Anatomy and osteohistology of the basal hadrosaurid dinosaur Eotrachodon from the uppermost Santonian (Cretaceous) of southern Appalachia.
The cranial and postcranial anatomy of the basal hadrosaurid dinosaur Eotrachodon orientalis, from the uppermost Santonian of southern Appalachia (southeastern U.S.A.), is described in detail. This animal is the only known pre-Campanian non-lambeosaurine hadrosaurid, and the most complete hadrosauroid known from Appalachia. E. orientalis possesses a mosaic of plesiomorphic and derived characters in the context of Hadrosauroidea. Characters shared with basal hadrosauroids include a short and sloping maxillary ectopterygoid shelf, caudally prominent maxillary jugal process, one functional tooth per alveolus on the maxillary occlusal plane, a jugal rostral process with a shallow caudodorsal margin and medioventrally facing articular facet, a vertical dentary coronoid process with a poorly expanded apex, and tooth crowns with accessory ridges. Derived characters shared with other hadrosaurids include a circumnarial depression compartmented into three fossae (as in brachylophosaurins and Edmontosaurus), a thin everted premaxillary oral margin (as in Gryposaurus, Prosaurolophus, and Saurolophus), and a maxilla with a deep and rostrocaudally extensive rostrodorsal region with a steeply sloping premaxillary margin (as in Gryposaurus). Eotrachodon orientalis differs primarily from the other hadrosauroid from the Mooreville Chalk of Alabama, Lophorhothon atopus, in having a slender and crestless nasal whose caudodorsal margin is not invaded by the circumnarial depression. Hadrosaurus foulkii, the only other known hadrosaurid from Appalachia, is distinct from E. orientalis in having dentary teeth lacking accessory ridges and a dorsally curved shaft of the ischium. A histological section of the tibia of the E. orientalis holotype (MSC 7949) suggests that this individual was actively growing at the time of death and, thus, had the potential to become a larger animal later in development.


Informal care and home-based palliative care: the health-related quality of life of carers.
Health is an important factor in the capacity of family and friends (informal carers) to continue providing care for palliative care patients at home. This study investigates associations between the health-related quality of life (HRQOL) of current informal carers and characteristics of the carers and their caregiving situation, in a sample of Australian carers of palliative care patients. The cross-sectional study used the Short Form-36 Health Survey to measure HRQOL. It found carers to have better physical health and worse mental health than the general population. Of 178 carers, 35% reported their health to be worse than it was one year ago. Multiple regression analyses found that the HRQOL of carers whose health had deteriorated in the previous year was associated with the patient's care needs but not the carer's time input, unlike the carers reporting stable health. Clinicians caring for palliative care patients should be alert to the potential health impairments of informal carers and ensure that they are adequately supported in their caregiving role and have access to appropriate treatment and preventive health care.


Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages.
Tyrosine kinase inhibitors (TKIs) are used in the clinical management of hematological neoplasms. Moreover, in solid tumors such as stage 4 neuroblastomas (NB), imatinib showed benefits that might depend on both on-target and immunological off-target effects. We investigated the effects of imatinib and nilotinib on human NK cells, monocytes, and macrophages. High numbers of monocytes died upon exposure to TKI concentrations similar to those achieved in patients. Conversely, NK cells were highly resistant to the TKI cytotoxic effect, were properly activated by immunostimulatory cytokines, and degranulated in the presence of NB cells. In NB, neither drug reduced the expression of ligands for activating NK receptors or upregulated that of HLA class I, B7-H3, PD-L1, and PD-L2, molecules that might limit NK cell function. Interestingly, TKIs modulated the chemokine receptor repertoire of immune cells. Acting at the transcriptional level, they increased the surface expression of CXCR4, an effect observed also in NK cells and monocytes of patients receiving imatinib for chronic myeloid leukemia. Moreover, TKIs reduced the expression of CXCR3 (in NK cells) and CCR1 (in monocytes). Monocytes also decreased the expression of M-CSFR, and low numbers of cells underwent differentiation toward macrophages. M0 and M2 macrophages were highly resistant to TKIs and maintained their phenotypic and functional characteristics. Importantly, also in the presence of TKIs, the M2 immunosuppressive polarization was reverted by TLR engagement, and M1-oriented macrophages fully activated autologous NK cells. Our results contribute to better interpreting the off-target efficacy of TKIs in tumors and to envisaging strategies aimed at facilitating antitumor immune responses.


A human vision based computational model for chromatic texture segregation.
We have developed a computational model for texture perception which has physiological relevance and correlates well with human performance. The model attempts to simulate the visual processing characteristics by incorporating mechanisms tuned to detect luminance-polarity, orientation, spatial frequency and color, which are characteristic features of any textural image. We obtained a very good correlation between the model's simulation results and data from psychophysical experiments with a systematically selected set of visual stimuli with texture patterns defined by spatial variations in color, luminance, and orientation. In addition, the model predicts correctly texture segregation performance with key benchmarks and natural textures. This represents a first effort to incorporate chromatic signals in texture segregation models of psychophysical relevance, most of which have treated grey-level images so far. Another novel feature of the model is the extension or the concept of spatial double opponency to domains beyond color, such as orientation and spatial frequency. The model has potential applications in the areas of image processing, machine vision and pattern recognition, and scientific visualization.


Alcohol abuse and cigarette smoking are associated with global DNA hypermethylation: results from the German Investigation on Neurobiology in Alcoholism (GINA).
Recent studies have shown that smoking and alcoholism may be associated with altered DNA methylation and that alcohol consumption might induce changes in DNA methylation by altering homocysteine metabolism. In this monocenter study, we included 363 consecutive patients referred for hospitalization for alcohol detoxification treatment. Blood samples were obtained on treatment days 1, 3, and 7 for measurement of global DNA methylation in leukocytes by liquid chromatography tandem mass spectrometry. Genomic DNA was used for genotyping the following seven genetic variants of homocysteine metabolism: cystathionine beta-synthase (CBS) c.844_855ins68, dihydrofolate-reductase (DHFR) c.594 + 59del19bp, methylenetetrahydrofolate-reductase (MTHFR) c.677C > T and c.1298A > C, methyltetrahydrofolate-transferase (MTR) c.2756A > G, reduced folate carrier 1 (RFC1) c.80G > A, and transcobalamin 2 c.776C > G. Multivariate linear regression showed a positive correlation of global DNA methylation with alcohol consumption and smoking on day 1 of hospitalization. DNA methylation was not correlated with homocysteine or vitamin plasma levels, nor with the tested genetic variants of homocysteine metabolism. This suggests a direct effect of alcohol consumption and smoking on DNA methylation, which is not mediated by effects of alcohol on homocysteine metabolism.


Longitudinal patterns of methamphetamine, popper (amyl nitrite), and cocaine use and high-risk sexual behavior among a cohort of san francisco men who have sex with men.
Most prior studies examining drug use among men who have sex with men (MSM) have been cross-sectional or retrospective and have not determined whether periods of increased drug use are associated with high-risk sexual behavior at the individual level. In this article, we describe patterns of use of methamphetamines, poppers, and sniffed cocaine and sexual risk behavior among 736 San Francisco MSM enrolled in the EXPLORE study and followed for up to 48 months. In longitudinal analysis, use of methamphetamines, poppers, and sniffed cocaine declined during follow-up. However, compared with older participants, younger participants were more likely to increase their drug use over time. Results of conditional logistic regression demonstrated that high-risk sexual behavior was more common during reporting periods characterized by increased methamphetamine, poppers, or sniffed cocaine use. This within-person analysis found that compared with periods of no drug use, periods of both light drug use (less than weekly use of drugs) and heavier drug use (at least weekly use of at least one drug) were significantly associated with increased risk of engaging in unprotected anal sex with an HIV-positive or unknown-status partner. These results suggest that even intermittent, recreational use of these drugs may lead to high-risk sexual behavior, and that, to reduce and prevent risks of HIV, no level of use of these drugs should be considered "safe." HIV prevention interventions should target MSM who report either light or heavy use of methamphetamines, poppers, and sniffed cocaine.


Value of Shear Wave Elastography for differentiating benign and malignant renal lesions.
To investigate the diagnostic accuracy of shear-wave elastography (SWE) for assessing malignant and benign kidneymasses. Forty patients with solid renal masses underwent US elastographic evaluation. SWE values of the lesions and adjacent cortical renal parenchyma and SWER were detected prospectively. Malignant tumors were recorded as group 1 and benign tumors were recorded as group 2. The highest elasticity values were 27.27±25.66 kPa for group 1 and 16.13±8.89 kPa for group 2. The mean±SD elasticity values for adjacent renal cortex for groups 1 and 2 were 2.7±2.08 and 2.75±1.35, respectively. For group 1, a negative correlation was observed between the age of the patients and SWER value (p=0.047, rs=‑0.401). There was also a negative correlation between the SWER value and the SWE value of adjacent renal cortex (p=0.004, rs=‑0.555). SWE is a noninvasive method that provides quantitative elasticity informationon tissues. Overlaps among different types of renal lesions may be due to heterogeneity of the lesions. Larger studygroups may clarify the other factors affecting SWE values under both normal and pathological conditions.


