Development of a Conceptual Model for the Patient Experience of Immunoglobulin A Nephropathy (IgAN): A Qualitative Literature Review.

INTRODUCTION: Immunoglobulin A nephropathy (IgAN) is a kidney disorder that can lead to progressive kidney disease. Currently, there lacks a comprehensive overview of the symptoms and impacts experienced by those living with IgAN that would help inform the selection or development of fit-for-purpose clinical outcome assessments (COA) to be used in clinical trials. The aim of this study was to develop a conceptual model of the adult and pediatric patient experience of IgAN, including disease signs and symptoms, treatment side effects, and impact on functioning and well-being. METHODS: This study comprised a systematic review and thematic analysis of qualitative studies with adults and children diagnosed with IgAN. Data sources were identified through an electronic database search of journal articles (MEDLINE, Embase, PsycINFO; June 2021), hand-searching of conference proceedings, patient advocacy group websites, and gray literature. Non-English articles were excluded. Identified data (patient/caregiver quotes, author summaries, and interpretations of patient experiences) were extracted from articles. Extracted data were qualitatively analyzed, aided by ATLAS.ti v7. Codes were applied to data; concepts (i.e., symptoms) were identified, named, and refined. A conceptual model was developed by grouping related concepts into domains. RESULTS: In total, five sources were identified for analysis: two journal articles, two online anthologies of patient stories, and one patient organization-sponsored "Voice of the Patient" meeting report. Conceptual model symptom domains included swelling/puffiness (edema), pain/aches/discomfort, fatigue, weight gain, sleep problems, urinary problems, and gastrointestinal problems. Impact domains included emotional/psychological well-being, physical functioning/activities of daily living, social functioning, work/school, and relationships. CONCLUSIONS: Secondary analysis of published qualitative literature permitted development of a novel conceptual model depicting the patient experience of IgAN; however, its depth is limited by a lack of available literature. Further qualitative research is recommended to refine and/or confirm the concepts and domains, determine any relationships between them, and explore the outcomes that are most meaningful to patients. The refined model will provide a useful tool to inform the selection, development, and/or amendment of COAs for use in future IgAN clinical trials.

Ejection Fraction, Biomarkers, and Outcomes and Impact of Vericiguat on Outcomes Across EF in VICTORIA.

BACKGROUND: Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF). OBJECTIVES: The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial. METHODS: Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and >33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro-B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined. RESULTS: The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and >33; P < 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF. CONCLUSIONS: Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%). (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

Soluble guanylate cyclase stimulators in patients with heart failure with reduced ejection fraction across the risk spectrum.

Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Soluble guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide-sGC-cyclic guanosine monophosphate cascade - a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower-risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher- and lower-risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, pre-clinical studies and post-hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects - these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow-up in a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally treated, low-risk HFrEF patients (i.e. those without recently worsening heart failure).

Vericiguat and NT-proBNP in patients with heart failure with reduced ejection fraction: analyses from the VICTORIA trial.

AIMS: Treatment response to vericiguat, based on baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) subgroups specified in the protocol, was evaluated in the heart failure (HF) VICTORIA trial population by post hoc analysis of combined lower three quartiles [Q1-Q3] vs. the upper quartile [Q4]. METHODS AND RESULTS: VICTORIA participants with available baseline NT-proBNP levels (n = 4805; 95.1% of total) were included. Compared with patients in Q1-Q3 (NT-proBNP: Q1, ≤1556 pg/mL; Q2, >1556-2816 pg/mL; and Q3, >2816-5314 pg/mL), patients in Q4 (NT-proBNP: >5314 pg/mL) were older (69.2 ± 12.0 vs. 66.6 ± 12.1 years), had lower mean ejection fraction (27.2 ± 8.3% vs. 29.5 ± 8.2%; P < 0.0001), and were more likely to be in New York Heart Association (NYHA) Class III (51.8 vs. 35.6%) or IV (2.4 vs. 1.0%). Compared with Q1-Q3, patients in Q4 had higher mean Meta-Analysis Global Group in Chronic Heart Failure risk score (27.3 ± 6.6 vs. 23.5 ± 6.4; P < 0.0001), had lower mean estimated glomerular filtration rate (eGFR; 51.5 ± 25.5 vs. 65.0 ± 26.8 mL/min/1.73 m2 ; P < 0.0001) and haemoglobin (12.8 ± 2.0 vs. 13.6 ± 1.9 g/dL; P < 0.0001), and more had atrial fibrillation (48.7% vs. 43.1%; P = 0.0007) and were randomized while hospitalized for HF (14.8 vs. 9.9%; P < 0.0001). Target dose was achieved in 72.3 and 63.7% of patients in Q1-Q3 and Q4, respectively (P < 0.0001). Primary outcome (composite of time to cardiovascular death or first HF hospitalization) rates were 24.5 and 31.7 per 100 patient-years for vericiguat and placebo in Q1-Q3 [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.69-0.88, P < 0.001] and 73.6 and 63.6 in Q4 (HR 1.15; 95% CI 0.99-1.34, P = 0.070). Serious adverse events were more frequent in NT-proBNP Q4 (total population) compared with Q1-Q3 (38.3 vs. 32.3%; P = 0.0001), driven mainly by the placebo group. Adverse events leading to death were more frequent in Q4 than Q1-Q3 (5.8 vs. 2.4%; P < 0.0001). CONCLUSIONS: Plasma NT-proBNP may help identify patients with worsening HF with reduced ejection fraction, in whom the beneficial effects of vericiguat may be highest. Patients with highest NT-proBNP values are probably too far advanced, suffering more co-morbidities, or still clinically unstable after decompensation to derive benefit from vericiguat.

