Asociación de experiencias adversas en la infancia con síntomas de asma en niños. Revisión bibliográfica / Association of adverse childhood experiences with asthma symptoms in children. A literature review

Las experiencias adversas en la infancia (EAI) tienen un impacto considerable en la salud física y mental de los niños y adolescentes. Esta revisión bibliográfica se centra en la asociación entre estas experiencias y la incidencia de síntomas asmáticos, así como en las alteraciones inmunológicas en la población pediátrica. Los estudios revisados muestran una correlación significativa entre la exposición a EAI y el asma, destacando la importancia de un enfoque biopsicosocial para su manejo. Además, se discuten las implicancias clínicas y las precauciones necesarias al interpretar estos hallazgos.

Adverse childhood experiences (ACEs) have a significant impact on the physical and mental health of children and adolescents. This literature review focuses on the association between these experiences and the incidence of asthma symptoms, as well as immunological alterations in the pediatric population. The reviewed studies show a significant correlation between ACE exposure and asthma, highlighting the importance of a biopsychosocial approach for its management. Additionally, the clinical implications and necessary precautions when interpreting these findings are discussed.

¿Cómo llega el paciente asmático al servicio de emergencias? Datos del estudio multicéntrico SABINA EMERGENCIAS / How Does the Asthmatic Patient Arrive at the Emergency Department? Data from the SABINA EMERGENCIAS Multicenter Study

Introducción: Los objetivos del control del asma son prevenir la aparición de síntomas y reducir el riesgo de exacerbaciones y mortalidad mediante educación médica, técnica inhalatoria, adherencia a medicación controladora e indicación de planes de acción (PA); pero los pacientes enfrentan exacerbaciones de diversa gravedad. Objetivos: El objetivo principal del estudio SABINA EMERGENCIAS fue describir la forma en que los pacientes concurren al servicio de emergencias (SE), considerando la frecuencia y uso de medicación de rescate. Objetivos secundarios: consultas al SE; uso de corticoides sistémicos (CS), agonistas beta-2 de acción corta (SABA) y tratamiento controlador; disponibilidad de PA. Material y Métodos: Estudio transversal, observacional, descriptivo, en cuatro hospitales del área metropolitana de Buenos Aires en adultos con asma. Resultados: n=323 (edad: 43,7±16,8 años; mujeres: 66,6%): 61,3% no eran seguidos por especialistas; 90,1% utilizaron SABA como rescate (mediana:10 inhalaciones; rango 0-100) la semana previa; 75,9% tuvieron ≥1 consulta al SE el año previo (mediana:2 [0-100]); 29,4% habían sido hospitalizados; 59,1% recibieron ≥1 ciclo de CS; mediana de consumo de SABA: 3 envases/año (0-23); 51,7% habían utilizado ≥3 envases; 30% no empleaban tratamiento de mantenimiento (23% usaba SABA); 75,9% no efectuaban terapia regular de mantenimiento; 77,1% no contaban con PA. Conclusión: Una reducida proporción de pacientes asmáticos que concurren al SE son seguidos por médicos especialistas, con alto consumo y elevada frecuencia de aplicación de SABA como rescate y baja adherencia al tratamiento de mantenimiento. Se remarca la necesidad de optimizar el manejo, con énfasis en la derivación al especialista, adherencia al tratamiento y prescripción de PA.

Introduction: The objectives of asthma control are to prevent the onset of symptoms and reduce the risk of exacerbations and mortality through medical education, inhaler technique, adherence to controller medication and indication of action plans (AP); but patients experience exacerbations of varying severity. Objective: The main objective of the SABINA EMERGENCIAS study was to describe how patients attend the emergency department (ED), considering the frequency and use of rescue medication. Secondary objectives: ED visits; use of systemic corticosteroids (SC), short-acting beta-2 agonists (SABA) and controller therapy; availability of AP. Methods: Cross-sectional, observational, descriptive study in 4 hospitals in the metropolitan area of Buenos Aires in adults with asthma. Results: n=323 (age:43.7±16.8 years; women:66.6%): 61.3% were not followed by specialists; 90.1% used SABA as rescue medication (median:10 puffs; range 0-100) the previous week; 75.9% had ≥1 visit to the ES the previous year (median: 2 [0-100]); 29.4% had been hospitalized; 59.1% received ≥1 cycle of CS; median SABA consumption: 3 cannisters/year (0-23); 51.7% had used ≥3 cannisters; 30% did not use maintenance therapy (23% used SABA); 75.9% did not perform regular maintenance therapy; 77.1% did not have an AP. Conclusion: A small proportion of asthmatic patients attending the ES are followed by specialist physicians, with high consumption and high frequency of SABA application as rescue medication and low adherence to maintenance treatment. The need to optimize management is highlighted, with emphasis on referral to specialists, adherence to treatment and prescription of APs.

