Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I.
By probing the quinone substrate binding site of mitochondrial complex I with a focused set of quinazoline-based compounds, we identified substitution patterns as being critical for the observed inhibition. The structure activity relationship study also resulted in the discovery of the quinazoline 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (EVP4593) as a highly potent inhibitor of the multisubunit membrane protein. EVP4593 specifically and effectively reduces the mitochondrial complex I-dependent respiration with no effect on the respiratory chain complexes II-IV. Similar to established Q-site inhibitors, EVP4593 elicits the release of reactive oxygen species at the flavin site of mitochondrial complex I. Recently, EVP4593 was nominated as a lead compound for the treatment of Huntingtons disease. Our results challenge the postulated primary mode-of-action of EVP4593 as an inhibitor of NF-κB pathway activation and/or store-operated calcium influx.


Coal and biomass to fuels and power.
Systems with CO(2) capture and storage (CCS) that coproduce transportation fuels and electricity from coal plus biomass can address simultaneously challenges of climate change from fossil energy and dependence on imported oil. Under a strong carbon policy, such systems can provide competitively clean low-carbon energy from secure domestic feedstocks by exploiting the negative emissions benefit of underground storage of biomass-derived CO(2), the low cost of coal, the scale economies of coal energy conversion, the inherently low cost of CO(2) capture, the thermodynamic advantages of coproduction, and expected high oil prices. Such systems require much less biomass to make low-carbon fuels than do biofuels processes. The economics are especially attractive when these coproduction systems are deployed as alternatives to CCS for stand-alone fossil fuel power plants. If CCS proves to be viable as a major carbon mitigation option, the main obstacles to deployment of coproduction systems as power generators would be institutional.


Predicting spring moth emergence in the pink bollworm (Lepidoptera: Gelechiidae): implications for managing resistance to transgenic cotton.
Cultural control methods have been central in the southwestern United States for reducing pink bollworm, Pectinophora gossypiella (Saunders), damage to cotton. Nevertheless, it is not clear at present how such methods could be integrated within the novel pest management framework allowed by introduction of cotton producing a toxin from Bacillus thuringiensis (Bt) for pink bollworm control. Using statewide pheromone trapping and climatic data in conjunction with deterministic simulation models, we investigated whether manipulation of cotton planting date and use of other cultural control methods could represent valuable tactics for control of the pink bollworm in Arizona. Accumulation of heat units from one January accurately predicted the rate of pink bollworm emergence from diapause in 15 cotton-producing regions. Significant variation in rate of emergence from diapause was present among regions, with earlier emergence at higher altitudes. Most adults emerge from diapause too early to reproduce successfully on cotton, a phenomenon known as suicidal emergence. A method for prediction of the fraction of suicidal emergence resulting from adoption of a given cotton planting date is presented. Results from simulation models suggest that manipulation of planting date and implementation of other control cultural methods reduce the rate of application of insecticides and delay the evolution of resistance to Bt cotton in the pink bollworm.


Evaluation of a Pain Management Education Program and Operational Guideline on Nursing Practice, Attitudes, and Pain Management.
Nurses lack adequate pain management knowledge, which can result in poorly managed postsurgical pain. This study aimed to develop, implement, and evaluate pain management education and operational guidelines to improve nursing knowledge and pain management. This quality improvement project employed convenience samples of surgical oncology nurses and postoperative patients. The intervention involved an online module, live education, and operational guideline for pain management. Nurses completed pre- and postintervention practice and attitudes surveys. Random chart reviews of intravenous narcotic administrations the day before discharge were completed to evaluate whether narcotic administration changed after intervention. Readmissions and Hospital Consumer Assessment of Healthcare Providers and Systems data were collected to determine whether the intervention influenced patient satisfaction. A statistically significant improvement in nursing practice and intravenous narcotic administrations demonstrated changes to pain management practices employed by the nursing staff. Although not statistically significant, fewer pain-related readmissions occurred postintervention. Findings demonstrate that targeted pain management continuing education, paired with operational guidelines, improves nursing practice and decreases intravenous narcotic administrations prior to discharge. J Contin Educ Nurs. 2018;49(4):178-185.


In vitro fermentability of human milk oligosaccharides by several strains of bifidobacteria.
This study was conducted to investigate the catabolism and fermentation of human milk oligosaccharides (HMO) by individual strains of bifidobacteria. Oligosaccharides were isolated from a pooled sample of human milk using solid-phase extraction, and then added to a growth medium as the sole source of fermentable carbohydrate. Of five strains of bifidobacteria tested (Bifidobacterium longum biovar infantis, Bifidobacterium bifidum, Bifidobacterium longum biovar longum, Bifidobacterium breve, and Bifidobacterium adolescentis), B. longum bv. infantis grew better, achieving triple the cell density then the other strains. B. bifidum did not reach a high cell density, yet generated free sialic acid, fucose and N-acetylglucosamine in the media, suggesting some capacity for HMO degradation. Thin layer chromatography profiles of spent fermentation broth suggests substantial degradation of oligosaccharides by B. longum bv. infantis, moderate degradation by B. bifidum and little degradation by other strains. While all strains were able to individually ferment two monosaccharide constituents of HMO, glucose and galactose, only B. longum bv. infantis and B. breve were able to ferment glucosamine, fucose and sialic acid. These results suggest that as a potential prebiotic, HMO may selectively promote the growth of certain bifidobacteria strains, and their catabolism may result in free monosaccharides in the colonic lumen.


Enhancing the health of medical students: outcomes of an integrated mindfulness and lifestyle program.
Medical students experience various stresses and many poor health behaviours. Previous studies consistently show that student wellbeing is at its lowest pre-exam. Little core-curriculum is traditionally dedicated to providing self-care skills for medical students. This paper describes the development, implementation and outcomes of the Health Enhancement Program (HEP) at Monash University. It comprises mindfulness and ESSENCE lifestyle programs, is experientially-based, and integrates with biomedical sciences, clinical skills and assessment. This study measured the program's impact on medical student psychological distress and quality of life. A cohort study performed on the 2006 first-year intake measured effects of the HEP on various markers of wellbeing. Instruments used were the depression, anxiety and hostility subscales of the Symptom Checklist-90-R incorporating the Global Severity Index (GSI) and the WHO Quality of Life (WHOQOL) questionnaire. Pre-course data (T1) was gathered mid-semester and post-course data (T2) corresponded with pre-exam week. To examine differences between T1 and T2 repeated measures ANOVA was used for the GSI and two separate repeated measures MANOVAs were used to examine changes in the subscales of the SCL-90-R and the WHOQOL-BREF. Follow-up t-tests were conducted to examine differences between individual subscales. A total of 148 of an eligible 270 students returned data at T1 and T2 giving a response rate of 55%. 90.5% of students reported personally applying the mindfulness practices. Improved student wellbeing was noted on all measures and reached statistical significance for the depression (mean T1 = 0.91, T2 = 0.78; p = 0.01) and hostility (0.62, 0.49; 0.03) subscales and the GSI (0.73, 0.64; 0.02) of the SCL-90, but not the anxiety subscale (0.62, 0.54; 0.11). Statistically significant results were also found for the psychological domain (62.42, 65.62; p < 0.001) but not the physical domain (69.11, 70.90; p = 0.07) of the WHOQOL. This study is the first to demonstrate an overall improvement in medical student wellbeing during the pre-exam period suggesting that the common decline in wellbeing is avoidable. Although the findings of this study indicate the potential for improving student wellbeing at the same time as meeting important learning objectives, the limitations in study design due to the current duration of follow-up and lack of a control group means that the data should be interpreted with caution. Future research should be directed at determining the contribution of individual program components, long-term outcomes, and impacts on future attitudes and clinical practice.


Partnership capacity for community health improvement plan implementation: findings from a social network analysis.
Many health departments collaborate with community organizations on community health improvement processes. While a number of resources exist to plan and implement a community health improvement plan (CHIP), little empirical evidence exists on how to leverage and expand partnerships when implementing a CHIP. The purpose of this study was to identify characteristics of the network involved in implementing the CHIP in one large community. The aims of this analysis are to: 1) identify essential network partners (and thereby highlight potential network gaps), 2) gauge current levels of partner involvement, 3) understand and effectively leverage network resources, and 4) enable a data-driven approach for future collaborative network improvements. We collected primary data via survey from n = 41 organizations involved in the Health Improvement Partnership of Maricopa County (HIPMC), in Arizona. Using the previously validated Program to Analyze, Record, and Track Networks to Enhance Relationships (PARTNER) tool, organizations provided information on existing ties with other coalition members, including frequency and depth of partnership and eight categories of perceived value/trust of each current partner organization. The coalition's overall network had a density score of 30 %, degree centralization score of 73 %, and trust score of 81 %. Network maps are presented to identify existing relationships between HIPMC members according to partnership frequency and intensity, duration of involvement in the coalition, and self-reported contributions to the coalition. Overall, number of ties and other partnership measures were positively correlated with an organization's perceived value and trustworthiness as rated by other coalition members. Our study presents a novel use of social network analysis methods to evaluate the coalition of organizations involved in implementing a CHIP in an urban community. The large coalition had relatively low network density but high degree centralization-meaning key organizations link organizations otherwise not tightly partnering. Coalition members rated each other highly on trust, a positive sign for future partnership development efforts. Examination of network maps reveal key organizations that can be targeted for future partnership facilitation and expansion. Future network data collection will enable exploration of longitudinal trends and exploration of network characteristics versus health behavior, status, and outcome changes.


