributes the robustness of spindle formation; however, whether such plasticity is present in other aspects of spindle formation is less well understood. Here, we review the known roles of the protein complexes responsible for spindle pole focusing, investigating the evidence that these, too, act co-ordinately and differentially, depending on cellular context. We describe relationships between MT minus-end directed motors dynein and HSET/Ncd, depolymerases including katanin and MCAK, and direct minus-end binding proteins such as nuclear-mitotic apparatus protein, ASPM and Patronin/CAMSAP. We further explore the idea that the focused spindle pole acts as a non-membrane bound condensate and suggest that the metaphase spindle pole be treated as a transient organelle with context-dependent requirements for function.


Fluctuating drowsiness following cardiac catheterisation: artery of Percheron ischaemic stroke causing bilateral thalamic infarcts.
An 81-year-old man underwent cardiac catheterisation to investigate breathlessness and left ventricular impairment of unknown cause. He had unobstructed coronary arteries. Immediately following the procedure, he became suddenly unresponsive with vertical gaze palsy, anisocoria and bilateral upgoing plantar responses. He made a rapid recovery to his premorbid state 25 min later with no residual focal neurological signs. He then had multiple unresponsive episodes, interspaced with complete resolution of symptoms and neurological signs. MRI of the brain identified bilateral medial thalamic infarcts and midbrain infarcts, consistent with an artery of Percheron territory infarction. By the time the diagnosis was reached, the thrombolysis window had elapsed. The unresponsive episodes diminished with time and the patient was discharged to inpatient rehabilitation. At 6-month review after the episode, the patient has a degree of progressive cognitive impairment.


Validation of a Hypothesis: Colonization of Black Smokers by Hyperthermophilic Microorganisms.
Newly erupted black smokers (hydrothermal vent chimneys) are sterile during their formation, but house hyperthermophilic microorganisms in substantial amounts in later stages. No direct experimental data exist by which mechanisms hyperthermophiles colonize newly erupted black smokers, but a scenario was proposed recently how this might happen. Here we combine high temperature light microscopy with electron microscopy to show that two hyperthermophilic Archaea, namely Pyrococcus furiosus and Methanocaldococcus villosus are able to adhere onto authentic black smoker material (BSM). We especially are able to directly observe the adhesion process via video recordings taken at high temperatures. These data validate the hypothesis that hyperthermophiles are transferred by serendipitous water currents to the outside of newly formed black smokers and react within seconds to the there prevailing high temperatures by very fast movements. They scan the surface of the hydrothermal chimneys via a much slower zigzag seek-movement and adhere via their flagella at a suitable place, building up biofilms.


Effectiveness of mirror therapy on upper limb function, activities of daily living, and depression in post-stroke depression patients.
This study aims to investigate the effects of mirror therapy (MT) on upper limb function, activities of daily living (ADLs), and depression in post-stroke depression patients. Between November 2018 and December 2019, a total of 60 post-stroke patients (33 males, 27 females; mean age: 58.45±11.13 years; range, 35 to 88 years) were included. The patients were randomly divided into either the cosntrol group (n=30) or the MT group (n=30). Regular occupational therapy was provided for the control group (two times per day for 30 min per session, five times per week over four weeks). Occupational therapy and MT were used to treat patients in the mirror group (one 30 min session once per day, five times per week over four weeks). Motor function (Fugl-Meyer Assessment of the Upper Extremity, FMA-UE), ADL (Modified Barthel Index, MBI) and depression (17-item Hamilton Depression Scale, HAMD-17) were used to evaluate the treatment outcomes. Before treatment, the mean HAMD-17, FMA-UE, and MBI scores showed no significant difference between the two groups (p>0.05). After treatment, the mirror group exhibited more significant improvements than the control group in terms of the mean HAMD-17, FM-UE, and MBI (p<0.05). After four weeks, the mean FMA-UE and MBI scores revealed more significant improvements than the baseline scores in the control group (p<0.01). The mean HAMD-17, FMA-UE, and MBI scores showed more significant improvements than the baseline scores in the MT group (p<0.001). Based on these results, MT can effectively improve motor function, ADLs, and depression in post-stroke depression patients. The curative effectiveness of MT seems to be more prominent than the regular occupational therapy.


Factors influencing responses to alarm pheromone by larvae of invasive cane toads, Bufo marinus.
If pheromonal communication systems of invasive species differ from those of native biota, it may be possible to control the invader by exploiting that difference. When injured, the larvae of cane toads, Bufo marinus, an invasive species of major concern in tropical Australia, produce species-specific chemical cues that alert conspecific tadpoles to danger. Repeated exposure to the alarm chemical reduces tadpole survival rates and body sizes at metamorphosis and, thus, could help control toad populations. To evaluate the feasibility of this approach, we need to know how the intensity of toad tadpole response to the alarm chemical is affected by factors such as water temperature, time of day, larval stage and feeding history, geographic origin of the tadpoles, and habituation. Information on these topics may enable us to optimize deployment, so that tadpoles encounter pheromone at the times and places that confer maximum effect. In our studies, tadpole density, nutritional state, larval stage, and geographic origin had little effect on the intensity of the alarm response, but tadpoles reacted most strongly in higher water temperatures and during daylight hours. Repeated, once-daily exposure to pheromone did not induce habituation, but repeated exposure at 15-min intervals did not elicit further responses after 2 h total exposure. The insensitivity of response to most factors tested means that the effectiveness of the pheromone as a control agent should be relatively robust.