[Epidemiological profile of allergic respiratory disease in Mexican children]. / Perfil epidemiológico de la enfermedad respiratoria alérgica en niños mexicanos.

OBJECTIVE: Report the prevalence and severity of the most common allergic diseases in children living in Monterrey, México. METHODS: Cross-sectional multi-center survey on the most common allergic diseases, completed by parents of 6-7-year-old children and by 13-14- year-old adolescents in the Monterrey metropolitan area, between January 2018 and December 2019. RESULTS: A total of 3,044 questionnaires were eligible for the analysis. Among children between 6-7 years old, 30.2% (n = 143/473) presented wheezing at any time in their life; with a higher prevalence in the male population. In the adolescent group, 26.4% reported having experienced wheezing at some point in their life, with a slight predominance in the female group (54.9%). CONCLUSIONS: Knowing the prevalence of allergic diseases in our population gives us tools to generate strategies that allow us to provide the best quality healthcare to our patients.

OBJETIVO: Reportar la prevalencia y gravedad de las enfermedades alérgicas más comunes en niños residentes en Monterrey, México. MÉTODOS: Encuesta multicéntrica transversal, acerca de las enfermedades alérgicas más comunes, completada por padres de niños de 6 aa 7 años y por adolescentes de 13 a 14 años del área metropolitana de Monterrey, entre enero de 2018 y diciembre de 2019. RESULTADOS: Un total de 3044 cuestionarios fueron elegibles para el análisis. Entre los niños de 6-7 años, 30.2% (n = 143/473) manifestaron sibilancias en algún momento de su vida; con mayor prevalencia en la población masculina. En el grupo de adolescentes el 26.4% refirió haber tenido sibilancias alguna vez en su vida, con un ligero predominio en el grupo femenino (54.9%). CONCLUSIONES: Conocer la prevalencia de las enfermedades alérgicas en la población brinda herramientas para generar estrategias para la mejor calidad asistencial en los pacientes.

[Severe asthma: Pathophysiology, diagnosis, and treatment]. / Asma grave: fisiopatología, diagnóstico y tratamiento.

Severe asthma is an entity with a complex diagnosis, requiring an adequate differential diagnosis and identification of endotypes for a correct approach and therapeutic process. In the present review, we show a synthesis of the current literature on the diagnosis, pathophysiology, and management of severe asthma, having critically analyzed the evidence in search engines such as Medline, Scopus, and Embase.

El asma grave es una enfermedad compleja, que requiere un enfoque y diagnóstico diferencial ordenado e identificación de endotipos para el correcto abordaje y tratamiento. El tratamiento farmacológico cuenta cada vez con más moléculas a disposición del personal médico para el control efectivo de los síntomas. Esta revisión muestra una síntesis de la bibliografía actual acerca del diagnóstico, fisiopatología y tratamiento del asma grave, mediante la lectura crítica previa de la evidencia científica en buscadores como Medline, Scopus y Embase.

Comparison of the effects of high-flow nasal cannula and bilevel positive airway pressure treatments as respiratory physiotherapy interventions for children with asthma exacerbation: a randomized clinical trial.