Enhancing imagined contact to reduce prejudice against people with schizophrenia.
Four studies investigated the effect of imagining intergroup contact on prejudice against people with schizophrenia. Experiments 1 and 2 demonstrated that a neutral imagined contact task can have negative effects, compared to a control condition, even when paired with incidental positive information (Experiment 2). Experiments 3 and 4 demonstrated, however, that an integrated positive imagined contact scenario does result in less intergroup anxiety and more positive attitudes, even toward this challenging group. Analyses of participants' descriptions of the imagined interactions in and across the first three studies confirm that positive and high quality imagined contact is important for reducing prejudice, but failing to ensure that imagined contact is positive may have deleterious consequences. We emphasize the importance of investigating the quality of the imagined contact experience, and discuss the implications for using imagined contact as a prejudice-reducing intervention.


Using pre-treatment EEG data to predict response to SSRI treatment for MDD.
The problem of identifying in advance the most effective treatment agent for various psychiatric conditions remains an elusive goal. To address this challenge, we propose a machine learning (ML) methodology to predict the response to a selective serotonin reuptake inhibitor (SSRI) medication in subjects suffering from major depressive disorder (MDD), using pre-treatment electroencephalograph (EEG) measurements. The proposed feature selection technique is a modification of the method of Peng et al [10] that is based on a Kullback-Leibler (KL) distance measure. The classifier was realized as a kernelized partial least squares regression procedure, whose output is the predicted response. A low-dimensional kernelized principal component representation of the feature space was used for the purposes of visualization and clustering analysis. The overall method was evaluated using an 11-fold nested cross-validation procedure for which over 85% average prediction performance is obtained. The results indicate that ML methods hold considerable promise in predicting the efficacy of SSRI antidepressant therapy for major depression.


Return to normal activities and work after living donor laparoscopic nephrectomy.
Transplant programs inform potential donors that they should be able to return to normal activities within ~2 weeks and to work by 6 weeks after laparoscopic nephrectomy. We studied actual time. Between 10/2004 and 9/2014, 911 donors having laparoscopic nephrectomy were surveyed 6 months post-donation. Surveys asked questions specific to their recovery experience, including time to return to normal activities and work and a description of their recovery time relative to pre-donation expectations. Of the 911, 646 (71%) responded: mean age at donation was 43.5±10.6 years; 65% were female, 95% were white, 51% were biologically related to their recipient, and 83% reported education beyond high school. Of the 646 respondents, a total of 35% returned to normal activities by 2 weeks post-donation; 79% by 4 weeks post-donation; 94% by 5-6 weeks; however, 6% took >6 weeks. Of the 646, 551 (85%) were working for pay; of these, mean time to return to work was 5.3±2.8 weeks; median, 5 weeks. Of the 551, a total of 14% returned to work in 1-2 weeks, 46% by 3-4 weeks, and 76% by 5-6 weeks. Importantly, 24% required >6 weeks before returning to work with the highest rates for donors in manual labor or a skilled trade. Significantly longer return to work was reported by females (vs males; P=.01), those without (vs those with) post-high school education (P=.010, those with longer hospital stay (P=.01), and those with a postoperative complication (P=.02). Of respondents, 37% described their recovery time as longer than expected. During the donor informed consent process, additional emphasis on realistic expectations around recovery to baseline activities and return to work is warranted.


Surgical management of giant presacral schwannoma: systematic review of published cases and meta-analysis.
Giant presacral schwannomas are rare sacral tumors found in less than 1 of every 40,000 hospitalizations. Current management of these tumors is based solely upon case reports and small case series. In this paper the authors report the results of a systematic review of the available English literature on presacral schwannoma, focused on identifying the influence of tumor size, tumor morphology, surgical approach, and extent of resection (EOR) on recurrence-free survival and postoperative complications. The medical literature (PubMed and EMBASE) was queried for reports of surgically managed sacral schwannoma, either involving 2 or more contiguous vertebral levels or with a diameter ≥ 5 cm. Tumor size and morphology, surgical approach, EOR, intraoperative and postoperative complications, and survival data were recorded. Seventy-six articles were included, covering 123 unique patients (mean age 44.1 ± 1.4 years, 50.4% male). The most common presenting symptoms were leg pain (28.7%), lower back pain (21.3%), and constipation (15.7%). Most surgeries used an open anterior-only (40.0%) or posterior-only (30%) approach. Postoperative complications occurred in 25.6% of patients and local recurrence was noted in 5.4%. En bloc resection significantly improved progression-free survival relative to subtotal resection (p = 0.03). No difference existed between en bloc and gross-total resection (GTR; p = 0.25) or among the surgical approaches (p = 0.66). Postoperative complications were more common following anterior versus posterior approaches (p = 0.04). Surgical blood loss was significantly correlated with operative duration and tumor volume on multiple linear regression (both p < 0.001). Presacral schwannoma can reasonably be treated with either en bloc or piecemeal GTR. The approach should be dictated by lesion morphology, and recurrence is infrequent. Anterior approaches may increase the risk of postoperative complications.


Retina-derived fetuin (RDF): analysis by immunocytochemistry, reverse transcriptase-polymerase chain reaction and Southern blot.
This study was undertaken to determine the presence of retina-derived fetuin (RDF) protein and its message in retinal tissues and retinal pigment epithelial (RPE) cells. The techniques utilized in this study included light micros-copy, immunochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot. Retinal tissues and sections from embryonic, early postnatal and adult normal rats and retinal pigment epithe-lial (RPE) cells from postnatal rats were immunostained for fetuin with a polyclonal fetuin antibody and a peroxidase conjugated-secondary antibody using immunocytochemistry and Western blot analyses. The cDNA generated from RNA isolated from early postnatal rat retinas and RPE was probed with primers for rat fetuin, amplified by PCR and the PCR products were analyzed by Southern blot. Fetuin (RDF) was immunolocalized to cells of the neuroepithelium in retinas of early postnatal rats and most prominently in the nuclei and perinuclear region of cultured neonatal rat RPE cells. In adult retinas, ganglion cells, inner segments of photoreceptor cells, some components of the outer plexiform layer, ganglion cells and optic nerve processes were immunoreactive for the fetuin protein. As shown by Western blot, fetuin (RDF) was higher in embryonic and early postnatal retinas than in late postnatal retinas, indicating that this protein may be developmentally regulated. Using RT-PCR, the message for rat fetuin was demonstrated in the retina and RPE of normal postnatal rats. Southern blot confirmed that the PCR product from the retina and RPE was generated from rat fetuin mRNA as well as from rat liver, the primary source of fetuin. Fetuin, termed retina-derived fetuin (RDF), is reported for the first time in retinal tissues. Fetuin is a cysteine protease inhibitor that may play a role in support of neuronal cell survival during early retinal development and the maintenance of neuronal activity. RDF may interact with other growth factors and cytokines in providing trophic support for neurons and possibly other cells of the developing retina.


The case to scale up edutainment as an effective public health communication intervention to combat the COVID-19 pandemic in Zimbabwe.
Efforts to control the coronavirus disease 2019 (COVID-19) pandemic have been negatively affected by myths, misconceptions and misinformation, fuelled by an "infodemic" spread via social media platforms. In response, The Zimbabwean COVID-19 response built on its experience with past public health communication strategies to employ edutainment strategies for COVID-19 awareness campaigns. This article discusses the different strategies and how they were employed. In this perspective piece, the authors discuss edutainment as an effective vehicle for reaching wider sectors of society. In tackling complex social issues with simple language, integrated into various entertainment formats, edutainment can bring about change in contexts where traditional strategies and actions may prove unsuccessful.


Liquid Crystal based adaptive optics system to compensate both low and high order aberrations in a model eye.
Based on a simple eye model system, a high resolution adaptive optics retina imaging system was built to demonstrate the availability of using liquid crystal devices as a wave-front corrector for both low and high order aberrations. Myopia glass was used to introduce large low order aberrations. A fiber bundle was used to simulate the retina. After correction, its image at different diopters became very clear. We can get a root mean square (RMS) correction precision of lower than 0.049lambda (lambda=0.63mum) for over to 10 diopters and the modulation transfer function (MTF) retains 511p/mm, which is nearly the diffraction limited resolution for a 2.7mm pupil diameter. The closed loop bandwidth was nearly 4 Hz, which is capable to track most of the aberration dynamics in a real eye.


Perception of pain in others: implication for caregivers.
SUMMARY The subjective nature of pain renders its perception in others a challenge for clinicians and informal caregivers responsible for its assessment and relief. Adequate perception of others' pain relies on different behavioral and neurophysiological mechanisms. Several individual, relational and contextual factors can influence the way the brain reacts to others' pain and the perception and assessment of this pain. This article focuses on recent neurophysiological and psychological evidence that characterizes these factors, and discusses their potential impact on the perception of others' pain in a caregiving context. Factors influencing the perception of pain in others are divided into factors related to the self (caregiver), factors related to the other (patient), and factors related to the relationship between those individuals and the context in which the pain is perceived. We propose that the perception of others' pain plays a crucial role in the treatment provided by clinicians and informal caregivers, and that further research could lead to improving decision-making regarding pain management.


