Development of a Machine Learning Algorithm for Drug Screening Analysis on High-Resolution UPLC-MSE/QTOF Mass Spectrometry.

BACKGROUND: Ultra-performance liquid chromatography (UPLC)-MSE/quadrupole time-of-flight (QTOF) high-resolution mass spectrometry employs untargeted, data-independent acquisition in a dual mode that simultaneously collects precursor ions and product ions at low and ramped collision energies, respectively. However, algorithmic analysis of large-scale multivariate data of comprehensive drug screening as well as the positivity criteria of drug identification have not been systematically investigated. It is also unclear whether ion ratio (IR), the intensity ratio of a defined product ion divided by the precursor ion, is a stable parameter that can be incorporated into the MSE/QTOF data analysis algorithm. METHODS: IR of 91 drugs were experimentally determined and variation of IR was investigated across 5 concentrations measured on 3 different days. A data-driven machine learning approach was employed to develop multivariate linear regression (MLR) models incorporating mass error, retention time, number of detected fragment ions and IR, accuracy of isotope abundance, and peak response using drug-supplemented urine samples. Performance of the models was evaluated in an independent data set of unknown clinical urine samples in comparison with the results of manual analysis. RESULTS: IR of most compounds acquired by MSE/QTOF were low and concentration-dependent (i.e., IR increased at higher concentrations). We developed an MLR model with composite score outputs incorporating 7 parameters to predict positive drug identification. The model achieved a mean accuracy of 89.38% in the validation set and 87.92% agreement in the test set. CONCLUSIONS: The MLR model incorporating all contributing parameters can serve as a decision-support tool to facilitate objective drug identification using UPLC-MSE/QTOF.

Knowledge, Perceptions, Attitudes and Practices of Midwives Regarding Maternal Influenza and Pertussis Vaccination: A Qualitative Study.

The coverage of maternal vaccination against pertussis and, particularly, influenza is lower than expected. The lack of recommendation from healthcare providers conditions non-vaccination in pregnant women. The purpose was to determine the knowledge, perceptions, attitudes and practices of midwives regarding maternal influenza and pertussis vaccination. A qualitative descriptive study based on semi-structured, face-to-face interviews with seventeen midwives was conducted, including purposive sampling and thematic analyses. Midwives had disparate knowledge and perceptions about the severity of influenza and pertussis in pregnant women, and influenza was not considered very serious. The vaccines were generally considered safe. However, because midwives did not have enough information about the safety of the influenza vaccine, there was a tendency not to recommend it. While most midwives had a positive attitude toward vaccination, their advocation for vaccination against influenza was not as clear as it was for pertussis. Not wanting to influence the decision and assuming an informative-facilitating role also led providers to recommend the influenza vaccine less frequently. Midwives are among the main sources of professional advice for pregnant women. Addressing their understanding and professional practices regarding maternal vaccination is key to change the attitude of pregnant women and thus increase vaccine uptake among them, particularly for influenza.

Understanding factors that influence the decision to be vaccinated against influenza and pertussis in pregnancy: A qualitative study.

AIMS AND OBJECTIVES: To identify how pregnant women perceive pertussis and influenza and the factors that influence their decision to be vaccinated. BACKGROUND: Suffering from influenza during pregnancy increases complications in the pregnant woman, foetus and newborn. Pertussis in children under six months of age causes severe complications. Maternal vaccination against influenza and pertussis is effective and safe. However, vaccination rates are insufficient. DESIGN: We conducted a qualitative descriptive study, using semi-structured interviews. This research adheres to the COREQ guidelines and checklist. METHODS: We carried out 18 semi-structured face-to-face interviews with pregnant women, using intentional sampling and thematic analysis. RESULTS: We identified an overarching theme, 'factors that influenced participants' decision to be vaccinated or not', which was composed of four subthemes that were in turn made up of 12 categories. The factors that influenced participants' decision to be vaccinated against influenza and pertussis were related to their knowledge of and their perception of risk for these diseases. Participants perceived the risk of pertussis to be greater, and they focused their concern on the newborn. The recommendations and convictions of nurse-midwives were the most important factors encouraging vaccination. Participants trusted their nurse-midwives and most reported that they would have been vaccinated if their midwife had recommended it. Other factors were linked to lack of information, fear and concerns about economic interests. CONCLUSIONS: The convictions and actions of the nurse-midwife in recommending vaccination to pregnant women are decisive. Strategies to improve vaccination rates should be directed to helping health professionals understand how their practice affects the final decision of pregnant women. RELEVANCE TO CLINICAL PRACTICE: Understanding the factors that limit vaccination rates among pregnant women provides valuable information to nurse-midwives that can help to improve vaccination strategies and practices. Increased maternal vaccination rates would reduce morbidity and mortality among pregnant women and newborns.

