The mechanism of cone cell death in Retinitis Pigmentosa.
Retinitis Pigmentosa (RP) is a group of diseases in which one of a large number of mutations causes death of rod photoreceptors. After rods die, cone photoreceptors slowly degenerate in a characteristic pattern. The mechanism of rod cell death varies depending upon the gene that is mutated and the rate that rods degenerate is an important prognostic feature, because cones do not begin to degenerate until almost all rods have been eliminated. Rod cell death causes night blindness, but visual disability and blindness result from cone degeneration and therefore it is critical to determine the mechanisms by which it occurs. The death of rods reduces oxygen consumption resulting in high tissue levels of oxygen in the outer retina. The excess oxygen stimulates superoxide radical production by mismatches in the electron transport chain in mitochondria and by stimulation of NADPH oxidase activity in cytoplasm. The high levels of superoxide radicals overwhelm the antioxidant defense system and generate more reactive species including peroxynitrite which is extremely damaging and difficult to detoxify. This results in progressive oxidative damage in cones which contributes to cone cell death and loss of function because drugs or gene transfer that reduce oxidative stress promote cone survival and maintenance of function. Compared with aqueous humor samples from control patients, those from patients with RP show significant elevation of carbonyl content on proteins indicating oxidative damage and a reduction in the ratio of reduced to oxidized glutathione indicating depletion of a major component of the antioxidant defense system from ongoing oxidative stress. The first step in clinical trials will be to identify doses of therapeutic agents that reverse these biomarkers of disease to assist in design of much longer trials with functional and anatomic endpoints.


Influence of the Angioplasty Revascularization Investigation National Heart, Lung, and Blood Institute Diabetic Clinical Alert on practice patterns: results from the National Cardiovascular Network Database.
In 1995, the Bypass Angioplasty Revascularization Investigation (BARI) found that patients with diabetes had a survival benefit when treated with surgical revascularization versus balloon angioplasty, prompting a National Heart Lung and Blood Institute (NHLBI) "Clinical Alert." The influence of the BARI findings and of the Clinical Alert on practice patterns is unknown. The practice patterns of coronary revascularization among patients with diabetes and multivessel coronary artery disease (CAD) were analyzed using data collected in 1994 to 1997 from 13 centers participating in the National Cardiovascular Network. The study population included patients with diabetes and multivessel CAD who underwent elective coronary revascularization (n=9619). Over the 4 years of the study, the Clinical Alert had no significant impact on the proportion of diabetic patients undergoing percutaneous revascularization (28.6% before versus 26.8% after the Clinical Alert; P=0.06). Among individual hospitals, the probability of diabetic patients receiving percutaneous revascularization varied by >13-fold (4.3% to 56.6%). Adjusting for clinical factors and the BARI Clinical Alert did not alter this variability. Among the investigators surveyed, although 91% were aware of the Clinical Alert and 76% felt the findings were valid, >50% felt the Clinical Alert had limited or no impact on their personal or institution's care patterns. Limited consensus exists regarding the most appropriate method of revascularization for diabetic patients with multivessel CAD. The results from a large, randomized, clinical trial and subsequent Clinical Alert had no measurable impact on this practice variability.


Modified messenger ribonucleic acid release from isolated hepatic nuclei after inhibition of polyadenylate formation.
Treatment of rats with Cordycepin (3'-deoxyadenosine), an inhibitor of nuclear poly(A) synthesis, selectively decreased the energy and cytosol-dependent release of a portion of the mRNA species from the isolated hepatic nuclei in a cell-free system by approximately 40%. An analysis of the differential binding of the transported mRNA containing poly(A) tracts to nitrocellulose filters, and to cellulose or poly(U)-Sepharose columns suggested that the poly(A) tracts in the mRNA transported from the isolated hepatic nuclei of Cordycepin-treated rats, are decreased in size. This size decrease was confirmed through an analysis of the average size of the poly(A) tracts, released from the messengers by ribonuclease activity, on sucrose density gradients.


[Role of the humoral factor and postsynaptic sensitization in heterosynaptic facilitation].
It is shown that heterosynaptic facilitation of the synaptic transmission in the giant neurons of the cerebral ganglion in Planorbis corneus develops due to the diffuse neurohumoral effects on the pre- and postsynaptic structures but not as a result of the local synaptic influences on the presynaptic mechanisms. Using the new biological object it has been confirmed that serotonin from the perfuse solution was a source of the facilitatory action on the n-cholinergic synaptic transmission. It was established that conditioning stimulations facilitated not only the n-cholinergic synaptic transmission but also the ionophoretic acetylcholine potentials. Amplitudes of EPSPs and acetylcholinic potentials increased 4-6 times, while the postsynaptic membrane impedance increased only by 20%. Based on such data it is summarized that sensitization of n-cholinergic receptors of the postsynaptic membrane contributed much to the heterosynaptic facilitation. The possible role of n-cholinergic receptors of the postsynapcit membrane in the processes of the heterosynaptic facilitation and of the conditional training is discussed.


Unusual case of spindle cell sarcoma metastases to right ventricle: a case report and a literature review.
Cardiac metastases from sarcoma are uncommon. Due to their rarity there is not a standard of care. However, complete cardiac metastases resection is the best option but most of patients has widespread disease. In these patients palliative radiotherapy (RT) might improve symptoms and prevent further cardiac function decline. Here we present the case of a symptomatic 30-year-old woman with spindle cell sarcoma metastasis of right ventriculum and widespread disease. The patient received radiotherapy to the heart with palliative intent. Cardiac metastases represent a challenging clinic problem. Treatment should be individualized in a multidisciplinary setting, when possible surgery seems to be the best options. However, radiotherapy even in case of widespread disease can improve clinical control symptoms by reducing the mass effect.


Care management and technology enhance care delivery.
Many health care delivery organizations have experienced a flattening in the rate of their ability to decrease health care costs. Providers--if they are willing to take responsibility for care management and make appropriate investments to support the initiatives--are the logical party to take responsibility for improving care and cost control. Taking responsibility for care management, however, requires the tactical deployment of information technology to enhance care management. This article outlines what is required for information technology to improve care and cut costs.


Dexamethasone after early-life seizures attenuates increased susceptibility to seizures, seizure-induced microglia activation and neuronal injury later in life.
Chronic epilepsy can begin with isolated early-life prolonged seizures followed by remission and the re-emergence of seizures later in life. Seizures are known to trigger a neuroinflammatory response to promote neuronal damage and increase the risk of epilepsy. We examined whether post-seizure anti-inflammatory treatment with dexamethasone after early-life seizures could decrease future seizure susceptibility and ameliorate heightened microglia activation and cell injury in response to later-life seizures. Using a "two-hit" model, early-life seizures (SZ) were induced in rats on postnatal day (P) 25 by systemic kainic acid (KA) injection followed by later-life KA at P39. P25 animals were administered anti-inflammatory drugs for 2 or 7 days after first KA exposure to inhibit seizure-induced inflammation. Hippocampal microglial activation was measured after first or second KA treatments to assay neuroinflammation, and the latency and severity of seizures to the second KA treatment were measured to determine seizure susceptibility. In situ end labeling for DNA fragmentation was used to compare KA-induced neuronal injury between treatment groups after the second KA administration. KA-SZ at P25 caused marked microglia activation within 48 hours. At P39, KA-SZ in rats without prior seizures caused a modest (2-fold) increase in microglia assayed 72 hours after KA. In contrast, microglia were markedly activated (5-fold) in response to a second KA-SZ at P39. Short-course (2 days) dexamethasone significantly decreased seizure-induced microglia activation at P25, and ameliorated the exaggerated microglia activation, cell injury, and heightened susceptibility to second-hit seizures. Although short-course dexamethasone was effective, longer term (7 days) administration of dexamethasone resulted in decreased weight gain and increased mortality in animals with or without KA-induced seizures. These data indicated that acute short-term steroid therapy after SZ could inhibit seizure-induced microglia activation and decrease the long-term damaging effects of early-life SZ. These results further implicate seizure-induced inflammation and activation of innate immunity mediated by microglia in the pathogenesis of childhood epilepsy.


Evolution of a course in veterinary clinical pathology: the application of case-based writing assignments to focus on skill development and facilitation of learning.
To encourage application and critical thinking, case-based writing assignments and grading rubrics were developed for use in a second-year core clinical pathology course. Objectives were to describe how this teaching technique was adapted to a large-class setting and how student perceptions of the learning experience guided modifications of this teaching technique over two presentations of the course and plans for a third presentation. Our goal was to enhance learning by encouraging application of course material to clinical situations and thereby improve students' ability to organize and communicate information. Furthermore, we evaluated the influence of instructor feedback on the learning process. With assistance from the University of Minnesota Center for Writing, assignments and grading rubrics were developed. Students completed course evaluation surveys designed to elicit feedback on the impact of the assignments. Increased learner confidence was reflected in larger self-reported increases in understanding of the material and ability to apply information and in increased feelings of preparedness for class and examinations. A large majority of students advocated the use of such assignments in the course in future years, and modifications to make grading and evaluation of assignments more efficient are underway. Investment of faculty and student time in case-based writing assignments in the veterinary clinical pathology curriculum appears to increase student engagement with material and learner confidence. Future studies should address the impact of this type of assignment more specifically on clinical reasoning and communication skills and on long-term retention of material.