OBJECTIVE: A high-flow nasal cannula is a practical and safe instrument that can be used for children with asthma exacerbation and promotes beneficial outcomes such as improved asthma severity scores and reduced hospitalization durations, salbutamol use, and oxygen use. To evaluate and compare the efficacy of high-flow nasal cannula treatment and that of bilevel positive airway pressure treatment as respiratory physiotherapy interventions for pediatric patients who are hospitalized because of asthma exacerbation. METHODS: During a randomized clinical trial, treatment was performed using a high-flow nasal cannula and bilevel positive airway pressure for hospitalized children with asthma. After randomization, data regarding lung function, vital signs, and severity scores (pulmonary index, pediatric asthma severity, and pediatric asthma scores) were collected. RESULTS: Fifty patients were included in this study (25 in the Bilevel Group and 25 in the high-flow nasal cannula group). After 45 minutes of therapy, an improvement in the forced expiratory volume in 1 second was observed. The high-flow nasal cannula group required fewer days of oxygen (O2) use, used fewer bronchodilators (number of salbutamol puffs), and required shorter hospitalization periods than the Bilevel Group (6.1±1.9 versus 4.3±1.3 days; 95% confidence interval, -5.0 to -0.6). CONCLUSION: A high-flow nasal cannula is a viable option for the treatment of asthma exacerbation because it can reduce the hospitalization period and the need for O2 and bronchodilators. Additionally, it is a safe and comfortable treatment modality that is as effective as bilevel positive airway pressure.ClinicalTrials.gov Identifier: NCT04033666.

Can Breastfeeding Prevent Long-Term Overweight and Obesity in Children? A Population-Based Cohort Study.

The aims of this study were to assess the impact of exclusive breastfeeding up to 6 months of age on reducing the incidence of overweight and obesity in children up to 10 years of age and to estimate the annual incidence of obesity and overweight in the study population. Our retrospective cohort analysis using electronic health records included children from zero to ten years old, born between 1 January 2006 and 31 December 2022, followed up at the Unidade Local de Saúde de Matosinhos (ULSM). Information on their comorbidity history was collected, and positive or negative control results were defined. In the first year of life, around 29% of the children on exclusive breastfeeding were obese and 20% were overweight. This trend was reversed by the age of 9. Asthma and allergic rhinitis were used as positive control outcomes and allergic dermatitis as a negative control outcome. There seems to be no relationship between exclusive and non-exclusive breastfeeding and the development of overweight or obesity at the age of 10. The results showed that breastfeeding is associated with a lower risk of asthma in the future.

[The silent correlate of rhinitis on lower airway]. / El impacto silencioso de la rinitis sobre la vía aérea inferior.

The respiratory tract, from the nose to the lung, behaves as an anatomical and pathophysiological unit under a holistic model. Lower airway abnormalities, such as bronchial hyperresponsiveness, reduced lung function and inflammation of the bronchial mucosa without clinical expression, have been observed in patients with rhinitis without asthma. These would be the consequence of a common systemic inflammatory phenomenon with simultaneous impact on the nose and lung. For unknown reasons, these patients do not exhibit a full clinical expression, which could mean an increased risk of developing asthma. In this review we address the frequency and characteristics of existing pulmonary abnormalities in children and adolescents with chronic rhinitis that derive from our previous research and, more recently, within the project "Allergic Respiratory Disease: The United Airway Concept" supported by the Universidad Católica de Córdoba, and a comparative analysis with the evidence provided by other authors in the medical literature.

El aparato respiratorio, desde la nariz al pulmón, se comporta como una unidad anatómica y fisiopatológica bajo un modelo holístico. Se han observado alteraciones pulmonares sin traducción clínica en pacientes con rinitis sin asma, que se manifiestan como hiperreactividad bronquial, reducción de la función pulmonar e inflamación bronquial. Estas serían consecuencia de un fenómeno inflamatorio sistémico con impacto simultáneo en nariz y pulmón, que por razones desconocidas no tiene una expresión clínica completa, pero que podrían significar un mayor riesgo de desarrollo de asma. En esta revisión abordamos la frecuencia y características de las anormalidades pulmonares existentes en niños y adolescentes con rinitis crónica derivadas de nuestras investigaciones previas y, más recientemente, del proyecto "Enfermedad Alérgica Respiratoria: El Concepto de Unidad de la Vía Aérea", línea de investigación acreditada por la Universidad Católica de Córdoba y un análisis comparativo con las evidencias aportadas por otros autores en la literatura médica.

Relation between air quality and asthma in high-altitude places, La Paz, Bolivia (3,600 m a.s.l.) / Relación entre la calidad del aire y el asma en habitantes de grandes altitudes, La Paz, Bolivia (3.600 m.s.n.m.).