[Magnitude, time trends and factors associate with anemia in children in the state of Paraíba, Brazil].
To estimate the magnitude of the anemia, to analyze the time trends and investigate the factors associated with this disturbance in children in the state of Paraíba, Brazil. A cross-sectional survey, of population-based, with 1108 children, aged 6 to 59 months, both sexes in the state of Paraíba. Hemoglobin (Hb) in venous blood was analyzed with an automatic counter. The social-economic and demographic characteristics of children were obtained by questionnaire. Proportions were compared by Pearson's chi-squared test, and the association between hemoglobin concentrations and potential risk factors was tested by regression model Poisson. The time trend of anemia was assessed by the increase/decreased in the prevalence of anemia, using as comparison the prevalence observed in the years 1982, 1992 and 2007. The prevalence of anemia (Hb < 11.0 g/dl) in the state of Paraíba was 36.5% (CI95% 33.7 to 39.3). It was observed that 1.3% (CI95% 0.7 to 1.8) were in severe form (Hb <7.0 g/dl), 11% (CI95% 9.4 to 13.5) in a moderate form and 87.6% (CI95% 79.1 to 91.2) in the mild form. There was an increase 88.5% in cases of anemia between the years 1982-1992 and stabilization in the prevalence between the years 1992-2007. The analysis adjusted Poisson model showed a greater susceptibility to anemia in children 6 to 24 months of age, those breastfed for six months or more, who co-inhabited with more than 04 people in the same household and lived in houses with less than 05 rooms. The results revealed that anemia remains an important public health problem in the state of Paraíba and despite having been shown an stabilization in the prevalence of anemia between 1992-2007, differently the prevalence observed between 1982-1992, this deficiency presents in high level, witch requires more effective measures of prevention and control.


Plotting basic control charts: tutorial notes for healthcare practitioners.
There is considerable interest in the use of statistical process control (SPC) in healthcare. Although SPC is part of an overall philosophy of continual improvement, the implementation of SPC usually requires the production of control charts. However, as SPC is relatively new to healthcare practitioners and is not routinely featured in medical statistics texts/courses, there is a need to explain the issues involved in the selection and construction of control charts in practice. Following a brief overview of SPC in healthcare and preliminary issues, we use a tutorial-based approach to illustrate the selection and construction of four commonly used control charts (xmr-chart, p-chart, u-chart, c-chart) using examples from healthcare. For each control chart, the raw data, the relevant formulae and their use and interpretation of the final SPC chart are provided together with a notes section highlighting important issues for the SPC practitioner. Some more advanced topics are also mentioned with suggestions for further reading.


Effectiveness of preventive back educational interventions for low back pain: a critical review of randomized controlled clinical trials.
A systematic search was conducted to study the efficiency of preventive educational interventions mainly focused on a biomechanical/biomedical model. The PubMed electronic database and the Cochrane Library were searched based on a combination of keywords related to low back pain (LBP) and posture education. Only randomized controlled trial (RCT) studying the efficiency on outcomes directly related to LBP of a preventive intervention programme mainly based on education of proper care of the back for subjects not seeking treatment were included. References of the articles meeting these inclusion criteria were also checked to identify other potential citations. Besides, a methodological study assessment of the included RCTs was performed. Nine studies, all conducted at the workplace were included in this review. Their mean quality level was low (5.1/12) and among the four studies with a huge sample size (n > 400 subjects), only one had an acceptable methodological quality score (6/12). The education interventions differed widely from one study to another. No significant differences between the control and education groups were found at the follow-up in eight out of the nine studies on the incidence of back pain, disability and sick leave. The results of the RCTs included in this review suggest that educational interventions mainly focused on a biomechanical/biomedical model are not effective in preventing LBP. However, taking into account the methodological quality level of the RCTs as well as the very short and heterogeneous interventions often proposed, additional high-quality studies with a longer education period are needed to conclude that such interventions are inefficient.


Oral Health of Children with Congenital Heart Disease at a Pediatric Health Science Centre.
This study aimed to examine the oral health status of seniors residing in Providence Health Care (PHC) long-term care facilities in 2002 and 2012. Staff dentists with the University of British Columbia Geriatric Dentistry Program made a complete oral health assessment of 799 elderly residents of 7 long-term care PHC facilities in 2002 and 381 residents in the 5 remaining PHC facilities in 2012. The 2012 data were divided into those for 275 residents who had received treatment in previous years and 106 new residents. All consenting residents were examined by dentists using the clinical oral disorder in elders (CODE) index detailing their medical and oral health status and medications. On completion of the oral health assessment, the dentist documented the need for specific dental treatment and reassessment. Comparing the cohorts from 2002 and 2012, the mean age of the residents who had CODE assessments increased from 85 years to 86 years, the proportion of men increased from 31% to 35%, the mean number of medical conditions per resident remained unchanged (2.6 to 2.5), but the mean number of prescribed medications has increased from 4.0 to 4.6. The percentage of residents with natural teeth increased from 56% to 76%. The proportion of edentulous residents recommended for denture-related treatment decreased from 21% to 10%. The 106 new residents in 2012 had higher treatment needs than the 275 original residents, but fewer required extractions than in 2002. Although the mean number of teeth per resident examined increased from 14.6 to 17.4 over the study period, the need for restorations remained at 20%, and the need for extraction of teeth decreased from 22% to 6%. The proportion of residents with healthy periodontium increased from 14% to 21%, but the need for dental hygiene services increased from 43% to 80%. The profile of long-term care residents who consented to an oral health assessment changed over the first decade of the new millennium, with an increase in mean age and number of prescribed medications, number of retained natural teeth and the need for dental hygiene services, but a decrease in the need for extractions.


The association between adiposity, mental well-being, and quality of life in extreme obesity.
To explore the cross-sectional association between adiposity, mental well-being, and quality of life in extreme obese individuals entering a UK specialist weight management service prior to treatment commencement. The sample comprised 263 extreme obese individuals who were referred to the service as a result of having a body mass index (BMI) ≥40 kg/m2 or ≥35 kg/m2 with a co-morbid health condition. In a retrospective analysis, routinely collected baseline clinical examination data and self-report questionnaires (Impact of Weight on Quality of Life: IWQOL-Lite, EQ5D-3L, and Hospital Anxiety and Depression Scale: HADS) were analysed to examine the cross-sectional association between adiposity and quality of life. The sample was predominantly female (74.8%) with mean BMI 47.0±7.9 kg/m2. Increasing adiposity was significantly negatively associated with quality of life, with an increase of 1 BMI unit associated with decreases of 1.93 in physical function (95% CI -2.86 - -1.00, p<0.001), 1.62 in self-esteem (95% CI -2.67 - -0.57, p<0.05), 2.69 in public distress (95% CI -3.75 - -1.62, p<0.001), 1.33 in work (95% CI -2.63 - -0.02, p<0.05), and 1.79 in total IWQOL-Lite scores (95% CI -2.65 - -0.93, p<0.001). Adiposity was associated with significantly increased risk of problems in mobility (OR = 3.44, 95% CI 1.47-8.05), and performing usual activities (OR = 2.45, 95% CI 1.10-5.46) in highest relative to lowest BMI tertile. The prevalence of experience of symptoms of anxiety (70.3%) and depression (66.2%) as measured by HADS was consistently high. We identified a high prevalence of psychological co-morbidity, including widespread experience of symptoms of anxiety and depressive disorders and reduced quality of life among these extreme obese individuals seeking weight management treatment. Clinical implications include the need for the incorporation of strategies to improve mental well-being into multi-disciplinary weight management interventions.


The value and use of social media as communication tool in the plant sciences.
Social media now complements many parts of our lives. Facebook, Twitter, YouTube and many other social networking sites allow users to share and interact with online content and to connect with like-minded people. Its strengths - rapid dissemination and amplification of content and the ability to lead informal conversations - make it a powerful tool to use in a professional context. This commentary explains the overall concept of social media and offers suggestions on usage and possible types of scientific content. It advises researchers on the potential benefits and how to take a strategic approach towards building a social media presence. It also presents examples of effective social media use within the plant science community. Common reasons for scientists to not engage with social media include the fear of appearing unprofessional, posting something wrong or being misunderstood, or a lack of confidence in their computer skills. With the rapid changes in academic publishing, dissemination and science communication, as well as the rise of 'altmetrics' to track online engagement with scientific content, digital literacy will become an essential skill in a scientist's tool kit.


The effects and costs of the universal parent group program - all children in focus: a study protocol for a randomized wait-list controlled trial.
In recent decades, parents have been involved in programs that aim to improve parenting style and reduce child behavior problems. Research of preventive parenting programs has shown that these interventions generally have a positive influence on both parents and children. However, to our knowledge there is a gap in the scientific literature when it comes to randomized controlled trials of brief, manual-based structured programs which address general parenting among the population, and focus on promoting health. A four-session universal health promotion parent group program named All Children in Focus was developed. It aims at promoting parental competence and children's positive development with the parent-child relationship as the target. There is currently no randomized controlled trial existing of the program. A prospective multicenter randomized wait-list controlled trial is being conducted. Approximately 600 parents with children ranging in age from 3-12 years have been recruited in eleven municipalities and city districts in the County of Stockholm, Sweden. Parents are randomized at baseline to an intervention group, which receives the program directly, or to a waiting-list control group, which participates in the program six months later. Changes in parenting and child health and development are assessed with measures immediately post-intervention and six months after the baseline. Observations of a minor group of parents and children are conducted to explore possible relations between parental reports and observed behaviors, as well as changes in the interaction between parent and child. Further, data collected within the evaluation will also be applied to evaluate the possible cost-effectiveness of the program. This paper describes a study protocol of a randomized controlled trial. Except for the quantitative outcome measures to evaluate the effectiveness of All Children in Focus, this protocol also describes health economic and qualitative analyses to deepen the knowledge of the program. We further discuss some issues regarding the implementation of the program in municipalities and city districts. Current Controlled Trials ISRCTN70202532.


