Attitudes, Self-Confidence, and Knowledge of Primary Care Professionals towards School Bullying.

Attitudes, practices, and knowledge about bullying were evaluated in a sample of 274 primary care professionals, including general practitioners, pediatricians, community, pediatric and school nurses, and residents of these specialties. This study was based on a mixed method with a parallel convergent design without dominance between phases, data were collected concurrently, and conversion of the results from both phases was carried out during data interpretation. The quantitative phase had a cross-sectional observational design, using The Healthcare Provider's Practices, Attitudes, Self-confidence, and Knowledge Regarding Bullying Questionnaire as an instrument. Descriptive and bivariate analyses were performed, which showed a positive correlation between higher self-confidence and knowledge scores and a greater predisposition to detect cases. However, although the dimensions of attitudes and knowledge yielded generally high data, low self-confidence was evident in addressing this problem. In addition, a lack of clear guidelines in the workplace was expressed, highlighting the need to create and provide specific resources to intervene in bullying in said context, which could develop an improvement in self-confidence, leading to greater well-being for the educational community regarding bullying.

Cross-Cultural Validation of the Healthcare Provider's Practices, Attitudes, Self-Confidence, and Knowledge Regarding Bullying Questionnaire.

How can we know the reality of the context of bullying in the field of primary health care? The aim of this study is to obtain a validated and reliable tool that allows measurement of the involvement of primary care professionals in addressing bullying through a systematic content validation process. A cross-cultural validation of the Healthcare Provider's Practices, Attitudes, Self-Confidence, and Knowledge Regarding Bullying Questionnaire was conducted for the Spanish perspective. This involved linguistic adaptation through translation-back-translation, content validity index (CVI) analysis, construct validity using confirmatory factor analysis (CFA), and internal consistency (Cronbach's α). The total CVI was 0.95, with individual item scores ≥ 0.78. CFA revealed a good fit for the three subscales, with discrimination indices (item-total correlation within the dimension) > 0.30. Cronbach's α for each dimension indicated a high level of reliability, with values of 0.735 for attitudes, 0.940 for self-confidence, and 0.895 for knowledge. The questionnaire is valid and reliable for evaluating the knowledge, attitudes, and self-confidence of primary care professionals in Spain regarding bullying. Its validity and reliability guarantee its potential use in other health settings and may lead to better training of professionals and school biopsychosocial health.

Anterior Insula-Associated Social Novelty Recognition: Pivotal Roles of a Local Retinoic Acid Cascade and Oxytocin Signaling.

OBJECTIVE: Deficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a "common core" brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive. This study aims to fill this knowledge gap. METHODS: To determine the role of the anterior insula in social cognition, the authors manipulated expression of Cyp26B1, an anterior insula-enriched molecule that is crucial for retinoic acid degradation and is involved in the pathology of neuropsychiatric conditions. Social cognition was mainly assayed using the three-chamber social interaction test. Multimodal analyses were conducted at the molecular, cellular, circuitry, and behavioral levels. RESULTS: At the molecular and cellular level, anterior insula-mediated social novelty recognition is maintained by proper activity of the layer 5 pyramidal neurons, for which retinoic acid-mediated gene transcription can play a role. The authors also demonstrate that oxytocin influences the anterior insula-mediated social novelty recognition, although not by direct projection of oxytocin neurons, nor by direct diffusion of oxytocin to the anterior insula, which contrasts with the modes of oxytocin regulation onto the posterior insula. Instead, oxytocin affects oxytocin receptor-expressing neurons in the dorsal raphe nucleus, where serotonergic neurons are projected to the anterior insula. Furthermore, the authors show that serotonin 5-HT2C receptor expressed in the anterior insula influences social novelty recognition. CONCLUSIONS: The anterior insula plays a pivotal role in social novelty recognition that is partly regulated by a local retinoic acid cascade but also remotely regulated by oxytocin via a long-range circuit mechanism.

Model-Based Predictions of HIV Incidence Among African Women Using HIV Risk Behaviors and Community-Level Data on Male HIV Prevalence and Viral Suppression.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical "placebo arm" for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP. METHODS: Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study. RESULTS: Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over 1 year of follow-up in the placebo groups of 4 completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% confidence interval: 3.2 to 4.2) among HIV Prevention Trials Network 082 participants in the absence of PrEP and other risk reduction interventions. CONCLUSIONS: We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.