Soluble GC stimulators and activators: Past, present and future.

The discovery of soluble GC (sGC) stimulators and sGC activators provided valuable tools to elucidate NO-sGC signalling and opened novel pharmacological opportunities for cardiovascular indications and beyond. The first-in-class sGC stimulator riociguat was approved for pulmonary hypertension in 2013 and vericiguat very recently for heart failure. sGC stimulators enhance sGC activity independent of NO and also act synergistically with endogenous NO. The sGC activators specifically bind to, and activate, the oxidised haem-free form of sGC. Substantial research efforts improved on the first-generation sGC activators such as cinaciguat, culminating in the discovery of runcaciguat, currently in clinical Phase II trials for chronic kidney disease and diabetic retinopathy. Here, we highlight the discovery and development of sGC stimulators and sGC activators, their unique modes of action, their preclinical characteristics and the clinical studies. In the future, we expect to see more sGC agonists in new indications, reflecting their unique therapeutic potential.

Clinical investigation of the biopharmaceutical characteristics of nifurtimox tablets - Implications for quality control and application.

Nifurtimox is approved in Chagas disease and has been used in endemic countries since the 1960s. Nifurtimox, available as a 120 mg tablet, is administered with food typically three times daily, and dose is adjusted for age and bodyweight. Accurately or reproducibly fragmenting the 120 mg tablet for dose adjustment in young children and those with low bodyweight is problematic. Based on the existing tablet formulation, new nifurtimox 30 mg and 120 mg tablets have been developed in a format that can be divided accurately into 15 mg and 60 mg fragments. In adults with chronic Chagas disease, we investigated whether nifurtimox bioavailability is affected by tablet dissolution rate, and whether different diets affect nifurtimox bioavailability. In an open-label, three-period cross-over study (n=36; ClinicalTrials.gov, NCT03350295), patients randomly received three 30 mg tablet formulations (slow, medium, or fast dissolution; a 4 × 30 mg dose of one formulation per period). In an open-label, four-period cross-over study (n=24; ClinicalTrials.gov, NCT03334838) patients randomly fasted or received one of three meal types (high-fat/high-calorie, low-fat, dairy-based) before ingesting nifurtimox (a 4 × 30 mg dose per period). Acceptance criteria for no difference between groups were 90% confidence intervals (CIs) of exposure ratios in the range 0.8-1.25. Nifurtimox bioavailability was unaffected by tablet dissolution kinetics. Ratios of area under the curve at final assessment (AUC(0-tlast) [90% CI]) were: fast/medium dissolution, 1.061 (0.990-1.137); slow/medium dissolution, 0.964 (0.900-1.033); fast/slow dissolution, 1.100 (1.027-1.179). Compared with a fasting state, nifurtimox bioavailability increased by 73% after a high-fat/high-calorie meal (AUC(0-tlast) ratio [90% CI], 1.732 [1.581-1.898]); smaller increases were seen with the other meal types (low-fat: 1.602 [1.462-1.755]; dairy-based: 1.340 [1.222-1.468]). Although type of diet can affect bioavailability, taking nifurtimox with food is most important.

