Quality of life and anxiety in adolescents with differentiated thyroid cancer.
Adolescents with differentiated thyroid cancer (DTC) require lifelong monitoring with a high possibility of reoperation or radioactive iodine. Although adult DTC survivors have similar or slightly worse quality of life (QOL), this has not been evaluated in the pediatric population. Our objective was to compare QOL and anxiety in adolescents with DTC to patients with acquired autoimmune hypothyroidism. In this cross-sectional pilot study, three validated questionnaires were administered to 16 adolescents with DTC and 16 controls for assessment of QOL and anxiety levels. These included teen and parent PedsQL, Multidimensional Anxiety Scale for Children, and Coddington Life Events Scales for Adolescents. The contribution of age, time since diagnosis, and biochemical variables were compared with the outcome measures. There were 16 DTC patients (seven males); 13 had papillary carcinoma, one had follicular carcinoma, and two had mixed type. At diagnosis, five DTC patients had lymph node involvement and two had lung metastases, although at time of assessment, only one DTC patient had lymph node involvement. DTC patients were older than control subjects (P=0.004) and had lower TSH levels than control subjects at time of assessment (P=0.013). QOL and anxiety levels did not differ between DTC patients compared with control subjects and with previously reported scores in a healthy cohort. QOL and anxiety level parameters were not influenced by age, time since diagnosis, or free T4 levels measured at the time of assessment. Adolescents with DTC have similar QOL and anxiety levels compared with autoimmune hypothyroidism patients and with a healthy normative population.


A network of dynamically coupled chaotic maps for scene segmentation.
In this paper, a computational model for scene segmentation based on a network of dynamically coupled chaotic maps is proposed. Time evolutions of chaotic maps that correspond to an object in the given scene are synchronized with one another, while this synchronized evolution is desynchronized with respect to time evolution of chaotic maps corresponding to other objects in the scene. In this model, the coupling range of each active element increases dynamically according to predefined rules until a saturated state is achieved, i.e., locally coupled chaotic maps corresponding to an object in the initial state will be coupled globally in the final state. Consequently, the advantage of both global coupling and local coupling are incorporated in a single scheme. In comparison to continuous models, this proposed model is suitable for computational implementation. Another significant benefit is that the good performance and transparent dynamics of the model are obtained by utilizing one-dimensional chaotic map instead of complex neuron as each element.


Substituted judgment in principle and practice: a national physician survey.
To describe the extent to which US physicians endorse substituted judgments in principle or accommodate them in practice. We surveyed a stratified, random sample of 2016 physicians by mail from June 25, 2010, to September 3, 2010. Primary outcome measures were agreement with 2 in-principle statements about substituted judgment and, after an experimental vignette that varied the basis used by a patient's surrogate to refuse life-saving treatment, responses indicating how appropriate it would be to overrule the surrogate's decision. Our response rate was 62% (1156 of 1875 respondents). When there is a conflict between what a surrogate believes a patient would have wanted (substituted judgment) and what the surrogate believes is in the patient's best interest, 4 of 5 physicians (78%) agreed that the surrogate should base their decision on substituted judgment. Yet we also found that 2 of 5 physicians (40%) agree that surrogates should make decisions they believe are in the patient's best interest, even if those seem to contradict the patient's prior wishes. In the experimental vignette, physicians were much more likely to oppose overruling a surrogate's refusal of life-sustaining medical treatment when that refusal was made on the basis of substituted judgment compared with when the refusal was made on the basis of the patient's best interest (50% vs 20%; odds ratio, 4.2; 95% CI, 2.7-6.3). Responses to the in-principle items about substituted judgment were not consistently associated with responses to the experimental vignette. US physicians largely agree, in principle, that surrogates should prioritize what the patient would have wanted over what they believe is in the patient's best interest, although many physicians are ambivalent in cases in which the 2 norms conflict. Even physicians who reject the principle of substituted judgment tend to treat substituted judgment as the preferred norm for surrogate decision making when responding to a clinical vignette.


Pruritus--itching for a cause and relief?
The mechanisms of pruritus, an unpleasant irritation on the skin that provokes an urge to scratch, are reviewed. Whilst symptomatic treatment is only partially effective, antihistamines remain the first choice of treatment. However, recent novel treatment using opiate antagonists, propofol (subhypnotic doses) and serotonin antagonists offer attractive alternatives.


CT evaluation of the lumbosacral spine.
The biologic cost-effectiveness of computed tomography (CT) versus myelography is so favorable to CT that it is now the method of choice for evaluating patients with less clear-cut clinical findings. CT is now used to detect lesions formerly difficult to diagnose, such as subluxation, arthrosis, facet osteophytes, and stenosis of the vertebral canal, as well as herniated disks and lateral disks. The findings in over 1,000 patients examined by CT for lumbosacral spinal pathology are documented. Associated or multiple abnormalities were present in about 60% of cases, with bulging or herniated disks occurring in 45% and 44%, respectively. Postsurgical arachnoiditis was seen in 43% of 64 patients studied for recurrence of symptoms after surgery.


Epidemiology of Crohn's disease of the colon.
There is no room for complacency concerning our knowledge of Crohn's disease of the colon, and this applies to epidemiology as to other aspects of diagnosis and management. In this presentation therefore "current knowledge" is first reviewed. Crohn's disease of the colon is shown to be a worldwide disorder with incidence rates of between one and four cases per 100,000 population per year and prevalence rates up to ten times this figure. This disease is most commonly found in Europe and North America, with a slight excess in females over males and a preponderance of young persons whose disease begins in early adult life. Two-thirds of cases have colonic involvement. Racial and ethnic studies have been confusing and there is some reason to doubt the simplistic assertion of the 1960's that the disease is most common in Jews. Genetic marker studies have been similarly inconclusive despite an apparent association with HLA-B27-as have most studies involving environmental factors such as diet, smoking and the contraceptive pill. The presentation next explores some important reasons why this current "knowledge" is suspect as well as inconclusive. There is a total lack of etiological data about Crohn's disease, and until recently no standard definition of the disease existed. Many epidemiological studies have selected cases from small groups rather than the whole population-a particularly difficult problem due to the protean nature of the disease. Observer variation in eliciting data presents a further problem as does the simplistic nature of the analysis carried out to date. Finally, some tentative solutions are proposed for current outstanding problems. It is argued that Popperian philosophy may form the basis for a working description of Crohn's disease and the World Organisation of Gastroenterology Crohn's disease study has proposed such a definition. Multi-national trials are clearly necessary if some of the problems listed earlier are to be overcome; as is the development of reproducible and relevant indices for assessing the severity of disease. However, in the last analysis the only real key to progress is an improvement in our fundamental understanding of the disease itself; and at the present time there seems very little prospect of progress on this front. Until such progress is made, the epidemiology of Crohn's disease will remain a difficult and muddled area.


Influence of dietary macronutrients on liver fat accumulation and metabolism.
The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the available observational and intervention studies that have investigated the influence of dietary macronutrients on liver fat content. Findings from observational studies are conflicting with some reporting that relative to healthy controls, patients with NAFLD consume diets higher in total fat/saturated fatty acids, whilst others find they consume diets higher in carbohydrates/sugars. From the limited number of intervention studies that have been undertaken, a consistent finding is a hypercaloric diet, regardless of whether the excess calories have been provided either as fat, sugar, or both, increases liver fat content. In contrast, a hypocaloric diet decreases liver fat content. Findings from both hyper- and hypo-caloric feeding studies provide some suggestion that macronutrient composition may also play a role in regulating liver fat content and this is supported by data from isocaloric feeding studies; fatty acid composition and/or carbohydrate content/type appear to influence whether there is accrual of liver fat or not. The mechanisms by which specific macronutrients, when consumed as part of an isocaloric diet, cause a change in liver fat remain to be fully elucidated.


Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.
Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases.


Silencing of a Unique Integrated Domain Nucleotide-Binding Leucine-Rich Repeat Gene in Wheat Abolishes Diuraphis noxia Resistance.
Plants respond in a similar manner to aphid feeding as to pathogen attack. Diuraphis noxia is a specialist aphid, feeding only on selected grasses that include wheat, barley, and oats. The wheat-Diuraphis noxia interaction is characterized by responses very similar to those seen in wheat-pathogen interactions with none of the underlying resistance pathways and genes characterized yet. From wheat harboring the Dn1 resistance gene, we have identified a nucleotide-binding leucine-rich repeat (NLR) gene containing two integrated domains (IDs). These are three C-terminus ankyrin repeat domains and an N-terminus WRKY domain. The NLR core of the gene can be traced through speciation events within the grass family, with a recent WRKY domain integration that is Triticum-specific. Virus-induced gene silencing of the gene in a resistant wheat line resulted in the abolishment of the resistance response and induced a highly susceptible phenotype. Silenced plants supported a higher number of aphids, similar to the susceptible near-isogenic line (NIL), and the intrinsic rate of increase of the aphids matched that of aphids feeding on the susceptible NIL. The presence of the gene is necessary for Dn1 resistance and we have named the gene Associated with Dn resistance 1 (Adnr1) to reflect this function.


