Society for Ambulatory Anesthesia consensus statement on preoperative selection of adult patients with obstructive sleep apnea scheduled for ambulatory surgery.
The suitability of ambulatory surgery for a patient with obstructive sleep apnea (OSA) remains controversial because of concerns of increased perioperative complications including postdischarge death. Therefore, a Society for Ambulatory Anesthesia task force on practice guidelines developed a consensus statement for the selection of patients with OSA scheduled for ambulatory surgery. A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Although the studies evaluating perioperative outcome in OSA patients undergoing ambulatory surgery are sparse and of limited quality, they do provide useful information that can guide clinical practice. Patients with a known diagnosis of OSA and optimized comorbid medical conditions can be considered for ambulatory surgery, if they are able to use a continuous positive airway pressure device in the postoperative period. Patients with a presumed diagnosis of OSA, based on screening tools such as the STOP-Bang questionnaire, and with optimized comorbid conditions, can be considered for ambulatory surgery, if postoperative pain can be managed predominantly with nonopioid analgesic techniques. On the other hand, OSA patients with nonoptimized comorbid medical conditions may not be good candidates for ambulatory surgery. What other guidelines are available on this topic? The American Society of Anesthesiologists (ASA) practice guidelines for management of surgical patients with OSA published in 2006. Why was this guideline developed? The ASA guidelines are outdated because several recent studies provide new information such as validated screening tools for clinical diagnosis of OSA and safety of ambulatory laparoscopic bariatric surgery in OSA patients. Therefore, an update on the selection of patients with OSA undergoing ambulatory surgery is warranted. How does this guideline differ from existing guidelines? Unlike the ASA guidelines, this consensus statement recommends the use of the STOP-Bang criteria for preoperative OSA screening and considers patients' comorbid conditions in the patient selection process. Also, current literature does not support the ASA recommendations that upper abdominal procedures are not appropriate for ambulatory surgery. Why does this guideline differ from existing guidelines? This consensus statement differs from existing ASA guidelines because of the availability of new evidence.


Gentamicin as an alternative to ceftriaxone in the treatment of gonorrhoea: the G-TOG non-inferiority RCT.
Gonorrhoea is a common sexually transmitted infection that can cause pain and discomfort, affect fertility in women and lead to epididymo-orchitis in men. Current treatment is with ceftriaxone, but there is increasing evidence of antimicrobial resistance reducing its effectiveness. Gentamicin is a potential alternative treatment requiring further evaluation. To assess the clinical effectiveness and cost-effectiveness of gentamicin as an alternative treatment to ceftriaxone in the treatment of gonorrhoea. A multicentre, parallel-group, blinded, non-inferiority randomised controlled trial. Fourteen sexual health clinics in England. Adults aged 16-70 years with a diagnosis of uncomplicated, untreated genital, pharyngeal or rectal gonorrhoea based on a positive Gram-stained smear on microscopy or a positive nucleic acid amplification test (NAAT). Participants were randomised using a secure web-based system, stratified by clinic. Participants, investigators and research staff assessing participants were blinded to treatment allocation. Allocation was to either 240 mg of gentamicin (intervention) or 500 mg of ceftriaxone (standard treatment), both administered as a single intramuscular injection. All participants also received 1 g of oral azithromycin. The primary outcome measure was clearance of Neisseria gonorrhoeae at all infected sites, confirmed by a negative Aptima Combo 2® (Hologic Inc., Marlborough, MA, USA) NAAT, at 2 weeks post treatment. We randomised 720 participants, of whom 81% were men. There were 358 participants in the gentamicin group and 362 in the ceftriaxone group; 292 (82%) and 306 (85%) participants, respectively, were included in the primary analysis. Non-inferiority of gentamicin to ceftriaxone could not be demonstrated [adjusted risk difference for microbiological clearance -6.4%, 95% confidence interval (CI) -10.4% to -2.4%]. Clearance of genital infection was similar in the two groups, at 94% in the gentamicin group and 98% in the ceftriaxone group, but clearance of pharyngeal infection and rectal infection was lower in the gentamicin group (80% vs. 96% and 90% vs. 98%, respectively). Reported pain at the injection site was higher for gentamicin than for ceftriaxone. The side-effect profiles were comparable between the groups. Only one serious adverse event was reported and this was deemed not to be related to the trial medication. The economic analysis found that treatment with gentamicin is not cost neutral compared with standard care, with average patient treatment costs higher for those allocated to gentamicin (£13.90, 95% CI £2.47 to £37.34) than to ceftriaxone (£6.72, 95% CI £1.36 to £17.84). Loss to follow-up was 17% but was similar in both treatment arms. Twelve per cent of participants had a negative NAAT for gonorrhoea at their baseline visit but this was balanced between treatment groups and unlikely to have biased the trial results. The trial was unable to demonstrate non-inferiority of gentamicin compared with ceftriaxone in the clearance of gonorrhoea at all infected sites. Clearance at pharyngeal and rectal sites was lower for participants allocated to gentamicin than for those allocated to ceftriaxone, but was similar for genital sites in both groups. Gentamicin was associated with more severe injection site pain. However, both gentamicin and ceftriaxone appeared to be well tolerated. Exploration of the genetic determinants of antibiotic resistance in N. gonorrhoeae will help to identify accurate markers of decreased susceptibility. Greater understanding of the immune response to infection can assist gonococcal vaccine development. Current Controlled Trials ISRCTN51783227. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 20. See the NIHR Journals Library website for further project information.


Emergency Department disposition decisions and associated mortality and costs in ICU patients with suspected infection.
Following emergency department (ED) assessment, patients with infection may be directly admitted to the intensive care unit (ICU) or alternatively admitted to hospital wards or sent home. Those admitted to the hospital wards or sent home may experience future deterioration necessitating ICU admission. We used a prospectively collected registry from two hospitals within a single tertiary care hospital network between 2011 and 2014. Patient information, outcomes, and costs were stored in the hospital data warehouse. Patients were categorized into three groups: (1) admitted directly from the ED to the ICU; (2) initially admitted to the hospital wards, with ICU admission within 72 hours of initial presentation; or (3) sent home from the ED, with ICU admission within 72 hours of initial presentation. Using multivariable logistic regression, we sought to compare outcomes and total costs between groups. Total costs were evaluated using a generalized linear model. A total of 657 patients were included; of these, 338 (51.4%) were admitted directly from the ED to the ICU, 246 (37.4%) were initially admitted to the wards and then to the ICU, and 73 (11.1%) were initially sent home and then admitted to the ICU. In-hospital mortality was lowest among patients admitted directly to the ICU (29.5%), as compared with patients admitted to the ICU from wards (42.7%) or home (61.6%) (P < 0.001). As compared with direct ICU admission, disposition to the ward was associated with an adjusted OR of 1.75 (95% CI, 1.22-2.50; P < 0.01) for mortality, and disposition home was associated with an adjusted OR of 4.02 (95% CI, 2.32-6.98). Mean total costs were lowest among patients directly admitted to the ICU ($26,748), as compared with those admitted from the wards ($107,315) and those initially sent home ($71,492) (P < 0.001). Cost per survivor was lower among patients directly admitted to the ICU ($37,986) than either those initially admitted to the wards ($187,230) or those sent home ($186,390) (P < 0.001). In comparison with direct admission to the ICU, patients with suspected infection admitted to the ICU who have previously been discharged home or admitted to the ward are associated with higher in-hospital mortality and costs.


Microethical decision making among baccalaureate nursing students: a qualitative investigation.
Nursing students frequently encounter microethical nursing practice problems during their clinical experience. The purpose of this study was to understand the lived experiences of senior-level baccalaureate students faced with making microethical clinical decisions in practice settings. A descriptive qualitative design was used, and five central themes emerged. A dominant finding was the experience of unapplied and forgotten ethics education revealing a mismatch between what faculty perceived was taught and students' experiences of that education. When faced with microethical decisions, participants trusted and deferred to staff nurse recommendations, even if the advice contradicted best-practice standards. Contextual naivete was brought out of concealment, contributing to the experience of moral disequilibrium (i.e., students felt conflicted about what they learned in school as best practice and what they observed being role modeled in the clinical environment). This study resulted in theory-guided implications for nursing education and recommendations for future study.


Family caregivers of elderly with dementia Relationship between religiosity, resilience, quality of life and burden.
There are gaps in knowledge regarding how the family caregiver deals with the burden of caring for elderly people with dementia. To evaluate the family caregivers' perception of quality of life (QoL), burden, resilience and religiosity and relate them with cognitive aspects and occurrence of neuropsychiatric symptoms of elderly with dementia. Data from the QoL-AD scale, caregivers' version, burden interview, resilience scale, Beck depression inventory and PDUREL of 50 family caregivers were correlated with disability assessment for dementia, neuropsychiatric inventory and clinical aspects of 50 elderly with dementia. Linear regression showed that resilience is related with better perceived QoL (p<0.001), severity of dementia (p=0.008), higher intrinsic religiosity (IR) (p=0.044) and lower occurrence of depressive symptoms (p=0.001). Increased burden of family caregivers was associated with a higher occurrence of neuropsychiatric symptoms, education of the elder with dementia, and worse perceived QoL (p<0.001). Lower level of organizational religiosity was associated with severity of dementia. The most resilient caregivers had higher QoL and IR, fewer depressive symptoms, and cared for elders with more severe dementia. Cognitive and sociodemographic aspects, as well as neuropsychiatric symptoms, in the elderly with dementia were associated with QoL and greater caregiver burden.


