Prevalence, T2 Biomarkers, and Cost of Severe Asthma in the Era of Biologics: The BRAVO-1 Study

Background: The last decade has seen new classifications of the pathophysiology of asthma that have changed the treatment options available. Objectives: To update data on the prevalence of T2 asthma, comorbidities, biomarker characterization, and costs of severe asthma in patients aged ≥12 years, taking into account new classifications and treatment options. Methods: Retrospective, observational, nationwide study using a top-down approach. Data were obtained from BIG-PAC®, an electronic medical record database of 1.7 million patients in Spain. The study population comprised patients aged ≥12 years who had received medical care during the period 2016-2017 and been diagnosed with asthma at least 1 year prior to the index date. Patients were followed for 1 year. Results: The prevalence of asthma was 5.5%. Asthma was severe in 3031 of these patients (7.7%), 81.2% of whom presented T2 asthma. Among patients with severe asthma, 64.1% had uncontrolled disease, 31.2% were oral corticosteroid–dependent (37% in the uncontrolled severe asthma group), and only 3.8% were receiving biologics. The most common T2 comorbidities were allergic rhinitis (66.1%), atopic dermatitis (29.1%), and chronic rhinosinusitis with nasal polyps (14.6%). Mortality rates in the total population and uncontrolled severe asthma groups were 4.2% and 5.5%, respectively. The total annual costs per patient with severe asthma were €5890 (uncontrolled) and €2841 (controlled). Conclusions: In the era of biologics, most severe asthma patients present T2 asthma. Despite the availability of new treatments, rates of oral corticosteroid–dependent patients with uncontrolled severe asthma remain high, although biologics continue to be underused. The costs of uncontrolled severe asthma are twice as high as those of controlled severe asthma. (AU)

Introducción: En la última década se han concadenado una serie de clasificaciones de la fisiopatología del asma que han cambiado las opciones de tratamientos disponibles. Objetivos: Actualizar los datos de prevalencia del asma T2, comorbilidades, caracterización de biomarcadores y costes del asma grave en pacientes ≥12 años en esta nueva situación. Métodos: Estudio retrospectivo, observacional y de ámbito nacional con un enfoque descendente. Los datos se obtuvieron de BIG-PAC®, una base de datos de historias clínicas electrónicas de 1,7 millones de pacientes en España. Se incluyeron pacientes ≥12 años que habían recibido atención médica durante el periodo 2016-2017 y que habían sido diagnosticados de asma al menos un año antes de la fecha índice y fueron seguidos durante un año. Resultados: La prevalencia del asma fue del 5,5%. De estos pacientes, 3.031 presentaban asma grave (7,7%), de los cuales el 81,2% presentaba asma T2. Entre los pacientes con asma grave, el 64,1% no estaban controlados, el 31,2% eran dependientes de corticosteroides orales (37% en el grupo de asma grave no controlada) y solo el 3,8% estaban en tratamiento con biológicos. Las comorbilidades T2 más frecuentes fueron la rinitis alérgica (66,1%), la dermatitis atópica (29,1%) y la rinosinusitis crónica con poliposis nasal (14,6%). Las tasas de mortalidad en los grupos de asma grave total y no controlada fueron del 4,2% y del 5,5%, respectivamente. Los costes totales anuales por paciente con asma grave fueron de 5.890 euros (no controlado) y 2.841 euros (controlado). Conclusiones: En la era de los biológicos, la mayoría de los pacientes con asma grave presentan asma T2. A pesar de la disponibilidad de nuevos tratamientos, las tasas de pacientes con asma grave no controlados y dependientes de corticosteroides orales siguen siendo altas, y los biológicos siguen estando infrautilizados. Los costes del asma grave no controlada duplican los del asma grave controlada. (AU)

Prevalence, T2-biomarkers and cost of severe asthma in the era of biologics: The BRAVO-1 study.