The Association Between Adolescent Residential Mobility and Adult Social Anxiety, BDNF and Amygdala-Orbitofrontal Functional Connectivity in Young Adults With Higher Education.
Background: Large-scale epidemiological studies demonstrate that house moves during adolescence lead to an increase in anxiety and stress-sensitivity that persists into adulthood. As such, it might be expected that moves during adolescence have strong negative and long-lasting effects on the brain. We hypothesized that moves during adolescence impair fear circuit maturation, as measured by the connectivity between amygdala and orbitofrontal cortex, and expression of brain-derived neurotrophic factor (BDNF). Methods: We examined young adults with middle and high economic status recruited from the community using clinical interviews, self-report questionnaires, functional magnetic resonance imaging during an emotional faces task and during a 10 min rest phase, and serum BDNF serum concentration. Results: Out of 234 young adults, 164 did not move between ages 10 and 16 (i.e., moves with change of school), 50 moved once, and 20 moved twice or more than twice. We found relationships between adolescent moving frequency and social avoidance (pcorr = 0.012), right amygdala-orbitofrontal cortex connectivity (pcorr = 0.016) and low serum BDNF concentrations in young adulthood (pcorr = 0.012). Perceived social status of the mother partly mitigated the effects of moving on social avoidance and BDNF in adulthood. Conclusions: This study confirms previous reports on the negative and persistent effects of residential mobility during adolescence on mental health. It suggests that these effects are mediated by impairments in fear circuit maturation. Finally, it encourages research into protecting factors of moving during adolescents such as the perceived social status of the mother.


Attention-based neural networks for clinical prediction modelling on electronic health records.
Deep learning models have had a lot of success in various fields. However, on structured data they have struggled. Here we apply four state-of-the-art supervised deep learning models using the attention mechanism and compare against logistic regression and XGBoost using discrimination, calibration and clinical utility. We develop the models using a general practitioners database. We implement a recurrent neural network, a transformer with and without reverse distillation and a graph neural network. We measure discrimination using the area under the receiver operating characteristic curve (AUC) and the area under the precision recall curve (AUPRC). We assess smooth calibration using restricted cubic splines and clinical utility with decision curve analysis. Our results show that deep learning approaches can improve discrimination up to 2.5% points AUC and 7.4% points AUPRC. However, on average the baselines are competitive. Most models are similarly calibrated as the baselines except for the graph neural network. The transformer using reverse distillation shows the best performance in clinical utility on two out of three prediction problems over most of the prediction thresholds. In this study, we evaluated various approaches in supervised learning using neural networks and attention. Here we do a rigorous comparison, not only looking at discrimination but also calibration and clinical utility. There is value in using deep learning models on electronic health record data since it can improve discrimination and clinical utility while providing good calibration. However, good baseline methods are still competitive.


Effect of plant oils and camelina expeller on milk fatty acid composition in lactating cows fed diets based on red clover silage.
Five multiparous Finnish Ayrshire cows fed red clover silage-based diets were used in a 5 × 5 Latin square with 21-d experimental periods to evaluate the effects of various plant oils or camelina expeller on animal performance and milk fatty acid composition. Treatments consisted of 5 concentrate supplements containing no additional lipid (control), or 29 g/kg of lipid from rapeseed oil (RO), sunflower-seed oil (SFO), camelina-seed oil (CO), or camelina expeller (CE). Cows were offered red clover silage ad libitum and 12kg/d of experimental concentrates. Treatments had no effect on silage or total dry matter intake, whole-tract digestibility coefficients, milk yield, or milk composition. Plant oils in the diet decreased short- and medium-chain saturated fatty acid (6:0-16:0) concentrations, including odd- and branched-chain fatty acids and enhanced milk fat 18:0 and 18-carbon unsaturated fatty acid content. Increases in the relative proportions of cis 18:1, trans 18:1, nonconjugated 18:2, conjugated linoleic acid (CLA), and polyunsaturated fatty acids in milk fat were dependent on the fatty acid composition of oils in the diet. Rapeseed oil in the diet was associated with the enrichment of trans 18:1 (Δ4, 6, 7, 8, and 9), cis-9 18:1, and trans-7,cis-9 CLA, SFO resulted in the highest concentrations of trans-5, trans-10, and trans-11 18:1, Δ9,11 CLA, Δ10,12 CLA, and 18:2n-6, whereas CO enhanced trans-13-16 18:1, Δ11,15 18:2, Δ12,15 18:2, cis-9,trans-13 18:2, Δ11,13 CLA, Δ12,14 CLA, Δ13,15 CLA, Δ9,11,15 18:3, and 18:3n-3. Relative to CO, CE resulted in lower 18:0 and cis-9 18:1 concentrations and higher proportions of trans-10 18:1, trans-11 18:1, cis-9,trans-11 CLA, cis-9,trans-13 18:2, and trans-11,cis-15 18:2. Comparison of milk fat composition responses to CO and CE suggest that the biohydrogenation of unsaturated 18-carbon fatty acids to 18:0 in the rumen was less complete for camelina lipid supplied as an expeller than as free oil. In conclusion, moderate amounts of plant oils in diets based on red clover silage had no adverse effects on silage dry matter intake, nutrient digestion, or milk production, but altered milk fat composition, with changes characterized as a decrease in saturated fatty acids, an increase in trans fatty acids, and enrichment of specific unsaturated fatty acids depending on the fatty acid composition of lipid supplements.


Difficulties with emotion regulation moderate the association between childhood history of maltreatment and cortisol reactivity to psychosocial challenge in postpartum women.
Exposure to child maltreatment can lead to long-term emotional difficulties and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. However, no prior work has examined emotion regulation as a moderator of the association between childhood history of maltreatment and cortisol response to psychosocial challenge. Amongst a sample of 140 postpartum women, associations between childhood maltreatment, emotion regulation, and cortisol response to a computerized Emotional Stroop paradigm were examined using structural equation modeling. Three saliva samples (baseline, 20- and 40-min post-challenge) were collected and later assayed for cortisol. Stepwise regression analyses revealed that difficulties with emotion regulation significantly moderated the association between maternal history of child maltreatment and cortisol reactivity (β=-0.17, CI.95=-0.31, -0.04, t=-2.51, p=0.01). Specifically, women with higher child maltreatment scores and greater difficulties with emotion regulation displayed reduced cortisol reactivity. This finding suggests that diminished emotion regulation capacity may uniquely contribute to blunted physiological reactivity in postpartum women exposed to higher levels of child maltreatment. As the postpartum period has significant implications for maternal well-being and infant development, these findings are discussed in terms of adaptive responsivity, maternal behaviour, and clinical practice.


Pentoxifylline (Trental)--a new drug for the treatment of peripheral chronic occlusive arterial disease.
Pentoxifylline (Trental), a xanthine analog, was evaluated for tolerance, safety and efficacy in the treatment of chronic arterial disease in a pilot study. Evaluation was performed in 35 cases. Twenty patients (Fontaine stage II or stage III severity) were given pentoxifylline in a daily dose of 1200 mg (Trental 400 t.i.d.) and 15 patients were given placebo for a period of eight weeks, respectively. Pentoxifylline was significantly more effective than the placebo in increasing both the initial and absolute claudication distance (ICD and ACD) in patients with peripheral chronic occlusive arterial disease (COAD). The subjective parameters such as paresthesias, muscular cramps and sensation of heaviness in the legs paralled the course of walking parameters. These results support the hypothesis that pentoxifylline in doses of 400 mg (slow release tablets) t.i.d. enhances blood flow via reducing blood viscosity and improving red cell flexibility in patients with intermittent claudication due to COAD. Pentoxifylline is thus regarded as a promising drug for the treatment of circulatory ischemic disorders, especially in intermittent claudication. It was well tolerated with minimal untoward effects.


The effect of visitors on the behavior of zoo-housed western lowland gorillas (Gorilla gorilla gorilla).
Primates, especially apes, are popular with the public, often attracting large crowds. These crowds could cause behavioral change in captive primates, whether positive, neutral, or negative. We examined the impact of visitors on the behavior of six western lowland gorillas (Gorilla gorilla gorilla), observing the troop over 6 weeks during high season (4.5 hr/day, 35 days, May-July 2016). We used focal scan sampling to determine activity budget and enclosure usage, and focal continuous sampling to identify bouts of anxiety-related behavior (visitor-directed vigilance, self-scratching, and aggression). Both daily zoo-entry numbers (VGATE ) and instantaneous crowds at the exhibit (VDENSITY ) were measured. Overall, VGATE had little effect across behaviors. However, consistent with the more acute time frame of measurement, VDENSITY was a better predictor of behavior; at high crowd volumes, we observed significant group-level changes in activity budget (increased inactivity, increased locomotion, and decreased environment-related behaviors), increase in some anxiety-related behaviors, and decreased enclosure usage. Although contributing similar effects, it could not be determined if crowd numbers, composition, or noise most affected the troop, nor any chronic effects of exposure to large crowds. Nevertheless, our findings suggest that measures to minimize the impacts of large crowds at the exhibit would be beneficial. Furthermore, we highlight potential discrepancies between common methods for measuring visitor numbers: VGATE is less sensitive to detecting visitor effects on behavioral indices than VDENSITY . Future studies should appropriately match the biological time frame of welfare indicators and visitor measures used to ensure the reliability of findings.


[Age-related characteristics of experimental hypothyroidism in rats].
The rate of both the synthesis of liver and plasma proteins and RNA-1 and RNA-2 polymerase activities in liver were studied in rats of various ages at experimental hypothyroidism. There has been marked more significant decrease in plasma protein synthesis with age. Both the rate of liver and plasma protein synthesis have been shown to be reduced at experimental hypothyroidism but synthesis of plasma proteins was inhibited to a greater extent. Considerable changes were observed neither in liver and plasma protein synthesis nor in the balance between these two groups of the protein synthesis in old rats. RNA-1 and RNA-2 polymerase activities decreased at hypothyroidism. At all ages the activity of bound enzymes decreased to a larger extent as compared to free forms. The activity of RNA-polymerase 2 was more inhibited than that of RNA-polymerase 1. Reducing protein- and RNA-synthetic processes in the liver with age correlated with the peculiarities of the carbohydrate metabolism: in those young animals with an impaired glucose tolerance the inhibitory effect of hypothyroidism on the intensity of protein and RNA synthesis was more potent as compared to old animals.