Structural and functional characterization of Kv6.2 a new gamma-subunit of voltage-gated potassium channel.
We have cloned and functionally expressed Kv6.2, a new member of the Kv6 subfamily of voltage-gated potassium channel subunits. The human Kv6.2 (KCNF2) gene was mapped at 18q22-18q23. Kv6.2 mRNA is preferentially expressed in rat and human myocard. Rat and human Kv6.2 subunits appear to be unable to form functional Kv channels in a heterologous expression system, but, when coexpressed with Kv2.1 alpha subunits, heteromultimeric Kv channels were formed mediating voltage-activated delayed-rectifier type outward currents. Their kinetics and conductance-voltage relationship were different from those mediated by homomultimeric Kv2.1 channels. Yeast two-hybrid reporter assays indicated that Kv6.2 amino-termini are able to interact specifically with the Kv2.1 amino-terminus. It is proposed that this protein protein interaction underlies Kv2.1/Kv6.2 subunit assembly and the expression of functional heteromultimeric Kv2.1/Kv6.2 channels. The most resiliant feature of the Kv2.1/Kv6.2 channels was their submicromolar sensitivity to the antiarrhythmic drug propafenone. The data suggest that delayed-rectifier type channels containing Kv6.2 subunits may contribute to cardiac action potential repolarization.


A marginal structural model approach to analyse work-related injuries: an example using data from the health and retirement study.
Biases may exist in the limited longitudinal data focusing on work-related injuries among the ageing workforce. Standard statistical techniques may not provide valid estimates when the data are time-varying and when prior exposures and outcomes may influence future outcomes. This research effort uses marginal structural models (MSMs), a class of causal models rarely applied for injury epidemiology research to analyse work-related injuries. 7212 working US adults aged ≥50 years, obtained from the Health and Retirement Study sample in the year 2004 formed the study cohort that was followed until 2014. The analyses compared estimates measuring the associations between physical work requirements and work-related injuries using MSMs and a traditional regression model. The weights used in the MSMs, besides accounting for time-varying exposures, also accounted for the recurrent nature of injuries. The results were consistent with regard to directionality between the two models. However, the effect estimate was greater when the same data were analysed using MSMs, built without the restriction for complete case analyses. MSMs can be particularly useful for observational data, especially with the inclusion of recurrent outcomes as these can be incorporated in the weights themselves.


Workload capacity measures for estimating allied health staffing requirements.
Workforce planning methodologies for the allied health professions are acknowledged as rudimentary despite the increasing importance of these professions to health care across the spectrum of health services settings. The objectives of this study were to (i) identify workload capacity measures and methods for profiling allied health workforce requirements from a systematic review of the international literature; (ii) explore the use of these methods in planning workforce requirements; (iii) identify barriers to applying such methods; and (iv) recommend further action. Future approaches to workforce planning were explored through a systematic review of the literature, interviews with key stakeholders and focus group discussions with representatives from the different professional bodies and health agencies in Victoria. Results identified a range of methods used to calculate workload requirements or capacity. In order of increasing data demands and costliness to implement, workload capacity methods can be broadly classified into four groups: ratio-based, procedure-based, categories of care-based and diagnostic or casemix-based. Despite inherent limitations, the procedure-based measurement approach appears to be most widely accepted. Barriers to more rigorous workforce planning methods are discussed and future directions explored through an examination of the potential of casemix and mixed-method approaches.


The role of gut microbes in satisfying the nutritional demands of adult and juvenile wild, black howler monkeys (Alouatta pigra).
In all mammals, growth, development, pregnancy, and lactation increase nutritional demands. Although primate field studies tend to focus on shifts in activity and diet as mechanisms to compensate for these demands, differences in digestive efficiency also are likely to be important. Because the gut microbiota can impact host digestive efficiency, we examined differences in activity budget, diet, and the gut microbial community among adult male (N = 4), adult female (N = 4), and juvenile (N = 5) wild black howler monkeys (Alouatta pigra) across a ten-month period in Palenque National Park, Mexico to determine how adult females and juveniles compensate for increased nutritional demands. Results indicate that adult females and juveniles consumed more protein and energy than adult males. Adult males, adult females, and juveniles also possessed distinct gut microbial communities, unrelated to diet. Juveniles exhibited a gut microbiota characterized by bacteria from the phylum Firmicutes, such as Roseburia and Ruminococcus, and demonstrated high fecal volatile fatty acid content, suggesting increased microbial contributions to host energy balances. Adult females possessed a higher Firmicutes to Bacteroidetes ratio, also suggesting increased energy production, and their gut microbiota was characterized by Lactococcus, which has been associated with folate biosynthesis. On the basis of these patterns, it appears that the gut microbiota differentially contributes to howler monkey nutrition during reproduction and growth. Determining the nutritional and energetic importance of shifts in activity, diet, and the gut microbiota in other nonhuman primate taxa, as well as humans, will transform our understanding of these life history processes and the role of host-microbe relationships in primate evolution.


Developmental switch in the short-term modification of unitary EPSPs evoked in layer 2/3 and layer 5 pyramidal neurons of rat neocortex.
Amplitudes of EPSPs evoked by repetitive presynaptic action potentials can either decrease (synaptic depression) or increase (synaptic facilitation). To determine whether facilitation and depression in the connections between neocortical pyramidal cells varied with the identity of the pre- or the postsynaptic cell and whether they changed during postnatal development, whole-cell voltage recordings were made simultaneously from two or three pyramidal cells in layers 2/3 and 5 of the rat sensorimotor cortex. Unitary EPSPs were evoked when pre- and postsynaptic neurons were in the same and in different layers. In young [postnatal day 14 (P14)] cortex, EPSPs evoked in all connected neurons depressed. The degree of depression was layer specific and was determined by the identity of the presynaptic cell. EPSPs evoked by stimulation of presynaptic layer 5 neurons depressed significantly more than did those evoked by stimulation of layer 2/3 neurons. In mature cortex (P28), however, the EPSPs evoked in these connected neurons facilitated to a comparable degree regardless of the layer in which pre- and postsynaptic neurons were located. The results suggest that in young cortex the degree of synaptic depression in connected pyramidal cells is determined primarily by whether the presynaptic cell was in layer 2/3 or 5 and that maturation of the cortex involves a developmental switch from depression to facilitation between P14 and P28 that eliminates the layer-specific differences. A functional consequence of this switch is that in mature cortex the spread of excitation between neocortical pyramidal neurons is enhanced when action potentials occur in bursts.


Seventy-five genetic loci influencing the human red blood cell.
Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.


A methodological systematic review of what's wrong with meta-ethnography reporting.
Syntheses of qualitative studies can inform health policy, services and our understanding of patient experience. Meta-ethnography is a systematic seven-phase interpretive qualitative synthesis approach well-suited to producing new theories and conceptual models. However, there are concerns about the quality of meta-ethnography reporting, particularly the analysis and synthesis processes. Our aim was to investigate the application and reporting of methods in recent meta-ethnography journal papers, focusing on the analysis and synthesis process and output. Methodological systematic review of health-related meta-ethnography journal papers published from 2012-2013. We searched six electronic databases, Google Scholar and Zetoc for papers using key terms including 'meta-ethnography.' Two authors independently screened papers by title and abstract with 100% agreement. We identified 32 relevant papers. Three authors independently extracted data and all authors analysed the application and reporting of methods using content analysis. Meta-ethnography was applied in diverse ways, sometimes inappropriately. In 13% of papers the approach did not suit the research aim. In 66% of papers reviewers did not follow the principles of meta-ethnography. The analytical and synthesis processes were poorly reported overall. In only 31% of papers reviewers clearly described how they analysed conceptual data from primary studies (phase 5, 'translation' of studies) and in only one paper (3%) reviewers explicitly described how they conducted the analytic synthesis process (phase 6). In 38% of papers we could not ascertain if reviewers had achieved any new interpretation of primary studies. In over 30% of papers seminal methodological texts which could have informed methods were not cited. We believe this is the first in-depth methodological systematic review of meta-ethnography conduct and reporting. Meta-ethnography is an evolving approach. Current reporting of methods, analysis and synthesis lacks clarity and comprehensiveness. This is a major barrier to use of meta-ethnography findings that could contribute significantly to the evidence base because it makes judging their rigour and credibility difficult. To realise the high potential value of meta-ethnography for enhancing health care and understanding patient experience requires reporting that clearly conveys the methodology, analysis and findings. Tailored meta-ethnography reporting guidelines, developed through expert consensus, could improve reporting.