Epidermal growth factor regulates NIKS keratinocyte proliferation through Notch signaling.
Cutaneous wound healing is a significant health issue in the US, often requiring skin grafts. StrataGraft (Stratatech Corporation, Madison, WI), a second-generation living human skin substitute created from NIKS human keratinocyte progenitors, was recently found to be a promising skin graft in phase I/II safety and efficacy clinical trial. NIKS proliferation is optimal in the presence of epidermal growth factor (EGF). Our preliminary data suggested that Notch signaling also plays a role in NIKS keratinocyte proliferation. Therefore, we hypothesized that EGF might stimulate NIKS proliferation by regulating Notch1 signaling. Notch1 messenger RNA (mRNA) levels from NIKS cells in monolayer culture were assessed by real-time polymerase chain reaction and Notch1 protein levels were detected by Western blot. To determine the role of EGF on Notch1 regulation, cells were incubated in basal media and then treated with EGF (10 ng/mL). A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to test NIKS cell proliferation. Cells were grown in basal media supplemented with EGF for 72 h in the presence or absence of N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) (0-30 μM), an inhibitor of Notch1 signaling. Notch1 mRNA levels were cell confluence-dependent, being more abundant in a subconfluent cell monolayer. We detected a 2-fold decrease in Notch1 mRNA expression and a reduction in active Notch1 protein level in response to EGF. EGF treatment stimulated NIKS cellular proliferation. However, co-treatment with DAPT inhibited NIKS proliferation to basal levels. Blocking Notch1 activation by DAPT alone inhibited NIKS cellular proliferation (P < 0.01%). Our results suggest that Notch1 is an essential downstream mediator of NIKS cellular proliferation via the EGF signaling pathway.


The role of flagella in Clostridium difficile pathogenesis: comparison between a non-epidemic and an epidemic strain.
Clostridium difficile is a major cause of healthcare-associated infection and inflicts a considerable financial burden on healthcare systems worldwide. Disease symptoms range from self-limiting diarrhoea to fatal pseudomembranous colitis. Whilst C. difficile has two major virulence factors, toxin A and B, it is generally accepted that other virulence components of the bacterium contribute to disease. C. difficile colonises the gut of humans and animals and hence the processes of adherence and colonisation are essential for disease onset. Previously it has been suggested that flagella might be implicated in colonisation. Here we tested this hypothesis by comparing flagellated parental strains to strains in which flagella genes were inactivated using ClosTron technology. Our focus was on a UK-outbreak, PCR-ribotype 027 (B1/NAP1) strain, R20291. We compared the flagellated wild-type to a mutant with a paralyzed flagellum and also to mutants (fliC, fliD and flgE) that no longer produce flagella in vitro and in vivo. Our results with R20291 provide the first strong evidence that by disabling the motor of the flagellum, the structural components of the flagellum rather than active motility, is needed for adherence and colonisation of the intestinal epithelium during infection. Comparison to published data on 630Δerm and our own data on that strain revealed major differences between the strains: the R20291 flagellar mutants adhered less than the parental strain in vitro, whereas we saw the opposite in 630Δerm. We also showed that flagella and motility are not needed for successful colonisation in vivo using strain 630Δerm. Finally we demonstrated that in strain R20291, flagella do play a role in colonisation and adherence and that there are striking differences between C. difficile strains. The latter emphasises the overriding need to characterize more than just one strain before drawing general conclusions concerning specific mechanisms of pathogenesis.


Identification of tomato bushy stunt virus host-specific symptom determinants by expression of individual genes from a potato virus X vector.
In this study, we analyzed the influence of two nested genes (p19 and p22) of tomato bushy stunt virus (TBSV) on disease symptoms in systemically infected plants and in local lesion hosts. The contribution of individual genes was determined by bioassays with an infectious clone of wild-type TBSV, with p19/p22 mutant derivatives, and by expression of individual TBSV genes from a heterologous potato virus X (PVX) vector. Our results showed that TBSV genes could be expressed at high levels from the PVX vector. The subcellular localization of these proteins as well as the ability of PVX-expressed p22 to trans complement TBSV cell-to-cell movement defective mutants indicate that the exogenously expressed proteins are functionally active. Inoculation studies with TBSV mutants and the PVX derivatives demonstrated that p19 induced a generalized necrosis upon systemic infection of Nicotiana benthamiana and N. clevelandii. In addition, p19 elicited the formation of local necrotic lesions in N. tabacum; however, in N. glutinosa and N. edwardsonii, the local lesion response was activated by p22. These results show that the p19 and p22 proteins of TBSV are important symptom determinants and that closely related plant species may contain different resistance genes that selectively respond to individual TBSV proteins.


Well-being at work--overview and perspective.
This paper provides an overview of and perspective on the concept of well-being at work. Well-being is a term that reflects not only on one's health but satisfaction with work and life. Well-being is a summative concept that characterizes the quality of working lives, including occupational safety and health (OSH) aspects, and it may be a major determinant of productivity at the individual, enterprise and societal levels. Based on a review of the literature and a recent conference, we suggest a model linking workforce well-being, productivity, and population well-being. To appraise the validity of the model, we consider five questions: (i) is there a robust and usable definition of workplace well-being? (ii) have the variables that influence well-being been aptly described and can they be measured and used in risk assessments? (iii) what is the nature of evidence that well-being is linked to productivity? (iv) what is the state of knowledge on the effectiveness of interventions to promote workplace well-being? and (v) should interventions aimed at improving well-being at work focus on more than work-related factors?


Maternal plasma levels of oxytocin during physiological childbirth - a systematic review with implications for uterine contractions and central actions of oxytocin.
Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. Basal levels of oxytocin increased 3-4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother's brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.


Deep sequencing identifies novel and conserved microRNAs in peanuts (Arachis hypogaea L.).
MicroRNAs (miRNAs) are a new class of small, endogenous RNAs that play a regulatory role in the cell by negatively affecting gene expression at the post-transcriptional level. miRNAs have been shown to control numerous genes involved in various biological and metabolic processes. There have been extensive studies on discovering miRNAs and analyzing their functions in model species, such as Arabidopsis and rice. Increasing investigations have been performed on important agricultural crops including soybean, conifers, and Phaselous vulgaris but no studies have been reported on discovering peanut miRNAs using a cloning strategy. In this study, we employed the next generation high through-put Solexa sequencing technology to clone and identify both conserved and species-specific miRNAs in peanuts. Next generation high through-put Solexa sequencing showed that peanuts have a complex small RNA population and the length of small RNAs varied, 24-nt being the predominant length for a majority of the small RNAs. Combining the deep sequencing and bioinformatics, we discovered 14 novel miRNA families as well as 75 conserved miRNAs in peanuts. All 14 novel peanut miRNAs are considered to be species-specific because no homologs have been found in other plant species except ahy-miRn1, which has a homolog in soybean. qRT-PCR analysis demonstrated that both conserved and peanut-specific miRNAs are expressed in peanuts. This study led to the discovery of 14 novel and 22 conserved miRNA families from peanut. These results show that regulatory miRNAs exist in agronomically important peanuts and may play an important role in peanut growth, development, and response to environmental stress.


Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage.
Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries. Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases. Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ(9)-tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior. Other considerations such as CBD's anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction. However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD's efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied. Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse. As the legal landscape for medical marijuana unfolds, it is important to distinguish it from "medical CBD" and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant.


A phase 3 trial of IV immunoglobulin for Alzheimer disease.
We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia. In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo. Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo. NCT00818662. This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.


Validation of the ActiGraph two-regression model for predicting energy expenditure.
The purpose of this study was to validate a two-regression model for predicting energy expenditure (EE) from ActiGraph GT1M accelerometer-generated activity counts using a whole-room indirect calorimeter and the doubly labeled water (DLW) technique. We also investigated if a low-pass filter (LPF) approach would improve the model's accuracy in the minute-to-minute EE prediction. Thirty-four healthy volunteers (age = 20-67 yr, body mass index = 19.3-52.1 kg.m) spent approximately 24 h in a room calorimeter while wearing a GT1M monitor and performed structured and self-selected activities followed by overnight sleep. The EE predicted by the models and expressed in metabolic equivalents (MET-minutes) during waking times was compared with the room calorimeter-measured EE. A subset of volunteers (n = 22) completed a 14-d DLW protocol in free living while wearing an ActiGraph. The average daily EE predicted by the models (MET-minutes) was compared with the DLW. Compared with the room calorimeter, the two-regression model overpredicted EE by 10.2% +/- 11.4% (1282 +/- 125 and 1174 +/- 152 MET.min, P < 0.001) and time spent in moderate physical activity (PA) by 36.9 +/- 46.0 min while underestimating the time spent in light PA by -48.3 +/- 55.0 min (P < 0.05). The LPF reduced the squared and mean absolute error in the EE prediction (P < 0.05) but not the prediction error in time spent in moderate or light PA (both P > 0.05). The EE measured by DLW (2108 +/- 358 MET.min.d) and predicted by both filtered and unfiltered models (2104 +/- 218 and 2192 +/- 228 MET.min.d, respectively) were similar (P > 0.05). The two-regression model with LPF showed good agreement with total EE measured using room calorimeter and DLW. However, the individual variability in assessing time spent in sedentary, low, and moderate PA intensities and related EE remains significant.