Primary healthcare renewal in Canada: a glass half empty?
Primary healthcare renewal was an important government initiative arising in the early 21st century. This sector of the healthcare system in Canada had been under-resourced and ignored for decades. Recent changes include the development of salaried models for physician care, the use of other professionals in primary care, the integration of inter-professional teams, funding for information management systems and some incentives to provide directed primary care services. However, these changes are limited by a lack of overall policy direction to drive innovation, the absence of a shift in the locus of control of healthcare, a lack of education for healthcare providers to support inter-professional team-based practices and a failure to be more accountable to the Canadian public's needs. Without these innovations, the primary healthcare system will again be overwhelmed by future healthcare needs. Based on these limitations, we question whether this renewal represents lasting change in primary healthcare or a band-aid solution to the continued issue of primary healthcare delivery.


Organotypic culture of breast tumor explants as a multicellular system for the screening of natural compounds with antineoplastic potential.
Breast cancer is the leading cause of death in women worldwide. The search for novel compounds with antitumor activity, with less adverse effects and higher efficacy, and the development of methods to evaluate their toxicity is an area of intense research. In this study we implemented the preparation and culture of breast tumor explants, which were obtained from precision-cut breast tumor slices. In order to validate the model we are proposing to screen antineoplastic effect of natural compounds, we selected caffeic acid, ursolic acid, and rosmarinic acid. Using the Krumdieck tissue slicer, precision-cut tissue slices were prepared from breast cancer samples; from these slices, 4 mm explants were obtained and incubated with the selected compounds. Viability was assessed by Alamar Blue assay, LDH release, and histopathological criteria. Results showed that the viability of the explants cultured in the presence of paclitaxel (positive control) decreased significantly (P < 0.05); however, tumor samples responded differently to each compound. When the explants were coincubated with paclitaxel and compounds, a synergic effect was observed. This study shows that ex vivo culture of breast cancer explants offers a suitable alternative model for evaluating natural or synthetic compounds with antitumor properties within the complex microenvironment of the tumor.


Skin Exposures, Hand Eczema and Facial Skin Disease in Healthcare Workers During the COVID-19 Pandemic: A Cross-sectional Study.
The COVID-19 pandemic has led to enhanced hygiene procedures and use of personal protective equipment, but also to increased attention to occupational skin disease in healthcare workers. The occurrence of hand and facial skin disease in > 5,000 Swedish healthcare workers was investigated in a questionnaire survey. Levels of skin exposure related to hygiene procedures and personal protective equipment were recorded. Caring for patients with COVID-19 entailed higher levels of wet work and face mask exposures, and was associated with higher 1-year prevalence of both hand eczema (36%) and facial skin disease (32%) compared with not being directly engaged in COVID-19 care (28% and 22%, respectively). Acne and eczema were the most common facial skin diseases; for both, a dose-dependent association with face mask use was found. Dose-dependent associations could be shown between hand eczema and exposure to soap and gloves, but not to alcohol-based hand disinfectants.


Parametric generation processes: spectral bandwidth and acceptance angles.
A systematic evaluation of the spectral bandwidth and two acceptance angles of parametric generation processes is presented. The spectral bandwidth and acceptance angles are determined by expanding the wave vector mismatch in a Taylor series and retaining terms through second order. This allows a determination of these parameters even when the first order term vanishes. Conditions where the first order term vanishes are presented and compared with similar cases where the first order term does not vanish.


A Conceptual Model for the Translation of Bioethics Research and Scholarship.
While the bioethics literature demonstrates that the field has spent substantial time and thought over the last four decades on the goals, methods, and desired outcomes for service and training in bioethics, there has been less progress defining the nature and goals of bioethics research and scholarship. This gap makes it difficult both to describe the breadth and depth of these areas of bioethics and, importantly, to gauge their success. However, the gap also presents us with an opportunity to define this scope of work for ourselves and to help shape the broader conversation about the impact of academic research. Because of growing constraints on academic funding, researchers and scholars in many fields are being asked to demonstrate and also forecast the value and impact of their work. To do that, and also to satisfy ourselves that our work has meaningful effect, we must understand how our work can motivate change and how that change can be meaningfully measured. In a field as diverse as bioethics, the pathways to and metrics of change will likewise be diverse. It is therefore critical that any assessment of the impact of bioethics research and scholarship be informed by an understanding of the nature of the work, its goals, and how those goals can and ought to be furthered. In this paper, we propose a conceptual model that connects individual bioethics projects to the broader goals of scholarship, describing the translation of research and scholarly output into changes in thinking, practice, and policy. One of the key implications of the model is that impact in bioethics is generally the result of a collection of projects rather than of any single piece of research or scholarship. Our goal is to lay the groundwork for a thoroughgoing conversation about bioethics research and scholarship that will advance and shape the important conversation about their impact.


Treatment of metastatic liver tumors by intermittent repetitive injection of an angiogenesis inhibitor using an implantable port system in a rabbit model.
Angiogenesis inhibitors are expected as a new type of anticancer drug, because they may prevent tumor neovascularization. Among several angiogenesis inhibitors, 6-o-(N-chloroacetylcarbamoyl)-fumagillol (TNP-470) is thought to inhibit the proliferation of migrating endothelial cells, as an aspect of angiogenesis, and attracts an attention for clinical application. We attempted to evaluate anticancer effects of intermittent repetitive intraportal injection of TNP-470 for metastatic liver tumor models and considered the usefulness and a role as an angiogenesis inhibitor, TNP-470, in the anti-cancer therapy using an implantable port system. We used 25 Japanese white rabbits with metastatic liver tumors made by intraportal injection of tumor cells (VX2-carcinoma), and divided those into five groups; group A was control group, group B was treated by repetitive subcutaneous injection of TNP-470 and group C, D, E was treated by repetitive intraportal injection of TNP-470, adriamycin, TNP-470 + adriamycin respectively 5 times at 2 or 3 days interval after tumor inoculation using implantable port systems. After 2 weeks, we evaluated anti-cancer effect of TNP-470 pathologically. In the number of grown tumors, there was no difference among five groups statisitically. But the mean tumor size of each group is smaller in order of group E, D, C, B, A and the differences were significant (P < 0.05) except between E and D group. And intratumoral neovascularization tended to be less in group B, C, E than in group A, D pathologically. We consider that intermittent repetitive injection of TNP-470 is more useful than systemic administration for metastatic liver tumors and the administration of angiogenesis inhibitor with other anti-cancer agents via an implantable port system will be one of the most effective therapeutic methods for them.


Pipeline embolization device dynamics: prediction of incomplete occlusion by elongation from nominal length.
According to benchtop studies, the oversizing of a Pipeline embolization device (PED) relative to the parent artery leads to a significant increase in porosity and potentially compromises aneurysm occlusion as well as transitional zone (TZ) formation around the neck of aneurysms. However, no clinical assessment has been reported. Here this potential was studied by measuring the dynamic changes of PEDs in the clinical time course. The authors retrospectively examined 124 anterior circulation unruptured aneurysms in 114 consecutive patients treated with a PED between July 2015 and December 2020 at their institution. The authors excluded 77 cases of 68 patients with adjunctive coil embolization or multiple stents that could affect the PED dynamics and measurements, and 47 aneurysms in 46 patients were included. Measurements were performed before, immediately after, and 6 months after treatment, and then at intervals of 6 months to 1 year after that for nonocclusion cases. Complete occlusion was achieved in 79.0% and incomplete occlusion in 21.0% at last follow-up. The PED length immediately after deployment was 136% nominal length. A multivariable regression analysis revealed that age (OR 1.11/year; p = 0.02) and PED elongation from nominal length (OR 1.31/mm; p = 0.012) were independently associated with a higher rate of incomplete occlusion at the last follow-up. TZ formation did not affect the occlusion rate. PED elongation from the nominal length is a new predictor of incomplete aneurysm occlusion. The PED showed vascular remodeling by changing its diameter and length in the clinical course. TZ formation was remodeled and did not affect the occlusion rate.


Perceived weight gain and eating disorder symptoms among LGBTQ+ adults during the COVID-19 pandemic: a convergent mixed-method study.
In this study, we further explore the role of COVID-19 pandemic-related stress, social support, and resilience on self-reported eating disorder symptoms (using the EDE-QS) and perceived weight gain among lesbian, gay, bisexual, transgender, and/or queer (LGBTQ+ adults) in the US context during the COVID-19 pandemic. Employing a convergent mixed method design, we surveyed 411 individuals, and conducted qualitative semi-structured follow-up interviews with 43 LGBTQ+ -identifying survey respondents. Using OLS regression and multinomial logistic regression, we modeled eating disorder symptoms and perceived weight gain among LGBTQ+ individuals (n = 120) and cisgender and heterosexual-identifying women (n = 230), to cisgender and heterosexual-identifying men (n = 61). We also explored complementary interview narratives among LGBTQ+ people by employing selective coding strategies. Study results suggest that LGBTQ+ individuals are likely experiencing uniquely high levels of pandemic-related stress, and secondly, that pandemic-related stress is associated with elevated eating disorder symptoms and higher risk of perceived weight gain. Nearly 1 in 3 participants reported eating disorder symptoms of potentially clinical significance. Social support, but not resilient coping, was found to be protective against increased eating disorder symptoms. Qualitative analyses revealed that LGBTQ+ individuals situated physical exercise constraints, challenging eating patterns, and weight concerns within their pandemic experiences. Clinicians of diverse specialties should screen for eating disorder symptoms and actively engage patients in conversations about their COVID-19-related weight gain and eating behaviors, particularly with LGBTQ+ -identifying adults.