Association between Age, Weight, and Dose and Clinical Response to Probiotics in Children with Acute Gastroenteritis.
Gastroenteritis is a common and impactful disease in childhood. Probiotics are often used to treat acute gastroenteritis (AGE); however, in a large multicenter randomized controlled trial (RCT) in 971 children, Lactobacillus rhamnosus GG (LGG) was no better than placebo in improving patient outcomes. We sought to determine whether the effect of LGG is associated with age, weight z score and weight percentile adjusted for age and sex, or dose per kilogram administered. This was a preplanned secondary analysis of a multicenter double-blind RCT of LGG 1 × 1010 CFU twice daily for 5 d or placebo in children 3-48 mo of age with AGE. Our primary outcome was moderate to severe gastroenteritis. Secondary outcomes included diarrhea and vomiting frequency and duration, chronic diarrhea, and side effects. We used multivariable linear and nonlinear models testing for interaction effects to assess outcomes by age, weight z score and weight percentile adjusted for age and sex, and dose per kilogram of LGG received. A total of 813 children (84%) were included in the analysis; 413 received placebo and 400 LGG. Baseline characteristics were similar between treatment groups. There were no differential interaction effects across ranges of age (P-interaction = 0.32), adjusted weight z score (P-interaction = 0.43), adjusted weight percentile (P-interaction = 0.45), or dose per kilogram of LGG received (P-interaction = 0.28) for the primary outcome. Whereas we found a statistical association favoring placebo at the extremes of adjusted weight z scores for the number of vomiting episodes (P-interaction = 0.02) and vomiting duration (P-interaction = 0.0475), there were no statistically significant differences in other secondary outcome measures (all P-interactions > 0.05). LGG does not improve outcomes in children with AGE regardless of the age, adjusted weight z score, and adjusted weight percentile of participants, or the probiotic dose per kilogram received. These results further strengthen the conclusions of low risk of bias clinical trials which demonstrate that LGG provides no clinical benefit in children with AGE.This trial was registered at clinicaltrials.gov as NCT01773967.


[Selenium in celiac disease].
Statistically significant lower levels of selenium (p less than 0.001) have been found both in 37 celiac subjects at free diet and in 36 at gluten-free diet with respect to controls. In patients at free diet the deficit of selenium can be attributed to malabsorption, while in patients at gluten-free diet it may be due to the diet itself. Recently low serum levels of selenium have been observed in several neoplasias; furthermore it's known that celiac patients show an increased incidence of gastrointestinal tumors related to known levels in standard population. Long term monitoring is therefore necessary to integrate diet with selenium in patients showing persistent deficit of this element.


Effectiveness of an Integrated Ambulatory Care Program in Health Care and Medication Use in Patients With Multimorbidity and Polypharmacy.
Multimorbidity increases risks, such as polypharmacy, inappropriate prescription, and functional decline. It also increases medical care utilization by older adults, placing a burden on health care systems. This study evaluated the effectiveness of an integrated ambulatory care program for health care and medication use in patients with multimorbidity and polypharmacy. We conducted a retrospective clinical review of adults with multimorbidity and polypharmacy who attended an integrated ambulatory care program at a 1193-bed university hospital between July 1 and September 30, 2019. This program involves multidisciplinary teamwork, comprehensive assessments, medication reviews, and case management. Outcomes, including the frequency of outpatient visits, emergency department visits, hospitalizations, chronic prescription medications, potentially inappropriate medications (PIMs), health care costs, and total medical expenditure, were compared before and after the program. The mean age of participants (n = 134) at baseline was 74.22 ± 9.75 years. The mean number of chronic diagnoses was 9.45 ± 3.38. Participants included 72 (53.7%) women. At the 1-year follow-up, participants showed a significant decrease in the annual frequency of outpatient visits (19.78 ± 9.98 to 13.90 ± 10.22, P < .001), emergency department visits (1.04 ± 1.70 to 0.73 ± 1.40, P = .029), and chronic disease medications (10.71 ± 3.96 to 9.57 ± 3.67, P < .001) across all age groups. There was also a reduction in the annual number of PIMs (from 1.31 ± 1.01 to 1.12 ± 0.93, P = .002) among patients aged 65 years. However, no effects were observed on annual hospitalization, duration of hospital stay, or total health care expenditure, possibly due to the high disease-related treatment cost for certain participants. Expanding integrated ambulatory care programs in Taiwan may help patients with multimorbidity reduce their use of outpatient and emergency services, chronic prescriptions, and PIMs.


Memory skills of boys with fragile X syndrome.
Multiple aspects of memory were examined in 42 boys with fragile X syndrome and a comparison group of 42 typically developing boys matched on MA. Working memory, incidental memory, and deliberate memory were assessed with a battery that included both free-recall and recognition tasks. Findings indicated that boys with fragile X syndrome performed more poorly than their matches on most measures. The exception was free recall, in which their accuracy was equal to that of the control participants. Results from analyses of a subset of boys with fragile X syndrome who exhibit characteristics of autism and their MA matches, though preliminary, support the conclusion that memory deficits are especially marked in boys who have fragile X syndrome and evidence autistic behaviors.


Radiomics Based Bayesian Inversion Method for Prediction of Cancer and Pathological Stage.
To develop a Bayesian inversion framework on longitudinal chest CT scans which can perform efficient multi-class classification of lung cancer. While the unavailability of large number of training medical images impedes the performance of lung cancer classifiers, the purpose built deep networks have not performed well in multi-class classification. The presented framework employs particle filtering approach to address the non-linear behaviour of radiomic features towards benign and cancerous (stages I, II, III, IV) nodules and performs efficient multi-class classification (benign, early stage cancer, advanced stage cancer) in terms of posterior probability function. A joint likelihood function incorporating diagnostic radiomic features is formulated which can compute likelihood of cancer and its pathological stage. The proposed research study also investigates and validates diagnostic features to discriminate accurately between early stage (I, II) and advanced stage (III, IV) cancer. The proposed stochastic framework achieved 86% accuracy on the benchmark database which is better than the other prominent cancer detection methods. The presented classification framework can aid radiologists in accurate interpretation of lung CT images at an early stage and can lead to timely medical treatment of cancer patients.


The role of anterior cingulate cortex in working memory is shaped by functional connectivity.
The anterior cingulate (AC) cortex seems to be similarly engaged by attentional and memory processes. We tested the hypothesis that this common activation is best explained by changes in the regions interacting (functionally connected) with AC. Subjects were tested on two variants of a 2-back working memory task: a standard version with strong attentional demands, and a cued version that more strongly promoted memory retrieval. AC activation, measured with functional MRI, was found in both tasks, although more sustained in the standard condition. The regions functionally connected to the AC, and the relation of these activity patterns to memory performance, were completely different across tasks. In the standard task, the pattern related to a speed-accuracy tradeoff, whereas the connectivity pattern unique to the cued task related only to better accuracy. By virtue of these changing patterns of functional connectivity, the contribution of AC to attention- and memory-driven performance was similarly changed.


Designs of broadband and wide-view patterned polarizers for stereoscopic 3D displays.
This work presents a new methodology to design patterned circular polarizers consisting of in-cell polarizers, in-cell retarders and biaxial films to achieve very wide viewing freedom for stereoscopic 3D color LCDs. The biaxial films with least materials and simple fabrication concepts are employed for off-axis compensation of the in-cell retarders. In the best result, the crosstalk ratio is less than 0.035 or 0.0082 respectively for over ± 60° or ± 40° viewing cone of the 3D display. As to the normal view of the proposed structure with glasses or LCD rotation, the crosstalk ratio is less than 0.11%, with 93.5% improvement as compared with the ± λ/4 patterned polarizer. The dispersion properties of materials have been considered in all simulations to mimic real situations.


Seasonal changes in the abundance of bacterial genes related to dimethylsulfoniopropionate catabolism in seawater from Ofunato Bay revealed by metagenomic analysis.
Ofunato Bay is located in the northeastern Pacific Ocean area of Japan, and it has the highest biodiversity of marine organisms in the world, primarily due to tidal influences from the cold Oyashio and warm Kuroshio Currents. Our previous results from performing shotgun metagenomics indicated that Candidatus Pelagibacter ubique and Planktomarina temperata were the dominant bacteria (Reza et al., 2018a, 2018b). These bacteria are reportedly able to catabolize dimethylsulfoniopropionate (DMSP) produced from phytoplankton into dimethyl sulfide (DMS) or methanethiol (MeSH). This study was focused on seasonal changes in the abundances of bacterial genes (dddP, dmdA) related to DMSP catabolism in the seawater of Ofunato Bay by BLAST+ analysis using shotgun metagenomic datasets. We found seasonal changes among the Candidatus Pelagibacter ubique strains, including those of the HTCC1062 type and the Red Sea type. A good correlation was observed between the chlorophyll a concentrations and the abundances of the catabolic genes, suggesting that the bacteria directly interact with phytoplankton in the marine material cycle system and play important roles in producing DMS and MeSH from DMSP as signaling molecules for the possible formation of the scent of the tidewater or as fish attractants.


Natural Progression of Routine Laboratory Markers after Spinal Trauma: A Longitudinal, Multi-Cohort Study.
Our objective was to track and quantify the natural course of serological markers over the 1st year following spinal cord injury. For that purpose, data on serological markers, demographics, and injury characteristics were extracted from medical records of a clinical trial (Sygen) and an ongoing observational cohort study (Murnau study). The primary outcomes were concentration/levels/amount of commonly collected serological markers at multiple time points. Two-way analysis of variance (ANOVA) and mixed-effects regression techniques were used to account for the longitudinal data and adjust for potential confounders. Trajectories of serological markers contained in both data sources were compared using the slope of progression. Our results show that, at baseline (≤ 2 weeks post-injury), most serological markers were at pathological levels, but returned to normal values over the course of 6-12 months post-injury. The baseline levels and longitudinal trajectories were dependent on injury severity. More complete injuries were associated with more pathological values (e.g., hematocrit, ANOVA test; χ2 = 68.93, df = 3, adjusted p value <0.001, and χ2 = 73.80, df = 3, adjusted p value <0.001, in the Sygen and Murnau studies, respectively). Comparing the two databases revealed some differences in the serological markers, which are likely attributable to differences in study design, sample size, and standard of care. We conclude that because of trauma-induced physiological perturbations, serological markers undergo marked changes over the course of recovery, from initial pathological levels that normalize within a year. The findings from this study are important, as they provide a benchmark for clinical decision making and prospective clinical trials. All results can be interactively explored on the Haemosurveillance web site (https://jutzelec.shinyapps.io/Haemosurveillance/) and GitHub repository (https://github.com/jutzca/Systemic-effects-of-Spinal-Cord-Injury).