BACKGROUND AND OBJECTIVES: The last decade has seen a new era of classifications of asthma pathophysiology which have changed the treatment options available. To update the figures of prevalence of T2 asthma, comorbidities, biomarker characterization and costs of severe asthma in patients≥12-years-old adapted to this new situation. METHODS: Retroprospective, observational, nationwide study using a top-down approach. Data were obtained from the BIG-PAC®, an electronic medical record database of 1.7 million patients in Spain. Patients≥12-years-old who had received medical care during the period 2016-2017 and diagnosed with asthma at least one year prior to the index date were included and followed for one year. RESULTS: Prevalence of asthma was 5.5%. Of these patients, asthma was severe in 3.031 (7.7%), 81.2% of whom presented T2 asthma. Among severe asthma patients, 64·1% were uncontrolled, 31.2% were Oral corticosteroids-dependent (37% in the uncontrolled severe asthma group) and only 3.8% were on biologics. The most common T2 comorbidities were allergic rhinitis (66·1%), atopic dermatitis (29·1%) and chronic rhinositis with nasal polyps (14.6%). Mortality rates in the total and the uncontrolled severe asthma groups were 4.2% and 5.5% respectively. The total annual costs per patient with severe asthma were 5.890€ (uncontrolled) and 2.841€ (controlled). CONCLUSIONS: In the era of biologics, most severe asthma patients present T2 asthma. Despite the availability of new treatments, the rates of uncontrolled and oral corticosteroids-dependent patients with severe asthma remain high, but biologics still underused. The costs of uncontrolled severe asthma are twice as high as those of controlled severe asthma.

Anatomy, pathophysiology and classification of posterior tibial tendon dysfunction.

OBJECTIVE: Adult acquired flatfoot deformity is generally associated with a collapsing medial longitudinal arch and a progressive loss of strength of the posterior tibial tendon (PTT). This condition is commonly associated with PTT dysfunction or rupture, which can have an arthritic or a traumatic etiology. Several causes have been proposed to explain the clinical evidence of tendon degeneration observed at the time of surgery including trauma, anatomical, mechanical, inflammatory and ischemic factors. MATERIALS AND METHODS: In this review, we analyzed anatomy, pathophysiology and existing classifications of posterior tibial tendon dysfunction. RESULTS: Anatomical features, and in particular vascularization, expose PTT to major degenerative disorders until rupture. A literature overview showed that a low blood supply of the gliding part of the tendon is linked to a dysfunction and/or a rupture of the PTT in the region located behind the medial malleolus. CONCLUSIONS: PTT low blood supply causes a dysfunction resulting in an abnormal loading of the foot's medial structures. This may be the reason why PTT dysfunction leads to an acquired flatfoot deformity. Conversely, flatfoot deformity may be a predisposing factor for the onset of PTT dysfunction.

Effectiveness of omalizumab in non-allergic severe asthma.

Omalizumab is an effective drug for allergic asthma. The purpose of this study was to evaluate the effectiveness and tolerance of this drug in non-allergic GINA step V asthma patients. This study was single-centre, prospective, open-label, observational, naturalistic. Non-allergic asthma patients requiring a mean dose of oral prednisolone of at least 5 mg/day during greater than or equal to 1 year or an accumulated oral corticosteroid dose/year greater than or equal to 1500 mg were enrolled. At entry and the end of the 12-month follow-up we measured blood eosinophilia and IgE concentration; at every monthly visit a forced spirometry and exhaled fraction of nitric oxide (NO) were carried out. The subjects were seven adult patients (5 female), age range 37-63 years, with the following mean values: IgE: 226.7+/-176 IU/mL; FVC 74+/-18 percent; FEV1 57+/-11 percent; NO: 21.2+/-7 ppb. The study was approved by the IRB of the hospital. One patient decided to stop treatment after 12 weeks and was excluded from the evaluation. We did not observe changes in eosinophil count, spirometry or NO values. Three patients considered responders did not need prednisolone during the follow-up. The mean daily dose of prednisolone fell from 6.6+/-8.1 mg/day at entry to 1.5+/-2.3 mg/day (p less than 0.16) at the end of follow-up. The mean monthly accumulated dose fell from 92+/-112 to 12+/-26 mg/month (p=0.26). Total blood IgE increased 1.93-fold. Side effects were only local: treatment tolerance was excellent; three out of six patients seemed to slightly benefit from anti-IgE treatment; to date there is no evidence strong enough to systematically prescribe omalizumab in non-allergic asthma patients.