Hematologic, iron-related, and acute-phase protein responses to sustained strenuous exercise.
This study was undertaken to gain insight into the mechanisms responsible for the hypoferremia occurring after severe exercise. To this end, 18 athletes who were competing in a 160-km triathlon involving canoeing, cycling, and running were evaluated before the race, immediately after the finish, and thereafter at 30 min, 24 h, and 48 h. The evaluation included plasma iron, total iron-binding capacity, lactoferrin, ferritin, haptoglobin, cortisol, various enzymes, and white cell count. The cortisol, white cell count, and lactoferrin were significantly increased immediately after the race, while the plasma iron and transferrin saturation were significantly decreased. There was a 40% but nonsignificant rise in the plasma ferritin at the completion of the race, while the C-reactive protein was raised by nearly 300% at 24 h. In contrast, haptoglobin declined significantly by 24 h but was normal again 24 h later. Quantitative considerations suggested that the lactoferrin was not responsible for removing transferrin iron from circulation and hence causing the hypoferremia. Instead, it seemed more likely that the iron-related changes were occurring as part of an acute phase response initiated by muscle injury.


Predictive Factors for Prostate Cancer in Biopsy of Patients with Prostate-Specific Antigen Levels Equal to or Less Than 4 ng/ml.
This study was conducted to identify the predictive factors for prostate cancer in patients with prostate-specific antigen (PSA) levels equal to or less than 4 ng/ml. A retrospective study of medical records was conducted on 292 patients with initial serum PSA ≤4 ng/ml among 2,305 patients who underwent prostate biopsy from January 2003 to December 2008. Prostate biopsy was performed on patients with PSA ≤4 ng/ml in the case of abnormal findings in the digital rectal examination (DRE) or transrectal ultrasonography (TRUS) or in those with a PSA level higher than the age-adjusted PSA levels. The patients were divided into the group diagnosed with prostate cancer and the non-prostate-cancer group. Subsequently, the variables of the two groups were compared. The patients' mean age was significantly higher in the prostate cancer group (n=28) than in the non-prostate-cancer group (n=264; p=0.033). In addition, for the patients with a PSA range of 2.0-2.9 ng/ml, their age (p=0.049) and PSA density (PSAD; p=0.042) were significantly higher and the prostate volume (p=0.028) was significantly smaller in the prostate cancer group than in the non-prostate-cancer group. Of the patients with PSA ≤4 ng/ml, the age of the patients who showed abnormal findings in the DRE or TRUS or who had a PSA level higher than the age-adjusted PSA level was a significant predictive factor for prostate cancer. In particular, for the PSA range of 2.0-2.9 ng/ml, a thorough screening test for prostate cancer was required if the patients had conditions such as higher age, smaller prostate, and higher PSAD.


Measurement of the ratio σ{tt}/σ{Z/γ{*}→ll} and precise extraction of the tt cross section.
We report a measurement of the ratio of the tt to Z/γ{*} production cross sections in sqrt[s]=1.96 TeV pp collisions using data corresponding to an integrated luminosity of up to 4.6 fb{-1}, collected by the CDF II detector. The tt cross section ratio is measured using two complementary methods, a b-jet tagging measurement and a topological approach. By multiplying the ratios by the well-known theoretical Z/γ{*}→ll cross section predicted by the standard model, the extracted tt cross sections are effectively insensitive to the uncertainty on luminosity. A best linear unbiased estimate is used to combine both measurements with the result σ{tt}=7.70±0.52 pb, for a top-quark mass of 172.5 GeV/c{2}.


Concealed semantic and episodic autobiographical memory electrified.
Electrophysiology-based concealed information tests (CIT) try to determine whether somebody possesses concealed information about a crime-related item (probe) by comparing event-related potentials (ERPs) between this item and comparison items (irrelevants). Although the broader field is sometimes referred to as "memory detection," little attention has been paid to the precise type of underlying memory involved. This study begins addressing this issue by examining the key distinction between semantic and episodic memory in the autobiographical domain within a CIT paradigm. This study also addresses the issue of whether multiple repetitions of the items over the course of the session habituate the brain responses. Participants were tested in a 3-stimulus CIT with semantic autobiographical probes (their own date of birth) and episodic autobiographical probes (a secret date learned just before the study). Results dissociated these two memory conditions on several ERP components. Semantic probes elicited a smaller frontal N2 than episodic probes, consistent with the idea that the frontal N2 decreases with greater pre-existing knowledge about the item. Likewise, semantic probes elicited a smaller central N400 than episodic probes. Semantic probes also elicited a larger P3b than episodic probes because of their richer meaning. In contrast, episodic probes elicited a larger late positive complex (LPC) than semantic probes, because of the recent episodic memory associated with them. All these ERPs showed a difference between probes and irrelevants in both memory conditions, except for the N400, which showed a difference only in the semantic condition. Finally, although repetition affected the ERPs, it did not reduce the difference between probes and irrelevants. These findings show that the type of memory associated with a probe has both theoretical and practical importance for CIT research.


Detection and Differentiation of Breast Cancer Sub-Types using a cPLA2α Activatable Fluorophore.
Cytosolic phospholipase A2α (cPLA2α) has been shown to be elevated in breast cancer and is a potential biomarker in the differentiation of molecular sub-types. Using a cPLA2α activatable fluorophore, DDAO arachidonate, we explore its ability to function as a contrast agent in fluorescence-guided surgery. In cell lines ranging in cPLA2α expression and representing varying breast cancer sub-types, we show DDAO arachidonate activates with a high correlation to cPLA2α expression level. Using a control probe, DDAO palmitate, in addition to cPLA2α inhibition and genetic knockdown, we show that this activation is a result of cPLA2α activity. In mouse models, using an ex vivo tumor painting technique, we show that DDAO arachidonate activates to a high degree in basal-like versus luminal-like breast tumors and healthy mammary tissue. Finally, we show that using an in vivo model, orthotopic basal-like tumors give significantly high probe activation compared to healthy mammary fat pads and surrounding tissue. Together we conclude that cPLA2α activatable fluorophores such as DDAO arachidonate may serve as a useful contrast agent for the visualization of tumor margins in the fluorescence-guided surgery of basal-like breast cancer.


Is there a relationship between venous insufficiency and knee osteoarthritis?
This study aims to evaluate whether there is a relationship between venous insufficiency (VI) and knee osteoarthritis (OA). Between February 2012 and May 2013, a total of 206 knees of 103 participants (14 males, 89 females; mean age 48.6±8.6 years; range, 30 to 69 years) were enrolled. The study group included 59 patients who were diagnosed with knee OA and the control group included 44 healthy volunteers without any complaint in their knee joints. Demographic and clinical characteristics of all participants were recorded. Venous system of the lower extremities was evaluated by Doppler ultrasonography. All knees were evaluated using conventional radiography based on the Kellgren-Lawrence (K&L) grading system and ultrasonography. Pain severity was evaluated using Likert pain scale and functioning was evaluated using Western Ontorio and McMaster Universities Osteoarthritis Index (WOMAC). Venous insufficiency was detected in 40.6% of the OA group and 15.9% of the control group (p=0.007). There was no statistically significant difference in the cartilage thicknesses and K&L grading regarding the presence of VI (p>0.05); however, the percentage of the radiographic medial tibial sclerosis was higher in patients with VI (60%) in the OA group (p>0.05). The WOMAC total scores were similar in both groups, while the WOMAC pain scores were higher in the patients with deep VI (p>0.05). Increased radiographic medial tibial sclerosis and higher WOMAC pain scores in patients with venous involvement in OA may lead to the hypothesis that venous system pathologies can affect the intraosseous microenvironment of the bone, resulting in pain and early subchondral bone involvement, consequently presenting as subchondral sclerosis.


Desmoplakin assembly dynamics in four dimensions: multiple phases differentially regulated by intermediate filaments and actin.
The intermediate filament (IF)-binding protein desmoplakin (DP) is essential for desmosome function and tissue integrity, but its role in junction assembly is poorly understood. Using time-lapse imaging, we show that cell-cell contact triggers three temporally overlapping phases of DP-GFP dynamics: (1) the de novo appearance of punctate fluorescence at new contact zones after as little as 3 min; (2) the coalescence of DP and the armadillo protein plakophilin 2 into discrete cytoplasmic particles after as little as 15 min; and (3) the cytochalasin-sensitive translocation of cytoplasmic particles to maturing borders, with kinetics ranging from 0.002 to 0.04 microm/s. DP mutants that abrogate or enhance association with IFs exhibit delayed incorporation into junctions, altering particle trajectory or increasing particle pause times, respectively. Our data are consistent with the idea that DP assembles into nascent junctions from both diffusible and particulate pools in a temporally overlapping series of events triggered by cell-cell contact and regulated by actin and DP-IF interactions.