Roux-en-Y Gastric Bypass and Antipsychotic Therapeutic Drug Monitoring: Two Cases.
Many patients with psychiatric conditions undergo bariatric surgery. The Roux-en-Y gastric bypass (RYGB) procedure alters medication pharmacokinetic properties and may have significant impact on drug response. Our report is the first to describe atypical antipsychotic therapeutic drug monitoring in patients who have undergone RYGB. The first patient is a 53-year-old female with a stable psychiatric condition undergoing a laparoscopic RYGB. Her medications prior and following the procedure include bupropion, fluvoxamine, lurasidone, methylphenidate, oxcarbazepine, and verapamil. A concentration steady-state lurasidone concentration obtained prior to the procedure was 20 ng/mL and returned at 8.1 ng/mL, 29 days after surgery. The second patient is a 42-year-old female psychiatric inpatient who had previously undergone an RYGB procedure. Medications on admission included phenytoin, oxcarbazepine, risperidone, and venlafaxine. The patient was believed to be a good candidate for a long-acting antipsychotic and paliperidone was chosen. After concentration-steady-state on 6 mg oral paliperidone, a 23.5-hour trough level was drawn. The patient was noted to be improved on the oral paliperidone, the paliperidone long-acting injection was given, and the patient was discharged. After discharge, the paliperidone concentration returned very low at 1.1 ng/mL. We describe the contributions of drug-drug interactions, medication release mechanisms, and food coadministration that may have affected our therapeutic drug monitoring. Our therapeutic drug monitoring results need to be replicated prior to use in the general population but suggest that oral extended-release drug formulations are particularly poor choices and that nonoral antipsychotic formulations may be preferred in some patients who have undergone RYBG.


Obstructive sleep apnea.
Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive collapse of the pharyngeal airway during sleep. Control of pharyngeal patency is a complex process relating primarily to basic anatomy and the activity of many pharyngeal dilator muscles. The control of these muscles is regulated by a number of processes including respiratory drive, negative pressure reflexes, and state (sleep) effects. In general, patients with OSA have an anatomically small airway the patency of which is maintained during wakefulness by reflex-driven augmented dilator muscle activation. At sleep onset, muscle activity falls, thereby compromising the upper airway. However, recent data suggest that the mechanism of OSA differs substantially among patients, with variable contributions from several physiologic characteristics including, among others: level of upper airway dilator muscle activation required to open the airway, increase in chemical drive required to recruit the pharyngeal muscles, chemical control loop gain, and arousal threshold. Thus, the cause of sleep apnea likely varies substantially between patients. Other physiologic mechanisms likely contributing to OSA pathogenesis include falling lung volume during sleep, shifts in blood volume from peripheral tissues to the neck, and airway edema. Apnea severity may progress over time, likely due to weight gain, muscle/nerve injury, aging effects on airway anatomy/collapsibility, and changes in ventilatory control stability.


LKB1 regulates polarity remodeling and adherens junction formation in the Drosophila eye.
The serine-threonine kinase LKB1 regulates cell polarity from Caenorhabditis elegans to man. Loss of lkb1 leads to a cancer predisposition, known as Peutz-Jeghers Syndrome. Biochemical analysis indicates that LKB1 can phosphorylate and activate a family of AMPK- like kinases, however, the precise contribution of these kinases to the establishment and maintenance of cell polarity is still unclear. Recent studies propose that LKB1 acts primarily through the AMP kinase to establish and/or maintain cell polarity. To determine whether this simple model of how LKB1 regulates cell polarity has relevance to complex tissues, we examined lkb1 mutants in the Drosophila eye. We show that adherens junctions expand and apical, junctional, and basolateral domains mix in lkb1 mutants. Surprisingly, we find LKB1 does not act primarily through AMPK to regulate cell polarity in the retina. Unlike lkb1 mutants, ampk retinas do not show elongated rhabdomeres or expansion of apical and junctional markers into the basolateral domain. In addition, nutrient deprivation does not reveal a more dramatic polarity phenotype in lkb1 photoreceptors. These data suggest that AMPK is not the primary target of LKB1 during eye development. Instead, we find that a number of other AMPK-like kinase, such as SIK, NUAK, Par-1, KP78a, and KP78b show phenotypes similar to weak lkb1 loss of function in the eye. These data suggest that in complex tissues, LKB1 acts on an array of targets to regulate cell polarity.


Heterologous gln/asn-rich proteins impede the propagation of yeast prions by altering chaperone availability.
Prions are self-propagating conformations of proteins that can cause heritable phenotypic traits. Most yeast prions contain glutamine (Q)/asparagine (N)-rich domains that facilitate the accumulation of the protein into amyloid-like aggregates. Efficient transmission of these infectious aggregates to daughter cells requires that chaperones, including Hsp104 and Sis1, continually sever the aggregates into smaller "seeds." We previously identified 11 proteins with Q/N-rich domains that, when overproduced, facilitate the de novo aggregation of the Sup35 protein into the [PSI(+)] prion state. Here, we show that overexpression of many of the same 11 Q/N-rich proteins can also destabilize pre-existing [PSI(+)] or [URE3] prions. We explore in detail the events leading to the loss (curing) of [PSI(+)] by the overexpression of one of these proteins, the Q/N-rich domain of Pin4, which causes Sup35 aggregates to increase in size and decrease in transmissibility to daughter cells. We show that the Pin4 Q/N-rich domain sequesters Hsp104 and Sis1 chaperones away from the diffuse cytoplasmic pool. Thus, a mechanism by which heterologous Q/N-rich proteins impair prion propagation appears to be the loss of cytoplasmic Hsp104 and Sis1 available to sever [PSI(+)].