Introduction. Asthma is a chronic disease affecting millions of people around the world. Air quality is a major factor in triggering asthma symptoms. Objective. To analyze air quality and asthma in high-altitude residents of La Paz, Bolivia. Materials and methods. In this analytical, descriptive, and retrospective study, we collected data from patients diagnosed with asthma at the Instituto Nacional del Tórax and the Instituto Boliviano de Biología de Altura. In addition, air quality monitoring of particulate matter was carried out at the stations of the Red de Monitoreo de la Calidad del Aire. Results. Women represented 56.9% of cases at the Instituto Nacional del Tórax and the Instituto Boliviano de Biología de Altura. In both institutions, the average age was 47 years and patients were overweight or obese. Increases in PM2.5 were recorded in autumn, winter and spring from 2014, 2016 to 2019 and 2015 in all four seasons. PM10 showed increases in autumn and winter from 2014 to 2020 within the established limits. We observed a positive and significant association between PM2,5 concentration and the spirometry parameters of forced vital capacity, peak expiratory flow, and "reversibility percentage" or "bronchodilator response percentage". The association of PM10 and forced vital capacity, forced expiratory volume in the first second, and peak expiratory flow, was also statistically significant. Conclusion. Asthma cases occur on average at 47 years of age in overweight or obese people. We observed a positive association between particles PM2,5 and PM10 with spirometric parameters, stronger with particulate matter PM2,5.

Introducción. El asma es una enfermedad crónica que afecta a millones de personas en todo el mundo. La calidad del aire es uno de los factores clave que puede desencadenar los síntomas del asma. Objetivo. Analizar la calidad del aire y su relación con el asma en habitantes de grandes altitudes en La Paz (Bolivia). Materiales y métodos. Se desarrolló un estudio analítico, descriptivo y retrospectivo. Se recolectaron datos de pacientes con diagnóstico de asma en el Instituto Nacional del Tórax y en el Instituto Boliviano de Biología de Altura. Además, se monitoreó la calidad del aire y su material particulado en las estaciones de la "Red de monitoreo de la calidad del aire". Resultados. El 56,9 % de los casos fueron mujeres del Instituto Nacional del Tórax y el 45,7 % del Instituto Boliviano de Biología de Altura. En ambas instituciones, la media de edad fue de 47 años y los pacientes presentaban sobrepeso u obesidad. Se registraron incrementos de material particulado fino (PM2,5) en otoño, invierno y primavera, en 2014, 2016-2019 y en las cuatro estaciones del 2015. El material particulado inhalable grueso (PM10) se incrementó en otoño e invierno del 2014 al 2020, dentro de los límites establecidos. Se observó una asociación positiva y significativa entre la concentración de material particulado PM2,5 y los parámetros espirométricos de capacidad vital forzada, flujo espiratorio máximo y el porcentaje de reversión. La relación de partículas PM10 y los parámetros espirométricos de capacidad vital forzada, volumen espiratorio máximo en el primer segundo y flujo espiratorio máximo, también fue estadísticamente significativa. Conclusión. Los casos de asma se presentaron en promedio a los 47 años y en personas con sobrepeso u obesidad. Se observó una asociación positiva entre el material particulado, PM2,5 y PM10, con los parámetros espirométricos, la cual fue más marcada con las partículas PM2,5.

Effect of photobiomodulation in an experimental in vitro model of asthma-Copd overlap.

The objective of the study was to evaluate the effect of photobiomodulation (PBM) with laser on the inflammatory process in an experimental in vitro model of ACO. The groups were: (1) human bronchial epithelial cells (BEAS-2B); (2) BEAS-2B cells treated with dexamethasone; (3) BEAS-2B cells irradiated with laser; (4) BEAS-2B cells stimulated with cigarette smoke extract (CSE) + House Dust Mite (HDM); (5) BEAS-2B cells stimulated with CSE + HDM and treated with dexamethasone; (6) BEAS-2B cells incubated with CSE + HDM and irradiated with laser. After 24 h, cytokines were quantified. There was a reduction in TNF-α, IL-1ß, IL-6, IL-4, IL-5, IL-13, IL-17, IL-21, IL-23, and an increase in IL-10 and IFN-γ in cells from the laser-irradiated ACO group compared to only ACO group. With these results, we can suggest that photobiomodulation acts in the modulation of inflammation observed in ACO, and may be a treatment option.

Sustained clinical and histopathological remission in a patient with eosinophilic esophagitis and type-2 comorbidities at 18 months after discontinuation of dupilumab.