Emergency ventilator for COVID-19.
The COVID-19 pandemic disrupted the world in 2020 by spreading at unprecedented rates and causing tens of thousands of fatalities within a few months. The number of deaths dramatically increased in regions where the number of patients in need of hospital care exceeded the availability of care. Many COVID-19 patients experience Acute Respiratory Distress Syndrome (ARDS), a condition that can be treated with mechanical ventilation. In response to the need for mechanical ventilators, designed and tested an emergency ventilator (EV) that can control a patient's peak inspiratory pressure (PIP) and breathing rate, while keeping a positive end expiratory pressure (PEEP). This article describes the rapid design, prototyping, and testing of the EV. The development process was enabled by rapid design iterations using additive manufacturing (AM). In the initial design phase, iterations between design, AM, and testing enabled a working prototype within one week. The designs of the 16 different components of the ventilator were locked by additively manufacturing and testing a total of 283 parts having parametrically varied dimensions. In the second stage, AM was used to produce 75 functional prototypes to support engineering evaluation and animal testing. The devices were tested over more than two million cycles. We also developed an electronic monitoring system and with automatic alarm to provide for safe operation, along with training materials and user guides. The final designs are available online under a free license. The designs have been transferred to more than 70 organizations in 15 countries. This project demonstrates the potential for ultra-fast product design, engineering, and testing of medical devices needed for COVID-19 emergency response.


Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain.
BCL6 encodes a transcription factor that represses genes necessary for the terminal differentiation of lymphocytes within germinal centers, and the misregulated expression of this factor is strongly implicated in several types of B cell lymphoma. The homodimeric BTB domain of BCL6 (also known as the POZ domain) is required for the repression activity of the protein and interacts directly with the SMRT and N-CoR corepressors that are found within large multiprotein histone deacetylase-containing complexes. We have identified a 17 residue fragment from SMRT that binds to the BCL6 BTB domain, and determined the crystal structure of the complex to 2.2 A. Two SMRT fragments bind symmetrically to the BCL6 BTB homodimer and, in combination with biochemical and in vivo data, the structure provides insight into the basis of transcriptional repression by this critical B cell lymphoma protein.


A test of the European Pleistocene refugial paradigm, using a Western Palaearctic endemic bird species.
Hewitt's paradigm for effects of Pleistocene glaciations on European populations assumes their isolation in peninsular refugia during glacial maxima, followed by re-colonization of broader Europe during interstadials. This paradigm is well supported by studies of poorly dispersing taxa, but highly dispersive birds have not been included. To test this paradigm, we use the dunnock (Prunella modularis), a Western Palaearctic endemic whose range includes all major European refugia. MtDNA gene tree, multilocus species tree and species delimitation analyses indicate the presence of three distinct lineages: one in the Iberian refugium, one in the Caucasus refugium, and one comprising the Italian and Balkan refugia and broader Europe. Our gene flow analysis suggests isolation of both the Iberian and Caucasus lineages but extensive exchange between Italy, the Balkans and broader Europe. Demographic stability could not be rejected for any refugial population, except the very recent expansion in the Caucasus. By contrast, northern European populations may have experienced two expansion periods. Iberia and Caucasus had much smaller historical populations than other populations. Although our results support the paradigm, in general, they also suggest that in highly dispersive taxa, isolation of neighbouring refugia was incomplete, resulting in large super-refugial populations.


The asbestos-carbon nanotube analogy: An update.
Nanotechnology is an emerging industry based on commercialization of materials with one or more dimensions of 100 nm or less. Engineered nanomaterials are currently incorporated into thin films, porous materials, liquid suspensions, or filler/matrix nanocomposites with future applications predicted in energy and catalysis, microelectronics, environmental sensing and remediation, and nanomedicine. Carbon nanotubes are one-dimensional fibrous nanomaterials that physically resemble asbestos fibers. Toxicologic studies in rodents demonstrated that some types of carbon nanotubes can induce mesothelioma, and the World Health Organization evaluated long, rigid multiwall carbon nanotubes as possibly carcinogenic for humans in 2014. This review summarizes key physicochemical similarities and differences between asbestos fibers and carbon nanotubes. The "fiber pathogenicity paradigm" has been extended to include carbon nanotubes as well as other high-aspect-ratio fibrous nanomaterials including metallic nanowires. This paradigm identifies width, length, and biopersistence of high-aspect-ratio fibrous nanomaterials as critical determinants of lung disease, including mesothelioma, following inhalation. Based on recent theoretical modeling studies, a fourth factor, mechanical bending stiffness, will be considered as predictive of potential carcinogenicity. Novel three-dimensional lung tissue platforms provide an opportunity for in vitro screening of a wide range of high aspect ratio fibrous nanomaterials for potential lung toxicity prior to commercialization.


Voluntary disenrollment from Medicare advantage plans: valuable signals of market performance.
To examine 2000-2005 trends in the reasons Medicare beneficiaries gave for disenrolling from their Medicare Advantage (MA) plans. We used data from 6 consecutive years of Consumer Assessment of Health Plans surveys, which asked about 33 possible reasons for disenrollment, including problems with plan information, out-of-pocket costs, plan benefits, and coverage. Respondents numbered more than 50,000 beneficiaries each year from a variety of MA plan types providing full Medicare benefits in place of traditional fee-for-service Medicare. The survey also collected demographic and health status information. We classified reasons for disenrollment into 2 key groups: (1) reasons related to plan information and (2) reasons related to cost/benefits problems. We examined whether disparities existed between vulnerable and less vulnerable populations that might reflect different experiences by these groups over time. Disparities between vulnerable and less vulnerable groups were present but generally diminished over time as competition intensified, with noticeable differences between African American and Hispanic subpopulations regarding problems with plan information. The premise of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 was that more plans would increase competition, resulting in higher-quality healthcare services. However, an increased number of plan choices complicates the health plan decision-making process for beneficiaries. With further expansion of plans and choices following implementation of Part D, efforts must continue to direct informational materials to all beneficiaries, particularly those in vulnerable subgroups. More help in interpreting the information may be required to maximize consumer benefits.


Process outgrowth and synaptic varicosity formation by adult photoreceptors in vitro.
To assess the regenerative capability of the photoreceptor synapse, we have isolated and cultured photoreceptors from the mature salamander retina. Both rod and cone photoreceptors were able to regenerate processes within 3 d of plating. Cells extended numerous actin-containing filopodia as well as a few neuritic processes. The neurites contained microtubules and formed synaptic vesicle-filled varicosities, as shown by immunostaining for tubulin and synaptic vesicle proteins and by electron microscopy. Furthermore, regenerated varicosities were capable of depolarization-induced vesicle labeling, suggesting that they can recycle synaptic vesicles and release neurotransmitter by synaptic vesicle exocytosis. Differences were observed between rod and cone cell synaptic regeneration in vitro, which resembled structural differences between their synaptic terminals in situ: rod cells formed multiple synaptic vesicle-filled varicosities along neurites at a distance from the soma, whereas cone cells tended to accumulate synaptic vesicles within the soma. The regeneration of neurites and synaptic vesicle-filled varicosities was abolished by microtubule depolymerizing agents, suggesting a role for microtubule-based vesicle transport in the formation of varicosities. Finally, process outgrowth and varicosity formation were independent of cell-cell contact and, indeed, proceeded in the complete absence of other cells. These findings suggest not only that differentiated photoreceptors are capable of synaptic renewal but that the regeneration of presynaptic-like terminals is an intrinsic ability of rod and cone cells.


Efficient measurement of point-to-set correlations and overlap fluctuations in glass-forming liquids.
Cavity point-to-set correlations are real-space tools to detect the roughening of the free-energy landscape that accompanies the dynamical slowdown of glass-forming liquids. Measuring these correlations in model glass formers remains, however, a major computational challenge. Here, we develop a general parallel-tempering method that provides orders-of-magnitude improvement for sampling and equilibrating configurations within cavities. We apply this improved scheme to the canonical Kob-Andersen binary Lennard-Jones model for temperatures down to the mode-coupling theory crossover. Most significant improvements are noted for small cavities, which have thus far been the most difficult to study. This methodological advance also enables us to study a broader range of physical observables associated with thermodynamic fluctuations. We measure the probability distribution of overlap fluctuations in cavities, which displays a non-trivial temperature evolution. The corresponding overlap susceptibility is found to provide a robust quantitative estimate of the point-to-set length scale requiring no fitting. By resolving spatial fluctuations of the overlap in the cavity, we also obtain quantitative information about the geometry of overlap fluctuations. We can thus examine in detail how the penetration length as well as its fluctuations evolve with temperature and cavity size.