An outbreak of methicillin-resistant Staphylococcus aureus infection in patients of a pediatric intensive care unit and high carriage rate among health care workers.
Methicillin-resistant Staphylococcus aureus (MRSA) has been the leading cause of nosocomial infections in many hospitals. To investigate the impact of carriage by health care workers (HCWs) on patient transmission, surveillance culture was performed following an outbreak of MRSA in a pediatric intensive care unit (PICU). Isolates from 61 HCWs and 10 environmental sites were collected. Pulsed-field gel electrophoresis (PFGE) and antibiogram analysis were performed to determine the clonal relationship between isolates and potential routes of transmission. The overall carriage rate of HCWs was 67.2% (41/61) for S. aureus and 26.2% (16/61) for MRSA. One MRSA was isolated from the 10 environmental sites sampled. Two major MRSA clusters were identified based on the PFGE patterns. Isolates with indistinguishable PFGE patterns (pulsotype A) were found in all patient isolates from the outbreak, from several HCWs plus the environmental isolate; all were resistant to ciprofloxacin, clindamycin, erythromycin, gentamicin, tetracycline, and trimethoprim-sulfamethoxazole. Interestingly, the isolate from a patient who had prolonged hospitalization in PICU had PFGE patterns (pulsotype B) distinct from the strains involved in the outbreak. This strain was susceptible to ciprofloxacin and trimethoprim-sulfamethoxazole, and was also found in several HCWs. Thus, there appeared to be 2 main MRSA clones circulating in the PICU of our hospital. Person-to-person and environment-to-person (or vice versa) transmissions are documented in this study. Strict hand washing before and after patient contact must be enforced and closely monitored, as it is the principal preventive measure in containing the spread of MRSA. To prevent the emergence of vancomycin-resistant MRSA and the further transmission of multidrug-resistant organisms, implementation of periodic and routine active surveillance cultures as part of infection control measures may also be evaluated.


Controlling conflict from interfering long-term memory representations.
Remembering is more than an activation of a memory trace. As retrieval cues are often not uniquely related to one specific memory, cognitive control should come into play to guide selective memory retrieval by focusing on relevant while ignoring irrelevant information. Here, we investigated, by means of EEG and fMRI, how the memory system deals with retrieval interference arising when retrieval cues are associated with two material types (faces and spatial positions), but only one is task-relevant. The topography of slow EEG potentials and the fMRI BOLD signal in posterior storage areas indicated that in such situations not only the relevant but also the irrelevant material becomes activated. This results in retrieval interference that triggers control processes mediated by the medial and lateral PFC, which are presumably involved in biasing target representations by boosting the task-relevant material. Moreover, memory-based conflict was found to be dissociable from response conflict that arises when the relevant and irrelevant materials imply different responses. The two types of conflict show different activations in the medial frontal cortex, supporting the claim of domain-specific prefrontal control systems.


Risk factors for central line-associated bloodstream infection in patients with major burns and the efficacy of the topical application of mupirocin at the central venous catheter exit site.
The aim of this study was to evaluate the efficacy of the topical administration of mupirocin and other practices in central venous catheter (CVC) care to prevent central line-associated bloodstream infections (CLABSI) in patients with major burns. Patients with major burns admitted to a burn ICU were divided into four groups and disinfected at the CVC exit site with single povidone iodine (PVP-I) or PVP-I plus topical mupirocin ointment three times a day or once a day, respectively. The bacterial colonization of the skin at the CVC exit site and CVC tips and the incidence of CLABSI were recorded, and the risk factors were analyzed. Administering mupirocin (RR=0.316, p=0.001), increasing the frequency of insertion-site care (RR=0.604, p=0.008), and avoiding cannulation at the burn site (RR=0.148, p<0.001) reduced skin colonization at the CVC insertion site. Topical administration of mupirocin significantly reduces both the bacterial colonization rate at CVC tips (RR=0.316, p=0.001) and the incidence of CLABSI (5.3 vs. 29.1 per 1000 catheter days, p<0.001). Mupirocin is effective in the prophylaxis of CLABSI. Other CVC care practices were also found to affect the level of bacterial colonization, but their efficacy in preventing CLABSI needs to be evaluated further.


Signalling crosstalk in plants: emerging issues.
The Oxford English Dictionary defines crosstalk as 'unwanted transfer of signals between communication channels'. How does this definition relate to the way in which we view the organization and function of signalling pathways? Recent advances in the field of plant signalling have challenged the traditional view of a signalling transduction cascade as isolated linear pathways. Instead the picture emerging of the mechanisms by which plants transduce environmental signals is of the interaction between transduction chains. The manner in which these interactions occur (and indeed whether the transfer of these signals is 'unwanted' or beneficial) is currently the topic of intense research.


Imaging tripartite synapses using super-resolution microscopy.
Astroglia are vital facilitators of brain development, homeostasis, and metabolic support. In addition, they are also essential to the formation and regulation of synaptic circuits. Due to the extraordinary complex, nanoscopic morphology of astrocytes, the underlying cellular mechanisms have been poorly understood. In particular, fine astrocytic processes that can be found in the vicinity of synapses have been difficult to study using traditional imaging techniques. Here, we describe a 3D three-colour super-resolution microscopy approach to unravel the nanostructure of tripartite synapses. The method is based on the SMLM technique direct stochastic optical reconstruction microscopy (dSTORM) which uses conventional fluorophore-labelled antibodies. This approach enables reconstructing the nanoscale localisation of individual astrocytic glutamate transporter (GLT-1) molecules surrounding presynaptic (bassoon) and postsynaptic (Homer1) protein localisations in fixed mouse brain sections. However, the technique is readily adaptable to other types of targets and tissues.


Nocturnal masseter EMG activity of healthy subjects in a natural environment.
Facial pain of patients with craniomandibular disorders might be caused by muscle overload. However, the activity of masticatory muscles of healthy individuals is still unknown. The aim of this study was therefore a first attempt to clarify this question by recording the masseter muscle activity of healthy subjects during sleep by means of portable recorders. The study was performed on 21 healthy subjects selected after telephone and questionnaire screenings and clinical examination from among randomly selected inhabitants of Zürich. The masseter EMG was recorded during seven nights in each subject's natural environment with the electrodes in reproducible position. The signal was analyzed for number, amplitude, and duration of contraction periods defined as signal portions above a threshold which could contain sub-threshold signal portions shorter than the standby time of 5 sec. The signal amplitude was expressed in percent of the amplitude recorded during maximum voluntary clenches (%MVC). An average of 71.9 +/- 28.7 contraction episodes per night (men, 74.7 +/- 30.1; women, 65.0 +/- 23.8; p = 0.043), i.e., of 10.5 +/- 3.8 per hour (men, 11.0 +/- 4.0; women, 9.3 +/- 3.0; p = 0.005), was found. The average mean amplitude was 26.2 +/- 6.4% MVC (men, 27.0 +/- 6.8; women, 24.4 +/- 4.5; p = 0.009). The duration of the episodes had a mode of 0.5 sec, and the group mean of the integral of the amplitude over time was 123.7 +/- 157.9% MVC (men, 138.9 +/- 184.0; women, 85.9 +/- 28.2; p = 0.005). Healthy subjects showed intermittent periods of masseter activity during sleep which, on average, were of rather low intensity and short duration.