Adherence in patients in the first year after kidney transplantation and its impact on graft loss and mortality: a cross-sectional and prospective study.
To explore the predictive value of adherence to their immunosuppressive medication in kidney transplant recipients in the first year after kidney transplantation as a determinant of graft loss and mortality up to 12 years (prospective analysis) and its association with sociodemographic and medical factors and social support (cross-sectional analysis). Poor adherence to their immunosuppressive medication in kidney transplant recipients remains the leading preventable cause of poor patient outcomes. Prospective and cross-sectional study. At baseline, 325 patients 3-12 months posttransplantation were invited to participate. Adherence was assessed using collateral reports - a combination of patients' self-evaluation and an estimate by their nephrologist. The patients provided sociodemographic and medical data and completed the End-Stage Renal Disease Symptom Checklist and Multidimensional scale of perceived social support. At follow-up (average 7·1 years), data on patients and graft survival were obtained. All data were collected from 2002-2013. Multinomial regression analysis and Cox regression were performed. A total of 297 patients (48·1 (12·8) years, 61·6% men) agreed to participate (response rate 91·4%); 67·4% were considered as fully adherent. Poor adherence was associated with higher risk of graft loss and mortality over 12 years. Female sex, higher education, higher perceived side effects of corticosteroids, better perceived cardiac and renal function and higher perceived family social support in the first year posttransplantation were associated with full adherence to immunosuppressive treatment. Patients with poor adherence to the immunosuppressive medication in the first year after kidney transplantation showed increased likelihood of graft loss and death over 12 years compared with the adherent patients.


Family planning and the burden of unintended pregnancies.
Family planning is hailed as one of the great public health achievements of the last century, and worldwide acceptance has risen to three-fifths of exposed couples. In many countries, however, uptake of modern contraception is constrained by limited access and weak service delivery, and the burden of unintended pregnancy is still large. This review focuses on family planning's efficacy in preventing unintended pregnancies and their health burden. The authors first describe an epidemiologic framework for reproductive behavior and pregnancy intendedness and use it to guide the review of 21 recent, individual-level studies of pregnancy intentions, health outcomes, and contraception. They then review population-level studies of family planning's relation to reproductive, maternal, and newborn health benefits. Family planning is documented to prevent mother-child transmission of human immunodeficiency virus, contribute to birth spacing, lower infant mortality risk, and reduce the number of abortions, especially unsafe ones. It is also shown to significantly lower maternal mortality and maternal morbidity associated with unintended pregnancy. Still, a new generation of research is needed to investigate the modest correlation between unintended pregnancy and contraceptive use rates to derive the full health benefits of a proven and cost-effective reproductive technology.


Both orexin receptors are expressed in rat ovaries and fluctuate with the estrous cycle: effects of orexin receptor antagonists on gonadotropins and ovulation.
Orexins are peptides controlling feeding, sleep, and neuroendocrine functions. They are synthesized by the hypothalamus with projections throughout the brain. Orexins and their orexin 1 (OX(1)) and orexin 2 receptors (OX(2)) are present outside the central nervous system. Here the expression of preproorexin (PPO), OX(1), and OX(2) was studied in rat ovaries. PPO, OX(1), and OX(2) were determined by quantitative real-time RT-PCR in ovaries of cycling Sprague-Dawley rats on all days of the cycle. Serum hormones and food consumption were determined. Ovarian OX(1) and OX(2) expression was then studied after ovulation blockade with Cetrorelix or Nembutal. Finally, proestrous rats were treated at 1400 and 1900 with a selective OX(1) antagonist (SB-334867-A) and/or a selective OX(2) antagonist (JNJ-10397049), and hormone levels, ovulation, and ovarian histology were studied. Both receptors' expression increased in the ovary between 1700 and 2300 of proestrus exclusively, in coincidence with hormone peaks, but not with the dark-light cycle or food intake. PPO was not detected. Cetrorelix or Nembutal prevented the increases of OX(1) and OX(2) while blunting gonadotropin peaks. SB-334867-A and JNJ-10397049, alone or combined, decreased serum gonadotropins and reduced ova number the following morning; ovaries showed a bloody (hyperemic and/or hemorrhagic) reaction with more preovulatory follicles and less corpora lutea. Here we demonstrate for the first time an increased ovarian expression of both OX(1) and OX(2), only during proestrous afternoon, and its hormone dependence but not dependence on the dark-light cycle. Two new receptor antagonists reduced proestrous gonadotropins and/or ova number while producing ovarian structural changes.


Detailed Wave Function Analysis for Multireference Methods: Implementation in the Molcas Program Package and Applications to Tetracene.
High-level multireference computations on electronically excited and charged states of tetracene are performed, and the results are analyzed using an extensive wave function analysis toolbox that has been newly implemented in the Molcas program package. Aside from verifying the strong effect of dynamic correlation, this study reveals an unexpected critical influence of the atomic orbital basis set. It is shown that different polarized double-ζ basis sets produce significantly different results for energies, densities, and overall wave functions, with the best performance obtained for the atomic natural orbital (ANO) basis set by Pierloot et al. Strikingly, the ANO basis set not only reproduces the energies but also performs exceptionally well in terms of describing the diffuseness of the different states and of their attachment/detachment densities. This study, thus, not only underlines the fact that diffuse basis functions are needed for an accurate description of the electronic wave functions but also shows that, at least for the present example, it is enough to include them implicitly in the contraction scheme.


Central projections from Johnston's organ in the locust: Axogenesis and brain neuroarchitecture.
Johnston's organ (Jo) acts as an antennal wind-sensitive and/or auditory organ across a spectrum of insect species and its axons universally project to the brain. In the locust, this pathway is already present at mid-embryogenesis but the process of fasciculation involved in its construction has not been investigated. Terminal projections into the fine neuropilar organization of the brain also remain unresolved, information essential not only for understanding the neural circuitry mediating Jo-mediated behavior but also for providing comparative data offering insights into its evolution. In our study here, we employ neuron-specific, axon-specific, and epithelial domain labels to show that the pathway to the brain of the locust is built in a stepwise manner during early embryogenesis as processes from Jo cell clusters in the pedicel fasciculate first with one another, and then with the two tracts constituting the pioneer axon scaffold of the antenna. A comparison of fasciculation patterns confirms that projections from cell clusters of Jo stereotypically associate with only one axon tract according to their location in the pedicellar epithelium, consistent with a topographic plan. At the molecular level, all neuronal elements of the Jo pathway to the brain express the lipocalin Lazarillo, a cell surface epitope that regulates axogenesis in the primary axon scaffold itself, and putatively during fasciculation of the Jo projections to the brain. Central projections from Jo first contact the primary axon scaffold of the deutocerebral brain at mid-embryogenesis, and in the adult traverse mechanosensory/motor neuropils similar to those in Drosophila. These axons then terminate among protocerebral commissures containing premotor interneurons known to regulate flight behavior.


Use of antibiotic-loaded cement in total knee arthroplasty.
Bone cement has the capacity to release antibiotic molecules if any antibiotic is included in it, and these elution properties are improved as cement porosity is increased. In vitro studies have shown high local antibiotic concentration for many hours or few days after its use. Antibiotic loaded bone cement (ALBC) is helpful when treating an infection in total knee arthroplasty (TKA) revision surgery. The purpose of this paper was to review the evidence for the routine use of ALBC in TKA in the literature, its pros and cons. Many authors have recommended the use of ALBC also in primary TKA for infection prophylaxis, but the evidence based on data from National Registries, randomized clinical trials and meta-analysis suggest a protective effect of ALBC against infection when used in hips, but not (or only mild) in knees. A possible explanation to this finding is that the duration and quantity of locally elevated antibiotic levels after surgery are smaller in TKA, due to the smaller amount of cement used for fixation in TKA-only a layer in the bone surface. There are some concerns about the routine use of ALBC in primary TKA as prophylaxis against infection: Firstly, there is a risk of hypersensivity or toxicity even when the chance is highly improbable. Secondly, there is a reduction in the mechanical properties of the cement, but this can be probably neglected if the antibiotic is used in low doses, not more than 1 g per 40 g cement package. Another significant concern is the increased economic cost, which could be overlooked if there were enough savings in treating fewer prosthetic infections. Finally, there is also a risk of selection of antibiotic-resistant strains of bacteria and this could be the main concern. If used, the choice of the antibiotic mixed in ALBC should consider microbiological aspects (broad antimicrobial spectrum and low rate of resistant bacteria), physical and chemical aspects (thermal stability, high water solubility), pharmacological characteristics (low risk to allergic reactions or toxicity) and economic aspects (not too expensive). The most commonly used antibiotics in ALBC are gentamicin, tobramycin and vancomycin. In conclusion, there is a paucity of randomized clinical trials in the use of ALBC in primary TKAs and the actual evidence of the effect of ALBC in reducing the risk of infection is insufficient. This, in addition to concerns about patient safety, risks of increase in the antibiotic resistance of microorganisms and the increase in costs in the procedure, lead us to recommend a cautious use of ALBC, perhaps only in high-risk patients (immunocompromised, morbidly obese, diabetic and patients with previous history of fracture or infection around the knee) unless the benefits of ALBC use were fully proven. Meanwhile, the rigorous use of peri-operative prophylactic systemic antibiotics and adoption of efficient antiseptic procedures and improved surgical techniques must be considered the gold standard in infection prevention in TKA surgery.


The Length of Gomco Clamp Timing and Its Effect on Bleeding.
Bleeding is the most common complication of circumcisions in newborns. Gomco clamps are used to perform neonatal circumcisions. Although a clamp time of 5 minutes is recommended, there is no evidence to support this recommendation. Circumcisions performed by attending physicians from the Division of Pediatric Hospital Medicine at an academic children's hospital were split into 2 groups. Group 1 had a clamp time of 5 minutes. Group 2 did not have a clamp time minimum. Nursing staff examined for bleeding at intervals of 15- and 30-minutes' postprocedure. Bleeding was determined to be significant if pressure and/or a microfibrillar collagen hemostat agent was applied. The study sample contained 23 physicians who saw a total of 1252 patients: 13 physicians (647 patients) in group 1 and 10 physicians (605 patients) in group 2. The average clamp time in group 2 was 2 minutes, 5 seconds. The estimated percentage of circumcisions that required microfibrillar collagen hemostat application was 5.1% (95% confidence interval [CI], 3.1-8.1) for group 1 and 5.6% (95% CI: 3.5-8.8]) for group 2. Circumcisions that had pressure applied were estimated to be 0.6% (95% CI: 0.2-1.7) for group 1 and 1.3% (95% CI: 0.5-3.1) for group 2. The difference between groups, in both categories, was not statistically significant. In this prospective study we evaluated clamp time duration and bleeding outcomes for neonatal circumcision. Clamp time does not appear to have an association with bleeding risk. Providers need not maintain a 5-minute clamp time to decrease postprocedural bleeding.