Making sense of the linear genome, gene function and TADs.
Topologically associating domains (TADs) are thought to act as functional units in the genome. TADs co-localise genes and their regulatory elements as well as forming the unit of genome switching between active and inactive compartments. This has led to the speculation that genes which are required for similar processes may fall within the same TADs, allowing them to share regulatory programs and efficiently switch between chromatin compartments. However, evidence to link genes within TADs to the same regulatory program is limited. We investigated the functional similarity of genes which fall within the same TAD. To do this we developed a TAD randomisation algorithm to generate sets of "random TADs" to act as null distributions. We found that while pairs of paralogous genes are enriched in TADs overall, they are largely depleted in TADs with CCCTC-binding factor (CTCF) ChIP-seq peaks at both boundaries. By assessing gene constraint as a proxy for functional importance we found that genes which singly occupy a TAD have greater functional importance than genes which share a TAD, and these genes are enriched for developmental processes. We found little evidence that pairs of genes in CTCF bound TADs are more likely to be co-expressed or share functional annotations than can be explained by their linear proximity alone. These results suggest that algorithmically defined TADs consist of two functionally different groups, those which are bound by CTCF and those which are not. We detected no association between genes sharing the same CTCF TADs and increased co-expression or functional similarity, other than that explained by linear genome proximity. We do, however, find that functionally important genes are more likely to fall within a TAD on their own suggesting that TADs play an important role in the insulation of these genes.


Analysis of Risk Factors and Long-Term Outcomes in Kidney Transplant Patients with Identified Lymphoceles.
The collection of lymphatic fluids (lymphoceles) is a frequent adverse event following renal transplantation. A variety of surgical and medical factors has been linked to this entity, but reliable data on risk factors and long-term outcomes are lacking. This retrospective single-center study included 867 adult transplant recipients who received a kidney transplantation from 2006 to 2015. We evaluated for patient and graft survival, rejection episodes, or detectable donor-specific antibodies (dnDSA) in patients with identified lymphoceles in comparison to controls. We identified 305/867 (35.2%) patients with lymphocele formation, of whom 72/867 (8.3%) needed intervention. Multivariate analysis identified rejection episode as an independent risk factor (OR 1.61, CI 95% 1.17-2.21, p = 0.003) for lymphocele formation, while delayed graft function was independently associated with symptomatic lymphoceles (OR 1.9, CI 95% 1.16-3.12, p = 0.011). Interestingly, there was no difference in detectable dnDSA between groups with a similar graft and patient survival in all groups after 10 years. Lymphoceles frequently occur after transplantation and were found to be independently associated with rejection episodes, while symptomatic lymphoceles were associated with delayed graft function in our cohort. As both are inflammatory processes, they might play a causative role in the formation of lymphoceles. However, development or intervention of lymphoceles did not lead to impaired graft survival in the long-term.


Deployment and the use of mental health services among U.S. Army wives.
Military operations in Iraq and Afghanistan have involved the frequent and extended deployment of military personnel, many of whom are married. The effect of deployment on mental health in military spouses is largely unstudied. We examined electronic medical-record data for outpatient care received between 2003 and 2006 by 250,626 wives of active-duty U.S. Army soldiers. After adjustment for the sociodemographic characteristics and the mental health history of the wives, as well as the number of deployments of the personnel, we compared mental health diagnoses according to the number of months of deployment in Operation Iraqi Freedom in the Iraq-Kuwait region and Operation Enduring Freedom in Afghanistan during the same period. The deployment of spouses and the length of deployment were associated with mental health diagnoses. In adjusted analyses, as compared with wives of personnel who were not deployed, women whose husbands were deployed for 1 to 11 months received more diagnoses of depressive disorders (27.4 excess cases per 1000 women; 95% confidence interval [CI], 22.4 to 32.3), sleep disorders (11.6 excess cases per 1000; 95% CI, 8.3 to 14.8), anxiety (15.7 excess cases per 1000; 95% CI, 11.8 to 19.6), and acute stress reaction and adjustment disorders (12.0 excess cases per 1000; 95% CI, 8.6 to 15.4). Deployment for more than 11 months was associated with 39.3 excess cases of depressive disorders (95% CI, 33.2 to 45.4), 23.5 excess cases of sleep disorders (95% CI, 19.4 to 27.6), 18.7 excess cases of anxiety (95% CI, 13.9 to 23.5), and 16.4 excess cases of acute stress reaction and adjustment disorders (95% CI, 12.2 to 20.6). Prolonged deployment was associated with more mental health diagnoses among U.S. Army wives, and these findings may have relevance for prevention and treatment efforts.


Scalable office-based health care.
The goal of health care is to provide high-quality care at an affordable cost for its patients. However, the population it serves has changed dramatically since the popularization of hospital-based health care. With available new technology, alternative health care delivery methods can be designed and tested. This study examines scalable office-based health care for small business, where health care is delivered to the office floor. This delivery was tested in 18 individuals at a small business in Minneapolis, Minnesota. The goal was to deliver modular health care and mitigate conditions such as diabetes, hyperlipidaemia, obesity, sedentariness and metabolic disease. The modular health care system was welcomed by employees - 70% of those eligible enrolled. The findings showed that the modular health care deliverable was feasible and effective. The data demonstrated significant improvements in weight loss, fat loss and blood variables for at risk participants. This study leaves room for improvement and further innovation. Expansion to include offerings such as physicals, diabetes management, smoking cessation and prenatal treatment would improve its utility. Future studies could include testing the adaptability of delivery method, as it should adapt to reach rural and under-served populations.


Pharmacologic characterization of GABAA/benzodiazepine receptor in rat hippocampus during aging.
We have characterized the pharmacologic properties of the gamma-aminobutyric acid (GABAA)/benzodiazepine receptor complex in hippocampal membranes from 3-month- and 24-month-old Wistar rats. No major changes were found in [3H]flunitrazepam or [3H]muscimol binding parameters. Neither the dissociation constant(s) nor the Bmax for either ligand seemed to be modified during aging in hippocampus. Furthermore, the allosteric interaction between the barbiturates binding site and the GABA binding site, determined by pentobarbital stimulation of [3H] muscimol binding, remained unaltered. However, there was a significant increase with aging in the efficacy of the GABA-enhancement of [3H]flunitrazepam binding. On the other hand, we have also detected a significant increase in the proportion of type I benzodiazepine receptor in 24-month-old hippocampal membranes. We propose that the age-related increase in the efficacy of GABA-enhancement of [3H]flunitrazepam binding could be correlated with the increase in the proportion of type I benzodiazepine receptor. Based on these results it is tempting to speculate that the age-dependent modifications on the GABAA/benzodiazepine receptor might reflect an age-dependent neuronal degeneration of the hippocampus or the hippocampal formation.


Hypertension, end-stage renal disease and mesangiocapillary glomerulonephritis in methamphetamine users.
Methamphetamine abuse has risen dramatically in South Africa. The chronic effects of abuse on the kidneys and blood pressure have not been documented. This study reviewed patients referred for evaluation of kidney disease and/or hypertension, who had been abusing methamphetamines. The records of patients referred to the renal unit between 2005 and 2013 who had been using methamphetamines were retrospectively reviewed. Patient demographics, biophysical parameters, blood pressure, renal function, renal ultrasound and biopsy findings, complications of chronic kidney disease and comorbidities were recorded. Forty-seven patients were included in the study. Their mean age was 29 years. Hypertension was present in 42 (89.4%) of patients, with malignant hypertension in 21 (44.7%). Forty-five (95.7%) had chronic kidney disease (CKD), and 26 (55.3%) had end-stage renal disease. Renal biopsies were performed in 24 patients. Twelve (50.0%) of the biopsies showed hypertensive changes and 14 (58.3%) mesangiocapillary glomerulonephritis type 1, with deposition of IgM and C3 complement. Methamphetamine use is associated with severe hypertension, mesangiocapillary glomerulonephritis and CKD.


3-phenylacetylamino-2,6-piperidinedione inhibition of rat Nb2 lymphoma cell mitogenesis.
3-Phenylacetylamino-2,6-piperidinedione (A10), an amino acid analog, has been reported to possess antineoplastic activity against certain neoplastic tissues. The antimitogenic properties of A10 were studied by determining its effect on prolactin (PRL)- and interleukin 2 (IL-2)-stimulated mitogenic responses in the rat Nb2 lymphoma cell line. The addition of A10 (1-12 mM) to PRL (0.4 ng/ml)-stimulated cells inhibited growth in a dose-dependent manner. DNA synthesis patterns studied by thymidine incorporation demonstrated that A10 was significantly inhibitory (25% at 20 hr; 50% at 40 hr, P less than 0.01). IL-2 stimulation of mitogenesis was also sensitive to A10 inhibition. The inhibition of PRL stimulated mitogenesis was reversible when A10 was removed after 24 hr of culture and A10 showed no toxicity in a chromium release assay. These data suggest that A10 effects may be cytostatic, rather than cytotoxic.


Structural basis for double-stranded RNA processing by Dicer.
The specialized ribonuclease Dicer initiates RNA interference by cleaving double-stranded RNA (dsRNA) substrates into small fragments about 25 nucleotides in length. In the crystal structure of an intact Dicer enzyme, the PAZ domain, a module that binds the end of dsRNA, is separated from the two catalytic ribonuclease III (RNase III) domains by a flat, positively charged surface. The 65 angstrom distance between the PAZ and RNase III domains matches the length spanned by 25 base pairs of RNA. Thus, Dicer itself is a molecular ruler that recognizes dsRNA and cleaves a specified distance from the helical end.