Adapting the Diabetes Prevention Program for low- and middle-income countries: preliminary implementation findings from lifestyle Africa.
Rates of cardiovascular disease and diabetes are rising in low- and middle-income countries (LMIC), but there is a dearth of research devoted to developing and evaluating chronic disease interventions in these settings, particularly in Africa. Lifestyle Africa is a novel, culturally adapted version of the Diabetes Prevention Program (DPP) being evaluated in an ongoing community-based cluster-randomized trial in an underresourced urban community in South Africa. The purpose of this study is to describe the adaptations and adaptation process used to develop the program and to report preliminary implementation findings from the first wave of groups (n = 11; 200 individuals) who participated in the intervention. The RE-AIM model and community advisory boards guided the adaptation process. The program was designed to be delivered by community health workers (CHWs) through video-assisted sessions and supplemented with text messages. Participants in the trial were overweight and obese members of existing chronic disease "support groups" served via CHWs. Implementation outcomes included completion of sessions, session attendance, fidelity of session delivery, and participant satisfaction. Results indicated that 10/11 intervention groups completed all 17 core sessions. Average attendance across all sessions and groups was 54% and the percentage who attended at least 75% of sessions across all groups was 35%. Fidelity monitoring indicated a mean of 84% of all required procedures were completed while overall communication skills were rated as "good" to "excellent". These preliminary results support the feasibility of culturally adapting the DPP for delivery by CHWs in underresourced settings in LMIC.


New Age in Israel: Formative ethos, identity blindness, and implications for healthcare.
This article presents a critical analysis of New Age culture. We draw on two empirical studies conducted in Israel and show that the lofty notions about freedom from the shackles of socially structured identities and the unifying potential this holds, as well as the claim regarding the basic equality of human beings, are utopian. Blindness toward ethno-national identity reinforces identification with a self-evident hegemonic perception, thereby leading to the exclusion of peripheral groups such as indigenous populations. This exclusion is manifested in the discourse symbolically as well as in the praxis of complementary and alternative medicine, which is one of the main fields in which New Age culture is involved. Thus, the unifying ethos in the New Age culture becomes an illusionary paradise. This article contributes to the study of power relationships between New Age culture in diverse Western countries and the native and peripheral populations of these countries, and to the sociological study of complementary and alternative medicine incorporated into health organizations.


Single shot interferometric method for measuring the nonlinear refractive index.
In this paper we are introducing a new single shot method for measuring the nonlinear refractive index of materials in a simple interferometric pump-probe configuration. The theoretical model proposed for extracting the nonlinear refractive index from the experimental fringe pattern and the experimental configuration are presented and discussed. The results obtained by this method are in good agreement with that obtained on the same sample using the conventional Z-scan method.


Dexmedetomidine vs other sedatives in critically ill mechanically ventilated adults: a systematic review and meta-analysis of randomized trials.
Conventional gabaminergic sedatives such as benzodiazepines and propofol are commonly used in mechanically ventilated patients in the intensive care unit (ICU). Dexmedetomidine is an alternative sedative that may achieve lighter sedation, reduce delirium, and provide analgesia. Our objective was to perform a comprehensive systematic review summarizing the large body of evidence, determining if dexmedetomidine reduces delirium compared to conventional sedatives. We searched MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov and the WHO ICTRP from inception to October 2021. Independent pairs of reviewers identified randomized clinical trials comparing dexmedetomidine to other sedatives for mechanically ventilated adults in the ICU. We conducted meta-analyses using random-effects models. The results were reported as relative risks (RRs) for binary outcomes and mean differences (MDs) for continuous outcomes, with corresponding 95% confidence intervals (CIs). In total, 77 randomized trials (n = 11,997) were included. Compared to other sedatives, dexmedetomidine reduced the risk of delirium (RR 0.67, 95% CI 0.55 to 0.81; moderate certainty), the duration of mechanical ventilation (MD - 1.8 h, 95% CI - 2.89 to - 0.71; low certainty), and ICU length of stay (MD - 0.32 days, 95% CI - 0.42 to - 0.22; low certainty). Dexmedetomidine use increased the risk of bradycardia (RR 2.39, 95% CI 1.82 to 3.13; moderate certainty) and hypotension (RR 1.32, 95% CI 1.07 to 1.63; low certainty). In mechanically ventilated adults, the use of dexmedetomidine compared to other sedatives, resulted in a lower risk of delirium, and a modest reduction in duration of mechanical ventilation and ICU stay, but increased the risks of bradycardia and hypotension.


Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer.
Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan-Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28-2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.


High-fidelity single-qubit gates for two-electron spin qubits in GaAs.
Single-qubit operations on singlet-triplet qubits in GaAs double quantum dots have not yet reached the fidelities required for fault-tolerant quantum information processing. Considering experimentally important constraints and using measured noise spectra, we numerically minimize the effect of decoherence (including high-frequency 1/f-like noise) and show, theoretically, that quantum gates with fidelities higher than 99.9% are achievable. We also present a self-consistent tuning protocol which should allow the elimination of individual systematic gate errors directly in an experiment.


Diversity of monogeneans and tapeworms in cypriniform fishes across two continents.
Cypriniformes, which exhibit a wide geographical distribution, are the most species-rich group of freshwater fishes. Despite considerable research on their parasites, no reliable estimates of their parasite diversity on a large geographical scale are available. In the present review, we analyse species richness of two parasitic flatworm groups (monogeneans and tapeworms) reported from cypriniform fishes in the two most intensively studied parts of the Holarctic region, Europe and North America. We also review knowledge on parasite speciation and host-parasite coevolution, and emphasise the risk of parasite co-introduction resulting from transfers of cypriniforms among different continents. As parasite diversity in European cypriniforms has been more intensively explored, we predicted a lower level of knowledge on parasite diversity in North American fishes, despite North America having a higher diversity of cypriniforms than Europe. Our data revealed a higher mean species richness of monogeneans and tapeworms per cypriniform species in Europe compared with North America. We showed that species richness of both parasite taxa in both continents is strongly affected by sample size, but that fish traits also play an important role in determining monogenean and tapeworm species richness in European cyprinoids. We recorded higher host specificity for cypriniform parasites in North America, even within parasite genera shared by cypriniforms on both continents. The host range of monogeneans parasitising cyprinoids on both continents was affected by phylogeny, indicating an effect of parasite life history on host specificity. The difference in parasite host range between the two continents could potentially be explained by either the low overall level of sampling activity in North America or an underestimation of parasite diversity in Europe. We suggest that future research efforts be focussed on cypriniforms in order to obtain reliable data for robust assessments of parasite species richness and phylogenies, to assess host-parasite coevolution and to reveal fish biogeography.


Temporal cytokine profiles in severely burned patients: a comparison of adults and children.
A severe burn leads to hypermetabolism and catabolism resulting in compromised function and structural changes of essential organs. The release of cytokines has been implicated in this hypermetabolic response. The severity of the hypermetabolic response following burn injury increases with age, as does the mortality rate. Due to the relationship between the hypermetabolic and inflammatory responses, we sought to compare the plasma cytokine profiles following a severe burn in adults and in children. We enrolled 25 adults and 24 children who survived a flame burn covering more than 20% of total body surface area (TBSA). The concentrations of 22 cytokines were measured using the Linco multiplex array system (St. Charles, MO, USA). Large perturbations in the expression of pro- and anti-inflammatory cytokines were seen following thermal injury. During the first week following burn injury, IFN-gamma, IL-10, IL-17, IL-4, IL-6, and IL-8 were detected at significantly higher levels in adults compared with children, P < 0.05. Significant differences were measured during the second week post-burn for IL-1beta (higher in children) and IL-5 (higher in adults), P < 0.05. IL-18 was more abundant in children compared with adults during the third week post-burn, P < 0.05. Between post-burn d 21 and d 66, IL-1alpha was detected at higher concentrations in pediatric compared with adult patients, P < 0.05. Only GM-CSF expression was significantly different at all time points; it was detected at lower levels in pediatric patients, P < 0.05. Eotaxin, G-CSF, IL-13, IL-15, IP-10, MCP-1, and MIP-1alpha were detected at significantly different concentrations in adult compared with pediatric patients at multiple time points, P < 0.05. There were no differences in IL-12, IL-2, IL-7, or TNF levels in adult compared with pediatric burn patients at any of these time points. Following severe flame burns, the cytokine profiles in pediatric patients differ compared with those in adult patients, which may provide insight with respect to the higher morbidity rate in adults. Furthermore, the dramatic discrepancies observed in plasma cytokine detection between children and adults suggest that these two patient populations may benefit from different therapeutic interventions to achieve attenuation of the post-burn inflammatory response.


Probing long-distance regulatory interactions in the Drosophila melanogaster bithorax complex using Dam identification.
A cis-regulatory region of nearly 300 kb controls the expression of the three bithorax complex (BX-C) homeotic genes: Ubx, abd-A and Abd-B. Interspersed between the numerous enhancers and silencers within the complex are elements called domain boundaries. Recently, many pieces of evidence have suggested that boundaries function to create autonomous domains by interacting among themselves and forming chromatin loops. In order to test this hypothesis, we used Dam identification to probe for interactions between the Fab-7 boundary and other regions in the BX-C. We were surprised to find that the targeting of Dam methyltransferase (Dam) to the Fab-7 boundary results in a strong methylation signal at the Abd-Bm promoter, approximately 35 kb away. Moreover, this methylation pattern is found primarily in the tissues where Abd-B is not expressed and requires an intact Fab-7 boundary. Overall, our work provides the first documented example of a dynamic, long-distance physical interaction between distal regulatory elements within a living, multicellular organism.