Psychological correlates of interest in genetic testing among Korean American adoptees and their parents.
Adopted persons increasingly have turned to genetic testing to obtain health information or to search for birth family. The present study investigated psychological factors that may contribute to interest among adoptees and their parents in genetic testing for the adoptee, including adoptees' ethnic identity development, their thoughts or curiosity about birth family (birth family thoughts), and the interaction of these two factors. Data were drawn from the second wave of a longitudinal study, conducted in 2014, on transracially, transnationally adopted Korean American adolescents and their adoptive parents. In a sample of 106 adolescent-parent dyads, 2 adolescents (1.89%) had undergone genetic testing. Among the dyads in which adolescents had not sought genetic testing, 47.12% of adolescents and 43.27% of parents indicated interest in genetic testing for the adolescent adoptee. Adolescents' interest in genetic testing was independent from parents' interest. Neither adolescent psychological adjustment nor physical health was related to interest in genetic testing in either adolescents or parents. Adolescents' birth family thoughts were related to adolescents' interest in genetic testing, but not to parents' interest in genetic testing for their child. This study showed ethnic identity exploration and resolution moderated the relationship between birth family thoughts and adolescents' interest in genetic testing. Results point to the relevance of birth family thoughts and identity development to genetic testing in transnational and transracial adolescent adoptees.


Dietary intake, supplement use, and survival among women diagnosed with early-stage breast cancer.
Previous studies examining the relationship between micronutrient intakes and survival following diagnosis of breast cancer have reported mixed results. This may be partly due to considerable variance in amounts of micronutrients consumed from diet and supplements across studies. Early-stage breast cancer survivors (N = 3081) completed four 24-h dietary and supplement recalls at the baseline assessment (1995 to 2000) and were followed for a median of 9.0 yr. Mean micronutrient intakes were compared to dietary reference intakes (DRI) to assess micronutrient adequacy for both users and nonusers of supplements. Cox regressions were performed to assess whether intakes of selected micronutrients were associated with all-cause mortality. Four hundred and twelve deaths occurred between baseline and August 2009. Among these women, more supplement users had adequate micronutrient intakes than nonusers for 15 out of 17 micronutrients. Less than 10% of supplement users (<2% of nonsupplement users) reported levels that exceeded the tolerable upper limit for each micronutrient except magnesium. After adjusting for age, tumor characteristics, and health status variables, micronutrient intakes were not significantly associated with all-cause mortality. Dietary supplements may improve overall micronutrient intakes of breast cancer survivors. However, vitamin and mineral intakes were not associated with all-cause mortality.


[Inhibitation of tumor angiogenesis, growth and metastasis by blocking VEGF paracrine pathway].
Solid tumors require an adequate vascular supply to grow beyond a certain dimension. It is known that formation of new blood vessels in tumor is mediated by unbalanced expression of angiogenic factors and their inhibitors. Among the former, the vascular endothelial growth factor (VEGF) has been assumed prime candidacy as a major positive physiological effector. To investigate the role of VEGF in angiogenesis associated with development of breast cancer, a sense VEGF and an anti-sense VEGF expression plasmids were constructed, and then were introduced into a human breast carcinoma cell line, MCF-7, expressing middle level of endogenous VEGF. Anti-sense VEGF(121) transfected MCF-7 cells that expressed reduced constitutive levels of VEGF and showed the same growing potential as untransfected MCF-7 cells in vitro, but it showed longer latency, smaller tumor, slower growth and prolonged survival time compared to parental or sense VEGF(165) transfected MCF-7 cells in vivo. Moreover, the tumors derived from anti-sense VEGF(121) transfected MCF-7 cells characterized by minimal vascularization and extensive necrosis. Finally, mice with primary subcutaneous tumors treated with intratumoral administration of anti-sense VEGF, or the plasmid expressing extracellular domain of the Flk-1 VEGF receptor (sFlk-1) followed by electroporation, showed significant tumor suppression. These results suggest that VEGF plays a major angiogenic role in breast cancer and a strategy, which blocks the VEGF paracrine pathway, may provide a means to control tumor growth topically without the risk of systemic antiangiogenesis.


The Synthesis of Novel Oxazolinylphosphinic Esters and Amides and Application to the Cyanosilylation of Aldehydes.
A new class of modular functionalized oxazolines are synthesized using a simple, novel one-pot method under inert moisture-free conditions. Then the oxazolines can be further elaborated to phosphine-containing oxazolines. The first step is to synthesize intermediates via the reaction of 2 - hydroxybenzonitrile or 2-aminobenzonitrile with chiral amino alcohols, subsequent reactions with phosphine chlorides, providing products in moderate yields. Product structures are fully characterized by NMR, IR, MS and X-Ray analyses. These compounds are found to be highly active catalysts for the cyanosilylation of prochiral benzaldehyde (20-96% yield).


The effect of mechanical stress on cartilage energy metabolism.
Cartilage is routinely subjected to varying mechanical stresses which are known to affect matrix turnover by a variety of pathways. Here we show that mechanical loads which suppress sulphate incorporation or protein synthesis by articular chondrocytes, also inhibit rates of oxygen uptake and of lactate production. Although the mechanisms have not been definitively identified, it has been shown that high hydrostatic pressures reduce the activity of the glucose transporter GLUT. Furthermore, fluid expression consequent on static loading changes intracellular pH and ionic strength; intracellular changes which would reduce the activity of glycolytic enzymes. Both pathways would thus lead to a fall in rates of glycolysis and a reduction in intracellular ATP, and - since ATP concentrations directly affect sulphation of proteoglycans - a rapid fall in sulphate incorporation. Our results suggest that load-induced changes in matrix synthesis in cartilage can occur by means other than changes in gene expression.


Webcam Use in the Neonatal Intensive Care Unit during the First Year of the SARS-CoV-2 Pandemic.
The aim of this study was to evaluate patterns of webcam use in families of patients admitted to a neonatal intensive care unit (NICU) during the first year of the pandemic and characterize the families who used the technology. Retrospective chart review of the medical records and logins of our live webcam system was conducted for 2020. From January 1, 2020 to December 31, 2020, 843 infants were admitted to the NICU, with lengths of stay range of 1 to 169 days. More than half (n = 496, 58.8%) of all families of infants admitted to the NICU used the webcam system during the period of study. The number of webcam users did not change between the pre-coronavirus disease 2019 (COVID-19) and during COVID-19 time periods, or during versus after NICU visitor restrictions. Among webcam users, the median (interquartile range) number of logins per day was 2.9 (2.9) and ranged from 0 to 44. There were significant differences among races, site of admission, and diagnosis groups. Families of White infants had more frequent use compared with families of Black infants. Families of infants admitted for surgical reasons had more frequent use compared with those admitted for medical reasons. Among 284 of the 496 (57.3%) webcam users, we documented logins from 37 states in the United States and from 10 different countries. Webcam use is common in the NICU. There was no increase in webcam use within the first year of the COVID-19 pandemic in the NICU. More studies are needed to evaluate how this technology is used in the NICU and its impact on patients and families. · Webcam use in the NICU is common.. · Visitor restrictions did not increase webcam use.. · We observed racial differences in webcam use..


The tragedy of the commons in microbial populations: insights from theoretical, comparative and experimental studies.
First principles of thermodynamics imply that metabolic pathways are faced with a trade-off between the rate and yield of ATP production. Simple evolutionary models argue that this trade-off generates a fundamental social conflict in microbial populations: average fitness in a population is highest if all individuals exploit common resources efficiently, but individual reproductive rate is maximized by consuming common resources at the highest possible rate, a scenario known as the tragedy of the commons. In this paper, I review studies that have addressed two key questions: What is the evidence that the rate-yield trade-off is an evolutionary constraint on metabolic pathways? And, if so, what determines evolutionary outcome of the conflicts generated by this trade-off? Comparative studies and microbial experiments provide evidence that the rate-yield trade-off is an evolutionary constraint that is driven by thermodynamic constraints that are common to all metabolic pathways and pathway-specific constraints that reflect the evolutionary history of populations. Microbial selection experiments show that the evolutionary consequences of this trade-off depend on both kin selection and biochemical constraints. In well-mixed populations with low relatedness, genotypes with rapid and efficient metabolism can coexist as a result of negative frequency-dependent selection generated by density-dependent biochemical costs of rapid metabolism. Kin selection can promote the maintenance of efficient metabolism in structured populations with high relatedness by ensuring that genotypes with efficient metabolic pathways gain an indirect fitness benefit from their competitive restraint. I conclude by suggesting avenues for future research and by discussing the broader implications of this work for microbial social evolution.


