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Background The VITALITY-HFpEF trial (Evaluate the Efficacy and Safety of the Oral sGC Stimulator Vericiguat to Improve Physical Functioning in Daily Living Activities of Patients With Heart Failure and Preserved Ejection Fraction) is designed to determine the efficacy and safety of a novel oral soluble guanylate cyclase stimulator, vericiguat, on quality of life and exercise tolerance in heart failure patients with preserved ejection fraction (HFpEF). Impaired physical functioning reduces the quality of life in patients with HFpEF. The primary goal of HF treatment along with improving survival is to improve function, reduce symptoms, and maximize quality of life. Abnormal cyclic guanosine monophosphate signaling may contribute to physical limitations in patients with HFpEF via central and peripheral mechanisms. Exploratory post hoc analyses from a prior trial showed that vericiguat can improve patient-relevant domains of the Kansas City Cardiomyopathy Questionnaire, especially the physical limitation score. Methods and Results VITALITY-HFpEF is a placebo-controlled, double-blind, multi-center, phase IIb trial of ≈735 patients, ≥45 years with HFpEF and ejection fraction ≥45% who will be randomized 1:1:1 to placebo, 10 mg, or 15 mg vericiguat. The primary end point is change in Kansas City Cardiomyopathy Questionnaire physical limitation score from baseline to week 24 and change in 6-minute walk test from baseline to week 24 is the secondary end point. Conclusions VITALITY-HFpEF is the first trial designed to assess the efficacy of vericiguat in patients with HFpEF using the Kansas City Cardiomyopathy Questionnaire physical limitation score as a novel primary end point. This study will also extend the prior dosing experience with vericiguat in HF by studying the safety and efficacy of a 15 mg dose. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT03547583.

Resumo Este trabalho utiliza um rico e inédito banco de dados sobre registros de ocorrências para investigar os fatores associados à violência escolar. Os crimes cometidos por agentes externos à escola (furtos e roubos) são explicados pelas condições socioeconômicas do entorno e pela riqueza pessoal e material disponível nas escolas, enquanto os atos violentos cometidos por alunos (depredação, vandalismo, ameaças e agressões) estão associados à composição demográfica do corpo discente e pelo seu background familiar. Também são identificados dois efeitos ainda não investigados na literatura. O primeiro refere-se ao papel da qualidade do professor. Já o segundo refere-se ao engajamento dos pais na vida escolar dos filhos e atividades da escola. Os resultados sugerem que a habilidade do professor em estabelecer um bom relacionamento com os estudantes e que a parceria da família com a escola são capazes de atuar sobre seu comportamento, inibindo seu engajamento em atos violentos. Abstract This work uses a rich and unique database on occurrences records to investigate the factors associated with school violence. The crimes committed by external agents to school (theft and robbery) are explained by the neighborhood socioeconomic conditions and the personal and material wealth available in schools, while violent acts committed by students (depredation, vandalism, threats and assaults) are associated with the students' demographic composition and his family background. We also identified two effects are not investigated in the literature. The first refers to the role of teacher quality. The second refers to the engagement in school life of children and school activities. The results suggest that the teacher's ability to establish a good relationship with the students and the partnership of the family with the school are able to act on their behavior, inhibiting their engagement in violence.

Importance: Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life.Objective: To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ).Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019.Interventions: Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1.Main Outcomes and Measures: The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks.Results: Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was-1.5 (95% CI,-5.5 to 2.5; P =.47) and between the 10-mg/d vericiguat and placebo groups was-0.5 (95% CI,-4.6 to 3.5; P =.80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m, 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was-5.5 m (95% CI,-19.7 m to 8.8 m; P =.45) and between the 10-mg/d vericiguat and placebo groups was-1.8 m (95% CI,-16.2 m to 12.6 m; P =.81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively.Conclusions and Relevance: Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ.Trial Registration: ClinicalTrials.gov Identifier: NCT03547583.

Background: Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH. Methods: We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n=84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints. Results: In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean±standard deviation 6MWD had increased by 33±42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups. Conclusions: Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed. Trial registration: ClinicalTrials.org NCT01784562. Registered February 4, 2013., SCOPUS: ar.j, info:eu-repo/semantics/published

Nós investigamos os fatores associados à violência escolar, a partir de um rico banco de dados inédito de registros de ocorrências escolares. Os crimes de furtos e roubos de bens e contra a pessoa, cometidos geralmente por agentes externos à escola, são explicados pelas condições socioeconômicas do entorno e pela riqueza disponível nas escolas. Já os atos violentos tipicamente cometidos por alunos – depredação, vandalismo, ameaças e agressões físicas e verbais – são explicados pela composição demográfica do corpo discente e pelo seu background familiar. Nós ainda apontamos dois efeitos ainda não investigados na literatura. O primeiro refere-se à qualidade do professor: a sua habilidade em estabelecer um bom relacionamento com os estudantes seria capaz de inibir o engajamento dos mesmos em atos violentos. Já o segundo fator mostra que a importância que os pais dão para os estudos e a parceria da família com a escola na formação dos estudantes também atuam positivamente sobre o bom comportamento de crianças e jovens.

Iodoacetoxylation of 3,6-di- O -acetyl-4- O -(2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-1,5-anhydro-2-deoxy- d - arabino -hex-1-enitol (hexa- O -acetyllactal) and the corresponding hexa- O -benzoyl derivative, gave the α-1,2- trans 1- O -acetyl-2-deoxy-2-iodo adducts with high stereoselectivity and good yields. These were treated with an excess of trimethylsilyl azide in the presence of trimethylsilyl trifluoromethanesulfonate affording the corresponding α-1,2- trans 2-deoxy-2-iodoglycosyl azides. In the presence of an alcohol, a Staudinger reaction at the anomeric azide ledin situ to an iminophosphorane which rearranged with elimination of iodine at C-2. The aziridine intermediate thus obtained reacted with a suitable alcohol to afford the corresponding lactosamine β-glycosides. The reaction occurred with double inversion of configuration at C-1 and C-2. Deprotection of the amine functionality and further transformation into the acetamido derivatives could be achieved without isolation of the intermediates. © 1997 Elsevier Science Ltd.

Iodoacetoxylation of 3,6-di- O -acetyl-4- O -(2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-1,5-anhydro-2-deoxy- d - arabino -hex-1-enitol (hexa- O -acetyllactal) and the corresponding hexa- O -benzoyl derivative, gave the α-1,2- trans 1- O -acetyl-2-deoxy-2-iodo adducts with high stereoselectivity and good yields. These were treated with an excess of trimethylsilyl azide in the presence of trimethylsilyl trifluoromethanesulfonate affording the corresponding α-1,2- trans 2-deoxy-2-iodoglycosyl azides. In the presence of an alcohol, a Staudinger reaction at the anomeric azide ledin situ to an iminophosphorane which rearranged with elimination of iodine at C-2. The aziridine intermediate thus obtained reacted with a suitable alcohol to afford the corresponding lactosamine β-glycosides. The reaction occurred with double inversion of configuration at C-1 and C-2. Deprotection of the amine functionality and further transformation into the acetamido derivatives could be achieved without isolation of the intermediates. © 1997 Elsevier Science Ltd.