The Reporting and Methodological Quality of Systematic Reviews Underpinning Clinical Practice Guidelines Focused on the Management of Cutaneous Melanoma: Cross-Sectional Analysis.
Clinical practice guidelines (CPGs) inform evidence-based decision-making in the clinical setting; however, systematic reviews (SRs) that inform these CPGs may vary in terms of reporting and methodological quality, which affects confidence in summary effect estimates. Our objective was to appraise the methodological and reporting quality of the SRs used in CPGs for cutaneous melanoma and evaluate differences in these outcomes between Cochrane and non-Cochrane reviews. We conducted a cross-sectional analysis by searching PubMed for cutaneous melanoma guidelines published between January 1, 2015, and May 21, 2021. Next, we extracted SRs composing these guidelines and appraised their reporting and methodological rigor using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklists. Lastly, we compared these outcomes between Cochrane and non-Cochrane SRs. All screening and data extraction occurred in a masked, duplicate fashion. Of the SRs appraised, the mean completion rate was 66.5% (SD 12.29%) for the PRISMA checklist and 44.5% (SD 21.05%) for AMSTAR. The majority of SRs (19/50, 53%) were of critically low methodological quality, with no SRs being appraised as high quality. There was a statistically significant association (P<.001) between AMSTAR and PRISMA checklists. Cochrane SRs had higher PRISMA mean completion rates and higher methodological quality than non-Cochrane SRs. SRs supporting CPGs focused on the management of cutaneous melanoma vary in reporting and methodological quality, with the majority of SRs being of low quality. Increasing adherence to PRISMA and AMSTAR checklists will likely increase the quality of SRs, thereby increasing the level of evidence supporting cutaneous melanoma CPGs.


Relationship of mindful awareness to neural processing of angry faces and impact of mindfulness training: A pilot investigation.
Mindfulness is paying attention, non-judgmentally, to experience in the moment. Mindfulness training reduces depression and anxiety and influences neural processes in midline self-referential and lateralized somatosensory and executive networks. Although mindfulness benefits emotion regulation, less is known about its relationship to anger and the corresponding neural correlates. This study examined the relationship of mindful awareness and brain hemodynamics of angry face processing, and the impact of mindfulness training. Eighteen healthy volunteers completed an angry face processing fMRI paradigm and measurement of mindfulness and anger traits. Ten of these participants were recruited from a Mindfulness-Based Stress Reduction (MBSR) class and also completed imaging and other assessments post-training. Self-reported mindful awareness increased after MBSR, but trait anger did not change. Baseline mindful awareness was negatively related to left inferior parietal lobule activation to angry faces; trait anger was positively related to right middle frontal gyrus and bilateral angular gyrus. No significant pre-post changes in angry face processing were found, but changes in trait mindful awareness and anger were associated with sub-threshold differences in paralimbic activation. These preliminary and hypothesis-generating findings, suggest the analysis of possible impact of mindfulness training on anger may begin with individual differences in angry face processing.


Impact of Participatory Design for Drug-Drug Interaction Alerts. A Comparison Study Between Two Interfaces.
Decision support systems for alert drug-drug interactions have been shown as valid strategy to reduce medical error. Even so the use of these systems has not been as expected, probably due to the lack of a suitable design. This study compares two interfaces, one of them developed using participatory design techniques (based on user centered design processes). This work showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction with the system.


Two-stage crystallization of charged colloids under low supersaturation conditions.
We report simulations on the homogeneous liquid-fcc nucleation of charged colloids for both low and high contact energy values. As a precursor for crystal formation, we observe increased local order at the position where the crystal will form, but no correlations with the local density. Thus, the nucleation is driven by order fluctuations rather than density fluctuations. Our results also show that the transition involves two stages in both cases, first a transition of liquid → bcc, followed by a bcc → hcp/fcc transition. Both transitions have to overcome free energy barriers, so that a spherical bcc-like cluster is formed first, in which the final fcc structure is nucleated mainly at the surface of the crystallite. This means that the second stage bcc-fcc phase transition is a heterogeneous nucleation in the partially grown solid phase, even though we start from a homogeneous bulk liquid. The height of the bcc → hcp/fcc free energy barrier strongly depends on the contact energies of the colloids. For low contact energy this barrier is low, so that the bcc → hcp/fcc transition occurs spontaneously. For the higher contact energy, the second barrier is too high to be crossed spontaneously by the colloidal system. However, it was possible to ratchet the system over the second barrier and to transform the bcc nuclei into the stable hcp/fcc phase. The transitions are dominated by the first liquid-bcc transition and can be described by classical nucleation theory using an effective surface tension.


Efficacy of the Fast Track Friendship Group Program for Peer-rejected Children: A Randomized-Controlled Trial.
To evaluate the benefits of the Fast Track Friendship Group program implemented as a stand-alone school-based intervention on the social cognitions, social behavior, peer and teacher relationships of peer-rejected students. Over four successive years, 224 peer-rejected elementary students (57% White, 17% Black, 20% Latinx, 5% multiracial; 68% male; grades 1-4; Mage = 8.1 years old) were identified using peer sociometric nominations and randomly assigned to the intervention (n = 110) or a treatment-as-usual control group (n = 114). Four school districts serving economically-disadvantaged urban and rural communities participated. Intervention involved weekly small group social skills training with classmate partners, with sessions tailored to address individual child needs. Consultation meetings held at the start and mid-point of intervention were designed to help teachers and parents support the generalization of targeted skills. Multi-level linear models, with children nested within schools (controlling for demographics and baseline scores) documented improvements in social-cognitive skills (direct assessments of emotion recognition and competent social problem-solving), social behavior (teacher ratings of social skills and externalizing behavior), and interpersonal relationships (peer sociometric nominations of peer acceptance and friendships, teacher-rated student-teacher closeness). Significant effects were generally small (ds = .19-.36) but consistent across child sex, grade level, and behavioral characteristics. The intervention proved feasible for high-fidelity implementation in school settings and produced significant improvements in the social adjustment of peer-rejected children, validating the approach as a school-based Tier 2 intervention.


The codevelopment of community involvement and generative concern pathways in emerging and young adulthood.
In this longitudinal Canadian study, we investigated the relationship between the developmental trajectories of community involvement and generative concern measured at ages 23, 26, and 32. Participants completed a questionnaire on youth involvement, the Youth Involvement Inventory (YII), and the Loyola Generativity Scale (LGS) at all 3 ages. A latent growth model (LGM) of community involvement predicting time-specific variance in the LGS revealed that: (a) higher levels of community involvement at age 23 predicted greater generative concern at ages 23 and 26, but not at age 32; (b) there were 3 specific indirect paths linking age 23 community involvement to age 32 generativity through earlier assessments of age 23 and age 26 generative concern; and finally (c) a more positive slope of community involvement over time predicted higher levels of generative concern at age 32. These findings suggest that early involvement in community commitments, and increases in community involvement across emerging adulthood, may lead individuals down a path toward a more generative personality in young adulthood. (PsycINFO Database Record


Patients' perspectives of bedside nursing handover.
Patient participation in handover is one aspect of patient-centred care, where patients are considered partners in care. Understanding the patient perspective provides a foundation for nurses to tailor their bedside handovers to reflect patients' thoughts and beliefs and encourage their active involvement in decision-making. This study examined patients' perspectives of participation in shift-to-shift bedside nursing handover. A descriptive case study was conducted with 10 patients in one Queensland hospital who had experienced bedside handover during their hospitalisation in 2009. Participants were asked their views about bedside handover including its benefits and limitations, their existing and potential role in handover, the role of family members, and issues related to confidentiality. Data were analysed using thematic content analysis. Four themes emerged from the analysis. First, patients appreciated being acknowledged as partners in their care. Second, they viewed bedside handover as an opportunity to amend any inaccuracies in the information being communicated. Third, some preferred passive engagement rather than being fully engaged in the handover. Fourth, most patients appreciated the inclusive approach of handover as nurse-patient interaction. Bedside handover provides an opportunity for patients to be involved as active participants in their care. They value having access to information on an ongoing basis, and although not all choose the same level of interaction, they see their role as important in maintaining accuracy, which promotes safe, high quality care.


Impact of B-type natriuretic peptide (BNP) on development of atrial fibrillation in people with Type 2 diabetes.
To examine if a simple biomarker can identify people with diabetes who are at high risk of atrial fibrillation. A retrospective cohort study was conducted at a single centre in people with Type 2 diabetes referred to our department between January 2000 and December 2007. In 517 consecutive people without any history, signs or symptoms of atrial fibrillation at baseline, the association between baseline B-type natriuretic peptide level and future atrial fibrillation incidence was examined, with adjustments for other potentially confounding factors. A total of 28 people were diagnosed with new-onset atrial fibrillation during a median 6-year follow-up. When people were categorized into three groups according to B-type natriuretic peptide clinical thresholds (20 and 100 pg/ml), hazard ratios for the development of atrial fibrillation in the middle and highest B-type natriuretic peptide groups were 2.8 and 9.4, respectively, compared with the lowest B-type natriuretic peptide group. Time-dependent receiver-operating curve analysis identified a threshold for B-type natriuretic peptide to detect atrial fibrillation development of 52.8 pg/ml (sensitivity 75.2%, specificity 68.8%). The B-type natriuretic peptide predictive value was independent of and similar to that of left atrial size and ventricular dimension. In people with Type 2 diabetes, high baseline B-type natriuretic peptide levels were significantly associated with future atrial fibrillation development.


Long-term memory requires polyADP-ribosylation.
PolyADP-ribose-polymerase 1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because polyADP-ribosylation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells, it is surprising that activation of the polymerase occurs during learning and is required for long-term memory. We suggest that fast and transient decondensation of chromatin structure by polyADP-ribosylation enables the transcription needed to form long-term memory without strand breaks in DNA.