Adolescent mental health promotion in Latin American countries: an integrative literature review. / Promoção em saúde mental de adolescentes em países da América Latina: uma revisão integrativa da literatura.

Health Promotion (HP) has recently been strengthened within public policies and still shows strong consonance with international determinations regarding childhood and adolescence in Latin America (LA). Debating HP becomes all the more urgent considering the increasing prevalence of psychological distress in this age group and the historical political construction of Latin American countries. This research aimed to identify and analyze, through an integrative review of the literature, the academic productions on strategies for mental HP of adolescents in LA and, thus, to visualize the actions and arouse reflections dialoguing with the Southern critics, represented by the Bogotá declaration. Six studies were selected after applying the inclusion and exclusion criteria. We identified that the main space where actions are developed is the school. The potential measures identified were professional training, group action, and strengthening primary and territorial care. We discussed that the historically structured socioeconomic reality of LA reflects an organization of HP actions. Furthermore, the visualization of strategies that enhance at low cost the improved mental health of adolescents can contribute to the current reflection.

A Promoção em Saúde (PS) apresenta um fortalecimento recente dentro das políticas públicas e quando se trata da infância e adolescência na América Latina (AL) observa-se ainda forte consonância com as determinações internacionais. Considerando o aumento de prevalência de sofrimento psíquico nesta faixa etária e a construção histórica política dos países latino-americanos abordar a PS se torna mais urgente. O objetivo desta pesquisa foi identificar e analisar, por meio de uma revisão integrativa da literatura, produções acadêmicas que tratam de estratégias de PS mental de adolescentes na AL e, assim, visibilizar as ações e provocar reflexões dialogadas com as críticas Sulistas, representadas pela declaração de Bogotá. Após a aplicação dos critérios de inclusão e exclusão, foram selecionados 6 estudos. Identificou-se que o principal espaço onde as ações são desenvolvidas é a escola. Além disso, como medidas potenciais foram identificadas a capacitação dos profissionais, a ação grupal e o fortalecimento da atenção primária e territorial. Discute-se que a realidade socioeconômica estruturada historicamente da AL reflete uma organização própria das ações em PS. Com isso, a visibilização das estratégias que potencializam a baixo custo uma melhora na saúde mental de adolescentes pode contribuir com a reflexão atual.

Promoção em saúde mental de adolescentes em países da América Latina: uma revisão integrativa da literatura / Adolescent mental health promotion in Latin American countries: an integrative literature review

Resumo A Promoção em Saúde (PS) apresenta um fortalecimento recente dentro das políticas públicas e quando se trata da infância e adolescência na América Latina (AL) observa-se ainda forte consonância com as determinações internacionais. Considerando o aumento de prevalência de sofrimento psíquico nesta faixa etária e a construção histórica política dos países latino-americanos abordar a PS se torna mais urgente. O objetivo desta pesquisa foi identificar e analisar, por meio de uma revisão integrativa da literatura, produções acadêmicas que tratam de estratégias de PS mental de adolescentes na AL e, assim, visibilizar as ações e provocar reflexões dialogadas com as críticas Sulistas, representadas pela declaração de Bogotá. Após a aplicação dos critérios de inclusão e exclusão, foram selecionados 6 estudos. Identificou-se que o principal espaço onde as ações são desenvolvidas é a escola. Além disso, como medidas potenciais foram identificadas a capacitação dos profissionais, a ação grupal e o fortalecimento da atenção primária e territorial. Discute-se que a realidade socioeconômica estruturada historicamente da AL reflete uma organização própria das ações em PS. Com isso, a visibilização das estratégias que potencializam a baixo custo uma melhora na saúde mental de adolescentes pode contribuir com a reflexão atual.