Varying Inoculum Dose to Assess the Roles of the Immune Response and Target Cell Depletion by the Pathogen in Control of Acute Viral Infections.

It is difficult to determine whether an immune response or target cell depletion by the infectious agent is most responsible for the control of acute primary infection. Both mechanisms can explain the basic dynamics of an acute infection-exponential growth of the pathogen followed by control and clearance-and can also be represented by many different differential equation models. Consequently, traditional model comparison techniques using time series data can be ambiguous or inconclusive. We propose that varying the inoculum dose and measuring the subsequent infectious load can rule out target cell depletion by the pathogen as the main control mechanism. Infectious load can be any measure that is proportional to the number of infected cells, such as viraemia. We show that a twofold or greater change in infectious load is unlikely when target cell depletion controls infection, regardless of the model details. Analyzing previously published data from mice infected with influenza, we find the proportion of lung epithelial cells infected was 21-fold greater (95% confidence interval 14-32) in the highest dose group than in the lowest. This provides evidence in favor of an alternative to target cell depletion, such as innate immunity, in controlling influenza infections in this experimental system. Data from other experimental animal models of acute primary infection have a similar pattern.

Predicted Effectiveness of Daily and Nondaily Preexposure Prophylaxis for Men Who Have Sex With Men Based on Sex and Pill-taking Patterns From the Human Immuno Virus Prevention Trials Network 067/ADAPT Study.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 067/Alternative Dosing to Augment PrEP Pill Taking (ADAPT) Study evaluated the feasibility of daily and nondaily human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. METHODS: An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the preexposure prophylaxis initiative (iPrEx) trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. RESULTS: We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85%, and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens. CONCLUSIONS: Our analysis suggests that PrEP was more effective among MSM in Thailand than in the United States as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, nondaily PrEP was less effective than daily PrEP, especially in the United States where the sex act coverage associated with daily use was substantially higher.

Dependence of CD8 T Cell Response upon Antigen Load During Primary Infection : Analysis of Data from Yellow Fever Vaccination.

A major question in immunology is what role antigen load plays in determining the size of the CD8 immune response. Is the amount of antigen important during recruitment, proliferation, and/or memory formation? Animal studies have shown that antigen is only strictly required early during activation of T cells, but the importance of antigen at later timepoints is unclear. Using data from 24 volunteers infected with the yellow fever vaccine virus (YFV), we analyzed the dependence of T cell proliferation upon viral load. We found that volunteers with high viral load initially have greater T cell responses, but by 28 days post-vaccination those with lower viral load are able to 'catch-up.' Using differential equation modeling we show that this pattern is consistent with viral load only affecting recruitment (i.e., programmed proliferation) as opposed to affecting recruitment and proliferation (i.e., antigen-dependent proliferation). A quantitative understanding of the dependence of T cell dynamics on antigen load will be of use to modelers studying not only vaccination, but also cancer immunology and autoimmune disorders.

A Mathematical Model of T1D Acceleration and Delay by Viral Infection.

Type 1 diabetes (T1D) is often triggered by a viral infection, but the T1D prevalence is rising among populations that have a lower exposure to viral infection. In an animal model of T1D, the NOD mouse, viral infection at different ages may either accelerate or delay disease depending on the age of infection and the type of virus. Viral infection may affect the progression of T1D via multiple mechanisms: triggering inflammation, bystander activation of self-reactive T-cells, inducing a competitive immune response, or inducing a regulatory immune response. In this paper, we create mathematical models of the interaction of viral infection with T1D progression, incorporating each of these four mechanisms. Our goal is to understand how each viral mechanism interacts with the age of infection. The model predicts that each viral mechanism has a unique pattern of interaction with disease progression. Viral inflammation always accelerates disease, but the effect decreases with age of infection. Bystander activation has little effect at younger ages and actually decreases incidence at later ages while accelerating disease in mice that do get the disease. A competitive immune response to infection can decrease incidence at young ages and increase it at older ages, with the effect decreasing over time. Finally, an induced Treg response decreases incidence at any age of infection, but the effect decreases with age. Some of these patterns resemble those seen experimentally.