Functional optimization of gene clusters by combinatorial design and assembly.
Large microbial gene clusters encode useful functions, including energy utilization and natural product biosynthesis, but genetic manipulation of such systems is slow, difficult and complicated by complex regulation. We exploit the modularity of a refactored Klebsiella oxytoca nitrogen fixation (nif) gene cluster (16 genes, 103 parts) to build genetic permutations that could not be achieved by starting from the wild-type cluster. Constraint-based combinatorial design and DNA assembly are used to build libraries of radically different cluster architectures by varying part choice, gene order, gene orientation and operon occupancy. We construct 84 variants of the nifUSVWZM operon, 145 variants of the nifHDKY operon, 155 variants of the nifHDKYENJ operon and 122 variants of the complete 16-gene pathway. The performance and behavior of these variants are characterized by nitrogenase assay and strand-specific RNA sequencing (RNA-seq), and the results are incorporated into subsequent design cycles. We have produced a fully synthetic cluster that recovers 57% of wild-type activity. Our approach allows the performance of genetic parts to be quantified simultaneously in hundreds of genetic contexts. This parallelized design-build-test-learn cycle, which can access previously unattainable regions of genetic space, should provide a useful, fast tool for genetic optimization and hypothesis testing.


Strong similarities in antigen fine specificity among DRB1* 1302-restricted tetanus toxin tt830-843-specific TCRs in spite of highly heterogeneous CDR3.
We investigated the Ag fine specificity of four TCRs that shared the same V beta segment but used V alpha s of three different subfamilies and displayed highly heterogeneous alpha and beta CDR3. The TCRs recognized the tetanus toxin tt830-843 (QYIKANSKFIGITE) epitope presented by DRB1*1302. By using a large panel of monosubstituted peptide analogues, we first defined the requirements for tt830-843 binding to DRB1*1302. We found that three residues, I832, N835, and G840, were critical for the interaction with DRB1*1302. Residues potentially contacted by the four TCRs were functionally defined by measuring the IL-2 response to the analogues. Except for the first and the last three residues, as well as I832 and G340, all of the others appeared to provide contacts with the four TCRs, indicating a considerable overlapping in the way these TCRs interact with the peptide. More importantly, and contrary to expectations, the two TCRs expressing the same V alpha/V beta germ-line segments showed a strikingly similar reactivity toward nearly all substitutions; moreover, more pronounced differences were observed when comparing TCRs using different V alpha segments. These results indicate that TCRs with entirely distinct CDR3s in the context of conserved V segments may not differ substantially in the way they recognize the ligand, and may provide new insights into understanding the formation of TCR/peptide/MHC ternary complexes. During these studies, we noticed that analogues with nonconservative substitutions at I832, which bound very unstably to DRB1*1302, could effectively stimulate T cells, suggesting a role of the TCR in contributing toward stabilization of peptide binding.


The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease.
Long non-coding RNAs (lncRNAs) are transcripts with low protein-coding potential that represent a large proportion of the transcriptional output of the cell. Many lncRNAs exhibit features indicative of functionality including tissue-restricted expression, localization to distinct subcellular structures, regulated expression and evolutionary conservation. Some lncRNAs have been shown to associate with chromatin-modifying activities and transcription factors, suggesting that a common mode of action may be to guide protein complexes to target genomic loci. However, the functions (if any) of the vast majority of lncRNA transcripts are currently unknown, and the subject of investigation. Here, we consider the putative role(s) of lncRNAs in neurodevelopment and brain function with an emphasis on the epigenetic regulation of gene expression. Associations of lncRNAs with neurodevelopmental/neuropsychiatric disorders, neurodegeneration and brain cancers are also discussed.


Pulmonary metastasectomy in colorectal cancer: health utility scores by EQ-5D-3L in a randomized controlled trial show no benefit from lung metastasectomy.
The aim was to assess the health utility of lung metastasectomy in the treatment of patients with colorectal cancer (CRC) using the EQ-5D-3L questionnaire. Multidisciplinary CRC teams at 14 sites recruited patients to a two-arm randomized controlled trial-Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). Remote randomization was used, stratified by site and with minimization for seven known confounders. Participants completed the EQ-5D-3L questionnaire together with other patient reported outcome measures at randomization and then again at 3, 6, 12 and 24 months. These were returned by post to the coordinating centre. Between December 2010 and December 2016, 93 participants were randomized, 91 of whom returned questionnaires. Survival and patient reported quality of life have been published previously, revealing no significant differences between the trial arms. Described here are patient reported data from the five dimensions of the EQ-5D-3L and the visual analogue scale (VAS) health state. No significant difference was seen at any time point. The estimated difference between control and metastasectomy patients was -0.23 (95% CI -0.113, 0.066) for the composite 0 to 1 index scale based on the descriptive system and 0.123 (95% CI -7.24, 7.49) for the 0 to 100 VAS scale. Following lung metastasectomy for CRC, no benefit was demonstrated for health utility, which alongside a lack of a survival or quality of life benefit calls into question the widespread use of the procedure.


Patterns of care for adults with newly diagnosed malignant glioma.
Patients with malignant glioma (grade III or IV) face a poor prognosis, and few evidence-based treatment guidelines are available. There is a dearth of prospective data on patterns of care for these patients. To provide benchmark data to enable comparison of individual practice patterns and outcomes. The Glioma Outcomes (GO) Project enrolled 788 patients at 52 clinical sites, both academic and community practices, between December 1997 and July 2000. The enrollment criteria included adult patients with primary grade III or IV glioma undergoing a first or second operation for diagnosis or treatment. The data collection instruments included questionnaire forms given at enrollment, during the perioperative period, and at follow-up intervals of 3 months until death or a maximum of 24 months. Of the patients recorded in the GO database, 565 patients with newly diagnosed tumors were used for this analysis. Patterns of care (surgical management, perioperative care, postoperative management). Most patients underwent magnetic resonance imaging (n = 518; 92%) and an attempt at tumor resection (n = 425; 75%). Cortical mapping (n = 107; 19%) and intraoperative image guidance (n = 161; 29%) were uncommon. Most received perioperative corticosteroids (n = 535; 99%) and antiepileptic medications (n = 497; 88%), but few received antidepressants (n = 38; 8%) or prophylactic heparin (n = 42; 7%). Most received adjuvant radiation therapy (n = 479; 87%), but fewer received chemotherapy (n = 300; 54%). Practice patterns varied significantly between academic and community settings. Reliance on magnetic resonance imaging, surgery, and radiation is generally accepted; however, relatively infrequent chemotherapy use may conflict with published literature, and frequent use of prophylactic antiepileptic medications contradicts established practice guidelines. Other practice patterns involving surgical adjuncts, prophylactic heparin, and antidepressants require further investigation to clarify appropriateness. Establishing further clinical guidelines may help reduce variability in practice patterns.


Drug Intoxication and the Need to Autopsy: A Diagnosis of Exclusion?
The recent surge in drug deaths has focused attention on the diagnosis of drug intoxication as a cause of death. In Maryland, the Department of Vital Records has shown an increase from 649 intoxication deaths in 2012 to 1259 in 2015. Preliminary data for 2016 document 1892 of these deaths. Many of the medicolegal death investigation offices in the United States are facing potential loss of accreditation. There is limited capacity to add more staff due to a lack of appropriately trained pathologists and budget constraints. The diagnosis of this intoxication and the need to autopsy all of these cases is a matter of debate, as many death investigation offices look for alternative means to maintain accreditation. The alternative to adding more staff is to reduce the autopsy caseload. Can this be done without compromising the intent of the medical examiner system and the law? Balancing this with being fiscally responsible may be a very real challenge and one that will test many death investigation systems due to this pandemic of drug deaths. If there is a need to reduce the autopsy caseload, it should be in cases other than where the diagnosis is one of exclusion.


Antibody seroconversion in asymptomatic and symptomatic patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Asymptomatic and symptomatic patients may transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their clinical features and immune responses remain largely unclear. We aimed to characterise the clinical features and immune responses of asymptomatic and symptomatic patients infected with SARS-CoV-2. We collected clinical, laboratory and epidemiological records of patients hospitalised in a coronavirus field hospital in Wuhan. We performed qualitative detection of anti-SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) using archived blood samples. Of 214 patients with SARS-CoV-2, 26 (12%) were asymptomatic at hospital admission and during hospitalisation. Most asymptomatic patients were ≤ 60 years (96%) and females (65%) and had few comorbidities (< 16%). Serum levels of white and red blood cells were higher in asymptomatic than in symptomatic patients (P-values < 0.05). During hospitalisation, IgG seroconversion was commonly observed in both asymptomatic and symptomatic patients (85% versus 94%, P-value = 0.07); in contrast, IgM seroconversion was less common in asymptomatic than in symptomatic patients (31% versus 74%, P-value < 0.001). The median time from the first virus-positive screening to IgG or IgM seroconversion was significantly shorter in asymptomatic than in symptomatic patients (median: 7 versus 14 days, P-value < 0.01). Furthermore, IgG/IgM seroconversion rates increased concomitantly with the clearance of SARS-CoV-2 in both asymptomatic and symptomatic patients. At the time of virus clearance, IgG/IgM titres and plasma neutralisation capacity were significantly lower in recovered asymptomatic than in recovered symptomatic patients (P-values < 0.01). Asymptomatic and symptomatic patients exhibited different kinetics of IgG/IgM responses to SARS-CoV-2. Asymptomatic patients may transmit SARS-CoV-2, highlighting the importance of early diagnosis and treatment.