Defining the conditions for the development of the emerging class of FeIII-based MRI contrast agents.
Fe(iii) complexes are attracting growing interest in chemists developing diagnostic probes for Magnetic Resonance Imaging because they leverage on an endogenous metal and show superior stability. However, in this case a detailed understanding of the relationship between the chemical structure of the complexes, their magnetic, thermodynamic, kinetic and redox properties and the molecular parameters governing the efficacy (relaxivity) is still far from being available. We have carried out an integrated 1H and 17O NMR relaxometric study as a function of temperature and magnetic field, on the aqua ion and three complexes chosen as reference models, together with theoretical calculations, to obtain accurate values of the parameters that control their relaxivity. Moreover, thermodynamic stability and dissociation kinetics of the Fe(iii) chelates, measured in association with the ascorbate reduction behaviour, highlight their role and mutual influence in achieving the stability required for use in vivo.


The relationship between dietary lipids and serum visfatin and adiponectin levels in postmenopausal women.
Cardiovascular diseases (CVD) are the leading cause of death in humans, particularly in postmenopausal women. Inflammation has been shown to play a basic role in the development of CVD. In light of the involvement of adipocytokines and dietary lipids in the induction of inflammation in CVD, this study was conducted to investigate the potential relationship between dietary lipids and two well-known adipocytokines, visfatin and adiponectin. A total of 374 postmenopausal women were randomly selected from 13 geographical clusters in Bushehr port. Serum visfatin and adiponectin were determined with an enzyme-linked immunosorbant assay technique and current dietary intake was recorded with a food frequency questionnaire and a 3-day recall. Each food and beverage was analyzed for macro- and micronutrient content. Bivariate correlation analysis showed a correlation between serum visfatin level and dietary SFA, n-6 PUFA and cholesterol intake. In multiple regression analyses, serum visfatin levels showed a significant positive correlation with dietary SFA (β=0.06, p=0.01), PUFA (β=0.02, p=0.02) and cholesterol (β=0.005, p=0.002) after controlling for age, diabetes, total energy intake and BMI. There was no significant relationship between dietary MUFA intake and serum visfatin level. No significant correlations were found between age- and BMI-adjusted adiponectin and dietary SFA, MUFA or n-6 PUFA intake (p>0.05). We found a positive relationship between dietary SFA, PUFA and cholesterol with serum visfatin level in postmenopausal women, and conclude that the postmenopause-induced inflammatory responses may be modulated at least in part by dietary modification.


[Experimental evaluation of efficiency of bioprophylactic complex aimed at reduction of toxic effects caused by copper oxide nanoparticles].
In subchronic intoxication via repeated intraperitoneal injection of copper oxide nanoparticles (diameter 20 nm, 19 times in dose of 10 mg/kg of rats, 3 times per week), findings are that oral intake of bioprotectors complex (pectine, polyvitamin and polymineral preparation, sodium glutaminate, glycine, acetylcysteine and fish oil preparation with high content of unsaturated fatty acids of omega-3 group) decreases copper accumulation in viscera (including statistically significantly in spleen) and slows development of pathologic changes in liver, brain and kidneys. With that, genotoxic effect of nanocopper also decreases--according to lower fragmentation of genome DNA in liver and spleen cells.


Preoperative Prediction of Lymph Node Metastasis in Patients With Early-T-Stage Non-small Cell Lung Cancer by Machine Learning Algorithms.
Background: Lymph node metastasis (LNM) is difficult to precisely predict before surgery in patients with early-T-stage non-small cell lung cancer (NSCLC). This study aimed to develop machine learning (ML)-based predictive models for LNM. Methods: Clinical characteristics and imaging features were retrospectively collected from 1,102 NSCLC ≤ 2 cm patients. A total of 23 variables were included to develop predictive models for LNM by multiple ML algorithms. The models were evaluated by the receiver operating characteristic (ROC) curve for predictive performance and decision curve analysis (DCA) for clinical values. A feature selection approach was used to identify optimal predictive factors. Results: The areas under the ROC curve (AUCs) of the 8 models ranged from 0.784 to 0.899. Some ML-based models performed better than models using conventional statistical methods in both ROC curves and decision curves. The random forest classifier (RFC) model with 9 variables introduced was identified as the best predictive model. The feature selection indicated the top five predictors were tumor size, imaging density, carcinoembryonic antigen (CEA), maximal standardized uptake value (SUVmax), and age. Conclusions: By incorporating clinical characteristics and radiographical features, it is feasible to develop ML-based models for the preoperative prediction of LNM in early-T-stage NSCLC, and the RFC model performed best.


The development and validation of the Perceived Health Competence Scale.
A sense of competence or self-efficacy is associated with many positive outcomes, particularly in the area of health behavior. A measure of a sense of competence in the domain of health behavior has not been developed. Most measures are either general measures of a general sense of self-efficacy or are very specific to a particular health behavior. The Perceived Health Competence Scale (PHCS), a domain-specific measure of the degree to which an individual feels capable of effectively managing his or her health outcomes, was developed to provide a measure of perceived competence at an intermediate level of specificity. Five studies using three different types of samples (students, adults and persons with a chronic illness) provide evidence for the reliability and validity of the PHCS. The eight items of the PHCS combine both outcome and behavioral expectancies. Results from the five studies indicate that the scale has good internal consistency and test-retest reliability. The construct validity of the scale is demonstrated through the support obtained for substantive hypotheses regarding the correlates of perceived health competence, such as health behavior intentions, general sense of competence and health locus of control.


The contribution of active play to the physical activity of primary school children.
To examine associations between active play and the physical activity of 10- to 11-year-old children. Cross-sectional study of 747, 10- tot11-year-olds, conducted between February 2008 and March 2009 in Bristol, UK. Mean minutes of moderate to vigorous physical activity (MVPA) and mean activity levels (counts per minute, CPM) were assessed by accelerometer. Frequency of active play was self-reported. Regression models indicated that frequent active play (5 or more days per week) was associated with mean daily activity levels (CPM) (girls: p=<0.01; boys: p=<0.01), but was only associated with mean daily MVPA for girls (p=<0.01). For leisure-time physical activity, active play was associated with children's CPM (girls: p=0.02; boys: p=<0.01) and MVPA (girls: p=<0.01; boys: p=0.03) on weekdays after school, but was only associated with weekend day CPM for boys (p=<0.01). Active play is associated with children's physical activity with after-school potentially being a critical period. Strategies to promote active play may prove to be a successful means of increasing children's physical activity.


Accumulation of rab4GTP in the cytoplasm and association with the peptidyl-prolyl isomerase pin1 during mitosis.
Transport through the endocytic pathway is inhibited during mitosis. The mechanism responsible for this inhibition is not understood. Rab4 might be one of the proteins involved as it regulates transport through early endosomes, is phosphorylated by p34(cdc2) kinase, and is translocated from early endosomes to the cytoplasm during mitosis. We investigated the perturbation of the rab4 GTPase cycle during mitosis. Newly synthesized rab4 was less efficiently targeted to membranes during mitosis. By subcellular fractionation of mitotic cells, we found a large increase of cytosolic rab4 in the active GTP-form, an increase not associated with the cytosolic rabGDP chaperone GDI. Instead, phosphorylated rab4 is in a complex with the peptidyl-prolyl isomerase Pin1 during mitosis, but not during interphase. Our results show that less efficient recruitment of rab4 to membranes and a bypass of the normal GDI-mediated retrieval of rab4GDP from early endosomes reduce the amount of rab4GTP on membranes during mitosis. We propose that phosphorylation of rab4 inhibits both the recruitment of rab4 effector proteins to early endosomes and the docking of rab4-containing transport vesicles. This mechanism might contribute to the inhibition of endocytic membrane transport during mitosis.


Scores on the dietary guideline index for children and adolescents are associated with nutrient intake and socio-economic position but not adiposity.
Diet quality indices reflect overall dietary patterns better than single nutrients or food groups. The study aims were to develop a measure of adherence with dietary guidelines applicable to child and adolescent populations in Australia and determine the association between index scores and food and nutrient intake, socio-demographic characteristics, and measures of adiposity. Data were analyzed from 4- to 16-y-old participants of the 2007 Australian Children's Nutrition and Physical Activity Survey (n = 3416). The Dietary Guideline Index for Children and Adolescents (DGI-CA) comprises 11 components: 5 core food groups, wholegrain bread, reduced-fat dairy foods, extra foods (nutrient poor and high in fat, salt, and added sugar), healthy fats/oils, water, and diet variety (possible score of 100). The index criteria were age specific. The mean DGI-CA score was low (53.6 ± 0.4), similar between boys and girls, and differed by age; the youngest children scored higher than the oldest children (P < 0.0001). Higher DGI-CA scores were associated with lower energy intake, energy density, total and saturated fat, and sugar intake; higher protein, carbohydrate, fiber, calcium, iron, vitamin C, vitamin A, folate, phosphorous, magnesium, zinc, and iodine intakes; and a higher polyunsaturated:saturated fat ratio (P < 0.0001). DGI-CA scores were associated with socio-economic characteristics and measures of family circumstance. Weak positive associations were observed between DGI-CA score and BMI or waist circumference Z-scores in the 4- to 10-y and 12- to 16-y age groups only. This index is the first validated index in Australia and one of the few international indices to describe the diet quality of children and adolescents.


[Prevalence of cognitive decline in people older than 70 years admitted in an internal medicine service].
Cognitive decline in older people is an important cause of burden for caregivers and assistance staff. It is a poor prognosis marker that favors the onset of different geriatric syndromes and increases the risk of institutionalization. As some causes of cognitive decline can be treated, its early diagnosis is fundamental for patients and caregivers. This, help us to design a care plan and a future follow up. The objective of this article is to measure the prevalence of Cognitive Decline before the onset of the acute disease that led patients older than 70 years, to an admission at the Internal Medicine Service. A prospective randomized study was performed in the Internal Medicine Service of the Hospital de Mataro, which included 100 patients older than 70 years. Presence of Cognitive Decline was evaluated through the Blessed Scale during the previous month of the onset of the disease that motivated the admission. 43% of the patients had Cognitive Decline (42% male and 44% female). The prevalence of CD in patients older than 80 years was over 60%. Many of the admitted patients of an Internal Medicine Service older than 70 years had criteria for Cognitive Decline before the onset of the acute disease. Its diagnosis, study and therapeutic plan before the patient's discharge is a great opportunity to improve the quality of assistance.