Abstract Health Promotion (HP) has recently been strengthened within public policies and still shows strong consonance with international determinations regarding childhood and adolescence in Latin America (LA). Debating HP becomes all the more urgent considering the increasing prevalence of psychological distress in this age group and the historical political construction of Latin American countries. This research aimed to identify and analyze, through an integrative review of the literature, the academic productions on strategies for mental HP of adolescents in LA and, thus, to visualize the actions and arouse reflections dialoguing with the Southern critics, represented by the Bogotá declaration. Six studies were selected after applying the inclusion and exclusion criteria. We identified that the main space where actions are developed is the school. The potential measures identified were professional training, group action, and strengthening primary and territorial care. We discussed that the historically structured socioeconomic reality of LA reflects an organization of HP actions. Furthermore, the visualization of strategies that enhance at low cost the improved mental health of adolescents can contribute to the current reflection.

Trabecular bone score improves fracture risk assessment in glucocorticoid-induced osteoporosis.

OBJECTIVE: To analyse the clinical utility of trabecular bone score (TBS) evaluation for fracture risk assessment in glucocorticoid (GC)-treated patients compared with BMD assessment. METHODS: One hundred and twenty-seven patients on GC treatment were included [mean age 62 (18) years, 63% women] in this cross-sectional study. The medical history, anthropometric data, lumbar and femoral BMD (DXA) [considering osteoporosis (OP): T-score ⩽-2.5], TBS (considering degraded microarchitecture: <1.230) and dorsolumbar X-ray [to assess vertebral fractures (VF)] were evaluated. BMD and TBS sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were evaluated to determine the diagnostic accuracy of the two methods. RESULTS: All patients were receiving GC treatment for autoimmune diseases during 47.7 (68.9) months at a mean daily dose of 14.5 mg; 17% had VF, 28% any type of fragility fracture (VF + non-VF), 29% OP and 52% degraded microarchitecture. Degraded microarchitecture was significantly more frequent than densitometric OP in patients with VF (76% vs 38%) and with any fragility fracture (69% vs 36%). For VF, TBS and BMD sensitivity, specificity, PPV, and NPV were 0.76, 0.53, 0.25 and 0.92, and 0.38, 0.72, 0.22 and 0.85, respectively. Specificity increased to 0.89 for VF and 0.9 for any fragility fracture on combining BMD+TBS. TBS had better ability than BMD to discriminate between patients with fracture, especially VF (area under the curve = 0.73). CONCLUSION: TBS seems to have greater discriminative power than BMD for fracture risk assessment in GC-treated patients, confirming the utility of this method as a complementary tool in the diagnosis of GC-induced OP.

Biological treatments in giant cell arteritis & Takayasu arteritis.

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the two main large vessel vasculitides. They share some similarities regarding their clinical, radiological and histological presentations but some pathogenic processes in GCA and TAK are activated differently, thus explaining their different sensitivity to biological therapies. The treatment of GCA and TAK essentially relies on glucocorticoids. However, thanks to major progress in our understanding of their pathogenesis, the role of biological therapies in the treatment of these two vasculitides is expanding, especially in relapsing or refractory diseases. In this review, the efficacy, the safety and the limits of the main biological therapies ever tested in GCA and TAK are discussed. Briefly, anti TNF-α agents appear to be effective in treating TAK but not GCA. Recent randomized placebo-controlled trials have reported on the efficacy and safety of abatacept and mostly tocilizumab in inducing and maintaining remission of GCA. Abatacept was not effective in TAK and robust data are still lacking to draw any conclusions concerning the use of tocilizumab in TAK. Furthermore, ustekinumab appears promising in relapsing/refractory GCA whereas rituximab has been reported to be effective in only a few cases of refractory TAK patients. If a biological therapy is indicated, and in light of the data discussed in this review, the first choice would be tocilizumab in GCA and anti-TNF-α agents (mainly infliximab) in TAK.

2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative.

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients' and clinicians' values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.

Acute dilated cardiomyopathy in a patient with beriberi and cryoglobulinaemic vasculitis: an unusual potential complication of two rare disorders.

We report the case of a 45-year-old patient who presented with acute dilated cardiomyopathy. During admission the patient was consecutively diagnosed with cryoglobulinaemic vasculitis and beriberi. In both diseases, cardiac involvement may occur as dilated cardiomyopathy. Thiamin deficiency was the final cause for the severe cardiac manifestations (cardiac acute beriberi or Shoshin syndrome), which returned to normal after thiamin supplementation.