Development and validation of a disease model for postmenopausal osteoporosis.
This article describes the development of a model for postmenopausal osteoporosis (PMO) based on Swedish data that is easily adaptable to other countries. The aims of the study were to develop and validate a model to describe the current/future burden of PMO in different national settings. For validation purposes, the model was developed using Swedish data and provides estimates from 1990. For each year of the study, the "incident cohort" (women experiencing a first osteoporotic fracture) was identified and run through a Markov model using 1-year cycles until 2020. Health states were based on the number of fractures and death. Fracture by site (hip, vertebral, and non-hip non-vertebral) was tracked for each health state. Transition probabilities reflected site-specific risk of death and subsequent fractures. Bone mineral density (BMD) was included as a model output; model inputs included population size and life tables from 1970 to 2020, incidence of fracture, relative risk of subsequent fractures based on prior fracture, relative risk of death following a fracture by site, and BMD by age (mean and standard deviation). Model predictions averaged across age groups estimated the incidence of hip, vertebral, and other osteoporotic fractures within a 5% margin of error versus published data. In Sweden, the number of osteoporotic fractures is expected to rise by 11.5% between 2009 and 2020, with a shift towards more vertebral fractures and multiple fractures. The current PMO disease model is easily adaptable to other countries, providing a consistent measure of present and future burden of PMO in different settings.


A tractable probabilistic model for Affymetrix probe-level analysis across multiple chips.
Affymetrix GeneChip arrays are currently the most widely used microarray technology. Many summarization methods have been developed to provide gene expression levels from Affymetrix probe-level data. Most of the currently popular methods do not provide a measure of uncertainty for the expression level of each gene. The use of probabilistic models can overcome this limitation. A full hierarchical Bayesian approach requires the use of computationally intensive MCMC methods that are impractical for large datasets. An alternative computationally efficient probabilistic model, mgMOS, uses Gamma distributions to model specific and non-specific binding with a latent variable to capture variations in probe affinity. Although promising, the main limitations of this model are that it does not use information from multiple chips and does not account for specific binding to the mismatch (MM) probes. We extend mgMOS to model the binding affinity of probe-pairs across multiple chips and to capture the effect of specific binding to MM probes. The new model, multi-mgMOS, provides improved accuracy, as demonstrated on some bench-mark datasets and a real time-course dataset, and is much more computationally efficient than a competing hierarchical Bayesian approach that requires MCMC sampling. We demonstrate how the probabilistic model can be used to estimate credibility intervals for expression levels and their log-ratios between conditions. Both mgMOS and the new model multi-mgMOS have been implemented in an R package, which is available at http://www.bioinf.man.ac.uk/resources/puma.


Somatostatin concentration responds to arginine in portal plasma: effects of fasting, streptozotocin diabetes, and insulin administration in diabetic rats.
Changes of somatostatin concentration in response to a single i.v. injection of arginine (400 mg/kg body weight) were examined in extracted portal plasma of normal and diabetic rats in the fully fed state and after 24 h or fasting, as well as in diabetic rats treated with insulin for one week. In both normal and diabetic animals fasted for 24 h, the basal level of somatostatin declined but the magnitude of the arginine-induced elevation of somatostatin was not affected, suggesting a physiologic role of the tetradecapeptide in nutrient homeostasis. When compared with intact rats, diabetic animals were shown to have increased levels of somatostatin before and after arginine administration, both of which were attenuated by insulin replacement therapy. These findings suggest that alterations of D cell function in streptozotocin diabetes may be related to either insulin deficiency or its metabolic consequences.


Effect of severe acidosis on vasoactive effects of epinephrine and norepinephrine in human distal mammary artery.
Acidosis is a very common pathologic process in perioperative management. However, how to correct severe acidosis to improve the efficacy of vasoconstrictors in hemodynamically unstable patients is still debated. The present study investigated whether severe extracellular acidosis influences the vasoactive properties of vasoconstrictors on human isolated arteries. Segments of intact distal internal mammary arteries were removed from 41 patients undergoing artery bypass grafting. The arterial rings were washed in Krebs-Henseleit solution and suspended in an organ bath. The rings were set at a pretension equivalent of 100 mm Hg, and the relaxation response to 10 μM acetylcholine was verified. Concentration-response curves for epinephrine, norepinephrine, methoxamine (α1A/D-adrenoceptor agonist), phenylephrine (equipotent agonist of α1A/B-adrenoceptors), and clonidine (α2-adrenoceptor agonist) were achieved under control conditions (pH 7.40) and under acidic conditions by substitution of the Krebs-Henseleit solution with a modified solution. Decreasing the pH from 7.40 to 7.20, 7.0, or 6.80 did not significantly alter the potency and efficacy of epinephrine and norepinephrine, although the standardized effect size was sometimes large. Severe acidosis (pH 6.80) did not significantly change the potency and efficacy of phenylephrine and clonidine, although it increased the efficacy and potency of methoxamine (P < .001 and P = .04 vs paired control conditions, respectively). Extracellular acidosis did not impair the vasoactive properties of epinephrine and norepinephrine in human medium-size arteries until pH 6.80. The results of the present study also suggest that acidosis might potentiate arterial responsiveness to vasoconstrictors, mostly by way of the α1D-adrenoceptor.


The Evolution of Consanguineous Marriages in the Archdiocese of Granada, Spain (1900-1979).
In the 20th century Spain maintained some of the highest rates of consanguineous marriage in Europe. In many regions these rates were still high in the 1950s and 1960s but then decreased rapidly, and by the 1970s a generalized transformation in mating patterns was under way. In the following decades the marriage of persons closely related by birth became rare. Consanguinity and inbreeding have been much studied in Spain but almost exclusively in the central and northern regions of the country. This is the first study of a whole large diocese in the southern region of Andalusia. This article is based on the analysis of 15,440 records of consanguineous unions registered between 1900 and 1979 in the Archbishopric of Granada in Andalusia. In this period, the rate of consanguinity up to second cousins was 5.51%, and the mean coefficient of inbreeding, α, was 2.04 × 10-3. There is a high range of variability within the research area: the rate of consanguinity was more than three times higher in rural areas (6.74%; α = 2.44 × 10-3) than in the capital city (2.03%; α = 0.93 × 10-3). There was a high frequency of unions between first cousins and first cousins once removed. These amounted to 35.3% and 13% of all consanguineous marriages, respectively, and contributed to 70% of α-values. Consanguinity here has been strongly related to local endogamy. Thus, 76% of all consanguineous couples were born in the same locality, and 89% resided in the same locality at marriage. By the end of the 1960s premarital migration increased and local endogamy started to decrease. On the other hand, inbreeding is inversely related to spatial endogamy. The more inbred couples, such as uncles-nieces (C12) or first cousins (C22), show significantly higher exogamy rates than second cousins (C33) and third cousins (C44), and higher rates of premarital migration. Neither males nor females in intrafamily unions seem to be significantly younger than those in nonconsanguineous unions. Considering their temporal evolution, consanguinity rates increased in the first third of the century, reaching a maximum in the late 1920s, when over 7.4% of all marriages were consanguineous (8.3% for the rural areas), and the resulting α-value was the highest of the century (α = 2.71 × 10-3 for the whole diocese; α = 3.00 × 10-3 for the rural areas). Rates of inbreeding remained high until the 1950s and decreased thereafter in a period of accelerated emigration to cities, urbanization, industrialization, and social modernization. Overall, levels of inbreeding are similar and sometimes larger than those found in dioceses in the northwest of Spain, although marriages between uncle and niece were less common. Some of the counties in the diocese had very high consanguinity levels, not only the isolated area of La Alpujarra, previously studied, but also other ecological and historical microregions (comarcas). These results indicate that the widely accepted north-south divisions of the Iberian Peninsula in terms of consanguinity and inbreeding patterns require considerable reevaluation.


α-Lipoic acid stabilized DTX/IR780 micelles for photoacoustic/fluorescence imaging guided photothermal therapy/chemotherapy of breast cancer.
Micellar nanoparticles have unique advantages as carriers for therapeutic or imaging agents, owing to their smaller size and better penetration of tumors. However, some agents, due to their physical or chemical properties, are difficult to load into micelles. IR780 is one of these agents, and is also a promising near-infrared dye for fluorescence imaging (FI)/photoacoustic imaging (PAI) and cancer photothermal therapy (PTT). Its hydrophobic and high crystallization structure results in limited bioavailability in vivo. It is difficult to load into micelles constructed from an amphiphilic block polymer with relatively low molecular weight. In this study, we use computer simulation and introduce another small biomolecule, α-lipoic acid, into the micelles constructed from a mPEG-PCL copolymer, to lower the energy of molecular interaction between MPEG-PCL and IR780, and expect to enhance the loading capacity of the micelles to IR780. The introduction of α-lipoic acid decreases the energy of molecular interaction between MEPG-PCL and IR780 from -46.18 kJ mol-1 to -196.52 kJ mol-1 and increases the loading capacity and stability of the mPEG-PCL micelles to IR780, which also maintains the loading capacity to DTX. We further construct DTX/IR780 co-loaded mPEG-PCL micelles for FI/PAI dual modal imaging guided PTT/chemotherapy of cancer. By FI and PAI evaluation in vitro and in vivo, we demonstrate that the DTX/IR780 co-loaded micelles can be used as FI and PAI probes. By further evaluating the therapeutic outcome of PTT/chemotherapy co-therapy of breast cancer, we demonstrate that the DTX/IR780 co-loaded mPEG-PCL micelles can serve as promising candidates for FI and PAI guided PTT/chemotherapy of breast cancer.


