Safety, tolerability and effects on clinical variables and laboratory markers of sodium bicarbonate inhalation in cystic fibrosis' patients

Orientadores: José Dirceu Ribeiro; Paul Marquis Quinton; Fernando Augusto de Lima MarsonTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: Disfunção qualitativa e/ou quantitativa da proteína CFTR causa diminuição da secreção de bicarbonato de sódio nas vias aéreas dos indivíduos com Fibrose Cística (FC). Apesar da eficácia do bicarbonato de sódio, sobre a reologia do muco, função pulmonar e seu poder bactericida ter sido muito estudado em animais, poucos estudos foram realizados em humanos. Objetivo: Avaliar a segurança, a tolerabilidade e os efeitos colaterais de bicarbonato de sódio por via inalatória, no escarro, em variáveis clínicas e laboratoriais de pacientes com FC. Método: Realizou-se um estudo piloto, clínico experimental, prospectivo, aberto, ("open-label") com escalonamento de doses de solução de NaHCO3 em pacientes com FC. Após 2-4 semanas de rastreio cada paciente recebeu, por via inalatória, bicarbonato de sódio a 4,2% por 30 dias, sendo: 1x/dia por 15 dias e 2xs/dia nos 15 dias seguintes. A seguir a dose de NaHCO3 foi aumentada para 8,4% (2xs/dia) por 15 dias e 15 dias sem inalações. Antes, durante e após os períodos de inalações com NaHCO3 todos os pacientes foram submetidos a: i) Coleta de escarro para análise de reologia, pH do escarro e presença de bactérias;; ii) Espirometria; iii) Teste do degrau (Harvard Step Test); iv) Questionário sobre qualidade de vida, v) Questionário de dispneia. Hemograma completo e gasometria venosa foram coletados antes e após o final do estudo. Resultados: Finalizaram o estudo 12/19 pacientes com FC e colonização crônica por Pseudomonas aeruginosa e bronquiectasias, com idades 22,895 ± 6,749 anos; 9/19 (47,37%) eram femininos. A reologia do escarro mostrou os valores de 8,34 ± 3,49Pa e de 2,21±0,8 Pa, na visita pré e os valores de 5,39±1,42Pa e de 1,64±0,4Pa, na última visita, respectivamente, para os valores de elasticidade (G¿) e de viscosidade (G¿¿), (p=0,3) e (p=0,36). Na visita 1, houve diminuição da elasticidade na primeira coleta após inalação com NaHCO3 à 4,2% de concentração e que com o tempo a elasticidade aumentou (p= 0,02). Houve diminuição da elasticidade do escarro em todas as visitas na amostra coletada após as inalações, (p=0,04). Os valores de viscosidade não apresentaram diferenças estatísticas com o uso de NaHCO3 entre as visitas. Não houve diferença nos valores da viscoelasticidade (G*) do escarro considerando o aumento progressivo da dosagem, período de intervenção e coleta sucessiva em uma mesma visita (p>0,05). Os valores do pH aumentaram com o uso do bicarbonato nas secreções respiratórias, significativamente, na primeira coleta de secreção (logo após a inalação com NaHCO3) para terceira e quartas visitas, quando a solução de NaHCO3 foi de 8,4%. Após a primeira e a última coleta, de cada visita, os valores de pH retornavam próximos dos valores da consulta de triagem (sem bicarbonato). Verificamos que, no período de 120 minutos para coleta do escarro, houve maior valor do pH na primeira visita, em relação a segunda (p=0,003). Na quarta e quinta visita, a primeira coleta apresentou um maior valor de pH em relação aos demais tempos de coleta. Na avaliação semi-quantitativa das bactérias observamos que 5/12 pacientes apresentaram redução, 5/12 mantiveram os valores durante o estudo e 2 apresentaram aumento nos valores após as inalações com NaHCO3. O Volume Expiratório Forçado no primeiro segundo (VEF1) foi avaliado em todas as visitas e não houve diferença estatística significativa nos valores, o que indica que não houve mudanças na função pulmonar com o uso das inalações (p>0,05). Porém, observamos queda do VEF1 no grupo de indivíduos na situação grave e um aumento na situação moderada. Em relação as medidas do pico de fluxo, os pacientes também não apresentaram alterações significativas. No Harvard step test houve associação da intervenção com os biomarcadores VO2 (p=0,023) e gasto energético (p=0,025). O VO2 foi menor antes do período de intervenção, quando comparado ao período pós intervenção (p = 0,030). O gasto energético foi menor antes do período de intervenção, quando comparado ao período pós intervenção e maior depois do período de intervenção, quando comparado ao período durante a intervenção (p = 0,049). E o período durante a intervenção teve valores intermediários ao antes e depois da intervenção, havendo um valor crescente do gasto energético durante o estudo. No escore de qualidade de vida houve melhora na pontuação dos pacientes entre o período antes da intervenção e a visita 5 (p=0,017). No questionário de dispneia, os pacientes apresentaram melhora com escore de 20 para 11, no início e no final do estudo respectivamente, porém os dados não foram significativos. Os pacientes não apresentaram alterações nos parâmetros do hemograma e da gasometria venosa durante o estudo. Nenhum paciente apresentou efeito adverso grave, e nos parâmetros clínicos de FR; FC; SaO2 e temperatura corporal. Conclusão: As análises dos desfechos estudados encorajam a possibilidade de usar o NaHCO3 por via inalatória, como agente terapêutico no manejo da FC. Porém, os achados sugerem que mais estudos devam ser realizados e