Changes in biomarkers after therapeutic intervention in temporal arteries cultured in Matrigel: a new model for preclinical studies in giant-cell arteritis.

BACKGROUND: Search for therapeutic targets in giant-cell arteritis (GCA) is hampered by the scarcity of functional systems. We developed a new model consisting of temporal artery culture in tri-dimensional matrix and assessed changes in biomarkers induced by glucocorticoid treatment. METHODS: Temporal artery sections from 28 patients with GCA and 22 controls were cultured in Matrigel for 5 days in the presence or the absence of dexamethasone. Tissue mRNA concentrations of pro-inflammatory mediators and vascular remodelling molecules was assessed by real-time RT-PCR. Soluble molecules were measured in the supernatant fluid by immunoassay. RESULTS: Histopathological features were exquisitely preserved in cultured arteries. mRNA concentrations of pro-inflammatory cytokines (particularly IL-1ß and IFNγ), chemokines (CCL3/MIP-1α, CCL4/MIP-1ß, CCL5/RANTES) and MMP-9 as well as IL-1ß and MMP-9 protein concentrations in the supernatants were significantly higher in cultured arteries from patients compared with control arteries. The culture system itself upregulated expression of cytokines and vascular remodelling factors in control arteries. This minimised differences between patients and controls but underlines the relevance of changes observed. Dexamethasone downregulated pro-inflammatory mediator (IL-1ß, IL-6, TNFα, IFNγ, MMP-9, TIMP-1, CCL3 and CXCL8) mRNAs but did not modify expression of vascular remodelling factors (platelet derived growth factor, MMP-2 and collagens I and III). CONCLUSIONS: Differences in gene expression in temporal arteries from patients and controls are preserved during temporal artery culture in tri-dimensional matrix. Changes in biomarkers elicited by glucocorticoid treatment satisfactorily parallel results obtained in vivo. This may be a suitable model to explore pathogenetic pathways and to perform preclinical studies with new therapeutic agents.

Cytostatic response of HepG2 to 0.57 MHz electric currents mediated by changes in cell cycle control proteins.

The capacitive-resistive electric transfer (CRet) therapy is a non-invasive technique that applies electrical currents of 0.4-0.6 MHz to the treatment of musculoskeletal injuries. Although this therapy has proved effective in clinical studies, its interaction mechanisms at the cellular level still are insufficiently investigated. Results from previous studies have shown that the application of CRet currents at subthermal doses causes alterations in cell cycle progression and decreased proliferation in hepatocarcinoma (HepG2) and neuroblastoma (NB69) human cell lines. The aim of the present study was to investigate the antiproliferative response of HepG2 to CRet currents. The results showed that 24-h intermittent treatment with 50 µA/mm(2) current density induced in HepG2 statistically significant changes in expression and activation of cell cycle control proteins p27Kip1 and cyclins D1, A and B1. The chronology of these changes is coherent with that of the alterations reported in the cell cycle of HepG2 when exposed to the same electric treatment. We propose that the antiproliferative effect exerted by the electric stimulus would be primarily mediated by changes in the expression and activation of proteins intervening in cell cycle regulation, which are among the targets of emerging chemical therapies. The capability to arrest the cell cycle through electrically-induced changes in cell cycle control proteins might open new possibilities in the field of oncology.

In vitro exposure to 0.57-MHz electric currents exerts cytostatic effects in HepG2 human hepatocarcinoma cells.

Capacitive-resistive electric transfer (CRET) therapy is a non-invasive technique currently applied to the treatment of skin, muscle and tendon injuries that uses 0.45-0.6 MHz electric currents to transdermically and focally increase the internal temperature of targeted tissues. Because CRET electrothermal treatment has been reported to be more effective than other thermal therapies, it has been proposed that the electric stimulus could induce responses in exposed tissues that are cooperative or synergic with the thermal effects of the treatment. Previous studies by our group, investigating the nature of the alleged electric response, have shown that short, repeated stimuli with 0.57-MHz currents at subthermal levels could provoke partial, cytotoxic effects on human neuroblastoma cells in vitro. The aim of the present study was to investigate the response from another human cell type, the human hepatocarcinoma HepG2 line, during and after the exposure to 0.57-MHz CRET currents at subthermal densities. The electric stimuli provoked a decrease in the proliferation rate of the cultures, possibly due to an electrically-induced blocking of the cell cycle in a fraction of the cellular population.