Relationship Between Labor and Delivery Unit Management Practices and Maternal Outcomes.
To define, measure, and characterize key competencies of managing labor and delivery units in the United States and assess the associations between unit management and maternal outcomes. We developed and administered a management measurement instrument using structured telephone interviews with both the primary nurse and physician managers at 53 diverse hospitals across the United States. A trained interviewer scored the managers' interview responses based on management practices that ranged from most reactive (lowest scores) to most proactive (highest scores). We established instrument validity by conducting site visits among a subsample of 11 hospitals and established reliability using interrater comparison. Using a factor analysis, we identified three themes of management competencies: management of unit culture, patient flow, and nursing. We constructed patient-level regressions to assess the independent association between these management themes and maternal outcomes. Proactive management of unit culture and nursing was associated with a significantly higher risk of primary cesarean delivery in low-risk patients (relative risk [RR] 1.30, 95% CI 1.02-1.66 and RR 1.47, 95% CI 1.13-1.92, respectively). Proactive management of unit culture was also associated with a significantly higher risk of prolonged length of stay (RR 4.13, 95% CI 1.98-8.64), postpartum hemorrhage (RR 2.57, 95% CI 1.58-4.18), and blood transfusion (RR 1.87, 95% CI 1.12-3.13). Proactive management of patient flow and nursing was associated with a significantly lower risk of prolonged length of stay (RR 0.23, 95% CI 0.12-0.46 and RR 0.27, 95% CI 0.11-0.62, respectively). Labor and delivery unit management varies dramatically across and within hospitals in the United States. Some proactive management practices may be associated with increased risk of primary cesarean delivery and maternal morbidity. Other proactive management practices may be associated with decreased risk of prolonged length of stay, indicating a potential opportunity to safely improve labor and delivery unit efficiency.


Injection treatment and back pain associated with degenerative lumbar spinal stenosis in older adults.
Lower back pain is one of the most common health-related complaints in the adult population. Thirty percent of Americans 65 years and older reported symptoms of lower back pain in 2004 (NCHS, 2006). Injection treatment is a commonly used non-surgical procedure to alleviate lower back pain in older adults. However, the effectiveness of injection treatment, particularly in older adults, has not been well documented. This study quantified the effectiveness of injection treatment on pain relief among adults 60 years and over who were diagnosed with degenerative lumbar spinal stenosis, a common cause of lower back pain in older adults. The variations of the effectiveness were examined by selected patient attributes. Prospective, non-randomized, observational human study. Single institution spine clinic. Patients scheduled for lumbar injection treatment between January 1 and July 1, 2008 were prospectively selected from the study spine clinic. Selection criteria included patients age 60 and over, diagnosed with degenerative lumbar spinal stenosis and no previous lumbar injection within 6 months or lumbar surgery within 2 years. The pain sub-score of the SF-36 questionnaire was used to measure pain at baseline and at one and 3 months post injection. Variations in longitudinal changes in pain scores by patient characteristics were analyzed in both unadjusted (univariate) analyses using one-way analysis of variance (ANOVA), and adjusted (multiple regression) analyses using linear mixed effects models. This study is limited by its sample size and observational design. Of 62 patients receiving epidural steroid injections, the mean Pain score at baseline was 27.4 (SD =13.6), 41.7 (SD = 22.0) at one month and 35.8 (SD = 19.0) at 3 months. Mean Pain scores improved significantly from baseline to one month (14.1 points), and from baseline to 3 months (8.3 points). Post injection changes in pain scores varied by body mass index (BMI) and baseline emotional health. Based on a linear mixed effects model analysis, higher baseline emotional health, as measured by the SF-36 Mental Component Score (MCS >/= 50), was associated with greater reduction in pain over 3 months when compared to lower emotional health (MCS), was associated with greater reduction in pain over 3 months when compared to lower emotional health (MCS <50). In patients with higher emotional health, pain scores improved by 14.1 (P < .05: 95% CI 6.9, 21.3). Patients who were obese also showed significant improvement in pain scores over 3 months compared to non-obese patients. In obese patients, pain scores increased by 7.9 (P <.05; 95% CI:1.0, 14.8) points. Lower back pain in older adults with degenerative lumbar spinal stenosis might be clinically significantly alleviated after injection treatment. Pain relief varies by a patients personal and clinical characteristics. Healthier emotional status and obesity appears to be associated with more pain relief experienced over 3 months following injection.


The FLAMES score accurately predicts mortality risk in burn patients.
The purposes of this study were to determine current mortality predictors in our thermally injured population, to develop and validate a new mortality predictive score, and to compare its predictive ability with those of the acute physiology and chronic health evaluation II (APACHE II) score, multiple organ dysfunction (MOD) score, and two burn-specific mortality predictive scores. A retrospective chart review of acute thermally injured (flame or scald) patients admitted during a 12-year period (1991-2003) to an adult regional burn center was performed. Patients admitted between January 1991 and February 1995 (derivation population) were included in the development of a mortality risk predictive score along with the patient's APACHE II score, MOD score, Smith's score, and the Age-Risk score. The new mortality risk predictive score was validated in a separate group of thermally injured patients (validation population) admitted to the same burn center between March 1995 and December 2003. Of 1,439 acute thermally injured patients admitted between 1991 and 2003, 96 (7%) were excluded because they received comfort measures only. Of the remaining 1,343 patients, 378 (28%) were included in the mortality risk score derivation, and 965 (72%) in its validation. In the derivation group, there were 260 (69%) flame burns and 118 (31%) scald burns, and 35 (9%) patients died in hospital. Increased age, day 1 APACHE II score, percent partial-thickness burn, percent full-thickness burn, and sex were the strongest predictors of mortality. With these factors, we developed the FLAMES score (Fatality by Longevity, APACHE II score, Measured Extent of burn, and Sex), which had an area under the receiver operating characteristic curve of 0.97 that was better (p < 0.001) than those of the APACHE II score (0.91), MOD score (0.89), Smith's score (0.93), and the Age-Risk score (0.94). The FLAMES score was tested in the validation population and the area under the receiver operating characteristic curve = 0.93 was better (p < 0.001) than those of the APACHE II score (0.83), Smith's score (0.91), and the Age-Risk score (0.72). The ability of the FLAMES score in predicting hospital mortality risk was validated in a regional burn center population.


Cramér-Rao lower bound analysis of phase diversity for sparse aperture optical systems.
Aberration detection of subapertures is critical to the resolution of a sparse aperture optical system. In this work, the Cramér-Rao lower bound (CRLB) expression of aberrations was first derived for the subapertures of a sparse aperture optical system. The aberrations were estimated by phase diversity, assuming that the photons follow the Poisson distribution. The derived formula has been applied to the Golay3 sparse aperture system to calculate the CRLB of the subapertures' aberrations with different defocus distances, fill factors, and ratios of photon numbers between the focal and defocal images. According to the CRLB criterion, the results indicate that the accuracy of aberration estimation increases as the fill factor of the sparse aperture system increases. The results also demonstrate that the optimal defocus distance of phase diversity is achieved when the CRLB reaches its minimum. The optimal ratio of photon numbers between the focal and defocal images is around 3∶7. However, for the piston error, more photons in the defocal image yield more accurate estimation results. This method can also be applied to the sparse aperture optical systems with other different configurations.


Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans.
It is unclear how subthalamic nucleus activity is modulated by the cerebral cortex. Here we investigate the effect of transcranial magnetic stimulation (TMS) of the cortex on oscillatory subthalamic local field potential activity in the 8-35 Hz (alpha/beta) band, as exaggerated synchronization in this band is implicated in the pathophysiology of parkinsonism. We studied nine patients with Parkinson's disease (PD) to test whether cortical stimulation can modulate synchronized oscillations in the human subthalamic nucleus. With patients at rest, single-pulse TMS was delivered every 5 s over each primary motor area and supplementary motor area at intensities of 85-115% resting motor threshold. Subthalamic local field potentials were recorded from deep brain stimulation electrodes implanted into this nucleus for the treatment of PD. Motor cortical stimulation suppressed beta activity in the subthalamic nucleus from approximately 0.2 to 0.6 s after TMS (repeated measures anova; main effect of time, P < 0.01; main effect of side, P = 0.03), regardless of intensity. TMS over the supplementary motor area also reduced subthalamic beta activity at 95% (P = 0.05) and 115% resting motor threshold (P = 0.01). The oscillatory activity decreased to 80 +/- 26% of baseline (averaged across sites and stimulation intensities). Suppression with subthreshold stimuli confirmed that these changes were centrally driven and not due to peripheral afference. The results may have implications for mechanisms underlying the reported therapeutic benefits of cortical stimulation.


Novel affinity binders for neutralization of vascular endothelial growth factor (VEGF) signaling.
Angiogenesis denotes the formation of new blood vessels from pre-existing vasculature. Progression of diseases such as cancer and several ophthalmological disorders may be promoted by excess angiogenesis. Novel therapeutics to inhibit angiogenesis and diagnostic tools for monitoring angiogenesis during therapy, hold great potential for improving treatment of such diseases. We have previously generated so-called biparatopic Affibody constructs with high affinity for the vascular endothelial growth factor receptor-2 (VEGFR2), which recognize two non-overlapping epitopes in the ligand-binding site on the receptor. Affibody molecules have previously been demonstrated suitable for imaging purposes. Their small size also makes them attractive for applications where an alternative route of administration is beneficial, such as topical delivery using eye drops. In this study, we show that decreasing linker length between the two Affibody domains resulted in even slower dissociation from the receptor. The new variants of the biparatopic Affibody bound to VEGFR2-expressing cells, blocked VEGFA binding, and inhibited VEGFA-induced signaling of VEGFR2 over expressing cells. Moreover, the biparatopic Affibody inhibited sprout formation of endothelial cells in an in vitro angiogenesis assay with similar potency as the bivalent monoclonal antibody ramucirumab. This study demonstrates that the biparatopic Affibody constructs show promise for future therapeutic as well as in vivo imaging applications.


Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals.
Gray matter pathology is increasingly recognized as an important feature of multiple sclerosis (MS), but the nature of the immune response that targets the gray matter is poorly understood. Starting with a proteomics approach, we identified contactin-2/transiently expressed axonal glycoprotein 1 (TAG-1) as a candidate autoantigen recognized by both autoantibodies and T helper (Th) 1/Th17 T cells in MS patients. Contactin-2 and its rat homologue, TAG-1, are expressed by various neuronal populations and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and myelin sides. The pathogenic significance of these autoimmune responses was then explored in experimental autoimmune encephalitis models in the rat. Adoptive transfer of TAG-1-specific T cells induced encephalitis characterized by a preferential inflammation of gray matter of the spinal cord and cortex. Cotransfer of TAG-1-specific T cells with a myelin oligodendrocyte glycoprotein-specific mAb generated focal perivascular demyelinating lesions in the cortex and extensive demyelination in spinal cord gray and white matter. This study identifies contactin-2 as an autoantigen targeted by T cells and autoantibodies in MS. Our findings suggest that a contactin-2-specific T-cell response contributes to the development of gray matter pathology.


Bladder urine oxygen tension for assessing renal medullary oxygenation in rabbits: experimental and modeling studies.
Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2 Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po2 from bladder urine Po2 Both intravenous infusion of [Phe(2),Ile(3),Orn(8)]-vasopressin and infusion of N(G)-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8-17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po2 during these stimuli correlated strongly with changes in medullary Po2 (within-rabbit r(2) = 0.87-0.90). Differences in the Po2 of saline infused into the ureter close to the kidney could be detected in the bladder, although this was diminished at lesser ureteric flow. Diffusion of oxygen across the wall of the bladder was very slow, so it was not considered in the computational model. The model predicts Po2 in the pelvic ureter (presumed to reflect medullary Po2) from known values of bladder urine Po2, urine flow, and arterial Po2 Simulations suggest that, across a physiological range of urine flow in anesthetized rabbits (0.1-0.5 ml/min for a single kidney), a change in bladder urine Po2 explains 10-50% of the change in pelvic urine/medullary Po2 Thus, it is possible to infer changes in medullary Po2 from changes in urinary Po2, so urinary Po2 may have utility as a real-time biomarker of risk of acute kidney injury.


Corticosteroids compromise survival in glioblastoma.
Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.


Mechanism of gene expression of Arabidopsis glutathione S-transferase, AtGST1, and AtGST11 in response to aluminum stress.
The gene expression of two Al-induced Arabidopsis glutathione S-transferase genes, AtGST1 and AtGST11, was analyzed to investigate the mechanism underlying the response to Al stress. An approximately 1-kb DNA fragment of the 5'-upstream region of each gene was fused to a beta-glucuronidase (GUS) reporter gene (pAtGST1::GUS and pAtGST11::GUS) and introduced into Arabidopsis ecotype Landsberg erecta. The constructed transgenic lines showed a time-dependent gene expression to a different degree in the root and/or leaf by Al stress. The pAtGST1::GUS gene was induced after a short Al treatment (maximum expression after a 2-h exposure), while the pAtGST11::GUS gene was induced by a longer Al treatment (approximately 8 h for maximum expression). Since the gene expression was observed in the leaf when only the root was exposed to Al stress, a signaling system between the root and shoot was suggested in Al stress. A GUS staining experiment using an adult transgenic line carrying the pAtGST11::GUS gene supported this suggestion. Furthermore, Al treatment simultaneously with various Ca depleted conditions in root region enhanced the gene expression of the pAtGST11::GUS in the shoot region. This result suggested that the degree of Al toxicity in the root reflects the gene response of pAtGST11::GUS in the shoot via the deduced signaling system. Both transgenic lines also showed an increase of GUS activity after cold stress, heat stress, metal toxicity, and oxidative damages, suggesting a common induction mechanism in response to the tested stresses including Al stress.


Assessing end-of-life preferences for advanced dementia in rural patients using an educational video: a randomized controlled trial.
Few studies have evaluated the end-of-life preferences of elderly patients in rural communities and whether preferences are associated with level of health literacy. Randomized controlled trial of a goals-of-care video decision aid of advanced dementia. Elderly subjects (65 years or older) at a primary care clinic in rural Louisiana. Half of subjects heard a verbal description of advanced dementia and the goals of care; the other half heard the same verbal description and then viewed the video decision aid. End points were the preferred goal of care in advanced dementia: life-prolonging care (cardiopulmonary resuscitation [CPR], etc.), limited care (hospitalization but not CPR), or comfort care (symptom relief). The principal category for analysis was the difference in proportions of subjects preferring comfort care for each characteristic including randomization group and health literacy level. Seventy-six subjects were randomized to the verbal (n = 43) or video (n = 33) arms of the study. Among subjects receiving the verbal description of advanced dementia and the goals of care, 31 (72%) preferred comfort; 5 (12%) chose limited; and 7 (16%) desired life-prolonging. In the video group, 30 (91%) preferred comfort; 3 (9%) chose limited; and none desired life-prolonging (χ(2) = 6.3, df = 2, p = 0.047). Factors associated with greater likelihood of opting for comfort included greater health literacy (unadjusted odds ratio [OR] 12.1; 95% confidence interval [CI], 2.4-62.6) and randomization to the video (unadjusted OR 3.9; 95% CI, 1.0-15.1). Rural subjects with higher health literacy were more likely to want comfort care compared to those with lower levels of health literacy. Furthermore, subjects who viewed a video decision aid were more likely to opt for comfort compared to those who solely listened to a verbal description. These findings suggest that video can help elicit preferences and that interventions to empower such patients need to be designed in a manner that is sensitive to health literacy.


A reconfiguration of the sex trade: How social and structural changes in eastern Zimbabwe left women involved in sex work and transactional sex more vulnerable.
Understanding the dynamic nature of sex work is important for explaining the course of HIV epidemics. While health and development interventions targeting sex workers may alter the dynamics of the sex trade in particular localities, little has been done to explore how large-scale social and structural changes, such as economic recessions-outside of the bounds of organizational intervention-may reconfigure social norms and attitudes with regards to sex work. Zimbabwe's economic collapse in 2009, following a period (2000-2009) of economic decline, within a declining HIV epidemic, provides a unique opportunity to study community perceptions of the impact of socio-economic upheaval on the sex trade. We conducted focus group discussions with 122 community members in rural eastern Zimbabwe in January-February 2009. Groups were homogeneous by gender and occupation and included female sex workers, married women, and men who frequented bars. The focus groups elicited discussion around changes (comparing contemporaneous circumstances in 2009 to their memories of circumstances in 2000) in the demand for, and supply of, paid sex, and how sex workers and clients adapted to these changes, and with what implications for their health and well-being. Transcripts were thematically analyzed. The analysis revealed how changing economic conditions, combined with an increased awareness and fear of HIV-changing norms and local attitudes toward sex work-had altered the demand for commercial sex. In response, sex work dispersed from the bars into the wider community, requiring female sex workers to employ different tactics to attract clients. Hyperinflation meant that sex workers had to accept new forms of payment, including sex-on-credit and commodities. Further impacting the demand for commercial sex work was a poverty-driven increase in transactional sex. The economic upheaval in Zimbabwe effectively reorganized the market for sex by reducing previously dominant forms of commercial sex, while simultaneously providing new opportunities for women to exchange sex in less formal and more risky transactions. Efforts to measure and respond to the contribution of sex work to HIV transmission need to guard against unduly static definitions and consider the changing socioeconomic context and how this can cause shifts in behavior.


Introduction of color-flow injection test to confirm intravascular location of peripherally placed intravenous catheters.
The incidence of infiltration and extravasation when using peripheral intravenous catheters is high in pediatric patients. Due to the lack of a gold standard test to confirm intravascular location of a peripherally placed intravenous catheter, we introduce a novel method, the color-flow injection test to assess the intravascular location of these catheters. For the color-flow injection test, 1 mL of normal saline was injected within 2 seconds in the distal intravenous catheter and changes in color-flow via ultrasonography were observed at the proximal draining veins. The primary objective of the study was to demonstrate feasibility of the color-flow injection test. A prospective study was conducted on children <18 years old undergoing general anesthesia. All peripheral intravenous catheters were subject to the color-flow injection test and standard confirmation tests. Out of the 100 patients enrolled, 22 patients came to the operating room with preexisting peripheral intravenous catheters. Intraoperatively, 105 attempts were made on 78 patients of which 27 catheters were considered as infiltrated during their placement. A final set of 100 catheters were considered for intraoperative usage after they had passed at least one of the standard confirmatory tests. For the color-flow injection test, the ideal sites for ultrasound evaluation of proximal draining veins were the axillary veins and femoral veins. The color-flow injection test was positive in 93 of the 100 catheters with color-flow changes noticed in the proximal veins during the saline injection. Of the 100 catheters, infiltration around seven catheter sites were observed within 2 hours of intraoperative usage and the color-flow injection test was negative in these seven catheters. The color-flow injection test was also negative in the 27 catheters that had infiltrated during their placement. The color-flow injection test was sensitive at 100% [95% confidence interval (CI)=95-100] and specific at 100% (95% CI=56-100) to indicate intravascular location. We were able to confirm intravascular location of peripheral intravenous catheters using the color-flow injection test in pediatric patients. The test can lead to early recognition of malfunctioning peripheral intravenous catheters and decrease rate of infiltration-extravasation injuries associated with their use.