CLOVE: classification of genomic fusions into structural variation events.
A precise understanding of structural variants (SVs) in DNA is important in the study of cancer and population diversity. Many methods have been designed to identify SVs from DNA sequencing data. However, the problem remains challenging because existing approaches suffer from low sensitivity, precision, and positional accuracy. Furthermore, many existing tools only identify breakpoints, and so not collect related breakpoints and classify them as a particular type of SV. Due to the rapidly increasing usage of high throughput sequencing technologies in this area, there is an urgent need for algorithms that can accurately classify complex genomic rearrangements (involving more than one breakpoint or fusion). We present CLOVE, an algorithm for integrating the results of multiple breakpoint or SV callers and classifying the results as a particular SV. CLOVE is based on a graph data structure that is created from the breakpoint information. The algorithm looks for patterns in the graph that are characteristic of more complex rearrangement types. CLOVE is able to integrate the results of multiple callers, producing a consensus call. We demonstrate using simulated and real data that re-classified SV calls produced by CLOVE improve on the raw call set of existing SV algorithms, particularly in terms of accuracy. CLOVE is freely available from http://www.github.com/PapenfussLab .


Novelty and uniqueness patterns of rare members of the soil biosphere.
Soil bacterial communities typically exhibit a distribution pattern in which most bacterial species are present in low abundance. Due to the relatively small size of most culture-independent sequencing surveys, a detailed phylogenetic analysis of rare members of the community is lacking. To gain access to the rarely sampled soil biosphere, we analyzed a data set of 13,001 near-full-length 16S rRNA gene clones derived from an undisturbed tall grass prairie soil in central Oklahoma. Rare members of the soil bacterial community (empirically defined at two different abundance cutoffs) represented 18.1 to 37.1% of the total number of clones in the data set and were, on average, less similar to their closest relatives in public databases when compared to more abundant members of the community. Detailed phylogenetic analyses indicated that members of the soil rare biosphere either belonged to novel bacterial lineages (members of five novel bacterial phyla identified in the data set, as well as members of multiple novel lineages within previously described phyla or candidate phyla), to lineages that are prevalent in other environments but rarely encountered in soil, or were close relatives to more abundant taxa in the data set. While a fraction of the rare community was closely related to more abundant taxonomic groups in the data set, a significant portion of the rare biosphere represented evolutionarily distinct lineages at various taxonomic cutoffs. We reason that these novelty and uniqueness patterns provide clues regarding the origins and potential ecological roles of members of the soil's rare biosphere.


Contextual determinants of adolescent mortality in South Africa.
South Africa has a large adolescent population (approximately 20% of the total population). The survival and development of these individuals are a priority among parents and the government. In an effort to better understand the factors contributing to adolescent mortality in South Africa, this study examined the effect of household and community factors on adolescent death. The study used data from Census 2001. Multilevel modelling was used to study the impact of community and household factors on adolescent mortality. A multivariate binary logistic 2-level model was developed. Odds ratios were produced and, statistically significant values (p<0.05) were discussed. There were 41,261 reported adolescent deaths from census data. This study found that having a few household assets, six or more people living in a residence, and high racial diversity is associated with increased odds of adolescent mortality in South Africa in 2001. Socio-economic status of the household and racial diversity within communities is likely to increase adolescent mortality in South Africa. However, there is need to examine the role of other community characteristics, such as number of schools, health facilities and employment opportunities in order to create a holistic profile of the contextual determinants of adolescent mortality in the country.


The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV.
Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photocarcinogenesis and photoaging, and an urgent need exists for improved strategies for skin photoprotection. The redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defense against environmental electrophilic insult, has recently emerged as an important determinant of cutaneous damage from solar UV, and the concept of pharmacological activation of Nrf2 has attracted considerable attention as a novel approach to skin photoprotection. In this study, we examined feasibility of using tanshinones, a novel class of phenanthrenequinone-based cytoprotective Nrf2 inducers derived from the medicinal plant Salvia miltiorrhiza, for protection of cultured human skin cells and reconstructed human skin against solar simulated UV. Using a dual luciferase reporter assay in human Hs27 dermal fibroblasts pronounced transcriptional activation of Nrf2 by four major tanshinones [tanshinone I (T-I), dihydrotanshinone (DHT), tanshinone IIA (T-II-A) and cryptotanshinone (CT)] was detected. In fibroblasts, the more potent tanshinones T-I and DHT caused a significant increase in Nrf2 protein half-life via blockage of ubiquitination, ultimately resulting in upregulated expression of cytoprotective Nrf2 target genes (GCLC, NQO1) with the elevation of cellular glutathione levels. Similar tanshinone-induced changes were also observed in HaCaT keratinocytes. T-I and DHT pretreatment caused significant suppression of skin cell death induced by solar simulated UV and riboflavin-sensitized UVA. Moreover, feasibility of tanshinone-based cutaneous photoprotection was tested employing a human skin reconstruct exposed to solar simulated UV (80 mJ/cm(2) UVB; 1.53 J/cm(2) UVA). The occurrence of markers of epidermal solar insult (cleaved procaspase 3, pycnotic nuclei, eosinophilic cytoplasm, acellular cavities) was significantly attenuated in DHT-treated reconstructs that displayed increased immunohistochemical staining for Nrf2 and γ-GCS together with the elevation of total glutathione levels. Taken together, our data suggest the feasibility of achieving tanshinone-based cutaneous Nrf2-activation and photoprotection.


Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study.
In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.


Interaction Promotes the Adaptation of Referential Conventions to the Communicative Context.
Coordination between speakers in dialogue requires balancing repetition and change, the old and the new. Interlocutors tend to reuse established forms, relying on communicative precedents. Yet linguistic interaction also necessitates adaptation to changing contexts or dynamic tasks, which might favor abandoning existing precedents in favor of better communicative alternatives. We explored this tension using a maze game task in which individual participants and interacting pairs had to describe figures and their positions in one of two possible maze types: a regular maze, in which the grid-like structure of the maze is highlighted, and an irregular maze, in which specific parts of the maze are salient. Participants repeated this task several times. Both individuals and interacting pairs were affected by the different maze layouts, initially using more idiosyncratic description schemes for irregular mazes and more systematic schemes for regular mazes. Interacting pairs, but not individuals, abandoned their unsystematic initial descriptions in favor of a more systematic approach, which was better adapted for repeated interaction. Our results show communicative conventions are initially shaped by context, but interaction opens up the possibility for change if better alternatives are available.


Preoperative and Postoperative Opioid Dependence in Patients Undergoing Anterior Cervical Diskectomy and Fusion for Degenerative Spinal Disorders.
Anterior cervical diskectomy and fusion (ACDF) is a procedure for effectively relieving radiculopathy. Opioids are commonly overprescribed in postsurgical settings and prescriptions vary widely among providers. We identify trends in opioid dependence before and after ACDF. We used the Truven Health MarketScan data to identify adult patients undergoing ACDF for degenerative cervical spine conditions between 2009 and 2015. Patients were segregated in four cohorts of preoperative and postoperative opioid nondependence (ND) or dependence (D) with 15 months of postoperative follow-up. A total of 25,403 patients with median age of 52 years (18-92) who underwent ACDF met the inclusion criteria. Breakdown of the four cohorts was as follows: prior nondependent who remain nondependent (NDND): 62.76% (n = 15,944); prior nondependent who become dependent (NDD): 4.6% (n = 1,168); prior dependent who become nondependent (DND): 14.03% (n = 3,564); and prior dependent who remain dependent (DD): 18.61% (n = 4,727). Opioid dependence decreased 9.43% postoperatively. Overall payments and 30-day readmissions increased 1.96 and 1.79 times for opioid dependent versus nondependent cohorts, respectively. Adjusted payments at 3 to 15 months were significantly increased for dependent cohorts with 3.56-fold increase for the DD cohort when compared with the NDND cohort. Length of stay, complications, medication refills, outpatient measures, and hospital admissions were also higher in those groups with postoperative opioid dependence when compared with those who were not opioid dependent. Opioid dependence after ACDF is associated with increased hospital readmissions, complication rates at 30 days, and payments within 3 months and 3 to 15 months postdischarge. Overall opioid dependence was decreased after ACDF procedure, however, a smaller number of opioid-dependent and opioid-naive patients became dependent postoperatively and should be followed carefully.


Outcome of the depressed elderly living in the community in Liverpool: a 5-year follow-up.
Comparatively little is known about the long-term natural history of depressive disorders in the elderly living in the community. This is a follow-up of a subsample of the Continuing Health in the Community study random sample of the elderly population living in Liverpool. The investigators followed up 120 cases of depression identified by a semi-structured interview schedule (GMS) for a period of 5 years. A similar number of other subjects defined as subcases of depression, other cases of mental illness and a random selection of non-cases were also included. The 5-year outcome for the cases of depression was worse than the outcome of the non-cases (relative mortality risk of 2.1, 95% confidence interval 1.1 to 3.9). Thirty-four per cent of the cases of depression died and 28% had dropped out during the follow-up. Of the 46 cases of depression who had a complete follow-up, 22% recovered from their symptoms, 30% were found to be AGECAT cases at one of the three follow-up waves, 24% were AGECAT cases at two of the three follow-up waves and the remaining 24% were AGECAT cases at each follow-up wave. Fifteen per cent of the surviving cases of depression were organic cases at the follow-up. Their anxiety comorbid state and depression score were identified as predictors of poor outcome. The findings of this study indicate that depressive disorders (most of which were untreated) found in the elderly community have a poor prognosis.


Midwifery and APRN Scope of Practice in Abortion Care in the Early Post-Roe Era: Everything Old Is New Again.
Over the past 10 years, there has been a rapid expansion of legal and legislative changes in abortion care provision for advanced practice clinicians (APCs), including nurse practitioners, midwives, and physician associates (formerly physician assistants), with most of that expansion occurring in the last several years. This expansion has occurred via several routes (eg, legislative, popular vote, court decision, attorney general opinion), and the patchwork of legal statuses nationally creates confusion for clinicians who are unclear on current regulations. This review explores the historical context of abortion practice for APCs, as well as the primary philosophical and legal concepts relevant to this role development. Since 2012, the number of states permitting abortion practice by APCs has more than quintupled, and the changes to abortion law in the United States in the wake of the 2022 Supreme Court decision in the case of Dobbs v. Jackson Women's Center creates a new imperative to understand the role of APCs in accessing abortion care. Additionally, although the research on abortion safety for APC abortion providers is well-established, the physician-centered paradigm of abortion care has limited the ability of APCs to develop expertise in this essential public and clinical health service.