Activation of protein serine/threonine kinases p42, p63, and p87 in Rous sarcoma virus-transformed cells: signal transduction/transformation-dependent MBP kinases.
We have used myelin basic protein immobilized in sodium dodecyl sulfate-polyacrylamide gels to identify protein kinases after gel electrophoresis, followed by protein kinase reactions. This technique has permitted us to detect three protein kinases in serum-deprived cells transformed by p60src. On induction of cellular transformation by a temperature-sensitive v-src, a p87 protein kinase is activated within 30 min and remains activated in fully transformed cells. The p63 protein kinase is not fully activated until 24 h but remains activated in transformed cells. The commonly studied p42MBPK is rapidly activated within 30 min, and its kinase activity decreases significantly by 24 h, when the p63 enzyme is fully activated. The p42MBPK, as well as the p63 and p87 enzymes, are stimulated by transforming p60c-src mutants but not normal c-src or nonmyristylated p60c-src. In addition, the kinase activity of p63 enzyme, but not of p42MBPK, can be induced in okadaic acid-treated chicken embryo fibroblasts, indicating that phosphatase 2A and/or phosphatase 1 may be involved in the regulation of its activity. Additional data indicate that either p42MBPK or p63 activity correlates with the stimulation of the protein kinase p90RSK. Thus, there may be two independent pathways leading to the activation of the RSK gene product.


AAV vectors containing rDNA homology display increased chromosomal integration and transgene persistence.
Although recombinant adeno-associated viral (rAAV) vectors are promising tools for gene therapy of genetic disorders, they remain mostly episomal and hence are lost during cell replication. For this reason, rAAV vectors capable of chromosomal integration would be desirable. Ribosomal DNA (rDNA) repeat sequences are overrepresented during random integration of rAAV. We therefore sought to enhance AAV integration frequency by including 28S rDNA homology arms into our vector design. A vector containing ~1 kb of homology on each side of a cDNA expression cassette for human fumarylacetoacetate hydrolase (FAH) was constructed. rAAV of serotypes 2 and 8 were injected into Fah-deficient mice, a model for human tyrosinemia type 1. Integrated FAH transgenes are positively selected in this model and rDNA-containing AAV vectors had a ~30× higher integration frequency than controls. Integration by homologous recombination (HR) into the 28S rDNA locus was seen in multiple tissues. Furthermore, rDNA-containing AAV vectors for human factor IX (hFIX) demonstrated increased transgene persistence after liver regeneration. We conclude that rDNA containing AAV vectors may be superior to conventional vector design for the treatment of genetic diseases, especially those associated with increased hepatocyte replication.


CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients.
CD44, a cell surface glycoprotein, plays important roles in the development, progression, and metastasis of various tumor types. The aim of this study was to investigate how the expression of CD44 isoforms influences the interaction with hyaluronic acid (HA) and how differential isoform expression impacts antitumoral responses in vivo to treatment with RG7356, a humanized anti-CD44 antibody inhibiting CD44-HA interaction. CD44 isoform expression on various tumor cell lines was analyzed by RNASeq while data on patients with different tumor types were obtained from the publicly available TCGA RNASeq dataset as well as a phase I clinical study (NCT01358903). We analyzed the link between HA production and CD44 isoform expression as well as the consequences of blocking the CD44-mediated cell adhesion to HA using RG7356. The correlation between CD44 isoform expression and antitumor response to RG7356 treatment was investigated in the corresponding murine xenograft in vivo models as well as in a subset of patients treated with RG7356 from a recently completed phase I clinical trial. CD44 isoform expression, in particular expression of CD44s, is associated with HA production and predicts response to treatment with RG7356 in tumor xenograft models. Furthermore, patient data suggest that CD44 isoform status is a potential predictive biomarker for clinical response to treatment with RG7356. We provide new insights into the close interplay between CD44 and HA and a potential biomarker to enrich patient responses to RG7356 in the clinic.


Protective roles of trigonelline against oxalate-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells: An in vitro study.
Fibrogenesis is a common feature for all types of chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the main processes involving renal fibrosis and its inhibition is considered as a preventive/therapeutic strategy for CKD. Trigonelline (TRIG), a plant alkaloid commonly found in herbs, coffee bean, soy bean and other edible food plants, has several beneficial effects on human health and has been proposed to reduce renal fibrosis but with unclear mechanisms. This study thus addressed cellular mechanism underlying the anti-fibrogenic effects of TRIG in renal tubular epithelial cells grown in vitro. EMT was successfully induced by oxalate treatment as indicated by morphological changes into spindle-shape cells, increased expression of mesenchymal proteins (fibronectin, vimentin and α-smooth muscle actin (α-SMA)), decreased expression of epithelial proteins (E-cadherin and zonula occludens-1 (ZO-1)) and increased activity of a profibrotic factor (matrix metalloproteinase-9 (MMP-9)). Interestingly, these oxalate-induced EMT features could be attenuated by TRIG pretreatment. Moreover, TRIG also prevented oxalate-induced cell migration, reactive oxygen species (ROS) overproduction, and down-regulation of Nrf-2 signaling molecule. These data indicated that TRIG could attenuate the effects of oxalate-induced EMT and thus may serve as the anti-fibrotic compound for prevention and/or treatment of CKD.


An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice.
Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis due to M. tuberculosis (Mtb), which kills millions of people each year. BCG variably protects children, but not adults against tuberculosis. BCG evades phagosome maturation, autophagy, and reduces MHC-II expression of antigen-presenting cells (APCs) affecting T-cell activation. To bypass these defects, an autophagy-inducing, TLR-2 activating C5 peptide from Mtb-derived CFP-10 protein was overexpressed in BCG in combination with Ag85B. Recombinant BCG85C5 induced a robust MHC-II-dependent antigen presentation to CD4 T cells in vitro, and elicited stronger TH1 cytokines (IL-12, IL-1β, and TNFα) from APCs of C57Bl/6 mice increasing phosphorylation of p38MAPK and ERK. BCG85C5 also enhanced MHC-II surface expression of MΦs by inhibiting MARCH1 ubiquitin ligase that degrades MHC-II. BCG85C5 infected APCs from MyD88 or TLR-2 knockout mice showed decreased antigen presentation. Furthermore, BCG85C5 induced LC3-dependent autophagy in macrophages increasing antigen presentation. Consistent with in vitro effects, BCG85C5 markedly expanded both effector and central memory T cells in C57Bl/6 mice protecting them against both primary aerosol infection with Mtb and reinfection, but was less effective among TLR-2 knockout mice. Thus, BCG85C5 induces stronger and longer lasting immunity, and is better than BCG against tuberculosis of mice.


Foveal and parafoveal contrast suppression are different: Mechanisms revealed by the study of healthy aging.
Visual contextual effects enable inference regarding neural mechanisms of cortical function, principally because of similarities between the stimulus properties influencing human perception and those modifying primate visual cortical neural responses. Most neurophysiology assesses nonfoveal cellular function and circuitry, while most human studies are foveal. Here we use parafoveal stimuli to measure center-surround perception of contrast in older and younger adults. We measure the influence of both near and far surround because neurophysiology demonstrates different circuitry for these areas. Contrast suppression from the near surround was reduced in older observers, while that from the far surround was intact. Our results are consistent with reduced intracortical inhibition with age and normal extrastriate feedback. Interestingly, in the same older observers, foveal surround suppression of contrast was strengthened relative to younger adults, demonstrating a clear distinction between foveal and parafoveal center-surround behavior. We assume that underlying alterations in cortical neurotransmitter levels with age should not differ substantially between the areas of visual cortex representing foveal and near foveal regions. Consequently, our results suggest regional differences in center-surround circuitry. That older adults have varied contextual effects of visual contrast as a function of retinal eccentricity suggests complex effects of aging on scene and object perception.


The prevalence and correlates of undiagnosed HIV among Australian gay and bisexual men: results of a national, community-based, bio-behavioural survey.
Gay and bisexual men (GBM) with undiagnosed HIV are believed to contribute disproportionately to HIV transmission in Australia but national prevalence estimates have been lacking. From November 2013 to November 2014, we recruited men at gay venues and events in six Australian states and territories. Of 7291 survey participants, 3071 men also provided an oral fluid sample for testing and decided whether to receive their test results or not. We calculated raw and population-weighted prevalence estimates and identified associations with undiagnosed infection using logistic regression. Of 3071 participants, 213 men tested HIV-positive (6.9%, 95% confidence interval [CI] 6.0 to 7.8%), of whom 19 (8.9%, 95% CI 5.8 to 13.5%) were previously undiagnosed. After weighting for the size of the gay and bisexual male population in each state or territory, national HIV prevalence was estimated to be 7.2% (95% CI 6.3 to 8.1), of which 9.1% (95% CI 6.0 to 13.6%) were estimated to be undiagnosed. Compared with HIV-negative participants, men with undiagnosed HIV were more likely to report meeting partners at sex venues, using antiretroviral drugs as pre-exposure prophylaxis, condomless anal intercourse with casual partners, using party drugs for sex, injecting drugs and using amyl nitrite, crystal methamphetamine or gamma hydroxybutyrate in the six months prior to the survey. The results indicate that the prevalence of undiagnosed HIV is relatively low among Australian GBM but is higher among men who report riskier sex and drug practices. The results underline the importance of targeted HIV prevention and frequent testing for men at increased risk of infection.


