Examining confidential wholesale margin estimates in European countries for the price negotiation of patented drugs in Germany: a statistical model.

BACKGROUND: Based on the legal framework laid down in section 130b (9) of Book V of the German Social Code, various criteria are relevant for the negotiated price for new patented drugs in Germany. European reference prices (ERPs) are one criterion. The ERP is based on the ex-factory prices (EFPs) of the countries included in the European country basket. However, in some of these countries, the EFP is not published due to confidential wholesale margins. Wholesale margins must therefore be estimated and deducted from purchase prices. In this context literature-based estimates to date do not assume regressive margins with higher pharmaceutical prices. This assumption is questionable and can lead to systematically underestimated country prices, especially for high-priced drugs. Percentage wholesale margins in the majority of European countries develop to a comparable extent regressively with increasing prices. It should therefore be examined (1) whether statistical models can predict the margins of individual countries, in principle and especially for countries where margins are unknown and regressive trends are likely, and (2) to what extent the estimation of margins improves when regressive statistical models are used to estimate margins instead of cross-price averages published in the literature. METHODS: Qualitative preliminary research explores the basic wholesale pricing mechanisms in countries with confidential wholesale margins. Wholesale margins for reimbursable drugs were then modeled for regulated European countries. Estimation quality and impact of the model was compared to estimations based on average margins. RESULTS: In both regulated countries and in countries with confidential wholesale margins, percentage margins of wholesalers develop regressively as drug prices rise. Regressive courses of margins can be resiliently modeled for the regulated countries using a power distribution with significantly lower mean squared errors in a linear mixed model in comparison to literature-based estimations with country-specific cross-price averages. CONCLUSION: If there is reason to believe that margins are regressive, confidential wholesale margins are expected to be better estimated by the power function based on margins of regulated countries than by the published country-specific average margins, reducing significantly inaccurate effects on margin estimations of high-price drugs.

Cardiogenic shock and chronic kidney disease: Dangerous liaisons.

BACKGROUND: Chronic kidney disease (CKD) is one of the leading causes of death worldwide, closely interrelated with cardiovascular diseases, ultimately leading to the failure of both organs - the so-called "cardiorenal syndrome". Despite this burden, data related to cardiogenic shock outcomes in CKD patients are scarce. METHODS: FRENSHOCK (NCT02703038) was a prospective registry involving 772 patients with cardiogenic shock from 49 centres. One-year outcomes (rehospitalization, death, heart transplantation, ventricular assist device) were analysed according to history of CKD at admission and were adjusted on independent predictive factors. RESULTS: CKD was present in 164 of 771 patients (21.3%) with cardiogenic shock; these patients were older (72.7 vs. 63.9years) and had more comorbidities than those without CKD. CKD was associated with a higher rate of all-cause mortality at 1month (36.6% vs. 23.2%; hazard ratio 1.39, 95% confidence interval 1.01-1.9; P=0.04) and 1year (62.8% vs. 40.5%, hazard ratio 1.39, 95% confidence interval 1.09-1.77; P<0.01). Patients with CKD were less likely to be treated with norepinephrine/epinephrine or undergo invasive ventilation or receive mechanical circulatory support, but were more likely to receive renal replacement therapy (RRT). RRT was associated with a higher risk of all-cause death at 1month and 1year regardless of baseline CKD status. CONCLUSIONS: Cardiogenic shock and CKD are frequent "cross-talking" conditions with limited therapeutic options, resulting in higher rates of death at 1month and 1year. RRT is a strong predictor of death, regardless of preexisting CKD. Multidisciplinary teams involving cardiac and kidney physicians are required to provide integrated care for patients with failure of both organs.

Oxytocin and social learning in socially anxious men and women.