LOH detected by microsatellite markers reveals the clonal origin of recurrent laryngeal squamous cell carcinoma.
The question of whether "recurrent" laryngeal carcinoma is truly a new tumour with a clonal origin that differs from that of the primary tumour has remained unanswered. The objective of this study was to determine whether recurrent tumours have the same genetic basis as primary tumours, as the answer to this question is important for the development of treatment strategies. Matched samples consisting of primary tumour, recurrent tumour and normal tissue were obtained from the same patient. A total of 37 patients with laryngeal cancer were examined for loss of heterozygosity (LOH) on the 3p, 5p, 7q, 8p, 9p, 13p, 17p and 18q chromosomal arms using PCR to amplify microsatellite markers. All patients were routinely followed up and 5-year survival rates were calculated using directly calculating method and Kaplan-Meier's method. A total of 28 out of 37 (75.6%) patients showed LOH at a minimum of one locus, and 19 out of 37 (51.3%) patients showed LOH at two loci. Primary and recurrent tumours in each patient showed identical allelic loss patterns and incidence rates. Patients without LOH had a longer average time to recurrence than patients with LOH (P<0.05). Additionally, patients with LOH had a longer average smoking duration prior to surgery than patients without LOH (P<0.05). The 5-year survival rates were 32.14%in patients with LOH versus 44.4% in patients without LOH. The data indicate that primary and recurrent tumours have the same clonal origin. This result implies that we failed to radically resect the primary tumours and/or micrometastases in these patients. Consequently, some form of adjunctive therapy may be necessary. Additionally, the data indicate that the recurrence of laryngeal squamous cell carcinoma is closely related to chromosomal aberrations (specifically LOH).


Intracranial hemorrhage associated with stent-assisted coil embolization of cerebral aneurysms: a cautionary report.
The introduction of the Neuroform microstent has facilitated the embolization of complex cerebral aneurysms, which were previously not amenable to endovascular therapy. Typically, the use of this stent necessitates the administration of dual antiplatelet therapy to minimize thromboembolic complications. Such therapy may increase the risk of hemorrhage in patients who require concurrent external ventricular drainage and/or subsequent permanent cerebrospinal fluid diversion. The authors' neurosurgical database was queried for all patients who underwent stent-assisted coil embolization for cerebral aneurysms and who required an external ventricular drain (EVD) or ventriculoperitoneal (VP) shunt placement for management of hydrocephalus. Thirty-seven patients underwent stent-assisted coil embolization for intracranial aneurysms at the authors' institution over a recent 2-year period. Seven of these patients required placement of an EVD and/or a VP shunt. Three of the 7 patients suffered an immediate intraventricular hemorrhage (IVH) associated with placement or manipulation of an EVD; 1 experienced a delayed intraparenchymal hemorrhage and an IVH; 1 suffered an aneurysmal rehemorrhage; and the last patient had a subdural hematoma (SDH) that resulted from placement of a VP shunt. This patient required drainage of the SDH and exchange of the valve. The necessity of dual antiplatelet therapy in the use of stent-assisted coil embolization increases the risk of intracranial hemorrhage and possibly rebleeding from a ruptured aneurysm. This heightened risk must be recognized when contemplating the appropriate therapy for a cerebral aneurysm and when considering the placement or manipulation of a ventricular catheter in a patient receiving dual antiplatelet therapy. Further study of intracranial procedures in patients receiving dual antiplatelet therapy is indicated.


Use of folic acid-containing supplements after a diagnosis of colorectal cancer in the Colon Cancer Family Registry.
Supplement use among cancer patients is high, and folic acid intake in particular may adversely affect the progression of colorectal cancer. Few studies have evaluated the use of folic acid-containing supplements (FAS) and its predictors in colorectal cancer patients. To assess the use of FAS, change in use, and its predictors after colorectal cancer diagnosis. We used logistic regression models to investigate predictors of FAS use and its initiation after colorectal cancer diagnosis in 1,092 patients recruited through the Colon Cancer Family Registry. The prevalence of FAS use was 35.4% before and 55.1% after colorectal cancer diagnosis (P = 0.004). Women were more likely than men to use FAS after diagnosis [odds ratio (OR), 1.47; 95% confidence interval (95% CI), 1.14-1.89], as were those consuming more fruit (P(trend) < 0.0001) or vegetables (P(trend) = 0.001), and U.S. residents (P < 0.0001). Less likely to use FAS after diagnosis were nonwhite patients (OR, 0.66; 95% CI, 0.45-0.97), current smokers (OR, 0.67; 95% CI, 0.46-0.96), and those with higher meat intake (P(trend) = 0.03). Predictors of FAS initiation after diagnosis were generally similar to those of FAS use after diagnosis, although associations with race and vegetable intake were weaker and those with exercise stronger. Our analysis showed substantial increases in the use of FAS after diagnosis with colorectal cancer, with use or initiation more likely among women, Caucasians, U.S. residents, and those with a health-promoting life-style. Studies of cancer prognosis that rely on prediagnostic exposure information may result in substantial misclassification.


Effect of substituted arginine compounds on superoxide production in the rabbit aorta.
Superoxide anion (O2-) blocks the vascular effect of endothelium-derived relaxing factor (EDRF). Previous reports implicate L-arginine or N alpha-substituted arginine compounds as precursors of EDRF. Employing a microassay for the measurement of O2- production by rabbit aortic rings, which is based on the established method of reduction of cytochrome c by O2-, we studied the interaction between O2- and EDRF using L-arginine, an N-substituted arginine compound, namely, N alpha-benzoyl-L-arginine ethyl ester (BAEE), sodium nitroprusside and NG-monomethyl-L-arginine (NMMA), a putative specific inhibitor of EDRF synthesis. Measurements of O2- production were made under basal conditions and upon stimulation with alloxan, the diabetogenic, O(2-)-generating compound. Both BAEE, an EDRF-generating agent (0.3 and 3.0 mM) and sodium nitroprusside, an NO-generating compound (1.7 and 3.4 microM), significantly reduced alloxan-stimulated O2- production, but L-arginine (0.6-3.0 mM) paradoxically increased O2- generation. NMMA (1.0 mM) blocked the inhibitory effect of BAEE on O2- production in an endothelium-dependent manner. Because NMMA is an inhibitor of EDRF, these results suggest that BAEE, but not L-arginine, reduces O2- produced by the endothelium of the rabbit aorta through a mechanism involving EDRF generation.


Increased urotensin I and II immunoreactivity in the urophysis of Gillichthys mirabilis transferred to low salinity water.
The function of the fish caudal neurosecretory system is uncertain, but a role in osmoregulation has been suggested by many investigators. Our objective was to determine if acclimation to water of different salinity has an effect on immunoreactive patterns and staining intensities of the two caudal neuropeptides, urotensins I (UI) and II (UII), in Gillichthys mirabilis. Five fish, originally maintained in seawater, were transferred to deionized fresh water (FW), and five were transferred to new seawater (SW). After 24 hr spinal cords were removed and fixed, FW and SW spinal cords were paired in blocks to receive identical treatment, and cryostat sections were double immunostained for both peptides using a double sequential immunofluorescence procedure. FW spinal cord exhibited increased staining intensities for both UI and UII in their urophyses (the neurohemal organ) compared to the SW spinal cords. The magnitude of intensity difference appeared greater for UI than for UII. In addition, the FW urophyses had more loci displaying intense, perivascular UI immunoreactivity than the SW urophyses. Thus, it appears that environmental salinity has an effect on the urophysial content of UI and UII in this euryhaline fish. The increased immunoreactivity in FW fish could reflect increased synthesis and storage, decreased release of the stored peptides, or decreased peptide degradation.


ERP evidence of a dichotic left-ear deficit in some dyslexic children.
Children with and without behavioral dichotic left-ear deficits participated in an event-related potential study with quasidichotic presentations of familiar fairy tale segments. Electrical activity was recorded from the scalp while the children listened for semantically and/or syntactically anomalous words from either the right side or the left side while competing segments of the fairy tale were simultaneously presented from the opposite side. Latencies and amplitudes were averaged for each target condition within the group with dichotic left-ear deficits (LED) and the group with normal dichotic listening performance (WNL). Individual global field power waveforms and topographic brain maps were generated for the average response in each of the two listening conditions, target right and target left. Cross-correlations were performed on the grand averaged global field power waveforms to measure the degree of synchrony between target right and target left responses in both groups. Integration functions were performed to compare the accumulated sum of voltages during target (right and left) and control (right and left) conditions. WNL children produced typical ERP responses to the target words in both target right and target left conditions. Responses from LED children were at delayed latencies in the target left condition and were at reduced amplitudes in both target conditions. Topographic brain maps revealed more lateralized scalp distributions and greater activation of frontal regions in LED children in the target left condition. Cross-correlational and integration function results demonstrated interaural asymmetries in responses from the LED children. Overall results suggest that slowed neural conduction times, poor interhemispheric transfer of neural activity, and a failure to suppress competing information arriving at the right ear may be involved in poor left-sided processing in children with behavioral left-ear dichotic deficits.