Alterations in Gas Exchange and Oxidative Metabolism in Rice Leaves Infected by Pyricularia oryzae are Attenuated by Silicon.

Rice blast, caused by Pyricularia oryzae, is the most important disease in rice worldwide. This study investigated the effects of silicon (Si) on the photosynthetic gas exchange parameters (net CO2 assimilation rate [A], stomatal conductance to water vapor [gs], internal-to-ambient CO2 concentration ratio [Ci/Ca], and transpiration rate [E]); chlorophyll fluorescence a (Chla) parameters (maximum photochemical efficiency of photosystem II [Fv/Fm], photochemical [qP] and nonphotochemical [NPQ] quenching coefficients, and electron transport rate [ETR]); concentrations of pigments, malondialdehyde (MDA), and hydrogen peroxide (H2O2); and activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione reductase (GR), and lypoxigenase (LOX) in rice leaves. Rice plants were grown in a nutrient solution containing 0 or 2 mM Si (-Si or +Si, respectively) with and without P. oryzae inoculation. Blast severity decreased with higher foliar Si concentration. The values of A, gs and E were generally higher for the +Si plants in comparison with the -Si plants upon P. oryzae infection. The Fv/Fm, qp, NPQ, and ETR were greater for the +Si plants relative to the -Si plants at 108 and 132 h after inoculation (hai). The values for qp and ETR were significantly higher for the -Si plants in comparison with the +Si plants at 36 hai, and the NPQ was significantly higher for the -Si plants in comparison with the +Si plants at 0 and 36 hai. The concentrations of Chla, Chlb, Chla+b, and carotenoids were significantly greater in the +Si plants relative to the -Si plants. For the -Si plants, the MDA and H2O2 concentrations were significantly higher than those in the +Si plants. The LOX activity was significantly higher in the +Si plants than in the -Si plants. The SOD and GR activities were significantly higher for the -Si plants than in the +Si plants. The CAT and APX activities were significantly higher in the +Si plants than in the -Si plants. The supply of Si contributed to a decrease in blast severity, improved the gas exchange performance, and caused less dysfunction at the photochemical level.

Habilidades cognitivo-linguísticas e sua relação com características respiratórias / Cognitive-linguistic skills and their relationship with respiratory characteristics

OBJETIVO: relacionar características respiratórias com o desempenho em habilidades cognitivo-linguísticas de crianças de uma escola pública da grande Belo Horizonte. MÉTODO: estudo transversal, observacional e descritivo. Das 180 crianças recrutadas 131 atenderam aos critérios de inclusão e exclusão. Foram avaliadas 66 crianças da 4ª série e 65 da 3ª série do ensino fundamental, de ambos os gêneros, com idades entre nove e dez anos. Foi utilizado um questionário para investigação das características respiratórias e um protocolo previamente publicado e adaptado a população brasileira para avaliação das habilidades cognitivo-linguísticas. As informações coletadas foram analisadas por meio dos testes de Mann-Whitney e Kruskal Wallis, ao nível de significância de 1%. RESULTADOS: não foi observado valor de p<0,01 na comparação entre as características respiratórias e as pontuações obtidas por cada série no teste das habilidades cognitivo-linguísticas. Observou-se que 59,1% dos alunos apresentaram escores no questionário de pesquisa das características respiratórias entre zero e quatro pontos, indicando pouco comprometimento respiratório. CONCLUSÃO: não foi encontrada relação significante entre o desempenho de habilidades cognitivo-linguísticas e a presença de características respiratórias em escolares de uma escola pública de Belo Horizonte, sendo que as crianças que apresentaram sinais e sintomas de alterações respiratórias não obtiveram desempenho abaixo daquelas sem estas alterações nas habilidades avaliadas.