Embodiment in attitudes, social perception, and emotion.
Findings in the social psychology literatures on attitudes, social perception, and emotion demonstrate that social information processing involves embodiment, where embodiment refers both to actual bodily states and to simulations of experience in the brain's modality-specific systems for perception, action, and introspection. We show that embodiment underlies social information processing when the perceiver interacts with actual social objects (online cognition) and when the perceiver represents social objects in their absence (offline cognition). Although many empirical demonstrations of social embodiment exist, no particularly compelling account of them has been offered. We propose that theories of embodied cognition, such as the Perceptual Symbol Systems (PSS) account (Barsalou, 1999), explain and integrate these findings, and that they also suggest exciting new directions for research. We compare the PSS account to a variety of related proposals and show how it addresses criticisms that have previously posed problems for the general embodiment approach.


Shape-switching microrobots for medical applications: the influence of shape in drug delivery and locomotion.
The effect of dynamic shape switching of hydrogel bilayers on the performance of self-folding microrobots is investigated for navigation in body orifices and drug release on demand. Tubular microrobots are fabricated by coupling a thermoresponsive hydrogel nanocomposite with a poly(ethylene glycol)diacrylate (PEGDA) layer, to achieve spontaneous and reversible folding from a planar rectangular structure. Graphene oxide (GO) or silica-coated superparamagnetic iron oxide nanoparticles are dispersed in the thermoresponsive hydrogel matrix to provide near-infrared (NIR) light sensitivity or magnetic actuation, respectively. The NIR light-responsive microstructures are fabricated for triggered drug delivery while magnetic nanocomposite-based microrobots are used to analyze the role of shape in locomotion. Experimental analysis and computational simulations of tubular structures show that drug release and motility can be optimized through controlled shape change. These concepts are finally applied to helical microrobots to show a possible way to achieve autonomous behavior.


Impacts of rising tropospheric ozone on photosynthesis and metabolite levels on field grown soybean.
The response of leaf photosynthesis and metabolite profiles to ozone (O3) exposure ranging from 37 to 116 ppb was investigated in two soybean cultivars Dwight and IA3010 in the field under fully open-air conditions. Leaf photosynthesis, total non-structural carbohydrates (TNC) and total free amino acids (TAA) decreased linearly with increasing O3 levels in both cultivars with average decrease of 7% for an increase in O3 levels by 10 ppb. Ozone interacted with developmental stages and leaf ages, and caused higher damage at later reproductive stages and in older leaves. Ozone affected yield mainly via reduction of maximum rate of Rubisco carboxylation (Vcmax) and maximum rates of electron transport (Jmax) as well as a shorter growing season due to earlier onset of canopy senescence. For all parameters investigated the critical O3 levels (∼50 ppb) for detectable damage fell within O3 levels that occur routinely in soybean fields across the US and elsewhere in the world. Strong correlations were observed in O3-induced changes among yield, photosynthesis, TNC, TAA and many metabolites. The broad range of metabolites that showed O3 dose dependent effect is consistent with multiple interaction loci and thus multiple targets for improving the tolerance of soybean to O3.


Flow diagnostics essential code: a simple and brief format for the summary of leukemia phenotyping.
Flow cytometry is a valuable part in the routine diagnostics of acute leukemia (AL). Although internationally recognized definitions of main AL subsets are available, there is currently no consensus format for the short summary of clinical flow cytometry reports. Since clinical reports are too long for most database purposes, there is a need for a standardized format of their short summaries. The Associazione Italiana Ematologia Oncologia Pediatrica--Berlin Frankfurt Muenster (AIEOP-BFM) Flow Network that encompasses reference diagnostics laboratories in Australia, Austria, Czechia, Germany, Israel, Italy, and Switzerland have designed a pro-forma for the summary of flow cytometry results in the diagnosis of leukemia. The process involved several meetings and other communications, during which the group established a consensus on the essentials that lead to the diagnostic conclusions in childhood AL. The "Flow Diagnostics Essential (FDE) Code" is a result from an agreement within the AIEOP-BFM Flow Network. In a standardized format, it reports the extent of the infiltration by a malignant clone, followed by description antigen expression as strong, weak or negative, and a diagnostic conclusion. A consensus brief format (the "FDE Code") has been designed as a brief summary of the diagnostic immunophenotype of childhood AL. It is also applicable for the diagnostic investigation of other malignancies by flow cytometry. The FDE code may be included in the final clinical report and/or used in the setting of a multicenter clinical trial database.


Biomechanical analysis of pedicle screw instrumentation systems in a corpectomy model.
Five different spinal implants, all using pedicle screw attachment to vertebrae, were examined in a one above/one below corpectomy model, to determine 1) the relative stiffness of each construct, 2) the stresses generated in the implant during loading, and 3) the relative fatigue susceptibility of each implant. Results indicated that the relative axial and torsional stiffnesses were similar for all the implants tested (DKS/Zielke, VSP/Steffee, AO Fixator Interne, Luque plate, AO Notched plate). Hence, each of the devices impart approximately the same stability to the spine in this highly unstable model. Stresses measured at the root of the pedicle screws were found to exceed the endurance limit of stainless steel in those systems in which the pedicle screws were attached rigidly to the plates (VSP/Steffee, AO Fixator Interne). Good agreement was found between the measured stresses and stresses derived from static calculations. Comparisons between the stresses from each implant gave a relative measure of fatigue susceptibility that was validated by in vitro cyclic testing. Implants with stresses exceeding the endurance limit failed during the cyclic test.