OBJECTIVE: This study extended a classic self-referential learning paradigm by investigating the effects of intranasally-administered oxytocin in high and low socially anxious participants during social learning, as a function of social anxiety levels and sex. METHODS: In a randomized double-blinded design, 160 participants were either given intranasal oxytocin (24 I.U.) or placebo. Subsequently, while lying in an MR scanner, participants were shown neutral faces that were paired with positively, neutrally, or negatively valenced self-referential sentences, during which we measured self-reported arousal and sympathy of the facial stimuli, pupil dilation, and changes in the brain-oxygen-level dependent signal. Four-factor mixed analyses of variance with the between-subjects factors group (high socially anxious vs. low socially anxious), substance (oxytocin vs. placebo), and sex (male vs. female) and the within-subjects factor sentence valence (positive vs. neutral vs. negative) were conducted for each measure, respectively. RESULTS: Administration of intranasal oxytocin yielded an increase in sympathy ratings in high socially anxious compared to low socially anxious individuals and decreased arousal ratings for positively-conditioned faces in low socially anxious participants. As an objective physiological measure of arousal, pupil dilation mirrored the behavioral results. Oxytocin effects on neural activation in the insula interacted with anxiety levels and sex: low socially anxious individuals yielded lower activation under oxytocin than placebo; the converse was observed in high socially anxious individuals. This interaction also differed between sexes, as men yielded higher activation levels than women. These findings were more prominent for positively- and negatively-conditioned faces. Within the amygdala, high socially anxious men yielded higher activation than high socially anxious women in the left hemisphere, and low socially anxious men yielded higher activation than low socially anxious women from positively- and negatively-conditioned faces, though no influence of oxytocin was detected. CONCLUSION: These results suggest oxytocin-induced behavioral, physiological, and neural changes as a function of social learning in socially low and high anxious individuals. These findings challenge the amygdalocentric view of the role of emotions in social learning, instead contributing to the growing body of findings implicating the insula therein, revealing an interaction between oxytocin, sex, and emotional valence. Such discoveries raise an interesting set of questions regarding the computational goals of regions such as the insula in emotional learning and how neural activity can play a diagnostic or prognostic role in social anxiety, potentially leading to new treatment opportunities that may combine oxytocin and neurofeedback differentially for men and women.

Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson's disease.

The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, a progressive age-related neurodegenerative disease for which there is no cure. HET-s is a soluble fungal protein that can form assembled amyloid fibrils in its prion state. We engineered HET-s(218-298) to form four different fibrillar vaccine candidates, each displaying a specific conformational epitope present on the surface of α-synuclein fibrils. Vaccination with these four vaccine candidates prolonged the survival of immunized TgM83+/- mice challenged with α-synuclein fibrils by 8% when injected into the brain to model brain-first Parkinson's disease or by 21% and 22% when injected into the peritoneum or gut wall, respectively, to model body-first Parkinson's disease. Antibodies from fully immunized mice recognized α-synuclein fibrils and brain homogenates from patients with Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Conformation-specific vaccines that mimic epitopes present only on the surface of pathological fibrils but not on soluble monomers, hold great promise for protection against Parkinson's disease, related synucleinopathies and other amyloidogenic protein misfolding disorders.

Práticas da Psicologia no contexto carcerário Brasileiro: uma revisão sistemática / Psychology practices in the Brazilian prison context: a systematic review

Este texto apresenta resultados de uma pesquisa que teve como objetivo compreender a atuação da(o) profissional psicóloga(o) no contexto carcerário brasileiro a partir da literatura produzida e publicada nas principais bases de dados vinculadas ao CNPq. Foi realizado um levantamento nas bases de dados no ano de 2020 e selecionados 7 trabalhos para análise. Identificou-se que a maioria das publicações é de 2015, possuindo concentração geográfica maior na região Sudeste. Predominam discussões sobre o papel que a(o) psicóloga(o) deve exercer nesse espaço e qual a sua real atuação. Constatou-se que as práticas mais exercidas por psicólogas(os) no sistema prisional são os atendimentos individuais, a avaliação psicológica e a elaboração de documentos. Considera-se a necessidade de maiores discussões e pesquisas sobre a atuação de psicólogas no contexto carcerário, bem como a realização destas discussões durante a formação em psicologia.