Evaluation of the LFA-REAL clinician-reported outcome (ClinRO) and patient-reported outcome (PRO): data from the Peruvian Almenara Lupus Cohort.
The Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL) clinician-reported outcome (ClinRO) and the LFA-REAL patient-reported outcome (PRO) were developed in order to capture manifestations of SLE from the perspective of both the clinician and the patient. The aim of this study is to compare the LFA-REAL ClinRO and PRO with other lupus disease activity measures. A cross-sectional analysis of patients from a single-centre cohort was performed using Spearman's correlation. Disease activity measures included were LFA-REAL ClinRO (range 0-1400), LFA-REAL PRO (range 0-1200), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), clinical SLEDAI-2K and Physician Global Assessment (PGA, range 0-100). Two hundred and twenty-seven patients with SLE were studied. The mean age was 46.3 (SD: 13.8); 212 (93.4%) were female. The mean (SD) LFA-REAL ClinRO was 25.4 (34.7), LFA-REAL PRO was 241.1 (187.6), PGA was 11.9 (15.4), SLEDAI-2K was 2.3 (3.3) and clinical SLEDAI-2K was 1.6 (2.9). The LFA-REAL ClinRO correlated with PGA (r=0.758, p<0.001), SLEDAI-2K (r=0.608, p<0.001) and clinical SLEDAI-2K (r=0.697, p<0.001); the LFA-REAL PRO correlated modestly with PGA (r=0.160, p=0.016), SLEDAI-2K (r=0.121, p=0.069), clinical SLEDAI-2K (r=0.143, p=0.031) and LFA-REAL ClinRO (r=0.161, p=0.015). The LFA-REAL ClinRO and the LFA-REAL PRO had good and weak correlations, respectively, with several physician-based disease activity measures in a cross-sectional study, suggesting their potential usefulness in establishing disease severity. Longitudinal studies will be required to determine their value in monitoring patients with SLE.


Socioeconomic Costs and Health Inequalities from Psoriasis: A Cohort Study.
To date, there are no nationwide studies of the social and economic burden of psoriasis to patients in Denmark. Incentives for health care management based on patient-related outcomes and value (IMPROVE) in psoriasis and psoriatic arthritis is a project aimed at assisting movement from activity-based to outcome-based health care management. One of the key objectives in IMPROVE is to describe the disease-associated socioeconomic burden of psoriasis. A case-matched study of the impact of psoriasis on patients' income, employment and health care costs in Denmark was performed. The IMPROVE study was a retrospective analysis of patients with a hospital diagnosis of psoriasis identified from the Danish National Patient Registry (NPR). In total, 13,025 psoriasis patients and 25,629 matched controls were identified from the NPR. Data from psoriasis patients and matched controls were compared for social and economic factors including income, employment, health care costs and risk of comorbidities. Psoriasis was associated with increased health care costs (mean annual costs +116% compared to control, p < 0.001), peaking in the year of referral to hospital for psoriasis and sustained thereafter. Both direct and indirect costs were significantly higher for patients with psoriasis than controls (p < 0.001). In the years before and immediately following hospital diagnosis, the rates of employment were lower in psoriasis patients than controls. Comorbidities, including cardiovascular (odds ratio 1.93 [95% CI 1.77-2.09]) and psychiatric conditions (odds ratio 2.61 [95% CI 2.30-2.97]), were more prevalent in patients with psoriasis than controls. In Denmark, psoriasis has a significant impact on health care costs, income and employment, and is associated with a range of comorbidities.


Omega-3 and omega-6 content of medicinal foods for depressed patients: implications from the Iranian Traditional Medicine.
Considering the increasing prevalence of depression in modern societies and the positive effects of omega-3 polyunsaturated fatty acids on depression, this study aims to investigate the omega-3 and omega-6 content of various foodstuffs, prescribed or prohibited by Iranian Traditional Medicine (ITM). Firstly, reliable sources of Iranian Traditional Medicine were reviewed in order to identify the prescribed and prohibited foodstuffs for depressed patients. Afterwards, according to the online database of United States Department of Agriculture (URL: http://ndb.nal.usda.gov/ndb/search/list), the ratio of linoleic acid to alpha linolenic acid (as representatives of omega-6 and omega-3, respectively) was identified in each foodstuff. Finally, the ratios of omega-6 to omega-3 were compared between seven food groups of vegetables, fruits, dry goods, high protein products, dairies, breads, and spices. Based on the resources of Iranian Traditional Medicine, the following foods are prescribed for depressed patients: basil, coriander, spinach, lettuce, squash, peppermint, dill, chicory, celery, beet, quince, cucumber, watermelon, grape, peach, pomegranate, banana, apple, currant, pistachio, dried fig, almond, egg, chicken, lamb, trout, milk, bread without bran, saffron, oregano, and coriander seeds. On the other hand, cabbage, eggplant, onion, garlic, broad beans, lentils, beef, whole wheat bread, and mustard are prohibited. It should be noted that omega-3 content in some prescribed foods is more than that of the prohibited ones. The present study showed that mint, basil, spinach, lettuce, squash, lamb, saffron, oregano, cucumber, pistachio, milk, and also wild trout can be considered as medicinal foods for depressed patients.


Epigenetic control of female puberty.
The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as principal contributors to this mechanism and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreased and methylation of their promoters increased before puberty. Inhibiting DNA methylation blocked both events and resulted in pubertal failure. The pubertal increase in Kiss1 expression was accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupted pulsatile gonadotropin-releasing hormone release, delayed puberty and compromised fecundity. Our results identify epigenetic silencing as a mechanism underlying the neuroendocrine control of female puberty.


Potential alternative progestin therapy for low-grade endometrial stromal sarcoma: A case report.
Low-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine tumor that sometimes recurs and advances. Hormonal treatment, especially high-dose progestins and aromatase inhibitors (AIs), has demonstrated efficacy against these tumors. Because the standard treatment period is uncertain and hormonal treatment is effective, hormonal agents are likely to be used long-term, especially when a residual tumor is present. However, the long-term use of high-dose progestins and AIs may cause thromboembolism, as well as musculoskeletal stiffness and pain. Dienogest, a relatively new progestin, has demonstrated safety after long-term administration; it also appears to have a more favorable long-term safety profile compared with other progestins and AIs. We encountered a young patient with recurrent LG-ESS that metastasized to the liver and exhibited resistance to high-dose medroxyprogesterone acetate (MPA). The patient was successfully treated with dienogest monotherapy. This is the first report describing the efficacy of dienogest against recurrent and metastatic LG-ESS that is resistant to MPA and other agents.


Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study.
The purpose of this study was to investigate the effects of vegan diet in patients with rheumatoid arthritis (RA) on blood lipids oxidized low-density lipoprotein (oxLDL) and natural atheroprotective antibodies against phosphorylcholine (anti-PCs). Sixty-six patients with active RA were randomly assigned to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 year. Thirty patients in the vegan group completed more than 3 months on the diet regimen. Blood lipids were analyzed by routine methods, and oxLDL and anti-PCs were analyzed by enzyme-linked immunosorbent assay. Data and serum samples were obtained at baseline and after 3 and 12 months. Mean ages were 50.0 years for the vegan group and 50.8 years for controls. Gluten-free vegan diet induced lower body mass index (BMI) and low-density lipoprotein (LDL) and higher anti-PC IgM than control diet (p < 0.005). In the vegan group, BMI, LDL, and cholesterol decreased after both 3 and 12 months (p < 0.01) and oxLDL after 3 months (p = 0.021) and trendwise after 12 months (p = 0.090). Triglycerides and high-density lipoprotein did not change. IgA anti-PC levels increased after 3 months (p = 0.027) and IgM anti-PC levels increased trendwise after 12 months (p = 0.057). There was no difference in IgG anti-PC levels. In the control diet group, IgM anti-PC levels decreased both after 3 and 12 months (p < 0.01). When separating vegan patients into clinical responders and non-responders at 12 months, the effects on oxLDL and anti-PC IgA were seen only in responders (p < 0.05). A gluten-free vegan diet in RA induces changes that are potentially atheroprotective and anti-inflammatory, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels.


Evoked and spontaneous pain assessment during tooth pulp injury.
Injury of the tooth pulp is excruciatingly painful and yet the receptors and neural circuit mechanisms that transmit this form of pain remain poorly defined in both the clinic and preclinical rodent models. Easily quantifiable behavioral assessment in the mouse orofacial area remains a major bottleneck in uncovering molecular mechanisms that govern inflammatory pain in the tooth. In this study we sought to address this problem using the Mouse Grimace Scale and a novel approach to the application of mechanical Von Frey hair stimuli. We use a dental pulp injury model that exposes the pulp to the outside environment, a procedure we have previously shown produces inflammation. Using RNAscope technology, we demonstrate an upregulation of genes that contribute to the pain state in the trigeminal ganglia of injured mice. We found that mice with dental pulp injury have greater Mouse Grimace Scores than sham within 24 hours of injury, suggestive of spontaneous pain. We developed a scoring system of mouse refusal to determine thresholds for mechanical stimulation of the face with Von Frey filaments. This method revealed that mice with a unilateral dental injury develop bilateral mechanical allodynia that is delayed relative to the onset of spontaneous pain. This work demonstrates that tooth pain can be quantified in freely behaving mice using approaches common for other types of pain assessment. Harnessing these assays in the orofacial area during gene manipulation should assist in uncovering mechanisms for tooth pulp inflammatory pain and other forms of trigeminal pain.


ISP: an optimal out-of-core image-set processing streaming architecture for parallel heterogeneous systems.
Image population analysis is the class of statistical methods that plays a central role in understanding the development, evolution, and disease of a population. However, these techniques often require excessive computational power and memory that are compounded with a large number of volumetric inputs. Restricted access to supercomputing power limits its influence in general research and practical applications. In this paper we introduce ISP, an Image-Set Processing streaming framework that harnesses the processing power of commodity heterogeneous CPU/GPU systems and attempts to solve this computational problem. In ISP, we introduce specially designed streaming algorithms and data structures that provide an optimal solution for out-of-core multiimage processing problems both in terms of memory usage and computational efficiency. ISP makes use of the asynchronous execution mechanism supported by parallel heterogeneous systems to efficiently hide the inherent latency of the processing pipeline of out-of-core approaches. Consequently, with computationally intensive problems, the ISP out-of-core solution can achieve the same performance as the in-core solution. We demonstrate the efficiency of the ISP framework on synthetic and real datasets.


Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones.
In our quest for new antibiotics able to address the growing threat of multidrug resistant infections caused by Gram-negative bacteria, we have investigated an unprecedented series of non-quinolone bacterial topoisomerase inhibitors from the Sanofi patrimony, named IPYs for imidazopyrazinones, as part of the Innovative Medicines Initiative (IMI) European Gram Negative Antibacterial Engine (ENABLE) organization. Hybridization of these historical compounds with the quinazolinediones, a known series of topoisomerase inhibitors, led us to a novel series of tricyclic IPYs that demonstrated potential for broad spectrum activity, in vivo efficacy, and a good developability profile, although later profiling revealed a genotoxicity risk. Resistance studies revealed partial cross-resistance with fluoroquinolones (FQs) suggesting that IPYs bind to the same region of bacterial topoisomerases as FQs and interact with at least some of the keys residues involved in FQ binding.


Bayesian combination of multiple plasma glucose predictors.
This paper presents a novel on-line approach of merging multiple different predictors of plasma glucose into a single optimized prediction. Various different predictors are merged by recursive weighting into a single prediction using regularized optimization. The approach is evaluated on 12 data sets of type I diabetes data, using three parallel predictors. The performance of the combined prediction is better, or in par, with the best predictor for each evaluated data set. The results suggest that the outlined method could be a suitable way to improve prediction performance when using multiple predictors, or as a means to reduce the risk associated with definite a priori model selection.


Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research.
Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.


Genomic and protein structural maps of adaptive evolution of human influenza A virus to increased virulence in the mouse.
Adaptive evolution is characterized by positive and parallel, or repeated selection of mutations. Mouse adaptation of influenza A virus (IAV) produces virulent mutants that demonstrate positive and parallel evolution of mutations in the hemagglutinin (HA) receptor and non-structural protein 1 (NS1) interferon antagonist genes. We now present a genomic analysis of all 11 genes of 39 mouse adapted IAV variants from 10 replicate adaptation experiments. Mutations were mapped on the primary and structural maps of each protein and specific mutations were validated with respect to virulence, replication, and RNA polymerase activity. Mouse adapted (MA) variants obtained after 12 or 20-21 serial infections acquired on average 5.8 and 7.9 nonsynonymous mutations per genome of 11 genes, respectively. Among a total of 115 nonsynonymous mutations, 51 demonstrated properties of natural selection including 27 parallel mutations. The greatest degree of parallel evolution occurred in the HA receptor and ribonucleocapsid components, polymerase subunits (PB1, PB2, PA) and NP. Mutations occurred in host nuclear trafficking factor binding sites as well as sites of virus-virus protein subunit interaction for NP, NS1, HA and NA proteins. Adaptive regions included cap binding and endonuclease domains in the PB2 and PA polymerase subunits. Four mutations in NS1 resulted in loss of binding to the host cleavage and polyadenylation specificity factor (CPSF30) suggesting that a reduction in inhibition of host gene expression was being selected. The most prevalent mutations in PB2 and NP were shown to increase virulence but differed in their ability to enhance replication and demonstrated epistatic effects. Several positively selected RNA polymerase mutations demonstrated increased virulence associated with >300% enhanced polymerase activity. Adaptive mutations that control host range and virulence were identified by their repeated selection to comprise a defined model for studying IAV evolution to increased virulence in the mouse.


Does competition really bring out the worst? Testosterone, social distance and inter-male competition shape parochial altruism in human males.
Parochial altruism, defined as increased ingroup favoritism and heightened outgroup hostility, is a widespread feature of human societies that affects altruistic cooperation and punishment behavior, particularly in intergroup conflicts. Humans tend to protect fellow group members and fight against outsiders, even at substantial costs for themselves. Testosterone modulates responses to competition and social threat, but its exact role in the context of parochial altruism remains controversial. Here, we investigated how testosterone influences altruistic punishment tendencies in the presence of an intergroup competition. Fifty male soccer fans played an ultimatum game (UG), in which they faced anonymous proposers that could either be a fan of the same soccer team (ingroup) or were fans of other teams (outgroups) that differed in the degree of social distance and enmity to the ingroup. The UG was played in two contexts with varying degrees of intergroup rivalry. Our data show that unfair offers were rejected more frequently than fair proposals and the frequency of altruistic punishment increased with increasing social distance to the outgroups. Adding an intergroup competition led to a further escalation of outgroup hostility and reduced punishment of unfair ingroup members. High testosterone levels were associated with a relatively increased ingroup favoritism and also a change towards enhanced outgroup hostility in the intergroup competition. High testosterone concentrations further predicted increased proposer generosity in interactions with the ingroup. Altogether, a significant relation between testosterone and parochial altruism could be demonstrated, but only in the presence of an intergroup competition. In human males, testosterone may promote group coherence in the face of external threat, even against the urge to selfishly maximize personal reward. In that way, our observation refutes the view that testosterone generally promotes antisocial behaviors and aggressive responses, but underlines its rather specific role in the fine-tuning of male social cognition.


Fighting Dog-Mediated Rabies in Namibia-Implementation of a Rabies Elimination Program in the Northern Communal Areas.
The major part of the global burden of dog-mediated rabies falls on Africa and Asia, where still an estimated 60,000 people die of the disease annually. Like in many African countries, dog-mediated rabies is a major public health concern in Namibia, costing the country an estimated 242 human deaths during the past two decades, in particular in the Northern Communal Areas (NCAs). Consequently, under the "One Health" concept, the Namibian government adopted a National Rabies Control Strategy in 2015, which strives to contribute to the global goal of ending dog-mediated human rabies deaths by 2030. A key component of this strategy was the implementation a dog rabies elimination program in the NCAs in 2016, being designed as a stepwise regional rollout strategy by building on experience gained in a pilot project area. The area of implementation covers approximately 263,376 km2 and 64 constituencies, with around 1.2 million inhabitants and estimated 93,000 dogs.


Plasmodium sporozoite disintegration during skin passage limits malaria parasite transmission.
During transmission of malaria-causing parasites from mosquitoes to mammals, Plasmodium sporozoites migrate rapidly in the skin to search for a blood vessel. The high migratory speed and narrow passages taken by the parasites suggest considerable strain on the sporozoites to maintain their shape. Here, we show that the membrane-associated protein, concavin, is important for the maintenance of the Plasmodium sporozoite shape inside salivary glands of mosquitoes and during migration in the skin. Concavin-GFP localizes at the cytoplasmic periphery and concavin(-) sporozoites progressively round up upon entry of salivary glands. Rounded concavin(-) sporozoites fail to pass through the narrow salivary ducts and are rarely ejected by mosquitoes, while normally shaped concavin(-) sporozoites are transmitted. Strikingly, motile concavin(-) sporozoites disintegrate while migrating through the skin leading to parasite arrest or death and decreased transmission efficiency. Collectively, we suggest that concavin contributes to cell shape maintenance by riveting the plasma membrane to the subtending inner membrane complex. Interfering with cell shape maintenance pathways might hence provide a new strategy to prevent a malaria infection.


Transcription factor Sp4 is required for hyperalgesic state persistence.
Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist-capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.


Five year long term results of total joint arthroplasties in the treatment of trapeziometacarpal osteoarthritis.
Trapeziometacarpal (TMC) osteoarthritis is a common disease. Patients with advanced disease who have failed conservative treatment have different surgical options, including total joint prosthesis. The aim of this study was to investigate the long-term outcome and complications of trapeziometacarpal (TMC) total arthroplasty. One hundred and forty-seven patients with TMC osteoarthritis were surgically treated with TMC arthroplasty, and one hundred and thirty-seven patients were seen for follow-up (102 women and 35 men). At follow -up patients were asked to complete a visual linearanalogue scale (VAS) for satisfaction with the result of the operation and persisting pain from the thumb, the Spanish validated Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire was used to evaluate function of the affected hand.(9) The radiological examination consisted of posterior-anterior and oblique radiographs. In preoperative radiographs Eaton-Little was used, and in postoperative radiographs were assessed with regard to implant loosening and alignment. The subjective outcome was satisfactory in 126 cases (92 %), 14 (12 %) patients would undergo the same procedure in the other hand. The DASH questionnaireswere 19.55 (range 5.6-33,5) on average, and EVA was 1 on average. The mean key pinch strength was 5.8 Kg at 5 years follow-up. The most frequent postoperative complication was De Quervain tenosynovitis (21%), other complications were: Cup loosening (3.6%), traumatic dislocation (3,6%). The prosthesis was removed in nine cases (7%). There were four intraoperative complications. The survival rate for ARPE prosthesis was 92,7% at 60,5 months. TMC total arthroplasty offers a reliable treatment alternative in patients with thumb carpometacarpal joint osteoarthrosis which conservatives' treatment had failed. The TMC joint prosthesis is an option for patients with TCM osteoarthritis, provides satisfactory outcomes and has a low failure rate.(www.actabiomedica.it).