Influence of partial volume correction in staging of head and neck squamous cell carcinoma using PET/CT.
Aim: PET/CT is widely used for the detection of lymph node involvement in head and neck squamous cell carcinoma (HNSCC). However, PET qualitative and quantitative capabilities are hindered by partial volume effects (PVE). Therefore, a retrospective study on 32 patients (57 lymph nodes) was carried out to evaluate the potential improvement of PVE correction (PVEC) in FDG PET/CT imaging for the diagnosis of HNSCC. Histopathological analysis of lymph nodes following neck dissection was used as the gold standard. Methods: A previously proposed deconvolution based PVEC approach was used to derive improved quantitative accuracy PET images, while the anatomical lymph node volumes were determined on the CT images. Different parameters including SUVmax and SUVmean were derived from both original and PVEC PET images for each patient. Results: Histopathology confirmed that SUVmax and SUVmean after PVEC allows a statistically significant differentiation of malignant and benign lymph nodes (p<0.05). The sensitivity of SUVmax and SUVmean was 64% and 57% respectively with or without PVEC. PVEC increased specificity from 71% to 76% for SUVmax and 57% to 66% for SUVmean. Corresponding accuracy increased from 66% to 71% for SUVmax and from 59% to 66% for SUVmean. However, the most accurate differentiation between benign and malignant nodes was obtained while using the magnitude of SUVmax increase after PVEC with a corresponding sensitivity, specificity and accuracy of 77%, 82% and 80% respectively. Conclusion: Our work shows that the use of partial volume effects correction allows a more accurate nodal staging using FDG PET imaging in HNSCC.


Residential treatment for parents and their children: the Village experience.
The Village South, Inc., in Miami, Florida, offers comprehensive substance abuse treatment and prevention services to adults, adolescents, and children. The Village's Families in Transition program, launched in the early 1990s as one of the Nation's first 11 federally funded programs for women with children, has provided services to nearly 800 parents and approximately 2,000 children. This article discusses the philosophy behind FIT's family focused residential treatment program, characterizes its participants, describes its challenges and successes, and points out research needs that have come to light through experience with mothers and children in treatment.


Synthesis of thymosin alpha 1 by fragment condensation using tert.-butyl side chain protection.
A novel synthesis of thymosin alpha 1 by classical methods using seven tert.-butyl side chain protected fragments is described. Optimum conditions were found for the final DCC/HOBt coupling of the two key intermediates; decapeptide and octadecapeptide. Thymosin alpha 1 was purified by two stages of preparative HPLC (partial purification with C8 and final purification with C18 reverse phase silica gel) to give a 30% overall yield for the final four stages of synthesis (including catalytic hydrogenation of octadecapeptide, coupling, deprotection and purification). The product was shown to be homogeneous by thin-layer and paper high voltage electrophoresis, isoelectric focusing analysis, thin-layer chromatography and high performance liquid chromatography. Amino acid analysis, optical rotation, 1H-n.m.r. spectroscopy, FAB mass spectroscopy and peptide mapping after tryptic digestion confirmed the structure of thymosin alpha 1. Three minor stereoisomer contaminants were isolated by HPLC and characterized as [D-Lys14]-thymosin alpha 1, [D-Lys17]-thymosin alpha 1 and [D-Ala3]-thymosin alpha 1 resulting from racemization at Lys14, Lys17 and Ala3 during the coupling of the fragments. A final contaminant, isolated by HPLC, was characterized as N alpha-isobutyloxycarbonyl-thymosin alpha 1 (15-28), which results from "wrong way opening" of an activated mixed anhydride.


Public's calorie literacy and perceived effectiveness of restaurant menu calorie labeling in the United Arab Emirates.
Restaurant menu calorie labeling is regarded as a promising, cost-effective, and innovative method that will have an impact on the food environment, raise awareness among consumers, and aid in global efforts to prevent obesity. This study aimed to assess the public's calorie literacy, dining practices, and perceived effectiveness of restaurant menu labeling implementation in the United Arab Emirates (UAE). A descriptive, web-based cross-sectional study was conducted among 1279 adults in the UAE. Socio-demographic characteristics, calorie literacy, and perceived effectiveness of restaurant menu labeling among participants were investigated. Chi-square analysis was used to compare indicators across demographic characteristics. More females than males completed the online survey, (56.1% and 43.9%). Most of the participants aged < 30 years old (54.8%), The majority of participants reported eating away from home at least once per week (89.6%). 66.0% of participants were knowledgeable about calorie definition, but only 37.1% knew about average daily energy requirements. Younger participants, with a normal BMI, and higher education levels reported a significantly higher likelihood of eating at a chain restaurant with caloric information on the menu (p <0.05). The majority of participants (76.0%) preferred to see calorie information and other nutrition information on menus. To conclude, menu labeling is a welcomed policy to be implemented in food outlets. Further investigation is necessary to ascertain the most efficacious method of presenting nutrition information to consumers to facilitate informed purchasing decisions considering the potential benefits of mandating calorie declaration in obesity prevention efforts.


Systematic review of spinal anaesthesia using bupivacaine for ambulatory knee arthroscopy.
The use of lidocaine in spinal anaesthesia is associated with transient neurological syndrome (TNS). Bupivacaine has a lower incidence of TNS as an alternative but it may have a prolonged action. This study systematically reviews the literature about the recovery profile of patients undergoing spinal anaesthesia, using bupivacaine for arthroscopic knee surgery. We identified 17 eligible randomized clinical trials (RCTs) (1268 patients). All the articles in this review, except one, used hyperbaric bupivacaine. Five trials compared different doses of bupivacaine (range 3-15 mg). Large doses of bupivacaine (10 and 15 mg) were associated with delayed recovery, and supine positioning was associated with a high incidence of failure. With unilateral positioning, a dose as low as 4-5 mg seems to be sufficient. Five trials comparing bupivacaine or levobupivacaine with ropivacaine showed no significant difference in the time to home discharge. When bupivacaine was combined with fentanyl in two trials, marginal delay in recovery was found [time to discharge (min); weighted mean difference (WMD) 14.1, 95% CI 11.9-40.1] and increased nausea and pruritus but had reduced postoperative pain. Unilateral and bilateral spinal anaesthesia were assessed in two trials, and the latter group was associated with early recovery and discharge [time to discharge (min); WMD -41.6, 95% CI -63.6 to -19.6). The results of our systematic review suggest that 4-5 mg of hyperbaric bupivacaine can effectively produce spinal anaesthesia for knee arthroscopy with unilateral positioning. Ropivacaine or the addition of adjuvants did not improve the recovery time. There is a need for tighter RCTs with more consistent endpoints.


Hepatic candidiasis: persistent pyrexia in a patient with acute myeloid leukaemia after recovery from consolidation therapy-induced neutropenia.
Fever, a frequent manifestation in acute leukaemia patients who develop treatment-induced neutropenia, usually resolves when the neutrophil count returns to normal irrespective of whether an infective agent is isolated or not. A persistent pyrexia following neutrophil recovery and associated with multiple negative microbiological cultures should signal a careful search for a deep-seated fungal infection in any leukaemic patient who is complete remission. We report here a 39-year-old Chinese man with acute myeloid leukaemia in first complete remission whose unresolved fever after recovery from consolidation therapy-induced neutropenia was ultimately confirmed to be caused by focal hepatic candidal microabscesses by an open liver biopsy.


The Canadian Long-Term Care Sector Collapse from COVID-19: Innovations to Support People in the Workforce.
The COVID-19 pandemic rattled Canada's long-term care (LTC) sector by exacerbating the ingrained systemic and structural issues, resulting in tragic consequences for the residents, family members and LTC staff. At the core of LTC's challenges is chronic under-staffing, leading to lower quality of care for residents and higher degrees of moral distress among staff. A rejuvenation of the LTC sector to support its workforce is overdue. A group of diverse and renowned researchers from across Canada set out to implement innovative evidence-informed solutions in various LTC homes. Their findings call for immediate action from policy makers and LTC decision makers.


Renal adaptation to dietary phosphate restriction in rats. Interactions with insulin and calcitriol.
Insulin may contribute to the increase in tubular reabsorption of phosphate during dietary phosphate restriction. Moreover, insulin is required for the stimulation of calcitriol under this experimental condition. To evaluate whether calcitriol plays a role in the antiphosphaturic effect of insulin during phosphate restriction, phosphate uptake was measured in brush border membrane vesicles (BBMVs) obtained from the following six experimental groups of rats: normal (0.8%)-phosphate diet for 1 wk, low (0.03%)-phosphate diet for 1 wk, normal-phosphate diet for 1 wk and streptozocin 48 h before the experiment, low-phosphate diet for 1 wk and streptozocin 48 h before the experiment, low-phosphate diet and streptozocin and exogenous insulin, and low-phosphate diet and streptozocin and exogenous calcitriol. BBMV phosphate uptake was higher in the nondiabetic rats on a low-phosphate diet than in the controls on a normal-phosphate diet. BBMV phosphate uptake was not different between diabetic rats on a normal-phosphate diet than in nondiabetic controls on the same diet. In contrast, BBMV was significantly lower in diabetic rats on a low-phosphate diet than in nondiabetic controls on the same diet. Exogenous insulin but not calcitriol restored the increase in BBMV phosphate uptake in diabetic rats on a low-phosphate diet. Plasma calcitriol levels were increased threefold in nondiabetic rats fed a low-phosphate diet. Streptozocin-induced diabetes abolished the adaptive increase in plasma calcitriol. Exogenous insulin and calcitriol administration to diabetic rats on a low-phosphate diet resulted in similar increases in plasma calcitriol levels. These results suggest that, during dietary phosphate restriction, insulin stimulates renal phosphate retention independently of its effect on calcitriol.