Au(III), Pd(II), Ni(II), and Hg(II) alter NF kappa B signaling in THP1 monocytic cells.
The transcription factor NFkappaB plays a key role in the tissue inflammatory response. Metal ions released into tissues from biomaterials (e.g., Au, Pd, Ni, Hg) are known to alter the binding of NFkappaB proteins to DNA, thereby modulating the effect of NFkappaB on gene activation and, ultimately, the tissue response to biomaterials. Little is known about the effect of these metals on key signaling steps prior to NFkappaB-DNA binding such as transcription factor activation or nuclear translocation, yet these steps are equally important to modulation of the pathway. Oxidative stress is known to alter NFkappaB proteins and is suspected to play a role in metal-induced NFkappaB signaling modulation. Our aim in the current study was to assess the effects of sublethal levels of Ni, Hg, Pd, and Au ions on NFkappaB activation and nuclear translocation in the monocyte, which is acknowledged as an important orchestrator of the biological response to materials and the pathogenesis of chronic disease. Sublethal concentrations of Au(III), Ni(II), Hg(II), and Pd(II) were added to cultures of human THP1 monocytic cells for 72 h. In parallel cultures, lipopolysaccharide (LPS) was added for the last 30 min to activate the monocytic cells. Then cellular cytoplasmic and nuclear proteins were isolated, separated by electrophoresis, and probed for IkappaBalpha degradation (activation) and NFkappaB p65 translocation. Protein levels were digitally quantified and statistically compared. The levels of reactive oxygen species (ROS) in the monocytic cells were measured as a possible mechanism of metal-induced NFkappaB modulation. Only Au(III) activated IkappaBalpha degradation by itself. Au(III) and Pd(II) enhanced LPS-induced IkappaBalpha degradation, but Hg(II) and Ni(II) suppressed it. Au(III), Ni(II), and Pd(II) activated p65 nuclear translocation without LPS, and all but Ni(II) enhanced LPS-induced translocation. Collectively, the results suggest that these metal ions alter activation and translocation of NFkappaB, each in a unique way at unique concentrations. Furthermore, even when these metals had no overt effects on signaling by themselves, all altered activation of signaling by LPS, suggesting that the biological effects of these metals on monocytic function may only be manifest upon activation. None of the metal ions elevated levels of ROS at 72 h, indicating that ROS were probably not direct modulators of the NFkappaB activation or translocation at this late time point.


Harm reduction for smokers with little to no quit interest: can tobacco policies encourage switching to e-cigarettes?
A pressing tobacco policy concern is how to help smokers who have little interest in quitting cigarettes, a group that often suffers severe health consequences. By switching from cigarettes to e-cigarettes, they could obtain nicotine, potentially with less harm. We examined if policy-relevant attributes of cigarettes/e-cigarettes might encourage these smokers to switch to e-cigarettes. An online survey and discrete choice experiment on a nationally-representative sample of adult smokers in the US who reported low interest in quitting (n=2000). We modelled preference heterogeneity using a latent class, latent variable model. We simulated policies that could encourage switching to e-cigarettes. Participants formed two latent classes: (1) those with very strong preferences for their own cigarettes; and (2) those whose choices were more responsive to policies. The latter group's choices were only somewhat responsive to menthol cigarette bans and taxes; the former group's choices were unresponsive. The policies studied seem unlikely to encourage harm reduction for individuals with little interest in quitting smoking.


Systemic sclerosis - continuing progress in developing clinical measures of response.
Few randomized controlled trials (RCT) have shown a demonstrable treatment effect in systemic sclerosis (SSc), making it difficult to evaluate outcome measures in this disease indication. Results from recent RCT, including those evaluating cyclophosphamide for SSc interstitial lung disease and endothelin receptor antagonists for pulmonary hypertension, have allowed analysis of certain organ-specific endpoints using the OMERACT filter. An earlier metaanalysis established that skin score, measures of Raynaud's, pulmonary function tests, blood pressure, pain, Health Assessment Questionnaire, and Medical Outcomes Survey Short-Form 36 are validated outcome measures in SSc. At OMERACT 8, data regarding validation of high-resolution computed tomography of the lungs, 6-minute walk test, and patient reported outcomes in SSc were presented. A Delphi exercise to develop consensus regarding a combined set of noninvasive measures for pulmonary arterial hypertension (PAH) is under way. Given the protean nature of this illness and its multiorgan system involvement, a composite responder index may be preferable. Another Delphi exercise is designed to develop consensus regarding a combined SSc response index to be validated in future RCT.


Multidimensional analysis of human intestinal fluid composition.
The oral administration of solid dosage forms is the commonest method to achieve systemic therapy and relies on the drug's solubility in human intestinal fluid (HIF), a key factor that influences bioavailability and biopharmaceutical classification. However, HIF is difficult to obtain and is known to be variable, which has led to the development of a range of simulated intestinal fluid (SIF) systems to determine drug solubility in vitro. In this study we have applied a novel multidimensional approach to analyse and characterise HIF composition using a published data set in both fasted and fed states with a view to refining the existing SIF approaches. The data set provided 152 and 172 measurements of five variables (total bile salt, phospholipid, total free fatty acid, cholesterol and pH) in time-dependent HIF samples from 20 volunteers in the fasted and fed state, respectively. The variable data sets for both fasted state and fed state are complex, do not follow normal distributions but the amphiphilic variable concentrations are correlated. When plotted 2-dimensionally a generally ellipsoid shaped data cloud with a positive slope is revealed with boundaries that enclose published fasted or fed HIF compositions. The data cloud also encloses the majority of fasted state and fed state SIF recipes and illustrates that the structured nature of design of experiment (DoE) approaches does not optimally cover the variable space and may examine media compositions that are not biorelevant. A principal component analysis in either fasted or fed state in combination with fitting an ellipsoid shape to enclose the data results in 8 points that capture over 95% of the compositional variability of HIF. The variable's average rate of concentration change in both fasted state and fed state over a short time scale (10 min) is zero and a Euclidean analysis highlights differences between the fasted and fed states and among individual volunteers. The results indicate that a 9-point DoE (8 + 1 central point) could be applied to investigate drug solubility in vitro and provide statistical solubility limits. In addition, a single point could provide a worst-case solubility measurement to define the lowest biopharmaceutical classification boundary or for use during drug development. This study has provided a novel description of HIF composition. The approach could be expanded in multiple ways by incorporation of further data sets to improve the statistical coverage or to cover specific patient groups (e.g., paediatric). Further development might also be possible to analyse information on the time dependent behaviour of HIF and to guide HIF sampling and analysis protocols.


Chronic postsurgical pain in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial.
Previous animal and clinical studies showed that nitrous oxide may produce long-term analgesia. The aim of this study was to evaluate the effect of nitrous oxide in preventing chronic postsurgical pain. We also explored whether methylenetetrahydrofolate reductase gene polymorphisms (1298A>C, 667C>T) would enhance nitrous oxide analgesia. We conducted a telephone interview at 12 months after surgery on 2924 (41.1%) patients enrolled in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia-II trial. Pain at the wound site was recorded using the modified brief pain inventory and the neuropathic pain questionnaire. General health status was measured using the EQ-5D questionnaire. Genotyping was performed in a subset of 674 Asian patients in Hong Kong. At 12 months after surgery, 356 (12.2%) patients reported chronic postsurgical pain at the wound site and 112 (3.8%) patients had severe pain and required regular analgesic interventions. Nitrous oxide did not affect the rate of chronic postsurgical pain (11.8% nitrous oxide group; 12.5% no nitrous oxide group), relative risk (95% confidence intervals): 0.94 (0.75-1.17), P=0.57. However, in a planned subgroup analysis, nitrous oxide reduced the risk of chronic postsurgical pain in Asian patients, relative risk (95% confidence intervals): 0.70 (0.50-0.98), P=0.031. Patients who were homozygous for either gene polymorphism and who received nitrous oxide during surgery were less likely to report chronic postsurgical pain. Nitrous oxide administration had no impact on chronic postsurgical pain, but benefits may still be possible in Asian patients and patients with variants in methylenetetrahydrofolate reductase gene. NCT00430989.


Mobile Phone Apps for University Students With Hazardous Alcohol Use: Study Protocol for Two Consecutive Randomized Controlled Trials.
About 50% of university students overconsume alcohol, and drinking habits in later adulthood are to some extent established during higher educational studies. Several studies have demonstrated that Internet-based interventions have positive effects on drinking habits among university students. Our recent study evaluated two mobile phone apps targeting drinking choices at party occasions via personalized feedback on estimated blood alcohol concentration (eBAC) for students with hazardous drinking. No changes in drinking parameters were found over a seven-week period apart from an increase in number of drinking occasions among men for one of the apps tested. Up to 30% of the study participants drank at potentially harmful levels: higher than the national recommended number of standard drinks per week (a maximum of 9 for women and 14 for men) in Sweden. (1) To evaluate improved versions of the two mobile phone apps tested in our prior trial, in a new, 3-armed randomized controlled trial among university students with at least hazardous drinking habits according to the Alcohol Use Disorders Identifications Test (AUDIT; Study 1). (2) After 6 weeks, to target study participants showing alcohol consumption higher than the national recommended levels for standard drinks per week by offering them participation in a second, 2-armed randomized trial evaluating an additional mobile phone app with skill enhancement tasks (Study 2). (3) To follow participants at 6, 12 and 18 weeks after recruitment to Study 1 and at 6 and 12 weeks after recruitment to Study 2. Two randomized controlled trials are conducted. Study 1: Students are recruited at four Swedish universities, via direct e-mail and advertisements on Facebook and student union web sites. Those who provide informed consent, have a mobile phone, and show at least hazardous alcohol consumption according to the AUDIT (≥6 for women; ≥8 points for men) are randomized into three groups. Group 1 has access to the Swedish government alcohol monopoly's app, Promillekoll, offering real-time estimated eBAC calculation; Group 2 has access to a Web-based app, PartyPlanner, developed by the research group, offering real-time eBAC calculation with planning and follow-up functions; and Group 3 participants are controls. Follow-up is conducted at 6, 12 and 18 weeks. Study 2. Participants who at the first 6-week follow-up show drinking levels higher than 9 (W) or 14 (M) standard drinks (12 g alcohol) per week, are offered participation in Study 2. Those who consent are randomized to either access to a skills training app, TeleCoach or to a wait-list control group. Latent Markov models for Study 1 and mixed models analyses for Study 2 will be performed. Study 2 data will be analyzed for publication during the spring of 2016; Study 1 data will be analyzed for publication during the fall of 2016. If mobile phone interventions for reducing hazardous alcohol use are found to be effective, the prospects for positively influencing substance use-related health among university students can considerably improve. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02064998 (Archived by WebCite at http://www.webcitation.org/6dy0AlVRP).