This text presents the results of a research that aimed to understand the role of professional psychologists in the Brazilian prison context, based on the literature produced and published in the main databases linked to the CNPq. A survey was carried out in the databases in the year 2020 and 7 works were selected for analysis. It was identified that most publications are from 2015, with a greater geographic concentration in the Southeast region. Discussions about the role that (o) psychologist (o) should play in this space and what is her real role prevail. It was found that the practices most exercised by psychologists in the prison system are individual care, psychological assessment and preparation of documents. There is a need for further discussions and research on the role of psychologists in the prison context, as well as these discussions during training in psychology.

Adsorção do azul de metileno em serragem de Pinus elliottii (pinus) e Drepanostachyum falcatum (bambu) / Methylene blue adsorption in Pinus elliottii (pine) and Drepanostachyum falcatum (bamboo) sawdust

RESUMO A cinética, o equilíbrio e os parâmetros termodinâmicos de adsorção foram investigados para a adsorção do corante azul de metileno (AM) por meio dos biossorventes Pinus elliottii (pinus) e Drepanostachyum falcatum (bambu). A cinética de adsorção foi descrita mais precisamente pelo modelo de pseudossegunda ordem, os dados de equilíbrio monocomponente foram mais bem representados pela isoterma de Langmuir, para as três temperaturas estudadas (15, 25 e 35°C), e os parâmetros termodinâmicos demonstraram que o processo de adsorção é exotérmico, de natureza química e não espontâneo. A máxima capacidade adsortiva do pinus foi de 47 mg L-1 e a do bambu, de 38 mg L-1 para os ensaios de adsorção realizados com AM (100 mg L-1 a 35°C). Por fim, os biossorventes foram considerados promissores para a remoção do adsorvato AM em matriz aquosa sob valor de pH próximo à neutralidade (6,5).

ABSTRACT Kinetics, equilibrium and thermodynamic adsorption parameters were investigated for the adsorption of the methylene blue dye (MB) by means of the biosorbents Pinus elliottii (pinus) and Drepanostachyum falcatum (bamboo). The adsorption kinetics were described more precisely by the pseudo-second order model; the monocomponent equilibrium's data were better represented by the Langmuir isotherm for the three temperatures studied (15, 25 and 35°C) and the thermodynamic parameters showed the adsorption process is exothermic, of a chemical nature and not spontaneous. The maximum adsorptive capacity of pinus was 47 mg L-1 and 38 mg L-1 bamboo for adsorption tests performed with MB (100 mg L-1 at 35°C). Finally, the biosorbents were considered promising for the adsorbate MB removal in aqueous matrix under pH value close to neutrality (6.5).

Linguística e psicopedagogia: contribuições para uma prática não medicalizante / Language and psicopedagogy: contributions to a practice not medicalized

Este artigo busca trazer contribuições da Linguística para o campo da Psicopedagogia no que tange à concepção de linguagem e do processo de aquisição e uso da leitura e escrita, tendo como objetivo orientar uma prática psicopedagógica não medicalizante. Para isso é traçada a crítica à concepção de linguagem presente na definição, diagnóstico e tratamento de Dislexia. Ao mesmo tempo, é proposto, através da análise de dados de leitura e escrita de duas crianças que receberam um diagnóstico equivocado de Dislexia, a descaracterização do que foi interpretado erroneamente como sintoma de patologia a partir de um aporte teórico e metodológico do campo da Linguística(AU)

This article seeks to bring contributions of linguistics to the field of Psychopedagogy regarding the conception of language and the process of acquisition and use of reading and writing, aiming to guide a psychopedagogical practice not medicalized. For it, is drawn a critique of the conception of language in the definition, diagnosis and treatment of dyslexia. At the same time, is proposed, by analyzing reading and writing data of two children who have received a misdiagnosis, the mischaracterization of what was misinterpreted as a symptom of pathology from a theoretical and methodological framework of the field of linguistics(AU)