com tamanho amostral maior para aprofundar o entendimento nas mudanças nas características clínicas e laboratoriais do escarro com o uso da inalação com NaHCO3 em pacientes com FC, incluindo a reologia do escarroAbstract: Introduction: Qualitative and / or quantitative deficiency of the CFTR protein causes decreased secretion of sodium bicarbonate in the airways of individuals with cystic fibrosis (CF). Despite of the efficacy of bicarbonato of sodium, about sputum reology, function pulmonary and its strength bactericida being been very study in animals, lack studies was in human. Objective: To assess the safety, tolerability and side effects of inhaled bicarbonate, sputum, clinical and laboratory variables of CF patients. Method: An experimental, prospective and open label study with dose escalation of NaHCO3 solution was performed in CF patients. After 2-4 weeks of screening, each patient received 4.2% sodium bicarbonate for 30 days in the inhalation route, being: 1x /day for 15 days and 2x/day for the next 15 days. The NaHCO3 dose was then increased to 8.4% (2x/day) for 15 days and 15 days without inhalation. Before, during and after the periods of inhalation with NaHCO3 all patients were submitted to: i) Sputum collection for rheology analysis, sputum pH and presence of bactéria; ii) Spirometry; ii) Harvard Step Test; iv) Questionnaire on quality of life; v) Dyspnea Questionnaire. Complete blood count and venous blood gases were collected before and after the end of the study. Results: Completed the study of the study 12/19 patients with CF and chronic colonization by Pseudomonas aeruginosa and bronchiectasis, with 22.895 ± 6.749 years; 9/19 (47.37%) were female. The sputum rheology had values of 8.34 ± 3.49 Pa and 2.21 ± 0.8 Pa, at the pre visit and values of 5.39 ± 1.42 Pa and 1.64 ± 0, 4Pa, at the last visit, for the values of elasticity (G ') and viscosity (G' '), (p = 0,3) and (p = 0,36). At visit 1, there was a decrease in elasticity in the first measurement after inhalation at 4.2% NaHCO3 concentration and with increased elasticity with the increase the time (p = 0.02). There was decrease elasticity of sputum at all visits in the sample collected after inhalation, (p = 0.04). Viscosity values were not present statistical difference with the use of NaHCO3 between visits. There was no difference in sputum viscoelasticity (G *) values considering the progressive increase of the dosage, intervention period and successive collection in the same visit (p> 0.05). The pH values increased with the use of bicarbonate in respiratory secretions, significantly at the first collection of secretion (shortly after inhalation with NaHCO3) for third and fourth visits, when the NaHCO3 solution was 8.4%. After the first and last collection of each visit, the pH values returned to the values of the screening. We verified that in the period of 120 minutes for sputum collection, there was a higher pH value at the first visit, in relation to the second visit (p = 0.003). In the fourth and fifth visits, the first collection presented a higher pH value in relation to the other collection times. In the semi-quantitative evaluation of bacteria, the values of 5/12 increased, 5/12 maintained values during the study and 2 values increase after the inhalations with NaHCO3. Forced Expiratory Volume in the first second (FEV1) was evaluated at all visits and there was no statistically significant difference in the values, indicating that there were no changes in pulmonary function with the use of inhalations (p> 0.05). However, we observed a decrease in FEV1 in the group of individuals in the severe situation and an increase in the moderate situation. Regarding peak flow measurements, the patients also did not present significant alterations. The Harvard step test there was association of intervention with the biomarkers VO2 (p = 0.023) and work (p = 0.025). The VO2 was lower before the intervention period when compared to the post-intervention period (p = 0.030) and the work was lower before the intervention period when compared to the post-intervention period (p = 0.049), work was higher after (p = 0.049), and the period during the intervention had intermediate values before and after the intervention, with an increasing value of work during the study. In the score of quality of life there was improve in the score between the period before the intervention and the visit 5 (p = 0,017). In the aspect of dyspnea, the patient with the score of 20 to 11, at the beginning and at the end of the study. The patients are not present change in the parameters of the hemogram and venous blood gases during the study. No patient presented severe side effects collateral, and the clinical results of heart rate; respiratory frequence; oxygen saturation and body temperature. Conclusion: The analysis of endpoints studied encourages the possibility of using NaHCO3 by the inhalation route, as a therapeutic agent in the management of CF. However, the findings suggest that further studies should be performed with a larger sample size to deepening understanding of changes in sputum clinical and laboratory characteristics with the use of NaHCO3 inhalation in CF patients, including sputum rheologyDoutoradoSaude da Criança e do AdolescenteDoutora em Ciências374949/2014-0CNP