[Clinical and experimental study on treatment of chronic hepatitis B with yanggan aoping mixture].
To assess the efficacy of Yanggan Aoping Mixture (YGAPM) in treating hepatitis B. Patients suffered from chronic hepatitis B were treated with YGAPM. Observe their short- and long-term efficacy and the change of serum hepatitis B virus marker. In experiment, the effect of YGAPM in treating rat's liver injury as well as HBV-infected tree shrew and duck HBV-infected ducks was observed. In 79 cases of chronic persistant hepatitis, the markedly effective rate was 60.76%, and follow-up studies on 40 cases, the further rasied to 70.00%. In 73 cases of chronic active hepatitis, the markedly effective rate was 60.27%, and further raised to 62.50% in 32 follow-up cases. In the treatment group, 85 (71.43%) of the 119 cases with HBeAg-positive turned to negative. Whereas in the control group, only 40 (44.94%) of 89 HBeAg-positive cases turned to negative, P < 0.01. Results of experimental study showed that negative conversion rate of tree shrew infected with HBV marker was raised, while infected duck blood with duck HBV DNA was inhibited. Those compared with the control group separately, the difference was remarkably significant. YGAPM is an effective drug in treating chronic hepatitis B, and it could effectively negative convert the HBV marker.


Vibrational energy dynamics of normal and deuterated liquid benzene.
Ultrafast Raman spectroscopy with infrared (IR) excitation is used to study vibrational energy dynamics of ambient temperature liquids benzene and benzene-d(6). After IR pumping of a CH-stretch or CD-stretch parent excitation, the redistribution of vibrational energy is probed with anti-Stokes Raman. Ten benzene or 12 benzene-d(6) vibrations out of 30 total have large enough cross sections to be observed. The pathways, quantum yields, and lifetimes for energy transfer among these vibrations are quantified. Using a CCl(4) molecular thermometer, we demonstrate an ultrafast Raman calorimetry method which allows measurement of the rate that benzene vibrational energy is dissipated into the bath. On the basis of energy conservation, we then determine the time-dependent dissipation of aggregate vibrational energy from the unobserved, "invisible" vibrations. During the approximately 1 ps IR excitation process, vibrational energy is coherently redistributed to several vibrational modes ("coherently" means the rate is faster than (T(2))(-1) of the pumped transition). This energy is then further redistributed in an incoherent intramolecular vibrational relaxation process with a 6 ps T(1) time constant. The subsequent dynamics involve energy transfer processes accompanied by vibrational energy dissipation to the bath. This vibrational cooling process has a half-life of 30 ps in benzene and 20 ps in benzene-d(6), and thermalization is complete in approximately 100 ps. The observed strongly Raman-active vibrations have about the same amount of energy per mode as the invisible vibrations. The invisible vibrational energy in benzene decays somewhat faster than the observed energy. These two decay rates are about the same in benzene-d(6).


Digoxin therapy for cor pulmonale: A systematic review.
Right heart failure is associated with increased mortality and morbidity. The optimal treatment for patients with RV failure is not established. The aim of this study is to conduct a systematic review of the literature to assess the relative benefits and harms of digoxin therapy in patients with RV failure. We performed a literature search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) on Nov. 4, 2014. We did not use publication type, period or language restrictions to the search strategy. Exclusions included: trials that excluded patients with RV failure, included patients requiring mechanical or intravenous inotropic support, review papers and case reports. The primary outcome was long-term efficacy outcomes of digoxin in right heart failure. Two reviewers screened titles and abstracts of identified citations independently and in duplication using calibration exercises and standardized screening forms. The search strategy identified 4097 citations, and 4 studies were included in this analysis (n=76 patients). Of the four studies, two assessed improvements in RVEF, two studies compared exercise capacity indexes, and one assessed symptoms with digoxin compared with placebo. No study assessed mortality outcomes. Overall, there was no statistically significant improvement in RVEF, exercise capacity, NYHA class, heart failure score, or body weight. There are few studies evaluating Digitalis use for RV failure, which are limited to patients with cor pulmonale. In these patients, Digitalis use provides no improvement in RVEF, exercise capacity, or NYHA class. Randomized clinical trials are needed to address this question.


[Isolation of the ribosomal fraction of Staphylococcus aureus and its physico-chemical characterization].
The preparations of staphylococcal ribosomes, pure and homogenous in their chemical composition, have been obtained by differential centrifugation of the cytoplasm. These preparations have been found to consist mainly of RNA and protein in the ratio 1.5:1. The characteristic feature of ribosomes has proved to be the presence of one symmetrical peak in centrifugation in sucrose density gradient and the relation of the optical density values at 260 nm and 280 nm equal to 2, which is peculiar only to purified ribosomes.


An In Vitro Study of the Number of Distal Roots and Canals in mandibular First Molars in Iranian Population.
The purpose of this study was to evaluate the number of distal roots and canals in mandibular first molars and their internal anatomy radiographically within Iranian population. A total of 310 distal roots of mandibular first molars were incorporated in this study and evaluated in terms of number of roots and number and types of canals. Root canal systems were studied in vitro by means of radiography and based on Vertucci's classifications. It was shown that 4.5% of the teeth in this study had two distal roots, of which, 100% indicated type I for both distobuccal and distolingual roots. Among all the teeth, 43.2% had two canals, 24.2% two apical foramina, and 38.7% two orifices in their distal roots. According to Vertucci's classification 54.9% of the teeth were type I, 19% type II, 1.9% type III, 14.2% type IV, 4.2% type V, 1% type VI, 0.3% type VII and 0% type VIII. In as many as 43.2% of all teeth assessed in this study, bicanaled distal roots were observed, dentists are always recommended to search for the second canal in distal roots of mandibular first molars. In case the second canal in the distal root is missed, failure of endodontic treatment will be anticipated. A rectangular type access cavity design allows better visualization and negotiation of the probable second canals within the distal roots of mandibular first molars.


Microbial organic fertilizer prepared by co-composting of Trichoderma dregs mitigates dissemination of resistance, virulence genes, and bacterial pathogens in soil and rhizosphere.
The use of manure, mycelium dregs and other waste as organic fertilizer is the main source of antibiotic resistance genes (ARGs) and pathogens in farmland. Composting of waste may effectively remove ARGs and pathogens. However, the profiles and drivers of changes in metal resistance genes (MRGs), biocide resistance genes (BRGs), and virulence genes (VGs) in soil-crop rhizosphere systems after compost application remain largely unknown. Here, we prepared two kinds of microbial organic fertilizers (MOF) by using Trichoderma dregs (TDs) and organic fertilizer mixing method (MOF1) and TDs co-composting method (MOF2). The effects of different types and doses of MOF on resistance genes, VGs and pathogens in soil-rhizosphere system and their potential mechanisms were studied. The results showed that co-composting of TDs promoted the decomposition of organic carbon and decreased the absolute abundance of ARGs and mobile genetic elements (MGEs) by 53.4-65.0%. MOF1 application significantly increased the abundance and diversity of soil ARGs, BRGs, and VGs, while low and medium doses of MOF2 significantly decreased their abundance and diversity in soil and rhizosphere. Patterns of positive co-occurrence between MGEs and VGs/MRGs/BRGs/ARGs were observed through statistical analysis and gene arrangements. ARGs/MRGs reductions in MOF2 soil were directly driven by weakened horizontal gene transfer triggered by MGEs. Furthermore, MOF2 reduced soil BRGs/VGs levels by shifting bacterial communities (e.g., reduced bacterial host) or improving soil property. Our study provided new insights into the rational use of waste to minimize the spread of resistomes and VGs in soil.


Proposal of a polarization-insensitive echelle grating demultiplexer based on a nanophotonic silicon-on-insulator platform through a dual-grating system.
In this Letter, we demonstrate theoretically the design of a polarization-insensitive echelle grating demultiplexer on a nanophotonic silicon-on-insulator platform. The polarization-insensitive performance is achieved through a dual-grating system, which utilizes different concave gratings for different polarizations. The first concave grating acts as a polarization to beam splitter as well, allowing light with the other polarization to pass through and be reflected by the second grating, which is designed separately; thus the same spectral responses are obtained for the two polarizations.


Expression of NANOG and NANOGP8 in a variety of undifferentiated and differentiated human cells.
The transcription factor NANOG is essential for maintaining pluripotency in embryonic stem cells. We have previously reported the expression of NANOG in adult human fibroblasts; here we present a more thorough investigation into the expression of NANOG in a panel of both differentiated and undifferentiated human cells. We utilize RT-PCR, qRT-PCR, cloning and sequencing, sequence alignment, restriction digestion, immunocytochemistry, Western blotting, and EMSA to investigate expression of NANOG in a variety of somatic, transformed and stem cell phenotypes. RT-PCR and qRT-PCR analysis revealed the presence of NANOG transcripts in all the cell types examined, albeit at magnitudes lower than human embryonic stem cells. Further investigation by single nucleotide polymorphism analysis of expressed transcripts in several cell types detected a NANOG pseudogene, NANOGP8, one of only two NANOG pseudogenes with the potential of encoding a similar size protein to embryonic NANOG (eNANOG). Our analysis demonstrates that although the NANOG protein is detected in nearly all cells examined, expression of the eNANOG and/or NANOGP8 transcript as well as the sub-cellular localization of the protein is cell type-specific. Additionally, smooth muscle cells, which express exclusively NANOGP8, display nuclear localization of NANOG protein, indicating that NANOGP8 is a protein coding gene possibly functioning as a transcription factor. Lastly, all cell types expressing eNANOG and/or NANOGP8 were found to be capable of binding a NANOG consensus sequence in vitro. We conclude that eNANOG is not exclusively expressed in undifferentiated cells and that both eNANOG and NANOGP8 may function as transcription factors in a cell type-specific manner.