Effect of enzymes on strawberry volatiles during storage, at different ripeness level, in different cultivars, and during eating.
Strawberry samples with enzyme activity and without enzyme activity (stannous chloride added) were measured for real-time formation of lipoxygenase (LOX) derived aroma compounds after 5 min pureeing using selected ion flow tube-mass spectrometry (SIFT-MS). The concentration of (Z)-3-hexenal and (E)-2-hexenal increased immediately after blending and gradually decreased over time, while hexanal concentration increased for at least 5 min in ground strawberries. The formation of hexanal was slower than the formation of (Z)-3-hexenal and (E)-2-hexenal in the headspace of pureed strawberries. The concentration of LOX aldehydes and esters significantly increased during refrigerated storage. Damaging strawberries increased the concentration of LOX aldehydes but did not significantly affect the concentration of esters. The concentrations of many of the esters were strongly correlated to their corresponded acids and/or aldehydes. The concentration of LOX-generated aldehydes decreased during ripening, while fruity esters increased. Different varieties had different aroma profiles and esters were the greatest percentage of the volatiles. The aroma release of some of the LOX-derived aldehydes in the mouthspace in whole strawberries compared to chopped strawberries showed that these volatiles are formed in the mouth during chewing. The persistence of LOX-derived compounds was higher than esters after swallowing. The mouthspace after and before swallowing persistence ratio of esters decreased as the chain length of the acid part of the ester compounds increased in whole strawberries. The storage studies showed that the concentrations of fruity and fresh volatiles increased during ripening and storage while damaging only increases the fresh volatiles. The nose, mouth, and headspace information can be used in the flavor industry to improve the formula of natural strawberry flavor by considering human perception during eating.


Interaction of irritability and anxiety on emotional responding and emotion regulation: a functional MRI study.
Irritability and anxiety frequently co-occur in pediatric populations. Studies separately looking at the neural correlates of these symptoms have identified engagement of similar neural systems - particularly those implicated in emotional processing. Both irritability and anxiety can be considered negative valence emotional states that might relate to emotion dysregulation. However, previous work has not examined the neural responding during the performance of an emotion regulation task as a function of interaction between irritability and anxiety simultaneously. This fMRI study involved 155 participants (90 with significant psychopathologies and 92 male) who performed the Affective Stroop Task, designed to engage emotion regulation as a function of task demands. The Affective Reactivity Index (ARI) was used to index irritability and the Screen for Child Anxiety Related Emotional Disorders (SCARED) was used to index anxiety. Levels of irritability, but not anxiety, was positively correlated with responses to visual images within the right rostro-medial prefrontal cortex and left anterior cingulate cortex during view trials. The second region of ventral anterior cingulate cortex showed a condition-by-emotion-by-ARI score-by-SCARED score interaction. Specifically, anxiety level was significantly correlated with a decreased differential BOLD response to negative relative to neutral view trials but only in the presence of relatively high irritability. Atypical maintenance of emotional stimuli within the rostro-medial prefrontal cortex may exacerbate the difficulties faced by adolescents with irritability. Moreover, increased anxiety combined with significant irritability may disrupt an automatic emotional conflict-based form of emotion regulation that is particularly associated with the ventral anterior cingulate cortex.


Caudate blood flow and volume are reduced in HIV+ neurocognitively impaired patients.
To evaluate the effects of HIV-associated neurocognitive impairment on caudate blood flow and volume. The authors performed continuous arterial spin labeled MRI on 42 HIV+ patients (23 subsyndromic and 19 HIV neurosymptomatic) on highly active antiretroviral therapy and 17 seronegative controls. They compared caudate blood flow and volume among groups. A stepwise decrease in both caudate blood flow and volume was observed with increasing HIV-associated neurocognitive impairment. Compared with seronegative controls, baseline caudate blood flow was reduced in HIV+ neurosymptomatic patients (p = 0.001) with a similar decreasing trend for subsyndromic HIV+ patients (p = 0.070). Differences in caudate volume were observed only for neurosymptomatic HIV+ patients compared with controls (p = 0.010). A Jonckheere-Terpstra test for trends was significant for both caudate blood flow and volume for each of the three subgroups. Pearson product moment correlation coefficients were not significant between caudate blood flow and volume for each group. Decreasing trends in caudate blood flow and volume were associated with significantly increasing HIV-associated neurocognitive impairment (HNCI), with the greatest decreases observed for more severely impaired patients. However, reductions in caudate blood flow and volume were poorly correlated. Changes in residual caudate blood flow may act as a surrogate biomarker for classifying the degree of HNCI.


Effects of Apis mellifera propolis on the activities of streptococcal glucosyltransferases in solution and adsorbed onto saliva-coated hydroxyapatite.
Propolis, a resinous hive product collected by Apis mellifera bees, has been used for thousands of years in folk medicine. Ethanolic extracts of propolis (EEP) have been shown to inhibit the activity of a mixture of crude glucosyltransferase (Gtf) enzymes in solution. These enzymes synthesize glucans from sucrose, which are important for the formation of pathogenic dental plaque. In the present study, the effects of propolis from two different regions of Brazil on the activity of separate, purified Gtf enzymes in solution and on the surface of saliva-coated hydroxyapatite (sHA) beads were evaluated. The EEP from Minas Gerais (MG; Southeastern Brazil) and Rio Grande do Sul (RS; Southern Brazil) were tested for their ability to inhibit the enzymes GtfB (synthesis of insoluble glucan), GtfC (insoluble/soluble glucan) and GtfD (soluble glucan). The effects of propolis on Gtf from Streptococcus sanguis (soluble glucan synthesis) was also explored. The EEP from both regions effectively inhibited the activity of all Gtfs in solution (75-95%) and on the surface of sHA beads (45-95%) at concentrations between 0.75 and 3.0 mg of propolis/ml. However, the two samples of propolis showed different levels of inhibition on each of the enzymes tested. In general, EEP RS demonstrated a significantly higher inhibitory activity on GtfB and C activities (both solution and surface assays) than EEP MG at concentrations between 0.047 and 0.187 mg/ml (p<0.05). EEP MG, on the other hand, exhibited a greater inhibitory effect on the activities of surface GtfD (at 0.375, 0.75 and 1.5 mg/ml) and S. sanguis Gtf (at 1.5 and 3.0 mg/ml; p<0.05). These data indicate that EEP is a potent inhibitor of Gtf enzymes in solution and adsorbed on an experimental pellicle; however, its effect on Gtf activity is variable depending on the geographical origin of the propolis samples. There is a need to identify the active compounds of propolis.


FAK is required for c-Met/β-catenin-driven hepatocarcinogenesis.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and most patients with HCC have limited treatment options. Focal adhesion kinase (FAK) is overexpressed in many HCC specimens, offering a potential target for HCC treatment. However, the role of FAK in hepatocarcinogenesis remains elusive. Establishing whether FAK expression plays a role in HCC development is necessary to determine whether it is a viable therapeutic target. In this study, we generated mice with hepatocyte-specific deletion of Fak and investigated the role of Fak in an oncogenic (c-MET/β-catenin, MET/CAT)-driven HCC model. We found that deletion of Fak in hepatocytes did not affect morphology, proliferation, or apoptosis. However, Fak deficiency significantly repressed MET/CAT-induced tumor development and prolonged survival of animals with MET/CAT-induced HCC. In mouse livers and HCC cell lines, Fak was activated by MET, which induced the activation of Akt/Erk and up-regulated cyclin D1 and tumor cell proliferation. CAT enhanced MET-stimulated FAK activation and synergistically induced the activation of the AKT/ERK-cyclin D1 signaling pathway in a FAK kinase-dependent manner. In addition, FAK was required for CAT-induced cyclin D1 expression in a kinase-independent fashion. Fak is required for c-Met/β-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC.


[Treatment of purulent wounds using vacuum-therapy].
The results of treatment of complex wounds in 115 patients, in 56 of whom vacuum-therapy was conducted, were analyzed. The duration of a bandage holding constitutes 1 - 3 days at average. The peculiarities of clinical course, the dynamics of the wounds microbic spillage, cellular content in the wounding prints, phagocytic activity and phagocytic number, the phagocytosis completeness index were estimated and calculated. Application of vacuum-therapy have promoted the earlier cleansing and epithelization of the wounds as well as the tissues reparation occurrence and the laboratory indices normalization.


Demodex-Mite Infestation in Cilia and its Association With Ocular Surface Parameters in Japanese Volunteers.
To investigate the presence of Demodex mites on the eyelashes of a Japanese population and to explore its associations with subjective ocular symptoms and clinical ocular surface signs, including lid margin findings and fluorescein breakup time (FBUT). Sixty-three Japanese Tokyo-based volunteers were examined (24 men and 39 women; mean±SD of age, 50.6±15.8 years). Eyelash sampling was performed by epilating three lashes from the center of the right upper eyelid. Eyelashes were tested for Demodex mites with a light microscope. The subjects completed questionnaires to assess subjective symptoms and risk factors for dry eye disease (DED) and underwent general examinations for DED, including FBUT and cornea-conjunctival staining with fluorescein. Meibomian gland function was also investigated in lid margin findings, vascularity and mucocutaneous junction movement, lid irregularity, plugging, pouting, and meibum secretion grade scores. Demodex mites were found in 20.6% (13/63) of the volunteers. Lid margin vascularity and meibum grades in the upper eyelid margins were significantly associated with the presence of Demodex mites. However, there were no significant differences in the diagnosis of meibomian gland dysfunction, FBUT, or ocular surface discomfort between the subjects with or without Demodex mites. Demodex mites are not rare in the cilia of a Japanese population. Lid margin vascularity and lower meibum quality may be associated with the presence of Demodex mites.