The benefits of diversity: heterogenous DC populations allow for both immunity and tolerance.

The immune system must simultaneously mount a response against foreign antigens while tolerating self. How this happens is still unclear as many mechanisms of immune tolerance are antigen non-specific. Antigen specific immune cells called T-cells must first bind to Immunogenic Dendritic Cells (iDCs) before activating and proliferating. These iDCs present both self and foreign antigens during infection, so it is unclear how the immune response can be limited to primarily foreign reactive T-cells. Regulatory T-cells (Tregs) are known to play a key role in self-tolerance. Although they are antigen specific, they also act in an antigen non-specific manner by competing for space and growth factors as well as modifying DC behavior to help kill or deactivate other T-cells. In prior models, the lack of antigen specific control has made simultaneous foreign-immunity and self-tolerance extremely unlikely. We include a heterogeneous DC population, in which different DCs present antigens at different levels. In addition, we include Tolerogenic DC (tDCs) which can delete self-reactive T-cells under normal physiological conditions. We compare different mathematical models of immune tolerance with and without Tregs and heterogenous antigen presentation. For each model, we compute the final number of foreign-reactive and self-reactive T-cells, under a variety of different situations. We find that even if iDCs present more self-antigen than foreign antigen, the immune response will be primarily foreign-reactive as long as there is sufficient presentation of self-antigen on tDCs. Tregs are required primarily for rare or cryptic self-antigens that do not appear frequently on tDCs. We also find that Tregs can only be effective when we include heterogenous antigen presentation, as this allows Tregs and T-cells of the same antigen-specificity to colocalize to the same set of DCs. Tregs better aid immune tolerance when they can both compete for space and growth factors and directly eliminate other T-cells. Our results show the importance of the structure of the DC population in immune tolerance as well as the relative contribution of different cellular mechanisms.

Chemoprevention of human actinic keratoses by topical DL-alpha-tocopherol.

Prior research shows that topical application of free, nonfatty acid-conjugated vitamin E (DL-alpha-tocopherol) prevents skin cancer in mice, as well as immunosuppression induced by UVB radiation. This study investigated the chemopreventive potential of DL-alpha-tocopherol in humans through monitoring surrogate end point biomarkers in sun-damaged skin. Contralateral arms of healthy human volunteers with actinic keratoses (AK) were randomly assigned to receive either 12.5% DL-alpha-tocopherol or placebo in a crème base for 6 months. Changes in number of AKs, levels of p53 protein expression, proliferating cell nuclear antigen, and polyamines were assessed along with skin and systemic vitamin E levels. Following treatment, plasma concentration levels of DL-alpha-tocopherol were unchanged, but skin levels were highly elevated (P < 0.001). Levels of p53 and proliferating cell nuclear antigen did not change significantly, whereas number of AKs declined insignificantly in both placebo and treatment arms. Regression models showed significant decreases in putrescine, spermidine, spermine, and total polyamine concentrations following treatment. Topically applied DL-alpha-tocopherol was substantially absorbed in skin, but the 6-month application did not significantly reduce numbers of preexisting AKs on moderately to severely sun-damaged forearms. Increases in polyamine synthesis are expected during tumor initiation and promotion; conversely, the significant reductions in polyamine levels resulting from the topical DL-alpha-tocopherol application are consistent with reductions in tumorigenesis potential. Topical tocopherol did not normalize established sun-induced lesions, but DL-alpha-tocopherol-induced reductions in polyamine metabolism are consistent with the inhibition of skin squamous cell carcinogenesis as seen in previous human trials and animal models.

Karyometry of breast epithelial cells acquired by random periareolar fine needle aspiration in women at high risk for breast cancer.