Children With Dyslexia and Typical Readers: Sex-Based Choline Differences Revealed Using Proton Magnetic Resonance Spectroscopy Acquired Within Anterior Cingulate Cortex.
Children with dyslexia exhibit slow and inaccurate reading, as well as problems in executive functions. Decreased signal activation in brain regions related to visual processing and executive functions has been observed with functional magnetic resonance imaging with reports of sex differences in brain patterns for visual processing regions. However, the underlying neurochemistry associated with deficits in executive functions for children with dyslexia has not been thoroughly evaluated. Reading ability and executive functions were assessed in fifty-three children [ages 8-12 years old, dyslexia (n = 24), and typical readers (n = 30)]. We employed short echo, single voxel, proton magnetic resonance spectroscopy to evaluate the perigenual anterior cingulate cortex (ACC). Pearson correlations were calculated between metabolite concentrations and measures of reading, processing speed, and executive function. Logistic regression models were used to determine the effects of brain metabolite concentrations, processing speed, and reading scores on dyslexia status. Differences by child's sex were also examined. Compared to typical readers, higher global executive composite t-score is associated with greater odds for dyslexia (OR 1.14; 95% CI 1.05, 1.23); increased processing speed appears to be protective for dyslexia (OR 0.95; 95% 0.89-1.00). After adjustment for multiple comparisons, females with dyslexia showed strong and significant negative correlations between processing speed and myo-inositol (r = -0.55, p = 0.005) and choline (r = -0.54, p = 0.005) concentrations; effect modification by sex was confirmed in linear regression models (psex∗Cho = 0.0006) and (psex∗mI = 0.01). These associations were not observed for males or the group as a whole. These findings suggest that children with dyslexia share difficulty in one or more areas of executive function, specifically those related to response time. Also, metabolite changes in the ACC may be present in children with dyslexia, especially for females, and may hold value as possible markers for dyslexia.


Overview of clinical use and side effect profile of valsartan in Chinese hypertensive patients.
We reviewed the Chinese and English literature for the efficacy and safety data of valsartan monotherapy or combination therapy in Chinese hypertensive patients. According to the data of ten randomized controlled trials, valsartan monotherapy was as efficacious as another angiotensin receptor blocker or other classes of antihypertensive drugs, excepting the slightly inferior diastolic blood pressure-lowering effect in comparison with calcium channel blockers. According to the data of six randomized controlled trials, valsartan combination, with hydrochlorothiazide, amlodipine, or nifedipine gastrointestinal therapeutic system, was more efficacious than monotherapy of valsartan, amlodipine, or nifedipine gastrointestinal therapeutic system. According to these trials, valsartan had an acceptable tolerability, regardless of whether it was used as monotherapy or in combination therapy. Nonetheless, several rare side effects have been reported, indicating that it should still be used with caution. This is of particular importance given that there are millions of hypertensive patients, worldwide, currently exposed to the drug.


Detection of sexually transmitted infections among transvestites and transsexual women in prison in the metropolitan region of Rio de Janeiro, Brazil.
To evaluate the seropositivity rate of rapid tests for HIV, syphilis and hepatitis B and C among transvestites and transgender women (transfeminine persons) inmates in the metropolitan region of Rio de Janeiro, analyzing the results based on sociodemographic, prison profile and access to health technologies to prevent sexually transmitted infections (STIs). Cross-sectional census-type study carried out with transfeminine in eleven male prisons in Rio de Janeiro, between the months of April and June 2021. The detection rates found were 34.4% for HIV, and 48.9% for syphilis, and 0.8% for type B and C hepatitis. Seropositivity for more than one infection was verified in 25.4% of participants, and HIV/syphilis was the most prevalent. An increase in the level of education (p=0.037) and having a steady partner in prison (p=0.041) were considered protective factors for STIs in this population. Difficulties were identified in accessing STI prevention technologies, such as male condoms, lubricating gel, rapid tests, and prophylactic antiretroviral therapies for HIV. HIV and syphilis seropositivity rates were high, but within the profile found in this population in other studies inside or outside prisons. The data found indicates the need to incorporate effective strategies for access to health technologies for the prevention of STIs. The scarcity of scientific publications containing epidemiological data on STIs in the transfeminine prison population limited deeper comparisons of the results obtained in this study.


Piezo-surgery in periodontics.
Periodontitis is a chronic inflammatory disease of the tooth-supporting structures. The treatment of this condition is primarily based on the removal of local factors and the restoration of the bony architecture. Furthermore, in the modern era of dentistry, successful implant therapy frequently necessitates strong osseous support. Traditionally, osseous surgery has been performed using either manual or motor-driven instruments. Both methods, however, have advantages and disadvantages. A novel surgical approach utilising a piezoelectric device has recently been introduced in the field of periodontology and oral implantology. This narrative review article discusses the numerous applications of this novel technique of piezosurgery in periodontology.


UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models.
Purpose: MERTK tyrosine kinase is ectopically expressed in 30% to 50% of acute lymphoblastic leukemias (ALL) and more than 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia.Experimental Design: Preclinical in vitro and in vivo assays using cell lines and primary leukemia patient samples were used to evaluate antileukemic effects of UNC2025.Results: UNC2025 potently inhibited prosurvival signaling, induced apoptosis, and reduced proliferation and colony formation in MERTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MERTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. In addition, UNC2025 increased sensitivity to methotrexate in vivo, suggesting that addition of MERTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction.Conclusions: The broad-spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, supports continued development of MERTK inhibitors for treatment of leukemia. Clin Cancer Res; 23(6); 1481-92. ©2016 AACR.


Distinct roles of the 7-transmembrane receptor protein Rta3 in regulating the asymmetric distribution of phosphatidylcholine across the plasma membrane and biofilm formation in Candida albicans.
Fungal pathogens such as Candida albicans exhibit several survival mechanisms to evade attack by antifungals and colonise host tissues. Rta3, a member of the Rta1-like family of lipid-translocating exporters has a 7-transmembrane domain topology, similar to the G-protein-coupled receptors and is unique to the fungal kingdom. Our findings point towards a role for the plasma membrane localised Rta3 in providing tolerance to miltefosine, an analogue of alkylphosphocholine, by maintaining mitochondrial energetics. Concurrent with miltefosine susceptibility, the rta3Δ/Δ strain displays increased inward translocation (flip) of fluorophore-labelled phosphatidylcholine (PC) across the plasma membrane attributed to enhanced PC-specific flippase activity. We also assign a novel role to Rta3 in the Bcr1-regulated pathway for in vivo biofilm development. Transcriptome analysis reveals that Rta3 regulates expression of Bcr1 target genes involved in cell surface properties, adhesion, and hyphal growth. We show that rta3Δ/Δ mutant is biofilm-defective in a rat venous catheter model of infection and that BCR1 overexpression rescues this defect, indicating that Bcr1 functions downstream of Rta3 to mediate biofilm formation in C. albicans. The identification of this novel Rta3-dependent regulatory network that governs biofilm formation and PC asymmetry across the plasma membrane will provide important insights into C. albicans pathogenesis.


Wheat germ in vitro translation to produce one of the most toxic sodium channel specific toxins.
Envenoming following scorpion sting is a common emergency in many parts of the world. During scorpion envenoming, highly toxic small polypeptides of the venom diffuse rapidly within the victim causing serious medical problems. The exploration of toxin structure-function relationship would benefit from the generation of soluble recombinant scorpion toxins in Escherichia coli. We developed an in vitro wheat germ translation system for the expression of the highly toxic Aah (Androctonus australis hector)II protein that requires the proper formation of four disulphide bonds. Soluble, recombinant N-terminal GST (glutathione S-transferase)-tagged AahII toxin is obtained in this in vitro translation system. After proteolytic removal of the GST-tag, purified rAahII (recombinant AahII) toxin, which contains two extra amino acids at its N terminal relative to the native AahII, is highly toxic after i.c.v. (intracerebroventricular) injection in Swiss mice. An LD50 (median lethal dose)-value of 10 ng (or 1.33 pmol), close to that of the native toxin (LD50 of 3 ng) indicates that the wheat germ in vitro translation system produces properly folded and biological active rAahII. In addition, NbAahII10 (Androctonus australis hector nanobody 10), a camel single domain antibody fragment, raised against the native AahII toxin, recognizes its cognate conformational epitope on the recombinant toxin and neutralizes the toxicity of purified rAahII upon injection in mice.