Rationale for the use of immunomodulatory therapies in the Global Initiative for Asthma (GINA) step V asthma other than oral glucocorticosteroids.

Asthma is a major problem worldwide, which is estimated to affect 300 million individuals. The global prevalence ranges from 1% to 18% of the population. The incidence, morbidity and mortality of the condition have increased over the last 50 years despite the development of new anti-asthmatic drugs. Fewer than 1% of the asthmatic population are steroid-dependent, but these patients consume most of the resources and time at asthma units. The consensus documents published by professional societies all support a stepwise therapeutic approach for asthma. However, patients who require frequent or continuous oral corticosteroid administration have received little attention. Due to the severe side-effects of oral corticosteroids when administered over long periods or at high doses, many drugs have been assessed in the search for a possible corticosteroid-sparing agent. Recently, the update of the Global Initiative for Asthma (GINA) introduced a new drug--omalizumab--as an alternative to oral corticosteroids in patients included in step V. Other alternatives include immunosuppressive drugs, among which methotrexate has been found to offer the best benefit/risk ratio. This paper will review, comment and criticize the evidence of the effectiveness of immunomodulatory drugs, as an alternative to oral glucocorticosteroid treatment in GINA step V asthma patients. The experience of the authors combined with the information of the literature will lead to the conclusion that methotrexate and omalizumab are the only advisable drugs and will clarify when and how these drugs should be used.

Chronic hypoxia induced ultrastructural changes in the rat adrenal zona glomerulosa.

The adrenal cortex plays an important role in adaptation to various forms of stress, including hypoxia. While physiological changes in the aldosterone metabolism during hypoxia have been extensively described, few studies have focused on the morphological changes in the adrenal glands under chronic hypoxia. We studied the ultrastructure of the zona glomerulosa of 6-month-old Wistar rats exposed to chronic normobaric hypoxia. Animals were divided into two groups: control (n=12) and hypoxic (n=12). In this latter group, the animals were kept at 7% O2 concentration after a gradual adaptation (21, 15, 12, 10, 8, 7 vol% O2). The duration of the study was 112 days. In comparison with normoxic rats, body weight and adrenal gland weight of hypoxic animals was significantly reduced by 18.5% (p=0.006) and 14.7% (p=0.001) respectively. The thickness of the zona glomerulosa decreased due to atrophy of cells. The main ultrastructural changes observed were: 1) a decrease in, or complete elimination of, lipid droplet content; 2) a marked increase in lysosome number; and 3) the presence of giant mitochondria. Our findings show that rats fail to adapt to severe chronic hypoxia. The ultrastructural changes in the zona glomerulosa found in the present study could reflect changes in the aldosterone pathway.

Experiencia de tutorías de alumnos con gran fracaso académico en su primer año en los estudios de medicina / Tutorship experience with medical students who had drastically failed the first year of their course

El presente artículo describe una experiencia de tutorías personalizadas llevadas a cabo en la Facultad de Medicina de la Universidad Autónoma de Barcelona con el objetivo de aumentar el éxito académico de los alumnos de primer curso que, durante el año anterior, habían tenido un gran fracaso académico. En la experiencia, llevada a cabo durante el curso 1997-1998, participaron de forma voluntaria 13 profesores y 19 alumnos. Los estudiantes fueron asignados de forma aleatoria a los diferentes tutores. Éstos debían orientar a los alumnos para optimizar sus aprendizajes y evitar un nuevo fracaso. La mayoría de los estudiantes participantes tuvieron un éxito total y sólo uno de ellos volvió a tener un gran fracaso. Así mismo, la mayoría de estudiantes en la misma situación que no habían participado en la experiencia volvieron a fracasar. A partir de los resultados obtenidos y de la satisfacción de los participantes, la experiencia fue valorada como muy positiva (AU)

An anatomical study of anastomoses between the laryngeal nerves.