Eosinophilic esophagitis (EoE) is a chronic, allergen-mediated, type-2 inflammatory disease with the potential to significantly impact an individual's quality of life. Conventional treatments often result in varied responses, prompting the need for novel therapeutic approaches. We present the case of a 19-year-old male with a medical history marked by eosinophilic esophagitis, severe atopic dermatitis (AD), asthma, and allergic rhinitis. Despite undergoing diverse topical and systemic interventions to address his AD and EoE, the patient's symptoms persisted. However, following the initiation of dupilumab therapy-a dual IL-4 and IL-13 receptor antagonist-the patient experienced a substantial reduction in his Eczema Area and Severity Index score. Notably, a marked improvement was also seen regarding his symptoms of eosinophilic esophagitis. A subsequent esophageal biopsy revealed a significant decrease in eosinophilic inflammation, consistent with established clinical and histologic remission criteria. These findings corroborate the patient's reported relief from symptoms. This case underscores the potential efficacy of dupilumab as a promising therapeutic agent in managing eosinophilic esophagitis. Dupilumab offers a dual benefit of alleviating symptoms and achieving histologic and clinical remission. This novel approach presents a noteworthy advancement in the treatment of EoE.

Effects of using wearable devices to monitoring physical activity in pulmonary rehabilitation programs for chronic respiratory diseases: A systematic review protocol.

INTRODUCTION: Pulmonary rehabilitation (PR) is an intervention aimed at the comprehensive care of individuals with chronic respiratory diseases. Patients with chronic obstructive pulmonary disease (COPD) and asthma present low levels of physical fitness because they avoid physical exercises due to the fear of triggering recurrent symptoms. Wearable devices have been integrated into behavioral modification interventions for physical activity in PR protocols. Therefore, this review aims to identify how wearable devices are being utilized for monitoring chronic respiratory diseases in pulmonary rehabilitation programs. METHODS AND ANALYSIS: Searches will be conducted on Medline, Cochrane Central Register of Controlled Trials, Embase (CENTRAL), CINAHL and PEDro electronic databases, as well as a search in the grey literature. We will include baseline data from randomized clinical trials reporting the use of wearable devices for monitoring physical activity in protocols for pulmonary rehabilitation programs for chronic respiratory diseases. Studies that discuss only the development of algorithms or applications for the assessment of diseases or unavailable full texts will be excluded. The main reviewer will conduct the initial search and exclusion of duplicates, while two independent reviewers will select studies, extract data, and assess the methodological quality using the PEDro tool. PROSPERO REGISTRATION NUMBER: CRD42024504137.

C-Phycocyanin Prevents Oxidative Stress, Inflammation, and Lung Remodeling in an Ovalbumin-Induced Rat Asthma Model.

Asthma is a chronic immunological disease related to oxidative stress and chronic inflammation; both processes promote airway remodeling with collagen deposition and matrix thickening, causing pulmonary damage and lost function. This study investigates the immunomodulation of C-phycocyanin (CPC), a natural blue pigment purified from cyanobacteria, as a potential alternative treatment to prevent the remodeling process against asthma. We conducted experiments using ovalbumin (OVA) to induce asthma in Sprague Dawley rats. Animals were divided into five groups: (1) sham + vehicle, (2) sham + CPC, (3) asthma + vehicle, (4) asthma + CPC, and (5) asthma + methylprednisolone (MP). Our findings reveal that asthma promotes hypoxemia, leukocytosis, and pulmonary myeloperoxidase (MPO) activity by increasing lipid peroxidation, reactive oxygen and nitrogen species, inflammation associated with Th2 response, and airway remodeling in the lungs. CPC and MP treatment partially prevented these physiological processes with similar action on the biomarkers evaluated. In conclusion, CPC treatment enhanced the antioxidant defense system, thereby preventing oxidative stress and reducing airway inflammation by regulating pro-inflammatory and anti-inflammatory cytokines, consequently avoiding asthma-induced airway remodeling.

Ecuadorian Provinces with High Morbidity and Mortality Rates Due to Asthma among the Working-Age Population: An Ecological Study to Promote Respiratory Health.