Probing the role of E272 in quinol oxidation of mitochondrial complex III.
Bifurcated electron transfer during ubiquinol oxidation is the key reaction of complex III catalysis, but the molecular basis of this process is still not clear. E272 of the conserved cytochrome b PEWY motif has been suggested as a ligand and proton acceptor for ubiquinol oxidation at center P. We introduced the two replacement mutations, E272D and E272Q, into the mitochondrially encoded cytochrome b gene by biolistic transformation to study their effects on substrate binding and catalysis. Both substitutions resulted in a lower ubiquinol cytochrome c reductase activity and affect the KM for ubiquinol. The E272 carboxylate stabilizes stigmatellin binding, and in accordance, both variants are resistant to stigmatellin. Large structural changes in the cofactor environment as well as in the binding pocket can be excluded. The mutations do not perturb the midpoint potentials of the heme groups. The sensitivity toward the respective distal and proximal niche inhibitors HDBT and myxothiazol is retained. However, both mutations provoke subtle structural alterations detected by redox FTIR. They affect binding and oxidation of ubiquinol, and they promote electron short-circuit reactions resulting in production of reactive oxygen species. The aspartate substitution modifies the environment of the reduced Rieske protein as monitored by EPR. Both variants alter the pH dependence of the enzyme activity. Diminished activity at low pH coincides with the loss of one protonatable group with a pKa of approximately 6.2 compared to three pKa values in the wild type, supporting the role of E272 in proton transfer. The conserved glutamate appears to influence the accurate formation of the enzyme-substrate complex and to govern the efficiency of catalysis.


Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: results from the TRACER trial.
This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo. In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization. Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83-1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74-1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15). NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.


An initial event in the insect innate immune response: structural and biological studies of interactions between β-1,3-glucan and the N-terminal domain of β-1,3-glucan recognition protein.
In response to invading microorganisms, insect β-1,3-glucan recognition protein (βGRP), a soluble receptor in the hemolymph, binds to the surfaces of bacteria and fungi and activates serine protease cascades that promote destruction of pathogens by means of melanization or expression of antimicrobial peptides. Here we report on the nuclear magnetic resonance (NMR) solution structure of the N-terminal domain of βGRP (N-βGRP) from Indian meal moth (Plodia interpunctella), which is sufficient to activate the prophenoloxidase (proPO) pathway resulting in melanin formation. NMR and isothermal calorimetric titrations of N-βGRP with laminarihexaose, a glucose hexamer containing β-1,3 links, suggest a weak binding of the ligand. However, addition of laminarin, a glucose polysaccharide (~6 kDa) containing β-1,3 and β-1,6 links that activates the proPO pathway, to N-βGRP results in the loss of NMR cross-peaks from the backbone (15)N-(1)H groups of the protein, suggesting the formation of a large complex. Analytical ultracentrifugation (AUC) studies of formation of the N-βGRP-laminarin complex show that ligand binding induces self-association of the protein-carbohydrate complex into a macro structure, likely containing six protein and three laminarin molecules (~102 kDa). The macro complex is quite stable, as it does not undergo dissociation upon dilution to submicromolar concentrations. The structural model thus derived from this study for the N-βGRP-laminarin complex in solution differs from the one in which a single N-βGRP molecule has been proposed to bind to a triple-helical form of laminarin on the basis of an X-ray crystallographic structure of the N-βGRP-laminarihexaose complex [Kanagawa, M., Satoh, T., Ikeda, A., Adachi, Y., Ohno, N., and Yamaguchi, Y. (2011) J. Biol. Chem. 286, 29158-29165]. AUC studies and phenoloxidase activation measurements conducted with the designed mutants of N-βGRP indicate that electrostatic interactions involving Asp45, Arg54, and Asp68 between the ligand-bound protein molecules contribute in part to the stability of the N-βGRP-laminarin macro complex and that a decreased stability is accompanied by a reduced level of activation of the proPO pathway. An increased level of β-1,6 branching in laminarin also results in destabilization of the macro complex. These novel findings suggest that ligand-induced self-association of the βGRP-β-1,3-glucan complex may form a platform on a microbial surface for recruitment of downstream proteases, as a means of amplification of the initial signal of pathogen recognition for the activation of the proPO pathway.


[Urinary Retention Due to Hematocolpos].
Hematocolpos is an obstruction of the menstrual flow due to an anomaly of the genital tract, with imperforate hymen being the most common one. It is an uncommon condition, with a prevalence of 1:1000 - 1:16 000. It is usually an asymptomatic condition until the onset of menarche, when there is accumulation of blood in the vagina (hematocolpos) or in the uterus (hematometra). A rare symptom of hematocolpos could be urinary retention. Our case report is about a 12-year-old girl, with no menarche and Tanner stage M4/P5, who was admitted to our emergency department with abdominal pain and urinary retention. A brief review of this rare condition is presented, in order to remind clinicians about its existence, so that it can be diagnosed and treated as quickly as possible.


Comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab, a human anti-tumor necrosis factor antibody, in Phase III clinical trials.
Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti-tumor necrosis factor (anti-TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab. Data from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy. No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times the upper limit of normal). Comprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB-endemic regions. Treatment for latent TB infection appeared effective, since no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti-TB medication was generally well tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF inhibitors, since prompt diagnosis and treatment can improve outcomes.


Misattributing speech and jumping to conclusions: a longitudinal study in people at high risk of psychosis.
Biases in cognition such as Jumping to Conclusions (JTC) and Verbal Self-Monitoring (VSM) are thought to underlie the formation of psychotic symptoms. This prospective study in people with an At Risk Mental State (ARMS) for psychosis examined how these cognitive biases changed over time, and predicted clinical and functional outcomes. Twenty-three participants were assessed at clinical presentation and a mean of 31 months later. Performance on a JTC and VSM tasks were measured at both time points. Relationships to symptom severity, level of function and the incidence of psychotic disorder were then examined. The levels of symptoms, function and VSM all improved over time, while JTC was stable. Five participants (22%) developed a psychotic disorder during the follow-up period, but the risk of transition was not related to performance on either task at baseline, or to longitudinal changes in task performance. JTC performance correlated with symptom severity at baseline and follow-up. Similarly, performance on the two tasks was not related to the level of functioning at follow-up. Thus, while the ARMS is associated with both VSM and JTC biases, neither predict the onset of psychosis or the overall functional outcome.


Of neoliberalism and global health: human capital, market failure and sin/social taxes.
This article tells a different but equally important story about neoliberalism and global health than the narrative on structural adjustment policies usually found in the literature. Rather than focus on macroeconomic structural adjustment policies, this story draws our attention to microeconomic taxation policies on tobacco, alcohol and sugar now widely recognised as the best strategy to control the global non-communicable disease epidemic. Structural adjustment policies are the product of the shift from statist to market-based development models, which was brought about by neoliberal thinkers like Peter Blau and Deepak Lal. In contrast, taxation policies are the result of a different epistemological rupture in international development: the move from economies and physical capital to people and human capital, advocated by Gary Becker and others. This move was part of wider change, which saw Chicago School economists, under the influence of rational choice theory, redefine the object of their discipline, from the study of markets to individual choices. It was this concern with people and their choices that made it possible for Becker and others to identify the importance of price for the demand for tobacco, alcohol and sugar. The same concern also made it easier for them to recognise that there were inefficiencies in the tobacco, alcohol and sugar markets that required government intervention. This story, I suggest, shows that structural adjustment policies and pro-market ideology do not exhaust the relationship between neoliberalism and global health and should not monopolise how we, as political and social scientists, conceive it.


Humanitarian nursing with Médecins Sans Frontières: Foregrounding the listening guide as a method for analysing oral history data.
To demonstrate how the listening guide contributed to oral history data analysis. To better understand the continuing inclination of nurses to engage in humanitarian work, foregrounding the nurses' lives. The voice-centred relational method or listening guide is a method of qualitative data analysis used to analyse oral history data. A conventional approach to oral history interviews was adopted; intervention into the "flow" of participants' narrative was kept to a minimum. A small number of prompts, how they came into nursing, recruitment to, life with and since Médecins Sans Frontières, were used. Oral history interviews were conducted with seven nurses who had worked for Médecins Sans Frontières. Interviews were digitally recorded. This paper will demonstrate the application of the listening guide to historical data analysis and critique its applicability and value. The listening guide advocates four readings (listenings) of the text. Firstly, locating the plot in the narrative; secondly, actively listening for the use of "I?" ("we", or "you"), the "self" in context of the story being told and "I poem" development; thirdly, listening for relationships and finally, locating accounts in relation to wider social, political and societal contexts. Analysis revealed: "becoming", "being" and "leaving" Médecins Sans Frontières as chronological thematic areas. At one extreme creating "I poems" foregrounded individual voices while cross-referencing to contemporaneous records of world events locates this in an International context. It is argued that subjecting historical data to the listening guide can enable legitimate, creative exploration and analysis of data.