Molecular evolution of glycoside hydrolase genes in the Western corn rootworm (Diabrotica virgifera virgifera).
Cellulose is an important nutritional resource for a number of insect herbivores. Digestion of cellulose and other polysaccharides in plant-based diets requires several types of enzymes including a number of glycoside hydrolase (GH) families. In a previous study, we showed that a single GH45 gene is present in the midgut tissue of the western corn rootworm, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae). However, the presence of multiple enzymes was also suggested by the lack of a significant biological response when the expression of the gene was silenced by RNA interference. In order to clarify the repertoire of cellulose-degrading enzymes and related GH family proteins in D. v. virgifera, we performed next-generation sequencing and assembled transcriptomes from the tissue of three different developmental stages (eggs, neonates, and third instar larvae). Results of this study revealed the presence of seventy-eight genes that potentially encode GH enzymes belonging to eight families (GH45, GH48, GH28, GH16, GH31, GH27, GH5, and GH1). The numbers of GH45 and GH28 genes identified in D. v. virgifera are among the largest in insects where these genes have been identified. Three GH family genes (GH45, GH48, and GH28) are found almost exclusively in two coleopteran superfamilies (Chrysomeloidea and Curculionoidea) among insects, indicating the possibility of their acquisitions by horizontal gene transfer rather than simple vertical transmission from ancestral lineages of insects. Acquisition of GH genes by horizontal gene transfers and subsequent lineage-specific GH gene expansion appear to have played important roles for phytophagous beetles in specializing on particular groups of host plants and in the case of D. v. virgifera, its close association with maize.


What did you do yesterday? A meta-analysis of sex differences in episodic memory.
To remember what one did yesterday is an example of an everyday episodic memory task, in which a female advantage has sometimes been reported. Here, we quantify the impact of sex on episodic memory performance and investigate whether the magnitude of the sex difference is modified by study-, task-, and sample-specific moderators. Analyses were based on 617 studies conducted between 1973 and 2013 with 1,233,921 participants. A 5-level random-effects meta-analysis showed an overall female advantage in episodic memory (g = 0.19, 95% CI [0.17, 0.21]). The material to be remembered affected the magnitude of this advantage, with a female advantage for more verbal tasks, such as words, sentences, and prose (g = 0.28, 95% CI [0.25, 0.30]), nameable images (g = 0.16, 95% CI [0.11, 0.22]), and locations (g = 0.16, 95% CI [0.11, 0.21]), and a male advantage in more spatial tasks, such as abstract images (g = -0.20, 95% CI [-0.35, -0.05]) and routes (g = -0.24, 95% CI [-0.35, -0.12]). Furthermore, there was a female advantage for materials that cannot easily be placed along the verbal-spatial continuum, such as faces (g = 0.26, 95% CI [0.20, 0.33]), and odor, taste, and color (g = 0.37, 95% CI [0.18, 0.55]). These differences have remained stable since 1973. For verbal episodic memory tasks, differences were larger in Europe, North America, Oceania, and South America than in Asia, and smaller in childhood and old age than for other ages. Taken together, results suggest that men may use their spatial advantage in spatially demanding episodic memory tasks, whereas women do well in episodic memory tasks that are verbalizable and tasks that are neither verbal nor spatial, such as remembering faces and odors/tastes/colors. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Spatial modelling and mapping of female genital mutilation in Kenya.
Female genital mutilation/cutting (FGM/C) is still prevalent in several communities in Kenya and other areas in Africa, as well as being practiced by some migrants from African countries living in other parts of the world. This study aimed at detecting clustering of FGM/C in Kenya, and identifying those areas within the country where women still intend to continue the practice. A broader goal of the study was to identify geographical areas where the practice continues unabated and where broad intervention strategies need to be introduced. The prevalence of FGM/C was investigated using the 2008 Kenya Demographic and Health Survey (KDHS) data. The 2008 KDHS used a multistage stratified random sampling plan to select women of reproductive age (15-49 years) and asked questions concerning their FGM/C status and their support for the continuation of FGM/C. A spatial scan statistical analysis was carried out using SaTScan™ to test for statistically significant clustering of the practice of FGM/C in the country. The risk of FGM/C was also modelled and mapped using a hierarchical spatial model under the Integrated Nested Laplace approximation approach using the INLA library in R. The prevalence of FGM/C stood at 28.2% and an estimated 10.3% of the women interviewed indicated that they supported the continuation of FGM. On the basis of the Deviance Information Criterion (DIC), hierarchical spatial models with spatially structured random effects were found to best fit the data for both response variables considered. Age, region, rural-urban classification, education, marital status, religion, socioeconomic status and media exposure were found to be significantly associated with FGM/C. The current FGM/C status of a woman was also a significant predictor of support for the continuation of FGM/C. Spatial scan statistics confirm FGM clusters in the North-Eastern and South-Western regions of Kenya (p<0.001). This suggests that the fight against FGM/C in Kenya is not yet over. There are still deep cultural and religious beliefs to be addressed in a bid to eradicate the practice. Interventions by government and other stakeholders must address these challenges and target the identified clusters.


Prediction of Major Depressive Disorder Following Beta-Blocker Therapy in Patients with Cardiovascular Diseases.
Incident depression has been reported to be associated with poor prognosis in patients with cardiovascular disease (CVD), which might be associated with beta-blocker therapy. Because early detection and intervention can alleviate the severity of depression, we aimed to develop a machine learning (ML) model predicting the onset of major depressive disorder (MDD). A model based on L1 regularized logistic regression was trained against the South Korean nationwide administrative claims database to identify risk factors for the incident MDD after beta-blocker therapy in patients with CVD. We identified 50,397 patients initiating beta-blockers for CVD, with 774 patients developing MDD within 365 days after initiating beta-blocker therapy. An area under the receiver operating characteristic curve (AUC) of 0.74 was achieved. A history of non-selective beta-blockers and factors related to anxiety disorder, sleeping problems, and other chronic diseases were the most strong predictors. AUCs of 0.62-0.71 were achieved in the external validation conducted on six independent electronic health records and claims databases in the USA and South Korea. In conclusion, an ML model that identifies patients at high-risk for incident MDD was developed. Application of ML to identify susceptible patients for adverse events of treatment may serve as an important approach for personalized medicine.


The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice.
In order to prime T cells, DCs integrate signals emanating directly from pathogens and from their noxious action on the host. DNGR-1 (CLEC9A) is a DC-restricted receptor that detects dead cells. Therefore, we investigated the possibility that DNGR-1 affects immunity to cytopathic viruses. DNGR-1 was essential for cross-presentation of dying vaccinia virus-infected (VACV-infected) cells to CD8(+) T cells in vitro. Following injection of VACV or VACV-infected cells into mice, DNGR-1 detected the ligand in dying infected cells and mediated cross-priming of anti-VACV CD8(+) T cells. Loss of DNGR-1 impaired the CD8+ cytotoxic response to VACV, especially against those virus strains that are most dependent on cross-presentation. The decrease in total anti-VACV CTL activity was associated with a profound increase in viral load and delayed resolution of the primary lesion. In addition, lack of DNGR-1 markedly diminished protection from infection induced by vaccination with the modified vaccinia Ankara (MVA) strain. DNGR-1 thus contributes to anti-VACV immunity, following both primary infection and vaccination. The non-redundant ability of DNGR-1 to regulate cross-presentation of viral antigens suggests that this form of regulation of antiviral immunity could be exploited for vaccination.


The effect of opioid antagonism and environmental restriction on plasma oxytocin and vasopressin concentrations in parturient gilts.
Oxytocin plays an important role at parturition due to its involvement in uterine contractions, foetal expulsion and the onset of maternal behaviour. The role of the related neurohypophysial hormone, vasopressin, is less clear; however, there is some evidence that it is also involved in maternal behaviour and its role in osmotic regulation is well established. The aim of this study was to investigate the inhibitory effects of endogenous opioids on these hormones during the expulsive phase of parturition in the pig, and to examine how opioid restraint interacts with environmental restriction. The subjects of this study were 31 Large Whitex Landrace primiparous sows (gilts). An indwelling jugular catheter was implanted under general anaesthesia at 12 days before the expected parturition day (EPD). From 5 days before the EPD 15 of the gilts were individually housed in a restrictive parturition crate without straw and 16 were individually housed in a straw-bedded pen. Blood samples were taken with increasing frequency towards and during parturition through a catheter extension to reduce disturbance. At 7.5 min after the birth of the first piglet half of the gilts in each environment received a dose of the opioid receptor antagonist naloxone (1 mg/kg, i.v.) with the remaining gilts receiving saline as a control. Overall, there was no effect of environment on either circulating oxytocin or vasopressin. However, both oxytocin and vasopressin were inhibited by endogenous opioids during the expulsive phase. The inhibitory effects of opioids on these hormones did not appear to have any adverse effects on the progress of parturition as judged by cumulative piglet birth intervals. The regulation of the opioid inhibition of oxytocin and vasopressin during parturition is discussed in relation to other neurotransmitters and whether opioid inhibition of these neurohypophysial hormones is part of the 'normal' physiological response to parturition or whether it is stress-induced.