Rationale for the clinical application of flow cytometry in patients with myelodysplastic syndromes: position paper of an International Consortium and the European LeukemiaNet Working Group.
An international working group within the European LeukemiaNet gathered, aiming to determine the role of flow cytometry (FC) in myelodysplastic syndromes (MDS). It was agreed that FC has a substantial application in disease characterization, diagnosis and prognosis. FC may also be useful in predicting treatment responses and monitoring novel and standard therapeutic regimens. In this article the rationale is discussed that flow cytometry should be integrated as a part of diagnostic and prognostic scoring systems in MDS.


Exploring individual- to population-level impacts of disease on coral reef sponges: using spatial analysis to assess the fate, dynamics, and transmission of Aplysina Red Band Syndrome (ARBS).
Marine diseases are of increasing concern for coral reef ecosystems, but often their causes, dynamics and impacts are unknown. The current study investigated the epidemiology of Aplysina Red Band Syndrome (ARBS), a disease affecting the Caribbean sponge Aplysina cauliformis, at both the individual and population levels. The fates of marked healthy and ARBS-infected sponges were examined over the course of a year. Population-level impacts and transmission mechanisms of ARBS were investigated by monitoring two populations of A. cauliformis over a three year period using digital photography and diver-collected data, and analyzing these data with GIS techniques of spatial analysis. In this study, three commonly used spatial statistics (Ripley's K, Getis-Ord General G, and Moran's Index) were compared to each other and with direct measurements of individual interactions using join-counts, to determine the ideal method for investigating disease dynamics and transmission mechanisms in this system. During the study period, Hurricane Irene directly impacted these populations, providing an opportunity to assess potential storm effects on A. cauliformis and ARBS. Infection with ARBS caused increased loss of healthy sponge tissue over time and a higher likelihood of individual mortality. Hurricane Irene had a dramatic effect on A. cauliformis populations by greatly reducing sponge biomass on the reef, especially among diseased individuals. Spatial analysis showed that direct contact between A. cauliformis individuals was the likely transmission mechanism for ARBS within a population, evidenced by a significantly higher number of contact-joins between diseased sponges compared to random. Of the spatial statistics compared, the Moran's Index best represented true connections between diseased sponges in the survey area. This study showed that spatial analysis can be a powerful tool for investigating disease dynamics and transmission in a coral reef ecosystem.


Chromosome-level genome assembly reveals homologous chromosomes and recombination in asexual rotifer Adineta vaga.
Bdelloid rotifers are notorious as a speciose ancient clade comprising only asexual lineages. Thanks to their ability to repair highly fragmented DNA, most bdelloid species also withstand complete desiccation and ionizing radiation. Producing a well-assembled reference genome is a critical step to developing an understanding of the effects of long-term asexuality and DNA breakage on genome evolution. To this end, we present the first high-quality chromosome-level genome assemblies for the bdelloid Adineta vaga, composed of six pairs of homologous (diploid) chromosomes with a footprint of paleotetraploidy. The observed large-scale losses of heterozygosity are signatures of recombination between homologous chromosomes, either during mitotic DNA double-strand break repair or when resolving programmed DNA breaks during a modified meiosis. Dynamic subtelomeric regions harbor more structural diversity (e.g., chromosome rearrangements, transposable elements, and haplotypic divergence). Our results trigger the reappraisal of potential meiotic processes in bdelloid rotifers and help unravel the factors underlying their long-term asexual evolutionary success.


Effect of a herbal medicine on fatty liver in rats fed ethanol chronically.
The objective of this study was to determine whether Cardiotopic Pills (CP) affects fatty liver in rats fed ethanol chronically. Male Wistar rats were treated with liquid diet that contained ethanol (36% of total calories) or an isocaloric carbohydrate instead of ethanol for 6 weeks. CP, an oral herbal medicine including Danshen (Salviae Miltiorrhiza), Panax notoginseny and Dyroblanops aromatica gaertn, have been clinically used for vascular diseases such as coronary diseases and cerebral infarction. CP was administered orally with the liquid diets for 2 weeks 0.4 mg/kg body weight/day with the liquid diet thereafter. Serum triglyceride and total cholesterol levels, total protein, albumin, and AST and ALT activities are measured. Histological examination was also carried out. In another set of experiments, autofluorescence of NAD(P)H, an indicator of mitochondrial O2 consumption and redox status, was measured by an intravital microscopy, and peroxisome proliferators-activated receptor-(PPAR)-alpha and gamma mRNA levels were evaluated by real time quantitative PCR methods. Chronic ethanol consumption elevated serum triglyceride level, and caused fatty degeneration of liver. After administration of CP, fatty degeneration was not observed in rats fed ethanol chronically. Elevation of serum triglyceride level was not noted after treatment with CP (Ethanol: 79.4 +/- 9.3 mg/dl, Ethanol+CP: 48.0 +/- 4.4, respectively, p<0.05). CP did not affect any other laboratory data or NAD(P)H levels. Chronic ethanol consumption did not affect PPAR-gamma mRNA levels, while it decreased PPAR-alpha mRNA levels in the liver. CP prevented the ethanol-induced decrease in PPAR-alpha mRNA levels. CP and its components could enhance expression of PPAR-alpha mRNA levels. These results suggest that CP may be useful to prevent alcoholic fatty liver via enhanced expression of PPAR-alpha.