PURPOSE: to relate respiratory characteristics with cognitive-linguistic skills performance of children from a public school of the region of Belo Horizonte. METHOD: a cross-sectional, observational and descriptive study. From the 180 enrolled children, 131 met the inclusion and exclusion criteria. We evaluated 66 children in the 4th grade and 65 children in the 3rd grade of the elementary education, from both genders, with ages going between nine and ten year old. We utilized a questionnaire for assessment of respiratory characteristics and a previously published protocol and adapted to the Brazilian population in order to assess the cognitive-linguistic skills. Data were analyzed using the Mann-Whitney and Kruskal Wallis test at a significance level of 1%. RESULTS: there was not observed a p-value <0.01 in comparison between the respiratory characteristics and the cognitive-linguistic skills’ score obtained by each series. We observed that 59.1% of students had scores in a questionnaire for assessment of respiratory characteristics between zero and four points, indicating some impairment in respiratory variables studied. We obtained a significant p value for comparisons between the performance in cognitive-linguistic skills and the presence of respiratory disorders in the studied series. CONCLUSION: no significant relationship was found between the performance of cognitive-linguistic skills and the presence of respiratory characteristics in students from the same public school of Belo Horizonte city, and the children who showed respiratory changes didn´t have performance below those without these changes in the assessed skills.

Diagnóstico radiográfico de coroas protéticas / Radiographic diagnosis of prosthetics crowns

O objetivo do presente estudo foi o de avaliar a presença e a ausência de falhas por meio de imagens radiográficas em coroas protéticas unitárias, em relação ao contorno proximal, contato proximal, excesso e falta de material, adaptação marginal e quanto ao término do preparo com a crista óssea alveolar. Participaram da pesquisa 292 pacientes inscritos para tratamento na Faculdade de Odontologia de Pernambuco - FOP/ UPE, onde, após avaliação clínica das coroas presentes, foi solicitada uma tomada radiográfica para melhor visualização. As imagens radiográficas foram analisadas através de um negatoscópio com lupa de três vezes de aumento. Todas as coroas analisadas apresentaram algum tipo de falha, identificando-se em uma mesma coroa mais de um defeito. Observou-se associação significante (p=0,034) entre a variável excesso de material em elementos anteriores, comparativamente aos elementos posteriores assim como associação (p=0,022) do término do preparo das coroas dos elementos posteriores em relação à proximidade da crista óssea alveolar. Concluiu-se, portanto, que a reabilitação protética deve não apenas restabelecer o princípio funcional e estético, mas principalmente o biológico, proporcionando uma harmonia com os tecidos periodontais e uma maior longevidade do trabalho restaurador. Este estudo, porém, observou uma forte presença de falhas na confecção de coroas protéticas.

The purpose of this study was to evaluate the presence and absence of failures by radiographic images of single prosthetic crowns, related to proximal contour, proximal contact, excess and lack of material, marginal fit and relation of the end of the preparation with the alveolar bone crest. Study participants included 292 patients enrolled for treatment at the Faculdade de Odontologia de Pernambuco - FOP/UPE, where after a clinical evaluation of the crowns, was conducted a radiographic procedure for optimal viewing. The radiographic images were analyzed using a negatoscope with a loupe with three times of increase. It was observed that all prosthetic crowns analyzed failed, identifying in a single crown more than one failure. It was observed significant association (p=0.034) between the variable excess of material in the anterior crowns, compared to posterior crowns, as well as association (p=0.022) between the cervical margin of the posterior crowns in relation to the proximity to the alveolar bone crest. It was concluded, therefore, that the prosthetics rehabilitation should not only restore the principle of aesthetic and functional, but mainly the biological, providing harmony between the prosthetic procedures and periodontal tissues and greater longevity of the restorative treatment, however this study observed a strong presence of failures in the confection of prosthetic crowns.

Exposiçäo ao hexaclorofeno durante a gravidez: efeitos sobre o desenvolvimento da prole de ratas eutróficas e de ratas desnutridas / Exposure to hexachlorophene during pregnancy: effects on the development of pups from eutrophic and malnourished rats

Foram estudados os efeitos da administraçäo de hexaclorofeno durante a prenhez sobre prole de ratos; avaliou-se também a interaçäo de desnutriçäo intra-uterina com a exposiçäo à droga. A administraçäo de 10mg/kg/dia de hexaclorofeno na última semana de gestaçäo aumentou o número de nati-mortos e diminuiu o peso ao nascimento. Houve recuperaçäo do peso corporal quando os filhotes foram amamentados logo após o nascimento por ratas eutróficas e näo tratadas com hexaclorofeno. Essa recuperaçäo foi mais lenta para as fêmeas, quando comparadas aos machos. A desnutriçäo näo potencializou o efeito do hexaclorofeno. Näo foram observadas diferenças na vida adulta entre os grupos näo tratados e tratados com hexaclorofeno, quanto à avaliaçäo da emocionalidade e da aprendizagem no labirinto Hebb-Williams