Midlife reactions to mastectomy and subsequent breast reconstruction.
The well-documented psychological disturbances that follow mastectomy have been said to be less frequent and intense in postclimacteric women. Data from our interviews with mastectomy patients, 12 of whom were postclimacteric, indicate otherwise. Their distress was often outwardly different, but inwardly still traumatic. During frequent, open-ended interviews, feelings were revealed of loss, depression, and shame about sexual feelings that the patients believed to be inappropriate to their age. These revelations were facilitated by the frequency of the interviews, the decreasing unconscious use of denial as time passed, and the knowledge of the possibility of breast reconstruction. The patients' need to pretend to themselves and others that the mastectomy was relatively unimportant added an extra burden to the usual stress of coping with midlife anxieties. Reconstruction decreased the mastectomized woman's feelings of dependence and mutilation.


A tactile sensor using single layer graphene for surface texture recognition.
Tactile sensors capable of texture recognition are essential for artificial skin functions. In this work, we describe a tactile sensor with a single sensor architecture made of single layer graphene that can recognize surface texture based on the roughness of the interacting surface. Resistance changes due to the local deformation of a local area of the single layer graphene are reflected in the resistance of the entire sensor. By introducing microstructures inspired by human finger prints, surface texture was successfully defined through fast Fourier transform analysis, and spatial resolution was easily achievable. This work provides a simple method utilizing a single sensor for surface texture recognition at the level of human sensation without using a matrix architecture which requires high density integration technology with force and vibration sensor elements.


Rapid Functional and Sequence Differentiation of a Tandemly Repeated Species-Specific Multigene Family in Drosophila.
Gene clusters of recently duplicated genes are hotbeds for evolutionary change. However, our understanding of how mutational mechanisms and evolutionary forces shape the structural and functional evolution of these clusters is hindered by the high sequence identity among the copies, which typically results in their inaccurate representation in genome assemblies. The presumed testis-specific, chimeric gene Sdic originated, and tandemly expanded in Drosophila melanogaster, contributing to increased male-male competition. Using various types of massively parallel sequencing data, we studied the organization, sequence evolution, and functional attributes of the different Sdic copies. By leveraging long-read sequencing data, we uncovered both copy number and order differences from the currently accepted annotation for the Sdic region. Despite evidence for pervasive gene conversion affecting the Sdic copies, we also detected signatures of two episodes of diversifying selection, which have contributed to the evolution of a variety of C-termini and miRNA binding site compositions. Expression analyses involving RNA-seq datasets from 59 different biological conditions revealed distinctive expression breadths among the copies, with three copies being transcribed in females, opening the possibility to a sexually antagonistic effect. Phenotypic assays using Sdic knock-out strains indicated that should this antagonistic effect exist, it does not compromise female fertility. Our results strongly suggest that the genome consolidation of the Sdic gene cluster is more the result of a quick exploration of different paths of molecular tinkering by different copies than a mere dosage increase, which could be a recurrent evolutionary outcome in the presence of persistent sexual selection.


Theoretical predictions of wurtzite III-nitride nano-materials properties.
In this paper, top-down and bottom-up approaches are used to predict material properties of group III-nitride nanostructures. The first approach calculates the melting temperature, melting enthalpy, Debye temperature and energy bandgap of InN, GaN and AlN through classical thermodynamics. The second approach calculates the surface energies in the liquid and solid states of the considered nitrides materials through molecular dynamics. Moreover, the liquid and solid surface energies of the zinc-blende and wurtzite III-V materials are compared. Finally, the phase diagram of a ternary III-nitride nanomaterial, AlGaN, is presented and the variation of its energy bandgap with composition is predicted.


Municipal wastewater effluent affects fish communities: A multi-year study involving two wastewater treatment plants.
Although effluent from municipal wastewater treatment plants (WWTPs) is a major stressor in receiving environments, relatively few studies have addressed how its discharge affects natural fish communities. Here, we assessed fish community composition over three years along a gradient of effluent exposure from two distinct WWTPs within an International Joint Commission Area of Concern on the Great Lakes (Hamilton Harbour, Canada). We found that fish communities changed with distance from both WWTPs, and were highly dissimilar between sites that were closest to and furthest from the wastewater outfall. Despite differences in the size and treatment technology of the WWTPs and receiving habitats downstream, we found that the sites nearest the outfalls had the highest fish abundances and contained a common set of signature fish species (i.e., round goby Neogobius melanostomus, green sunfish Lepomis cyanellus). Non-native and stress tolerant species were also more abundant near one of the studied WWTPs when compared to the reference site, and the number of young-of-the-year fish collected did not vary along the effluent exposure gradients. Overall, we show that fish are attracted to wastewater outfalls raising the possibility that these sites may act as an ecological trap.


The bone disease of preterm birth: a biomechanical perspective.
The bone disease of preterm birth has traditionally been explained by a decrease in bone formation from insufficient availability of calcium and phosphorus. However, there is emerging evidence that there is increased bone resorption in the bone disease of preterm birth, an observation that indicates some other explanation for this condition. The biomechanical model of postnatal bone formation states that, through a regulatory feedback system in the bone called the mechanostat, bone is able to respond to increased bone loading by increasing bone strength and to decreased bone loading by decreasing bone strength. It is suggested that this increased bone resorption in the markedly preterm infant compared with the term infant is secondary to decreased bone loading. Application of this model to the fetus and preterm infant suggests that intrauterine bone loading of the fetus from movement and kicking against the uterus is critical for normal fetal bone formation. The associated muscle growth from this activity also contributes to bone loading. The markedly preterm infant is deprived of much of this critical time period of intrauterine bone accretion, and bone formation occurs in the less favorable extrauterine environment, where there is significantly less bone loading.


Automatic imitation.
"Automatic imitation" is a type of stimulus-response compatibility effect in which the topographical features of task-irrelevant action stimuli facilitate similar, and interfere with dissimilar, responses. This article reviews behavioral, neurophysiological, and neuroimaging research on automatic imitation, asking in what sense it is "automatic" and whether it is "imitation." This body of research reveals that automatic imitation is a covert form of imitation, distinct from spatial compatibility. It also indicates that, although automatic imitation is subject to input modulation by attentional processes, and output modulation by inhibitory processes, it is mediated by learned, long-term sensorimotor associations that cannot be altered directly by intentional processes. Automatic imitation provides an important tool for the investigation of the mirror neuron system, motor mimicry, and complex forms of imitation. It is a new behavioral phenomenon, comparable with the Stroop and Simon effects, providing strong evidence that even healthy adult humans are prone, in an unwilled and unreasoned way, to copy the actions of others.


Nanomechanics of lipid bilayers: heads or tails?
Understanding the effect of mechanical stress on membranes is of primary importance in biophysics. Here we use force spectroscopy AFM to quantitatively characterize the nanomechanical stability of supported lipid bilayers as a function of their chemical composition. The onset of plastic deformation reveals itself as a repetitive jump in the approaching force curve, which represents a molecular fingerprint for the bilayer mechanical stability. By systematically probing a set of chemically distinct supported lipid bilayers (SLBs), we first show that both the headgroup and tail have a decisive effect on their mechanical properties. While the mechanical stability of the probed SLBs linearly increases by 3.3 nN upon the introduction of each additional -CH(2)- in the chain, it exhibits a significant dependence on the phospholipid headgroup, ranging from 3 nN for DPPA to 66 nN for DPPG. Furthermore, we also quantify the reduction of the membrane mechanical stability as a function of the number of unsaturations and molecular branching in the chemical structure of the apolar tails. Finally, we demonstrate that, upon introduction of cholesterol and ergosterol, contrary to previous belief the mechanical stability of membranes not only increases linearly in the liquid phase (DLPC) but also for phospholipids present in the gel phase (DPPC). Our results are discussed in the framework of the continuum nucleation model. This work highlights the compelling effect of subtle variations in the chemical structure of phospholipid molecules on the membrane response when exposed to mechanical forces, a mechanism of common occurrence in nature.


Cultural diversity and saccade similarities: culture does not explain saccade latency differences between Chinese and Caucasian participants.
A central claim of cultural neuroscience is that the culture to which an individual belongs plays a key role in shaping basic cognitive processes and behaviours, including eye movement behaviour. We previously reported a robust difference in saccade behaviour between Chinese and Caucasian participants; Chinese participants are much more likely to execute low latency express saccades, in circumstances in which these are normally discouraged. To assess the extent to which this is the product of culture we compared a group of 70 Chinese overseas students (whose primary cultural exposure was that of mainland China), a group of 45 participants whose parents were Chinese but who themselves were brought up in the UK (whose primary cultural exposure was western European) and a group of 70 Caucasian participants. Results from the Schwartz Value Survey confirmed that the UK-Chinese group were culturally similar to the Caucasian group. However, their patterns of saccade latency were identical to the mainland Chinese group, and different to the Caucasian group. We conclude that at least for the relatively simple reflexive saccade behaviour we have investigated, culture cannot explain the observed differences in behaviour.


The immune response fails to control HIV early in initial virus spread.
Discontinued antiretroviral therapy (ART) results in uncontrolled HIV replication in most cases. How the virus population that persists during ART escapes immune control remains unknown. In this issue of the JCI, Mitchell and authors investigated plasmacytoid dendritic cells (pDCs) from the blood of individuals living with HIV. After ART was discontinued and as the virus began to spread, an apparently functional pDC response emerged. Notably, these pDCs were initially capable of producing high levels of type I IFN, but rapidly lost this capacity, even before the virus became readily detectable in blood. This study suggests that dysfunctional pDCs are a key initial mechanism associated with poor HIV control. These innate immune responses might be targeted in the emerging efforts to cure HIV disease.