Story power: the secret weapon.
The objective is to introduce story power as an untapped vehicle to inform, equip, and challenge leaders to drive change that can save lives, save money, and build value in communities through adoption of the National Quality Forum Safe Practices. A review of storytelling best practices from industry complemented findings from a direct survey of hospital safety leaders who presented a video story to hospital personnel. The video captured the story of death of a child from failed communication and teamwork. Interviews of safety leaders at 675 hospitals who had presented the video to hospital staff revealed that more than 90% of the respondents strongly recommended use of the video by other organizations as a tool to reduce harm to patients. Three hundred sixty-three organizations showed it to more than 100 viewers. Two hundred seventy-six institutions reported that between 50 and 100 people viewed the video at each institution. Of the 675 organizations that presented the video, 84.9% believe that it either saved lives or positively affected patients. Respondents from 205 hospitals believed that more than 50 patients had been positively impacted by changes in care inspired by viewing the video. Health care leaders have much to learn from storytelling practices from other industries, such as film and business, that they can apply to driving patient safety and improving the care they deliver. However, they must face the fear of reputational and financial risk that transparency through storytelling will create when they honestly address shortfalls that cause harm to the patients they serve. The National Quality Forum Safe Practices provide a roadmap for leaders. However, they must become personally engaged in the action. They can do so by activating their teams using stories as weapons against the fears that pose barriers to improvement of preventable harm.


Crucial elements and technical implementation of intelligent monitoring networks.
Growing complexity of water monitoring instrumentation leads to specialized solutions in respect to sensor integration across several measurement device suppliers. Despite efforts of standardization for data interfaces and protocols, problems regarding the combination of several devices to gain the complete picture in terms of water quality remain. This assessment, especially accomplished from the perspective of a catchment area, requires a transition from sole use of data collectors toward an implementation of intelligent measurement networks. Several challenges and bottlenecks concerning distributed data collection are discussed starting with data acquisition up to the user-scope of utilizing data processing software. Finally, experiences using automated data inspection and export tools are discussed and a brief overview of expectable long-term data availability is given.


Synthesis of alphavirus-specified RNA.
UV irradiation of chicken fibroblasts infected with Semliki Forest or Sindbis virus has been used to investigate the mechanism of synthesis of 42S and 26S RNA, the major plus-strand virus-specified RNAs formed during the multiplication of standard virus particles. From an analysis of the kinetics of UV inactivation of the synthesis of these two RNAs, we conclude (i) that 26S RNA is formed by internal transcriptive initiation from a point about two-thirds of the way from the 3' end of the 42S negative-strand template; (ii) that there exists a population of plus-strand synthesizing complexes whose members are each capable of synthesizing both 42S and 26S RNA; and (iii) that, on a time-averaged basis, each complex in wild-type virus-infected cells contains one virus polymerase mediating 42S RNA synthesis and three mediating 26S RNA synthesis. The RNA phenotypes of 15 RNA(-)ts mutants of Sindbis virus have been examined after temperature shift to the restrictive temperature. Under these conditions, cells infected with three mutants, N2, N7, and E268, synthesized four to six times as much 42S RNA (relative to 26S RNA) as wild-type virus-infected cells. These studies were extended by examining, in detail, the RNA and polypeptide phenotypes of mutants N2 and E268. These experiments showed that, in N2- and E268-infected cells, one of the virus-specified nonstructural (NS) polypeptides (NS p89; H. Brzeski and S. I. T. Kennedy, J. Virol. 22:420-429, 1977) is thermolabile after shift up to restrictive temperature. This finding, together with the observation that, after shift, the 26S/42S RNA ratio in N2-infected cells changes markedly in favor of 42S RNA synthesis, leads us to conclude that, of the three NS polypeptides, NS p89 modulates 26S RNA synthesis.


Radiation-dose-dependent functional synergisms between ATM, ATR and DNA-PKcs in checkpoint control and resection in G2-phase.
Using data generated with cells exposed to ionizing-radiation (IR) in G2-phase of the cell cycle, we describe dose-dependent interactions between ATM, ATR and DNA-PKcs revealing unknown mechanistic underpinnings for two key facets of the DNA damage response: DSB end-resection and G2-checkpoint activation. At low IR-doses that induce low DSB-numbers in the genome, ATM and ATR regulate epistatically the G2-checkpoint, with ATR at the output-node, interfacing with the cell-cycle predominantly through Chk1. Strikingly, at low IR-doses, ATM and ATR epistatically regulate also resection, and inhibition of either activity fully suppresses resection. At high IR-doses that induce high DSB-numbers in the genome, the tight ATM/ATR coupling relaxes and independent outputs to G2-checkpoint and resection occur. Consequently, both kinases must be inhibited to fully suppress checkpoint activation and resection. DNA-PKcs integrates to the ATM/ATR module by regulating resection at all IR-doses, with defects in DNA-PKcs causing hyper-resection and G2-checkpoint hyper-activation. Notably, hyper-resection is absent from other c-NHEJ mutants. Thus, DNA-PKcs specifically regulates resection and adjusts the activation of the ATM/ATR module. We propose that selected DSBs are shepherd by DNA-PKcs from c-NHEJ to resection-dependent pathways for processing under the regulatory supervision of the ATM/ATR module.


Cost-utility analysis of stenting versus endarterectomy in the International Carotid Stenting Study.
The International Carotid Stenting Study was a multicenter randomized trial in which patients with symptomatic carotid artery stenosis were randomly allocated to treatment by carotid stenting or endarterectomy. Economic evidence comparing these treatments is limited and inconsistent. We compared the cost-effectiveness of stenting versus endarterectomy using International Carotid Stenting Study data. We performed a cost-utility analysis estimating mean costs and quality-adjusted life years per patient for both treatments over a five-year time horizon based on resource use data and utility values collected in the trial. Costs of managing stroke events were estimated using individual patient data from a UK population-based study (Oxford Vascular Study). Mean costs per patient (95% CI) were US$10,477 ($9669 to $11,285) in the stenting group (N = 853) and $9669 ($8835 to $10,504) in the endarterectomy group (N = 857). There were no differences in mean quality-adjusted life years per patient (3.247 (3.160 to 3.333) and 3.228 (3.150 to 3.306), respectively). There were no differences in adjusted costs between groups (mean incremental costs for stenting versus endarterectomy $736 (95% CI -$353 to $1826)) or adjusted outcomes (mean quality-adjusted life years gained -0.010 (95% CI -0.117 to 0.097)). The incremental net monetary benefit for stenting versus endarterectomy was not significantly different from zero at the maximum willingness to pay for a quality-adjusted life year commonly used in the UK. Sensitivity analyses showed little uncertainty in these findings. Economic considerations should not affect whether patients with symptomatic carotid stenosis undergo stenting or endarterectomy.


Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty.
A widely used technique for coordinate-based meta-analyses of neuroimaging data is activation likelihood estimation (ALE). ALE assesses the overlap between foci based on modeling them as probability distributions centered at the respective coordinates. In this Human Brain Project/Neuroinformatics research, the authors present a revised ALE algorithm addressing drawbacks associated with former implementations. The first change pertains to the size of the probability distributions, which had to be specified by the used. To provide a more principled solution, the authors analyzed fMRI data of 21 subjects, each normalized into MNI space using nine different approaches. This analysis provided quantitative estimates of between-subject and between-template variability for 16 functionally defined regions, which were then used to explicitly model the spatial uncertainty associated with each reported coordinate. Secondly, instead of testing for an above-chance clustering between foci, the revised algorithm assesses above-chance clustering between experiments. The spatial relationship between foci in a given experiment is now assumed to be fixed and ALE results are assessed against a null-distribution of random spatial association between experiments. Critically, this modification entails a change from fixed- to random-effects inference in ALE analysis allowing generalization of the results to the entire population of studies analyzed. By comparative analysis of real and simulated data, the authors showed that the revised ALE-algorithm overcomes conceptual problems of former meta-analyses and increases the specificity of the ensuing results without loosing the sensitivity of the original approach. It may thus provide a methodologically improved tool for coordinate-based meta-analyses on functional imaging data.


Antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from a Phase 2 clinical trial of ridinilazole (SMT19969) and vancomycin.
We evaluated the antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from participants in a Phase 2 study of ridinilazole, a novel targeted-spectrum agent for treatment of C. difficile infection. Participants received ridinilazole (200 mg twice daily) or vancomycin (125 mg four times daily) for 10 days (ClinicalTrials.gov: NCT02092935). The MICs of ridinilazole and comparators for C. difficile isolates from stool samples were determined by agar dilution. Toxin gene profiling was performed by multiplex PCR and ribotype identification by capillary electrophoresis. Eighty-nine isolates were recovered from 88/100 participants (one participant had two strains at baseline). The median colony count (cfu/g stool) was 1.9 × 104 (range: 2.5 × 102-7.0 × 106). Twelve participants (three received ridinilazole and nine received vancomycin) experienced recurrence, confirmed by immunoassays for free toxin in stool samples. The ribotype of eight out of nine isolates obtained at recurrence matched those of the initial isolates. All isolates, including those obtained at recurrence, were susceptible to ridinilazole within the expected range [median (range) MIC: 0.12 (0.06-0.5) mg/L]. The median (range) vancomycin MIC was 1 (0.5-4.0) mg/L. At baseline, 13.6% and 13.3% of samples in the ridinilazole and vancomycin groups were positive for VRE, increasing to 23.7% and 29.7% by day 40, respectively. Common ribotypes included 014-20 (14 isolates), 027 (13), 106 (7), 002 (7), 078-126 (4), 001 (4), 087 (3) and 198 (3). Toxin gene profiling of nearly all baseline isolates (98.9%) revealed a binary toxin gene (cdtA/cdtB) prevalence of 35%. Ridinilazole potently inhibited recovered C. difficile isolates. Recurrence was not associated with altered susceptibility.


Multiple regions of chromosome 4 demonstrating allelic losses in breast carcinomas.
Allelotyping studies suggest that allelic losses at one or both arms of chromosome 4 are frequent in several tumor types, but information about breast cancer is scant. A recent comparative genomic hybridization analysis revealed frequent losses of chromosome 4 in breast carcinomas. In an effort to more precisely locate the putative tumor suppressor gene(s) on chromosome 4 involved in the pathogenesis of breast carcinomas, we performed loss of heterozygosity studies using 19 polymorphic microsatellite markers. After precise microdissection of archival surgical cases, we analyzed DNA obtained from 44 breast carcinomas for loss of heterozygosity. In addition, DNA from tumor cell lines derived from 14 of these 44 breast carcinomas were also analyzed. We observed deletions of chromosome 4 at multiple sites in both tumor cell lines and breast carcinomas. The deletions in cell lines and their corresponding tumors were extensive in nature, whereas they were more localized in noncultured breast carcinomas. The localized deletions in the noncultured breast carcinomas clearly defined four nonoverlapping regions of frequent deletions: 4q33-34 (76%); 4q25-26 (63%); 4p15.1-15.3 (57%); and 4p16.3 (50%). Our results suggest that there may be multiple putative tumor suppressor genes, located on both arms of chromosome 4, whose inactivation is important in the pathogenesis of breast cancer.


The Prospective Impact of Family Functioning and Parenting Practices on Court-Involved Youth's Substance Use and Delinquent Behavior.
Court-involved youth exhibit high rates of psychiatric symptoms, substance use, and delinquency, yet little is known about the contributing roles of caregiver and family factors. The current study examined whether family functioning and parental monitoring mediate the relationship between caregiver and youth psychiatric symptoms (at first court contact) and youth substance use and delinquency (two years later). Participants were 400 first-time offending court-involved youth (Mage = 14.5 years; 57.3% male; 45.6% non-Latinx White, 42.0% Latinx) and an involved caregiver (Mage = 41.0 years; 87.2% female; 53.0% non-Latinx White, 33.8% Latinx). Structural equation modeling revealed that caregiver and youth psychiatric symptoms were prospectively associated with worse family functioning, which was in turn related to higher levels of youth delinquency and greater likelihood of substance use. The results support the notion of addressing the needs of justice-involved youth and families holistically rather than treating youth as "the problem" in isolation.