Neoadjuvant treatment for newly diagnosed advanced ovarian cancer: where do we stand and where are we going?
Newly diagnosed high grade serous epithelial ovarian cancer (EOC) patients are treated with radical surgery followed by adjuvant platinum and taxane combination chemotherapy. In EOC patients where upfront surgery is contraindicated for medical reasons (e.g., comorbidities or poor performance status), or where complete cytoreduction cannot be achieved, neoadjuvant chemotherapy (NACT) prior to interval debulking surgery (IDS), and adjuvant chemotherapy is an alternative therapeutic option. There is currently a lack of consensus about who are the best candidates to receive NACT, and some authors have even suggested that this approach could be harmful in a subset of patients via promotion of early chemoresistance. Standard and novel imaging techniques together with a better molecular characterization of the disease have the potential to improve selection of patients, but ultimately well designed randomised clinical trials are needed to guide treatment decisions in this setting. The advent of new and effective treatment options (antiangiogenics and PARP inhibitors), now approved for use in the first line and relapse settings has opened the way to clinical trials aiming to investigate these agents as substitute or in addition to chemotherapy in the neoadjuvant setting in molecularly selected EOC patients. Here, we will review the evidence supporting the use of NACT in newly diagnosed EOCs, data highlighting the importance of its use in selected patients, new imaging methodologies and biomarkers that can guide patient selection.


Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).
Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels to ensure safe practice by reducing the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the good ovarian response needed for assisted reproduction treatment. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered. To assess the effect of monitoring controlled ovarian hyperstimulation (COH) in IVF and ICSI cycles in subfertile couples with TVUS only versus TVUS plus serum estradiol concentration, with respect to rates of live birth, pregnancy and OHSS. We searched the Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, the National Research Register, and web-based trial registers such as Current Controlled Trials. The last search was conducted in May 2014. There was no language restriction applied. All references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. Only randomised controlled trials that compared monitoring with TVUS only versus TVUS plus serum estradiol concentrations in women undergoing COH for IVF and ICSI treatment were included. Three review authors independently selected the studies, extracted data and assessed risk of bias. They resolved disagreements by discussion with the rest of the authors. Outcomes data were pooled and summary statistics were presented when appropriate. The quality of the evidence was rated using the GRADE methods. With this update, four new studies were identified resulting in a total of six trials including 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment.None of the six studies reported our primary outcome of live birth rate. Pooled data showed no evidence of a difference in clinical pregnancy rate per woman between monitoring with TVUS only and combined monitoring (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests that compared with women with a 34% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate in women using TVUS only was between 29% and 44%.There was no evidence of a difference between the groups in the reported cases of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that compared with women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate in women monitored by TVUSS only was between 2% and 8%.There was no evidence of a difference between the groups in the mean number of oocytes retrieved pre woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence).The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. This review update found no evidence from randomised trials to suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. A combined monitoring protocol including both TVUS and serum estradiol may need to be retained as precautionary good clinical practice and as a confirmatory test in a subset of women to identify those at high risk of OHSS. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome.


Post-acute sequelae of covid-19 six to 12 months after infection: population based study.
To describe symptoms and symptom clusters of post-covid syndrome six to 12 months after acute infection, describe risk factors, and examine the association of symptom clusters with general health and working capacity. Population based, cross sectional study SETTING: Adults aged 18-65 years with confirmed SARS-CoV-2 infection between October 2020 and March 2021 notified to health authorities in four geographically defined regions in southern Germany. 50 457 patients were invited to participate in the study, of whom 12 053 (24%) responded and 11 710 (58.8% (n=6881) female; mean age 44.1 years; 3.6% (412/11 602) previously admitted with covid-19; mean follow-up time 8.5 months) could be included in the analyses. Symptom frequencies (six to 12 months after versus before acute infection), symptom severity and clustering, risk factors, and associations with general health recovery and working capacity. The symptom clusters fatigue (37.2% (4213/11 312), 95% confidence interval 36.4% to 38.1%) and neurocognitive impairment (31.3% (3561/11 361), 30.5% to 32.2%) contributed most to reduced health recovery and working capacity, but chest symptoms, anxiety/depression, headache/dizziness, and pain syndromes were also prevalent and relevant for working capacity, with some differences according to sex and age. Considering new symptoms with at least moderate impairment of daily life and ≤80% recovered general health or working capacity, the overall estimate for post-covid syndrome was 28.5% (3289/11 536, 27.7% to 29.3%) among participants or at least 6.5% (3289/50 457) in the infected adult population (assuming that all non-responders had completely recovered). The true value is likely to be between these estimates. Despite the limitation of a low response rate and possible selection and recall biases, this study suggests a considerable burden of self-reported post-acute symptom clusters and possible sequelae, notably fatigue and neurocognitive impairment, six to 12 months after acute SARS-CoV-2 infection, even among young and middle aged adults after mild infection, with a substantial impact on general health and working capacity. German registry of clinical studies DRKS 00027012.


Transcriptome analysis of frontal cortex in alcohol-preferring and nonpreferring rats.
Although it is widely accepted that alcohol abuse and alcoholism have a significant genetic component of risk, the identities of the genes themselves remain obscure. To illuminate such potential genetic contributions, DNA macroarrays were used to probe for differences in normative cortical gene expression between rat strains genetically selected for alcohol self-administration preference, AA (Alko, alcohol) and P (Indiana, preferring), or avoidance, ANA (Alko, nonalcohol) and NP (Indiana, nonpreferring). Among 1,176 genes studied, six demonstrated confirmable, differential expression following comparison of ethanol-naive AA and ANA rats. Specifically, the mRNA level for metabotropic glutamate receptor 3 (mGluR3) was down-regulated in the AA vs. ANA lines. In contrast, calcium channel subunit alpha2delta1 (cacna2d1), vesicle-associated membrane protein 2 (VAMP2), syntaxin 1 (both syntaxin 1a and 1b; STX1a and STX1b), and syntaxin binding protein (MUNC-18) mRNAs were found to be increased in frontal cortex following comparison of AA with ANA animals. Bioinformatic analysis of these molecular targets showed that mGluR3 and cacna2d1 fall within chromosomal locations reported to be alcohol-related by the Collaborative Study on the Genetics of Alcoholism (COGA) as well as quantitative trait loci (QTL) studies. To determine further whether these differences were strain specific, the above-mentioned genes were compared in ethanol-preferring (P) and -nonpreferring (NP) selected lines. VAMP2 was the only gene that displayed statistically different mRNA levels in a comparison of P and NP rats. In conclusion, the altered cortical gene expression illuminated here would have the effect of altering neurotransmitter release in AA rats (compared with ANA rats). Such alterations, however, might not be a universal characteristic of all animal models of alcohol abuse and will also require further investigation in post-mortem human samples.


Functional correlates of TSH, fT3 and fT4 in Alzheimer disease: a F-18 FDG PET/CT study.
The present study was aimed to investigate the relationships between thyroid stimulating hormone (TSH), freeT3 (fT3) and freeT4 (fT4) and brain glucose consumption as detectable by means of 2-deoxy-2-(F-18) fluoro-D-glucose (F-18 FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in a selected population with Alzheimer disease (AD). We evaluated 87 subjects (37 males and 50 females, mean age 70 (±6) years old) with AD. All of them were subjected to TSH, fT3 and fT4 assay and to cerebrospinal fluid amyloid (Aβ1-42) and tau [phosphorylated-tau (p-tau) and total-tau (t-tau)] assay prior PET/CT examination. Values for TSH, fT3 and fT4 were in the normal range. The relationships were evaluated by means of statistical parametric mapping (SPM8) using age, sex, MMSE, scholarship and CSF values of amyloid and tau as covariates. We found a significant positive correlation between TSH values and cortical glucose consumption in a wide portion of the anterior cingulate cortex bilaterally (BA32) and left frontal lobe (BA25) (p FWE-corr <0.001; p FDRcorr <0.000; cluster extent 66950). No significant relationships were found between cortical F-18 FDG uptake and T3 and T4 serum levels. The results of our study suggest that a cortical dysfunction in anterior cingulate and frontal lobes may affect serum values of TSH in AD patients.


Reversible posterior leukoencephalopathy syndrome following sunitinib therapy: a case report and review of the literature.
Sunitinib is one of the standard targeted therapies used in metastatic renal cell carcinoma. It is generally a reasonably tolerated oral systemic therapy but can be occasionally associated with life-threatening toxicities. We present a case of reversible posterior encephalopathy, which is a rare but recognised side effect of the treatment.


Personalizing death in the intensive care unit: the 3 Wishes Project: a mixed-methods study.
Dying in the complex, efficiency-driven environment of the intensive care unit can be dehumanizing for the patient and have profound, long-lasting consequences for all persons attendant to that death. To bring peace to the final days of a patient's life and to ease the grieving process. Mixed-methods study. 21-bed medical-surgical intensive care unit. Dying patients and their families and clinicians. To honor each patient, a set of wishes was generated by patients, family members, or clinicians. The wishes were implemented before or after death by patients, families, clinicians (6 of whom were project team members), or the project team. Quantitative data included demographic characteristics, processes of care, and scores on the Quality of End-of-Life Care-10 instrument. Semistructured interviews of family members and clinicians were transcribed verbatim, and qualitative description was used to analyze them. Participants included 40 decedents, at least 1 family member per patient, and 3 clinicians per patient. The 159 wishes were implemented and classified into 5 categories: humanizing the environment, tributes, family reconnections, observances, and "paying it forward." Scores on the Quality of End-of-Life Care-10 instrument were high. The central theme from 160 interviews of 170 persons was how the 3 Wishes Project personalized the dying process. For patients, eliciting and customizing the wishes honored them by celebrating their lives and dignifying their deaths. For families, it created positive memories and individualized end-of-life care for their loved ones. For clinicians, it promoted interprofessional care and humanism in practice. Impaired consciousness limited understanding of patients' viewpoints. The 3 Wishes Project facilitated personalization of the dying process through explicit integration of palliative and spiritual care into critical care practice. Hamilton Academy of Health Science Research Organization, Canadian Intensive Care Foundation.