Asthma is a significant public health concern. This study identified the provinces with the highest morbidity and mortality rates due to asthma among the working-age population (15-69 years) in the Republic of Ecuador. The secondary objective was to explain the possible differences attributable to occupational exposure. This nationwide ecological study was conducted in 24 provinces between 2016 and 2019. Government databases were used as sources of information. Age-standardized rates were calculated for codes J45 and J46. The hospitalization morbidity rate for asthma decreased from 6.51 to 5.76 cases per 100,000 working-age population, and the mortality rate has consistently been low and stable from 0.14 to 0.15 deaths per 100,000 working-age population. Geographic differences between the provinces were evident. The risk of hospitalization and death due to asthma was higher in the Pacific coast (Manabí with 7.26 and 0.38, Esmeraldas with 6.24 and 0.43, Los Ríos with 4.16 and 0.40, El Oro with 7.98 and 0.21, Guayas with 4.42 and 0.17 and the Andean region (Azuay with 6.33 and 0.45, Cotopaxi (5.84 and 0.48)). The high rates observed in provinces with greater agricultural and industrial development could be national heterogeneity's main determinants and act as occupational risk factors. The contribution of occupational hazards in each province should be examined in depth through ad hoc studies. The findings presented here provide valuable information that should prompt further detailed studies, which will assist in designing public policies aimed at promoting and safeguarding the respiratory health of the population, particularly that of workers. We believe that this study will inspire the creation of regional networks for the research and surveillance of occupational health.

A critical analysis of the effect of OM-85 for the prevention of recurrent respiratory tract infections or wheezing/asthma from systematic reviews with meta-analysis.

Acute respiratory tract infections (RTIs) are one of the most common causes of pediatric consultations/hospitalizations and a major trigger for asthma exacerbations. Some consensus statements have recommended the use of immunostimulants to boost natural defenses against severe or repeated infections. One of the most common immunostimulants is OM-85; while several randomized clinical trials (RCTs) have evaluated its efficacy in preventing acute RTIs and wheezing/asthma exacerbations, results have been conflicting. Similarly, various systematic reviews with meta-analyses (SRMs) on OM-85 have used different strategies, populations, and outcomes; moreover, SRM conclusions are limited when the original studies are highly heterogeneous or have a low quality, hindering the generalizability of the findings. Here we summarize the evidence on the effect of OM-85 to prevent acute RTIs, wheezing/asthma episodes, or loss of asthma control in children, by including and critically evaluating all SRMs published to date. We searched for SRMs on OM-85 in three publication databases and found nine SRMs (seven for RTI, and two for wheezing/asthma). Among those, one had a high confidence evaluation of quality (AMSTAR-2 tool) and found a reduction in the total number of acute RTIs among the OM-85 group. Overall, no strong recommendations can be derived from the existing literature, mainly due to the high heterogeneity among included RCTs and SRMs. Further, large, high-quality RCTs are needed to confirm the true efficacy of OM-85 for the prevention of acute RTIs, asthma development, and asthma exacerbations.

Association and correlation of patient symptom perception and asthma control - a rapid literature review.

BACKGROUND: Several studies suggest that patients often under-estimate their asthma symptoms and over-estimate their level of asthma control, potentially putting them at risk of undertreatment with inhaled corticosteroids. OBJECTIVE: To determine the association and correlation between patient symptom perception and asthma control. METHODS: A rapid literature review comprising searches in MEDLINE, Embase and Cochrane Library identified English language articles published between 2011-2021 that included a statistical measure of the association or correlation between perceptions of symptoms and asthma control in patients with asthma (adults and/or children). [PROSPERO CRD42021230152]. The Joanna Briggs Institute (JBI) instrument was used for study quality appraisal. RESULTS: Of 22 identified studies, nine presented association data and 13 reported correlation analyses. Eight of nine association studies showed a discordance between patients perceived symptoms and level of asthma control or lung function; among these, patients more frequently overestimated their asthma control than they underestimated their asthma control. Of 10 studies reporting correlation coefficients, all reported a statistically significant correlation between increased symptoms and worse asthma control; however, the strength of the correlation was shown to be only weak or moderate in most studies (coefficients numerically ranged from 0.12 to 0.74). CONCLUSION: Many patients with asthma tend to overestimate their level of asthma control. Although more frequent or worse symptoms were shown to be statistically significantly correlated with worsening asthma control, there was wide variation in correlation strengths, most showing weak or moderate correlations. Research to further understand the reasons for patient symptom misperceptions are warranted.