Evaluation of a medical program: the students' perspective

Sem informação65674074

Polyphasic identification and typing Trichophytum rubrum strains of clinical origin

The dermatophyte Trychophytum rubrum is the most frequent aetiological agent of dermatophytosis in humans around the world representing a major public health problem, not just for European countries but also for tropical countries where climate conditions allow major propagation for this ascomycete. For instance, in Portugal, T. rubrum was the dermatophyte most frequently isolated (83.3%) in a toenail onychomycosis geriatric population survey [1]. The identification, pathogenicity, biology, and epidemiology of T. rubrum, is of interest for both dermatologists and medical mycologists [1,2]. Currently, in many countries and clinical laboratories, the T. rubrum strains isolated from lesions are primarily identified by conventional culture-based methods, including colony morphology and slide culture only. This approach does not provide evidence of intraspecific variations with a lack of information to track infections, determine common sources of infections and recurrence or reinfection after treatment, and analyse their virulence and drug resistance [3]. The aim of this work is to use a polyphasic approach to study T. rubrum from different geographic origins in order to identify intraspecific characteristics with clinical interest. Materials and Methods About 40 European and South American T. rubrum and reference strains were used. Macro and micro morphological techniques, urease assay, dermatophyte milk agar test and hair perforation test (HPT) where combined with molecular biology techniques, such as the analysis of internal transcribed spacer (ITS) region, Trubrum specific primers for species differentiation among close related species, mating type MAT1-1 -box characterisation and DNA fingerprinting (e.g., (GACA)4). Results and conclusions Culturally T. rubrum strains showed on the plates white and cottony colonies on the obverse and blood-red pigment on the reverse. T. rubrum strains were urease negative and inhibited in dermatophyte milk agar. In the HPT, which is useful to differentiate T. rubrum from T. interdigitale, any strain was able to perforate the hair despite normal growth being observed. The analysis of ITS region confirmed all the strains as a T. rubrum species as well as the Trubrum primers generate a typical amplicon of 200 bp. The DNA fingerprinting is now explored in order to find the best approach to differentiate intraspecific variations and/or geographic differences. In conclusion, there are several techniques that can be applied to identify and characterise T. rubrum from different origins depending of the technologies available in each clinical laboratory or country.info:eu-repo/semantics/publishedVersio

Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis.

BACKGROUND:Among the many consequences of loss of CFTR protein function, a significant reduction of the secretion of bicarbonate (HCO3-) in cystic fibrosis (CF) is a major pathogenic feature. Loss of HCO3- leads to abnormally low pH and impaired mucus clearance in airways and other exocrine organs, which suggests that NaHCO3 inhalation may be a low-cost, easily accessible therapy for CF. OBJECTIVE:To evaluate the safety, tolerability, and effects of inhaled aerosols of NaHCO3 solutions (4.2% and 8.4%). METHODS:An experimental, prospective, open-label, pilot, clinical study was conducted with 12 CF volunteer participants over 18 years of age with bronchiectasis and pulmonary functions classified as mildly to severely depressed. Sputum rheology, pH, and microbiology were examined as well as spirometry, exercise performance, quality-of-life assessments, dyspnea, blood count, and venous blood gas levels. RESULTS:Sputum pH increased immediately after inhalation of NaHCO3 at each clinical visit and was inversely correlated with rheology when all parameters were evaluated: [G' (elasticity of the mucus) = - 0.241; G″ (viscosity of the mucus) = - 0.287; G* (viscoelasticity of the mucus) = - 0.275]. G* and G' were slightly correlated with peak flow, forced expiratory volume in 1 s (FEV1), and quality of life; G″ was correlated with quality of life; sputum pH was correlated with oxygen consumption (VO2) and vitality score in quality of life. No changes were observed in blood count, venous blood gas, respiratory rate, heart rate, peripheral oxygen saturation of hemoglobin (SpO2), body temperature, or incidence of dyspnea. No adverse events associated with the study were observed. CONCLUSION:Nebulized NaHCO3 inhalation appears to be a safe and well tolerated potential therapeutic agent in the management of CF. Nebulized NaHCO3 inhalation temporarily elevates airway liquid pH and reduces sputum viscosity and viscoelasticity