Imaging-based observational databases for clinical problem solving: the role of informatics.
Imaging has become a prevalent tool in the diagnosis and treatment of many diseases, providing a unique in vivo, multi-scale view of anatomic and physiologic processes. With the increased use of imaging and its progressive technical advances, the role of imaging informatics is now evolving--from one of managing images, to one of integrating the full scope of clinical information needed to contextualize and link observations across phenotypic and genotypic scales. Several challenges exist for imaging informatics, including the need for methods to transform clinical imaging studies and associated data into structured information that can be organized and analyzed. We examine some of these challenges in establishing imaging-based observational databases that can support the creation of comprehensive disease models. The development of these databases and ensuing models can aid in medical decision making and knowledge discovery and ultimately, transform the use of imaging to support individually-tailored patient care.


Burden of celiac disease in the Mediterranean area.
To estimate the burden of undiagnosed celiac disease (CD) in the Mediterranean area in terms of morbidity, mortality and health cost. For statistics regarding the population of each country in the Mediterranean area, we accessed authoritative international sources (World Bank, World Health Organization and United Nations). The prevalence of CD was obtained for most countries from published reports. An overall prevalence rate of 1% cases/total population was finally estimated to represent the frequency of the disease in the area, since none of the available confidence intervals of the reported rates significantly excluded this rate. The distribution of symptoms and complications was obtained from reliable reports in the same cohort. A standardized mortality rate of 1.8 was obtained from recent reports. Crude health cost was estimated for the years between symptoms and diagnosis for adults and children, and was standardized for purchasing power parity to account for the different economic profiles amongst Mediterranean countries. In the next 10 years, the Mediterranean area will have about half a billion inhabitants, of which 120 million will be children. The projected number of CD diagnoses in 2020 is 5 million cases (1 million celiac children), with a relative increase of 11% compared to 2010. Based on the 2010 rate, there will be about 550,000 symptomatic adults and about 240,000 sick children: 85% of the symptomatic patients will suffer from gastrointestinal complaints, 40% are likely to have anemia, 30% will likely have osteopenia, 20% of children will have short stature, and 10% will have abnormal liver enzymes. The estimated standardized medical costs for symptomatic celiac patients during the delay between symptom onset and diagnosis (mean 6 years for adults, 2 years for children) will be about €4 billion (€387 million for children) over the next 10 years. A delay in diagnosis is expected to increase mortality: about 600,000 celiac patients will die in the next 10 years, with an excess of 44.4% vs age- and sex-matched controls. In the near future, the burden of CD will increase tremendously. Few Mediterranean countries are able to face this expanding epidemic alone.


Erythema multiforme due to arsenic trioxide in a case of acute promyelocytic leukemia: A diagnostic challenge.
Erythema multiforme (EM) is an acute, self-limited, Type IV hypersensitivity reactions associated with infections and drugs. In this case of acute promyelocytic leukemia, EM diagnosed during the induction phase was mistakenly attributed to vancomycin used to treat febrile neutropenia during that period. However, the occurrence of the lesions of EM again during the consolidation phase with arsenic trioxide (ATO) lead to a re-evaluation of the patient and both the Naranjo and World Health Organization-Uppsala Monitoring Centre scale showed the causality association as "probable." The rash responded to topical corticosteroids and antihistamines. This rare event of EM being caused by ATO may be attributed to the genetic variation of methyl conjugation in the individual which had triggered the response, and the altered metabolic byproducts acted as a hapten in the subsequent keratinocyte necrosis.


Cryptosporidiosis. Traveler's diarrhea in two families.
Intestinal cryptosporidiosis was diagnosed in three infants (aged 6 to 21 months), one child (aged 3 years), and two adult members of two families after their return from travel to the African continent. Examination of stools from all patients revealed acid-fast cryptosporidial oocysts on direct fecal smears stained by the modified cold Kinyoun technique. Five of the six were symptomatic with watery diarrhea, anorexia, and abdominal pain. Elevated anticryptosporidial titers were detected in five patients, two of whom were asymptomatic. Cryptosporidiosis should be included in the differential diagnosis of traveler's diarrhea.


Climate change & health: the case for sustainable development.
The Earth's climate has been stable for around 10,000 years, though it has been very variable in earlier periods and has occasionally changed abruptly through natural processes. Industrialization and population growth have brought an exponential rise in the use of carbonaceous fuels, which is now having an observable impact on the composition of the atmosphere. Carbon dioxide levels are already substantially above pre-industrial levels, and rising appreciably year on year. Climate models suggest that the anthropogenic rise in carbon dioxide and other greenhouse gases will lead to rapid climate change over the twenty-first century, with an increase in global average temperatures in the region of two to five degrees Celsius. This will present problems of adaptation for many natural systems and have largely negative effects on human health through both direct and indirect mechanisms. There is also a possibility of unpredicted catastrophic impacts arising from non-linear effects of climate change, which may have more damaging effects on human and other populations. Policy responses have to be directed towards both adaptation needs and mitigation. Mitigation in particular presents formidable social, political and technological challenges, but it may bring net health benefits in the short as well as the longer term.


Periodical assessment of genitourinary and gastrointestinal toxicity in patients who underwent prostate low-dose-rate brachytherapy.
To compare the periodical incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicity in patients who underwent prostate low-dose-rate brachytherapy between the monotherapy group (seed implantation alone) and the boost group (in combination with external beam radiation therapy (EBRT)). A total of 218 patients with a median follow-up of 42.5 months were enrolled. The patients were divided into 2 groups by treatment modality, namely, the monotherapy group (155 patients) and the boost group (63 patients). The periodical incidence rates of GU and GI toxicity were separately evaluated and compared between the monotherapy group and the boost group using the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 3.0. To elucidate an independent factor among clinical and postdosimetric parameters to predict grade 2 or higher GU and GI toxicity in the acute and late phases, univariate and multivariate logistic regression analyses were carried out. Of all patients, 78.0% showed acute GU toxicity, and 7.8% showed acute GI toxicity, while 63.8% showed late GU toxicity, and 21.1% showed late GI toxicity. The incidence rates of late GU and GI toxicity were significantly higher in the boost group. Multivariate analysis showed that the International Prostate Symptom Score (IPSS) before seed implantation was a significant parameter to predict acute GU toxicity, while there were no significant predictive parameters for acute GI toxicity. On the other hand, combination with EBRT was a significant predictive parameter for late GU toxicity, and rectal volume (mL) receiving 100% of the prescribed dose (R100) was a significant predictive parameter for late GI toxicity. The boost group showed higher incidence rates of both GU and GI toxicity. Higher IPSS before seed implantation, combination with EBRT and a higher R100 were significant predictors for acute GU, late GU and late GI toxicity.


Morphological variation of the thoracolumbar vertebrae in Macropodidae and its functional relevance.
The present study was designed to investigate how the form of the marsupial thoracolumbar vertebrae varies to cope with the particular demands of diverse loading and locomotor behaviors. The vertebral columns of 10 species of Macropodidae, with various body masses and modes of locomotion, together with two other arboreal marsupials, koala and cuscus, were selected. Seventy-four three-dimensional landmark coordinates were acquired on each of the 10 last presacral vertebrae of the 70 vertebral columns. The interspecific variations of the third lumbar vertebra (L3, which approximates the mean) and the transitional patterns of the thoracolumbar segments were examined using the combined approach of generalized Procrustes analysis (GPA) and principal components analysis (PCA). The results of analyses of an individual vertebra (L3) and of the transitional patterns indicate significant interspecific differences. In the L3 study the first PC shows allometric shape variation, while the second PC seems to relate to adaptation for terrestrial versus arboreal locomotion. When the L3 vertebrae of the common spotted cuscus and koala are included for comparison, the vertebra of the tree kangaroo occupies an intermediate position between the hopping kangaroo and these arboreal marsupials. The L3 vertebrae in the arboreal marsupials possess a distinct dorsoventrally expanded vertebral body, and perpendicularly orientated spinous and transverse processes. The results of the present study suggest that vertebral shape in the kangaroo and wallaroos provides a structural adaptation to hopping through a relatively enlarged loading area and powerful lever system. In contrast, the small-sized bettongs (or rat kangaroos) have a relatively flexible column and elongated levers for the action of back muscles that extend and laterally flex the spine. The complex pattern of vertebral shape transition in the last 10 presacral vertebrae was examined using PCAs that compare between species information about vertebral shape variation along the thoracolumbar column. The results reinforce and emphasize important aspects of the patterns of variation seen in the detailed analysis of the third lumbar vertebra. The results also imply that size, spinal loading pattern, and locomotor behavior exert an influence on shaping the vertebra. Further, the morphological adaptations are consistent within these marsupials and this opens up the possibility that this kind of analysis may be useful in making functional inferences from fossil material.


Hypoxia-Induced Activation of JAK/STAT3 Signaling Pathway Promotes Trophoblast Cell Viability and Angiogenesis in Preeclampsia.
BACKGROUND To explore the effect of hypoxic preconditioning on the JAK/STAT3 signaling pathway and its effect on trophoblast cell viability and angiogenesis in preeclampsia (PE). MATERIAL AND METHODS Placental tissues from normal pregnant women and PE patients were collected to detect the expression levels of JAK and STAT3. Trophoblast cells separated from the PE patients were assigned to 4 groups. The expression levels of phosphorylated p-JAK and p-STAT3 were measured by Western blot. Cell viability, colony-forming ability, and cell apoptosis were assessed. The levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS The expression levels of JAK and STAT3 were higher in the placental tissues of PE patients than in those of normal pregnant women. Compared with the blank group, in the hypoxia group the expression levels of p-JAK and p-STAT3 were increased, cell viability was promoted, the number of colonies was increased, cell apoptosis was inhibited, and the levels of VEGF, bFGF, and HGF were all elevated. However, in comparison with the hypoxia group, the expression levels of p-JAK and p-STAT3 were reduced, the cell viability was inhibited, the colonies were decreased, the levels of VEGF, bFGF, and HGF were all decreased, and cell apoptosis was promoted in the hypoxia + si-JAK group. CONCLUSIONS These findings indicate that hypoxic preconditioning may contribute to activation of the JAK/STAT3 signaling pathway, thus promoting trophoblast cell viability and angiogenesis in PE.