An exploration of patients' experiences of participation in a randomised controlled trial of the Manchester Acute Coronary Syndromes (MACS) decision rule.
As an important part of a pilot study to determine the feasibility of a large randomised controlled trial (RCT) comparing use of the Manchester Acute Coronary Syndromes (MACS) decision rule with standard care, we aimed to explore patient attitudes and potential barriers to participation in a trial of this nature. We conducted a qualitative study nested within a pilot RCT comparing use of the MACS rule (which could enable some patients with chest pain to be discharged earlier) with standard care. Semi-structured interviews with consenting participants were conducted with reference to a bespoke topic guide. Interviews were audio recorded, transcribed verbatim and analysed using the Framework method with an inductive approach. The 10 interviewees expressed that participation in the trial was generally acceptable. All but one recommended participation to others. Participants who were in pain or anxious at the time of arrival reported that the initial invitation to participate in the trial was sometimes made too early. The approach was welcome, providing they had been given time to settle. Interviewees welcomed the opportunity that trial participation offered for them to play a more active role in their healthcare and to reduce unnecessary waiting time. Participants appeared to like the fact that participation in the trial might mean they could return home sooner and welcomed the provision of follow-up. Although several participants described being generally sceptical of medical research, they were amenable to participation in this trial. This appears to be because they agreed with the need for research in this field and perceived the intervention as non-invasive. Patients were positive about their participation in this RCT comparing the MACS rule with standard care. A number of areas for improving trial design were identified and should be considered in the planning of future large trials. ISRCTN 86818215 RESEARCH ETHICS COMMITTEE REFERENCE: 13/NW/0081 UKCRN REGISTRATION ID: 14334.


Breast cancer chemotherapy vascular toxicity: a review of mediating mechanisms and exercise as a potential therapeutic.
Breast cancer chemotherapy, although very potent against tumour tissue, results in significant cardiovascular toxicity. The focus of research in this area has been predominantly towards cardiotoxicity. There is limited evidence detailing the impact of such treatment on the vasculature despite its central importance within the cardiovascular system and resultant detrimental effects of damage and dysfunction. This review highlights the impact of chemotherapy for breast cancer on the vascular endothelium. We consider the most likely mechanisms of endothelial toxicity to be through direct damage and dysfunction of the endothelium. There are sharp consequences of these detrimental effects as they can lead to cardiovascular disease. However, there is potential for exercise to alleviate some of the vascular toxicity of chemotherapy, and the evidence for this is provided. The potential role of exercise in protecting against vascular toxicity is explained, highlighting the recent in-human and animal model exercise interventions. Lastly, the mediating mechanisms of exercise protection of endothelial health is discussed, focusing on the importance of exercise for endothelial health, function, repair, inflammation and hyperlipidaemia, angiogenesis, and vascular remodelling. These are all important counteracting measures against chemotherapy-induced toxicity and are discussed in detail.


A yeast model for the study of human DFNA5, a gene mutated in nonsyndromic hearing impairment.
A mutation in human DFNA5 is associated with autosomal dominant nonsyndromic hearing impairment. The function of DFNA5 protein remains unknown and no experimental model has been described so far. Here we describe fission yeast Schizosaccharomyces pombe as a model organism for studying the function of heterologously expressed DFNA5. We have expressed wild-type as well as mutant DFNA5 alleles under control of regulatable nmt1 promoter. Yeast cells tolerated expression of wild-type DFNA5, while expression of the mutant DFNA5 allele, which is responsible for nonsyndromic autosomal dominant hearing impairment, led to cell cycle arrest. We identified new rat and horse DFNA5 homologues and we describe a domain of homology shared between DFNA5 and the Mcm10 family of DNA replication proteins. Genetic interactions between heterologously expressed DFNA5 and a fission yeast cdc23 (mcm10) mutant support a possible link between DFNA5 and Mcm10 proteins.


Mental health of displaced and refugee children resettled in high-income countries: risk and protective factors.
We undertook a systematic search and review of individual, family, community, and societal risk and protective factors for mental health in children and adolescents who are forcibly displaced to high-income countries. Exposure to violence has been shown to be a key risk factor, whereas stable settlement and social support in the host country have a positive effect on the child's psychological functioning. Further research is needed to identify the relevant processes, contexts, and interplay between the many predictor variables hitherto identified as affecting mental health vulnerability and resilience. Research designs are needed that enable longitudinal investigation of individual, community, and societal contexts, rather than designs restricted to investigation of the associations between adverse exposures and psychological symptoms. We emphasise the need to develop comprehensive policies to ensure a rapid resolution of asylum claims and the effective integration of internally displaced and refugee children.


Vertical junction silicon microdisk modulators and switches.
Vertical junction resonant microdisk modulators and switches have been demonstrated with exceptionally low power consumption, low-voltage operation, high-speed, and compact size. This paper reviews the progress of vertical junction microdisk modulators, provides detailed design data, and compares vertical junction performance to lateral junction performance. The use of a vertical junction maximizes the overlap of the depletion region with the optical mode thereby minimizing both the drive voltage and power consumption of a depletion-mode modulator. Further, the vertical junction enables contact to be made from the interior of the resonator and therein a hard outer wall to be formed that minimizes radiation in small diameter resonators, further reducing the capacitance and drive power of the modulator. Initial simple vertical junction modulators using depletion-mode operation demonstrated the first sub-100 fJ/bit silicon modulators. With more intricate doping schemes and through the use of AC-coupled drive signals, 3.5 μm diameter vertical junction microdisk modulators have recently achieved a communications efficiency of 3 fJ/bit, making these modulators the smallest and lowest power modulators demonstrated to date, in any material system. Additionally, the demonstration was performed at 12.5 Gb/s, required a peak-to-peak signal level of only 1 V, and achieved bit-error-rates below 10(-12) without requiring signal pre-emphasis. As an additional benefit to the use of interior contacts, higher-order active filters can be constructed from multiple vertical-junction modulators without interference of the electrodes. Doing so, we demonstrated second-order active high-speed bandpass switches with ~2.5 ns switching speeds, and power penalties of only 0.4 dB. Through the use of vertical junctions in resonant modulators, we have achieved the lowest power consumption, lowest voltage, and smallest silicon modulators demonstrated to date.