OBJECTIVE: To establish whether karyometry was likely to detect change in the proportion of abnormal cells in random periareolar fine needle aspiration (RPFNA) specimens from high-risk women in a 6-month prevention trial with an aromatase inhibitor. STUDY DESIGN: Papanicolaou-stained ThinPrep slides of RPFNA samples from 11 of 42 women were digitally recorded at high resolution, with 200 cells measured per slide, at baseline (BL) and at the end of study (ES) after 6 months. The nuclear chromatin pattern characteristics were assessed by multivariate analytic techniques; determination of nuclear abnormalities was performed and cells that showed expression of abnormality were identified. RESULTS: The BL FNA samples contain approximately 90% cells with a chromatin pattern as expected in a normal cell population. A small subpopulation of cells had deviations from normal. At ES the proportion of these cells was reduced, to a statistically significant degree,from < 10% to 2-5%. CONCLUSION: Nuclear karyometry is a promising technique for characterizing the proportion of cells deviating from normal in cytologic specimens and should be explored further as an intermediate endpoint in prevention trials.

Clinical blood flow quantification with segmented k-space magnetic resonance phase velocity mapping.

PURPOSE: To evaluate the accuracy of segmented k-space magnetic resonance phase velocity mapping (PVM) in quantifying aortic blood flow from through-plane velocity measurements. MATERIALS AND METHODS: Two segmented PVM schemes were evaluated, one with seven lines per segment (seg-7) and one with nine lines per segment (seg-9), in twenty patients with cardiovascular disease. A non-segmented (non-seg) PVM acquisition was also performed to provide the reference data. RESULTS: There was agreement between the aortic flow curves acquired with segmented and non-segmented PVM. The calculated systolic and total flow volume per cycle from the seg-7 and the seg-9 scans correlated and agreed with the flow volumes from the non-seg scans (differences < 5%). Sign tests showed that there were no statistically significant differences (P-values > 0.05) between the segmented and the non-segmented PVM measurements [corrected]. Seg-9, which was the fastest among the three sequences, provided adequate spatial and temporal resolution (> 10 phases per cycle). CONCLUSION: Segmented k-space PVM shows great clinical potential in blood flow quantification.

Evaluation of iron overload by single voxel MRS measurement of liver T2.

PURPOSE: To overcome the difficulty of poor signal-to-noise ratio of magnetic resonance imaging (MRI) in evaluating heavy iron overload by using a single voxel magnetic resonance spectroscopy (MRS) technique. MATERIALS AND METHODS: A single voxel STEAM pulse sequence with a minimum TE of 1.5 msec and a sampling volume of 36.6 cm(3) was developed and applied to 1/T2 measurement of the liver in 14 patients with thalassemia whose liver iron concentration was determined through biopsy. RESULTS: The iron level ranged from 0.23 to 37.15 mg Fe/g dry tissue with a median value of 18.06. In all cases, strong MR signals were obtained. 1/T2 was strongly correlated with the liver iron concentration (r = 0.95, P < 0.00005). CONCLUSION: The single voxel MRS measurement of T2 in liver iron overload overcomes the difficulty of lack of detectable signals in conventional MRI when the iron level is high. There is an excellent correlation between the iron level and 1/T2.

Ultrafast flow quantification with segmented k-space magnetic resonance phase velocity mapping.

Magnetic resonance (MR) phase-velocity mapping (PVM) is routinely being used clinically to measure blood flow velocity. Conventional nonsegmented PVM is accurate but relatively slow (3-5 min per measurement). Ultrafast k-space segmented PVM offers much shorter acquisitions (on the order of seconds instead of minutes). The aim of this study was to evaluate the accuracy of segmented PVM in quantifying flow from through-plane velocity measurements. Experiments were performed using four straight tubes (inner diameter of 5.6-26.2 mm), under a variety of steady (1.7-200 ml/s) and pulsatile (6-90 ml/cycle) flow conditions. Two different segmented PVM schemes were tested, one with five k-space lines per segment and one with nine lines per segment. Results showed that both segmented sequences provided very accurate flow quantification (errors<5%) under both steady and pulsatile flow conditions, even under turbulent flow conditions. This agreement was confirmed via regression analysis. Further statistical analysis comparing the flow data from the segmented PVM techniques with (i) the data from the nonsegmented technique and (ii) the true flow values showed no significant difference (all p values>>0.05). Preliminary flow measurements in the ascending aorta of two human subjects using the nonsegmented sequence and the segmented sequence with nine lines per segment showed very close agreement. The results of this study suggest that ultrafast PVM has great potential to measure blood velocity and quantify blood flow clinically.