The reservoir area dependent thermal transport at the nanoscale interface.
The reservoir area dependent thermal transport at nanoscale two-dimensional and one-dimensional interfaces is investigated by the non-equilibrium Green's function method. For the two-dimensional nanoscale interface composed of graphene sheets, the reservoir area is identical to the contact area S at the interface. As S increases from few atoms, the interfacial thermal conductance σ per S (Λ = σ/S) is negatively dependent on S due to the decrease of phonon transmission per S. With S increasing to several square nanometers, Λ converges to a constant value. However, for the one-dimensional nanoscale interface composed of nested carbon nanotubes (NCNTs), it is σ instead of Λ that converges to a constant value because the reservoir in one-dimensional nanoscale NCNTs has a fixed area, which can only provide finite transport channels. There are two competitive factors influencing the thermal transport at the interface in the NCNT model. One is phonon mode coupling and the other is phonon scattering. These two factors lead to an interesting trend of σ that as the overlap between NCNTs increases, σ increases at first and then decreases and converges to a constant value. These findings indicate that the thermal transport behavior has a strong dependence on the contact details and reservoir area at the nanoscale interface.


Polyketides from the marine-derived fungus Aspergillus falconensis: In silico and in vitro cytotoxicity studies.
Fermentation of the marine-derived fungus Aspergillus falconensis, isolated from sediment collected from the Red Sea, Egypt on solid rice medium containing 3.5% NaCl yielded a new dibenzoxepin derivative (1) and a new natural isocoumarin (2) along with six known compounds (3-8). Changes in the metabolic profile of the fungus were induced by replacing NaCl with 3.5% (NH4)2SO4 that resulted in the accumulation of three further known compounds (9-11), which were not detected when the fungus was cultivated in the presence of NaCl. The structures of the new compounds were elucidated by HRESIMS and 1D/2D NMR as well as by comparison with the literature. Molecular docking was conducted for all isolated compounds on crucial enzymes involved in the formation, progression and metastasis of cancer which included human cyclin-dependent kinase 2 (CDK-2), human DNA topoisomerase II (TOP-2) and matrix metalloproteinase 13 (MMP-13). Diorcinol (7), sulochrin (9) and monochlorosulochrin (10) displayed notable stability within the active pocket of CDK-2 with free binding energy (ΔG) equals to -25.72, -25.03 and -25.37 Kcal/mol, respectively whereas sulochrin (9) exerted the highest fitting score within MMP-13 active center (ΔG = -33.83 Kcal/mol). In vitro cytotoxic assessment using MTT assay showed that sulochrin (9) exhibited cytotoxic activity versus L5178Y mouse lymphoma cells with an IC50 value of 5.1 µM and inhibition of migration of MDA-MB 231 breast cancer cells at a concentration of 70 µM.


Whole-slide imaging digital pathology as a platform for teleconsultation: a pilot study using paired subspecialist correlations.
-Whole-slide imaging technology offers promise for rapid, Internet-based telepathology consultations between institutions. Before implementation, technical issues, pathologist adaptability, and morphologic pitfalls must be well characterized. -To determine whether interpretation of whole-slide images differed from glass-slide interpretation in difficult surgical pathology cases. -Diagnostically challenging pathology slides from a variety of anatomic sites from an outside laboratory were scanned into whole digital format. Digital and glass slides were independently diagnosed by 2 subspecialty pathologists. Reference, digital, and glass-slide interpretations were compared. Operator comments on technical issues were gathered. -Fifty-three case pairs were analyzed. There was agreement among digital, glass, and reference diagnoses in 45 cases (85%) and between digital and glass diagnoses in 48 (91%) cases. There were 5 digital cases (9%) discordant with both reference and glass diagnoses. Further review of each of these cases indicated an incorrect digital whole-slide interpretation. Neoplastic cases showed better correlation (93%) than did cases of nonneoplastic disease (88%). Comments on discordant cases related to digital whole technology focused on issues such as fine resolution and navigating ability at high magnification. -Overall concordance between digital whole-slide and standard glass-slide interpretations was good at 91%. Adjustments in technology, case selection, and technology familiarization should improve performance, making digital whole-slide review feasible for broader telepathology subspecialty consultation applications.


Optimization of Innovative Three-Dimensionally-Structured Hybrid Vesicles to Improve the Cutaneous Delivery of Clotrimazole for the Treatment of Topical Candidiasis.
New three-dimensionally-structured hybrid phospholipid vesicles, able to load clotrimazole in a high amount (10 mg/mL), were obtained for the first time in this work by significantly reducing the amount of water (≤10%), which was replaced with a mixture of glycerol and ethanol (≈90%). A pre-formulation study was carried out to evaluate the effect of both the composition of the hydrating medium and the concentration of the phospholipid on the physico-chemical properties of hybrid vesicles. Four different three-dimensionally-structured hybrid vesicles were selected as ideal systems for the topical application of clotrimazole. An extensive physico-chemical characterization performed using transmission electron microscopy (TEM), cryogenic transmission electron microscopy (cryo-TEM), 31P-NMR, and small-angle X-ray scattering (SAXS) displayed the formation of small, multi-, and unilamellar vesicles very close to each other, and was capable of forming a three-dimensional network, which stabilized the dispersion. Additionally, the dilution of the dispersion with water reduced the interactions between vesicles, leading to the formation of single unilamellar vesicles. The evaluation of the in vitro percutaneous delivery of clotrimazole showed an improved drug deposition in the skin strata provided by the three-dimensionally-structured vesicles with respect to the commercial cream (Canesten®) used as a reference. Hybrid vesicles were highly biocompatible and showed a significant antifungal activity in vitro, greater than the commercial cream Canesten®. The antimycotic efficacy of formulations was confirmed by the reduced proliferation of the yeast cells at the site of infection in vivo. In light of these results, clotrimazole-loaded, three-dimensionally-structured hybrid vesicles appear to be one of the most innovative and promising formulations for the treatment of candidiasis infections.


Which cognitive functions subserve clustering and switching in category fluency? Generalisations from an extended set of semantic categories using linear mixed-effects modelling.
Clustering and switching are hypothesised to reflect the automatic and controlled components in category fluency, respectively, but how they are associated with cognitive functions has not been fully elucidated, due to several uncertainties. (1) The conventional scoring method that segregates responses by semantic categories could not optimally dissociate the automatic and controlled components. (2) The temporal structure of individual responses, as characterised by mean retrieval time (MRT) and mean switching time (MST), has seldom been analysed alongside the more well-studied variables, cluster size (CS) and number of switches (NS). (3) Most studies examined only one to a few semantic categories, raising concerns of generalisability. This study built upon a distance-based automatic clustering procedure, referred to as temporal-semantic distance procedure, to thoroughly characterise the category fluency performance. Linear mixed-effects (LME) modelling was applied to re-examine the differential associations of clustering and switching with cognitive functions with a sample of 80 university students. Our results revealed that although lexical retrieval speed (LRS) is clearly the determining factor for effective clustering and switching, matrix reasoning and processing speed also have significant roles to play, possibly in the processes of identifying and validating the semantic relationships. Interestingly, total fluency score was accurately predicted by the four clustering/switching indices alone; including the cognitive variables did not significantly improve the prediction. These findings underline the importance of the clustering and switching indices in explaining the category fluency performance and the cognitive demands in category fluency.


Striatal dopamine integrates cost, benefit, and motivation.
Striatal dopamine (DA) release has long been linked to reward processing, but it remains controversial whether DA release reflects costs or benefits and how these signals vary with motivation. Here, we measure DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) while independently varying costs and benefits and apply behavioral economic principles to determine a mouse's level of motivation. We reveal that DA release in both structures incorporates both reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release. Furthermore, optogenetically evoked DA release was also heavily dependent on sunk cost. Our results reconcile previous disparate findings by demonstrating that striatal DA release simultaneously encodes cost, benefit, and motivation but in distinct manners over different timescales. Future work will be necessary to determine whether the reduction in phasic DA release in highly motivated animals is due to changes in tonic DA levels.


Preclinical Molecular Imaging for Precision Medicine in Breast Cancer Mouse Models.
Precision and personalized medicine is gaining importance in modern clinical medicine, as it aims to improve diagnostic precision and to reduce consequent therapeutic failures. In this regard, prior to use in human trials, animal models can help evaluate novel imaging approaches and therapeutic strategies and can help discover new biomarkers. Breast cancer is the most common malignancy in women worldwide, accounting for 25% of cases of all cancers and is responsible for approximately 500,000 deaths per year. Thus, it is important to identify accurate biomarkers for precise stratification of affected patients and for early detection of responsiveness to the selected therapeutic protocol. This review aims to summarize the latest advancements in preclinical molecular imaging in breast cancer mouse models. Positron emission tomography (PET) imaging remains one of the most common preclinical techniques used to evaluate biomarker expression in vivo, whereas magnetic resonance imaging (MRI), particularly diffusion-weighted (DW) sequences, has been demonstrated as capable of distinguishing responders from nonresponders for both conventional and innovative chemo- and immune-therapies with high sensitivity and in a noninvasive manner. The ability to customize therapies is desirable, as this will enable early detection of diseases and tailoring of treatments to individual patient profiles. Animal models remain irreplaceable in the effort to understand the molecular mechanisms and patterns of oncologic diseases.