OBJECTIVE: To systematize the anatomy of the connecting branches between laryngeal nerves. METHODS: Microdissection of 90 larynges obtained from necropsies (57 men and 33 women; age range, 41-95 y). RESULTS: Anastomoses between the internal and recurrent nerves appeared in four different patterns: 1) Galen's anastomosis, as the connection between the dorsal branches of both nerves (100%); 2) arytenoid plexus, as the connection between the arytenoid branches of both nerves, in relation with the arytenoid muscle, and divided in a deep part (100%) and a superficial part (86%); 3) cricoid anastomosis, previously only described in cows, located in the front of the cricoid lamina (6/10 cases); and 4) thyroarytenoid anastomosis, as the connection of a descending branch of the internal laryngeal nerve and an ascending branch of the recurrent nerve (14%). Anastomosis between the internal laryngeal and the external laryngeal nerves appeared as a connecting branch throughout the foramen thyroideum (21%). Anastomosis between the external laryngeal and recurrent nerves appeared as a connecting branch throughout the cricothyroid muscle (68%). CONCLUSION: At least two anastomoses (Galen's anastomosis and arytenoid plexus) appeared in 21% of hemilarynges, and 79% of cases had three or more anastomoses between the laryngeal nerves. The different prevalence of this complex anastomotic pattern suggests functional differences in the sensory and motor innervation of individual subjects.

Idiopathic azygos vein aneurysm: a rare cause of mediastinal mass.

Venous aneurysm of the azygos arch is a very rare cause of mediastinal mass and is usually an incidental finding on chest radiography. Nowadays the diagnosis is made by non-invasive tests such as thoracic CT scanning and/or magnetic resonance imaging. The case is described of an asymptomatic woman in whom a mediastinal mass due to an azygos vein aneurysm was diagnosed by non-invasive procedures, the aetiology of which, in all probability, was idiopathic.

Right coronary artery arising from the left aortic sinus in a heart with left coronary dominance: a post-mortem description--a case report.

The authors report the post-mortem description of the coronary arterial circulation of an 81-year-old man. The heart showed a concordant atrioventricular and ventricle-arterial disposition. The coronary artery distribution presented left dominance. No myocardial scars were observed. The ostium of the right coronary artery (RCA) was located in the left aortic sinus just in front of the opening of the left coronary artery. The ostium was slit-like and its maximum diameter was 5 mm. The RCA began between the aorta and the pulmonary trunk and ended as a small right marginal artery. The absence of heart disease and the man's survival until an advanced age were probably due to the fact that the RCA supplied only a small portion of the right ventricle, given the left coronary dominance.

[Pulmonary hypoplasia in adults: embryology, clinical presentation and diagnostic methods. Our experience and review of the literature]. / Hipoplasia pulmonar en el adulto: embriología, presentación clínica y métodos diagnósticos. Experiencia propia y revisión de la literatura.

We report five patients diagnosed of pulmonary hypoplasia (PH) in adulthood (age > 18 years, range 45 to 67 years). PH was left-sided in four cases. The malformations found were 2 cases of renal agenesis, 2 diaphragmatic hernias and 1 hiatal hernia. Lung function data were FEV1 0.88 +/- 0.32 L; FVC 1.30 +/- 0.52 L; FEV 1/FVC 68.5 +/- 5%. Arterial gases (with FiO2 0.21) were PaO2 63.6 +/- 24 and PaCO2 47.1 +/- 11.2 mmHg. Three cases were referred for monitoring of respiratory insufficiency (2 requiring home oxygen therapy) and two for radiographic study of chest disease. The diagnoses were made by computerized tomography (CT) of the chest. Congenital diseases due to underdeveloped lungs in the pseudoglandular phase are rarely diagnosed in adults (48 cases, including ours, have been found in the literature), and PH is rarely diagnosed, possibly because the anomalies observed are attributed to old infections. Clinical presentation is highly variable, depending in large measure on a history of smoking and repeated respiratory infections. Chest CT is at present the diagnostic tool of choice.