A search for ultra-high-energy photons at the Pierre Auger Observatory exploiting air-shower universality

The Pierre Auger Observatory is the most sensitive detector to primary photons with energies above ∼0.2 EeV. It measures extensive air showers using a hybrid technique that combines a fluorescence detector (FD) with a ground array of particle detectors (SD). The signatures of a photon-induced air shower are a larger atmospheric depth at the shower maximum (X$_{max}$) and a steeper lateral distribution function, along with a lower number of muons with respect to the bulk of hadron-induced background. Using observables measured by the FD and SD, three photon searches in different energy bands are performed. In particular, between threshold energies of 1-10 EeV, a new analysis technique has been developed by combining the FD-based measurement of X$_{max}$ with the SD signal through a parameter related to its muon content, derived from the universality of the air showers. This technique has led to a better photon/hadron separation and, consequently, to a higher search sensitivity, resulting in a tighter upper limit than before. The outcome of this new analysis is presented here, along with previous results in the energy ranges below 1 EeV and above 10 EeV. From the data collected by the Pierre Auger Observatory in about 15 years of operation, the most stringent constraints on the fraction of photons in the cosmic flux are set over almost three decades in energy

Study on multi-ELVES in the Pierre Auger Observatory

Since 2013, the four sites of the Fluorescence Detector (FD) of the Pierre Auger Observatory record ELVES with a dedicated trigger. These UV light emissions are correlated to distant lightning strikes. The length of recorded traces has been increased from 100 μs (2013), to 300 μs (2014-16), to 900 μs (2017-present), to progressively extend the observation of the light emission towards the vertical of the causative lightning and beyond. A large fraction of the observed events shows double ELVES within the time window, and, in some cases, even more complex structures are observed. The nature of the multi-ELVES is not completely understood but may be related to the different types of lightning in which they are originated. For example, it is known that Narrow Bipolar Events can produce double ELVES, and Energetic In-cloud Pulses, occurring between the main negative and upper positive charge layer of clouds, can induce double and even quadruple ELVES in the ionosphere. This report shows the seasonal and daily dependence of the time gap, amplitude ratio, and correlation between the pulse widths of the peaks in a sample of 1000+ multi-ELVES events recorded during the period 2014-20. The events have been compared with data from other satellite and ground-based sensing devices to study the correlation of their properties with lightning observables such as altitude and polarity

Studies of the mass composition of cosmic rays and proton-proton interaction cross-sections at ultra-high energies with the Pierre Auger Observatory

In this work, we present an estimate of the cosmic-ray mass composition from the distributions of the depth of the shower maximum (Xmax) measured by the fluorescence detector of the Pierre Auger Observatory. We discuss the sensitivity of the mass composition measurements to the uncertainties in the properties of the hadronic interactions, particularly in the predictions of the particle interaction cross-sections. For this purpose, we adjust the fractions of cosmic-ray mass groups to fit the data with Xmax distributions from air shower simulations. We modify the proton-proton cross-sections at ultra-high energies, and the corresponding air shower simulations with rescaled nucleus-air cross-sections are obtained via Glauber theory. We compare the energy-dependent composition of ultra-high-energy cosmic rays obtained for the different extrapolations of the proton-proton cross-sections from low-energy accelerator data

Study of downward Terrestrial Gamma-ray Flashes with the surface detector of the Pierre Auger Observatory

The surface detector (SD) of the Pierre Auger Observatory, consisting of 1660 water-Cherenkov detectors (WCDs), covers 3000 km2 in the Argentinian pampa. Thanks to the high efficiency of WCDs in detecting gamma rays, it represents a unique instrument for studying downward Terrestrial Gamma-ray Flashes (TGFs) over a large area. Peculiar events, likely related to downward TGFs, were detected at the Auger Observatory. Their experimental signature and time evolution are very different from those of a shower produced by an ultrahigh-energy cosmic ray. They happen in coincidence with low thunderclouds and lightning, and their large deposited energy at the ground is compatible with that of a standard downward TGF with the source a few kilometers above the ground. A new trigger algorithm to increase the TGF-like event statistics was installed in the whole array. The study of the performance of the new trigger system during the lightning season is ongoing and will provide a handle to develop improved algorithms to implement in the Auger upgraded electronic boards. The available data sample, even if small, can give important clues about the TGF production models, in particular, the shape of WCD signals. Moreover, the SD allows us to observe more than one point in the TGF beam, providing information on the emission angle