Foramen thyroideum: a comparative study in embryos, fetuses, and adults.

The incidence and characteristics of foramen thyroideum (FT) in embryonic and/or fetal larynges have not been established. In the present study, 90 adult larynges and 53 embryonic-fetal larynges were studied. The incidence of FT during the embryonic-fetal period (57%) was statistically different from the adult period (31%) (P = 0.005). All the FT found in the adult period contained vessels and/or nerves, while in the embryonic and fetal period only 63% presented neurovascular elements (P < 0.001). The origin of FT in the embryonic period and its persistence during adult life is discussed.

[Clinical features and ultrastructure of primary ciliary dyskinesia and Young syndrome]. / Clínica y ultraestructura de la discinesia ciliar primaria y el síndrome de Young.

A study was conducted of the clinical manifestations and ultrastructure in a series of seven patients with repeated pulmonary infections and infertility (3 cases with primary ciliary dyskinesia [PCD] and 4 with the young syndrome [YS]). Clinical and functional respiratory changes were more marked among cases of PCD. The seminogram showed azoospermia in cases with YS and hypospermia with marked hypomotility in cases with PCD. A nasal mucosa biopsy specimen was obtained from all patients to perform a transmission electron microscopy (EM) investigation. Patients with YS did not have pathognomonic ultrastructural changes, whereas patients with PCD had a large number of ciliary abnormalities (23.3% +/- 1.5%); 14% +/- 7% of them corresponded to nonspecific ciliary changes and the remaining abnormalities to congenital ciliary changes (ciliary disorientation in three cases, defective radial spokes in one case and microtubule transposition in one case). EM is a useful technique which is recommended for the differential diagnosis in this group of patients.

Pulmonary hypoplasia presented in adulthood as a chronic respiratory failure: report of two cases. Embryology, clinical symptoms and diagnostic procedures.

We report 2 cases of pulmonary hypoplasia diagnosed in adulthood presenting clinically as chronic respiratory failure. Both patients met criteria for chronic bronchitis and had shown repeated respiratory infections and increasing dyspnoea. The spirometry showed a severe non-defined ventilatory disturbance and the arterial blood gases showed the presence of marked hypoxaemia. The altered chest X-ray, arterial blood gases and spirometry had been attributed to chronic bronchitis. The CT scan was instrumental in establishing the diagnosis of pulmonary hypoplasia.

Morphologic characteristics of the fossa ovalis as an anatomic basis for transseptal catheterization.

Interest in transseptal catheterization has increased in recent decades, due to the fact that the technique has acquired a degree of security similar to other procedures. For a correct transseptal catheterization technique, it is essential to know the exact location of the fossa ovalis, its points of reference, and those morphologic parameters which allow us to assume precisely its dimensions. For this purpose, 97 human fresh hearts were studied (age range: 17-94 years; mean 63.74 +/- 18.50, 62 (64%) men and 35 (36%) women). The major and minor diameters of the fossa ovalis and the thickness of the intervenous tubercle were measured. In 22% of the cases, the fossa ovalis was permeable. Correlative tests between morphologic and general parameters were made. A positive correlation between cardiac weight and fossa ovalis area, and cardiac weight and thickness of the anterior limbus of the fossa was obtained.

An unusual clinical presentation of bilateral schizencephaly.

We present a case with a characteristic magnetic resonance image (MRI) of bilateral open-lipped schizencephaly and atypical clinical presentation. The patient is still alive and in good health in her forties, she has never presented seizures, and although the motor dysfunction is well correlated with cerebral lobe involvement, neurobehavioral dysfunction is not proportional to the MR image of the cerebral malformation.