French-Canadian families from Saguenay-Lac-Saint-Jean: a new founder population for APECED.

PURPOSE: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is more prevalent in some founder populations, but relatively unexplored in Canada. This study aimed at investigating the French-Canadian patients through phenotypic and genotypic characterization. METHOD: Phenotype and demographic characterization were done for 12 affected individuals belonging to eight unrelated families. Samples from 11 cases were analyzed in a molecular clinical laboratory, and muscle biopsies were reviewed for two individuals with a limb-girdle muscle dystrophy. RESULTS: The clinical phenotype was similar to that observed in European Caucasian populations but differed in the non-endocrine spectrum from the American-reported series of cases. Two cases exhibited a limb-girdle muscle dystrophy, and we found preliminary evidence of a mitochondrial dysfunction, since all three biopsies examined showed COX-deficient fibers in excess of what would be expected for age. Electron microscopy showed mitochondrial accumulation without abnormal cristea or inclusions. The c.1616C > T variant in the AIRE gene was responsible for 100% of APECED cases in the French-Canadian population of Saguenay-Lac-Saint-Jean in Quebec, Canada. CONCLUSIONS: We report the first series of French-Canadian cases affected with APECED. The Saguenay-Lac-Saint-Jean region was uncovered as a new founder population for this condition. Muscle biopsy findings expanded the range of previously described APECED-related myopathology. Long term follow-up of our genetically homogeneous French-Canadian cases may help determine if the c.1616C > T variant increases the risk of muscle involvement. A neonatal screening program is under consideration to prevent undesired life-threatening endocrine manifestations.

Use of a vibrating mesh nebulizer for allergen challenge.

BACKGROUND: Allergen inhalation tests are a valuable research tool. The allergen dose producing an early asthmatic response (EAR) can be predicted from methacholine responsiveness and allergen skin test endpoint (STE). The Wright® jet nebulizer, which is both inefficient and increasingly difficult to obtain, has been used historically. We assessed the Solo® vibrating mesh nebulizer as an alternative for allergen and methacholine challenges. METHODS: Eighteen mild atopic asthmatics completed the study. Doubling concentration allergen prick skin tests were performed to determine the STE in allergen units/mL. The Wright® protocol was used to measure the methacholine provocation dose causing a 20% forced expired volume in one second (FEV1) fall (PD20) (µg) and the allergen PD20 (units). The Solo® protocol (0.5 mL nebulized to completion, tidal breathing inhalation) was used to determine both methacholine PD20 and allergen PD20. The nebulizer order was randomized and separated by ≥ 2 weeks. RESULTS: All data were log transformed. The allergen PD20, predicted from the methacholine PD20 and the STE, was within 2 doubling doses of the PD20 measured with the Wright® and 2.64 doubling doses of that measured with Solo®. The Wright® allergen PD20 correlated with the Wright® methacholine PD20 (r = 0.74) and the STE (r = 0.78) and more strongly with the product of the two (Wright® methacholine PD20 × STE, r = 0.91, p < 0.00001). The Solo® allergen PD20 showed similar relationships with the Solo® methacholine PD20 (r = 0.61), the STE (r = 0.75) and the product of the two (Solo® methacholine PD20 × STE, r = 0.83, p < 0.00002). The Wright® and the Solo® methacholine geometric mean PD20s were not significantly different (49.3 and 54.5 µg respectively, p = 0.62). The Wright® allergen PD20 was slightly but significantly lower than the Solo® allergen PD20 (geometric means 6.7 and 10.5 units respectively, p = 0.003). CONCLUSION: The Solo® allergen PD20 showed the same relationship with methacholine responsiveness and STE as did the Wright®. The Solo® allergen PD20 was slightly but significantly higher than the Wright® allergen PD20. The Solo® vibrating mesh nebulizer was well tolerated and is an acceptable alternative for allergen challenge.Trial registration clinicaltrials.gov: NCT03491358.

Comparative features of Asthma with frequent or infrequent exacerbations: A longitudinal study of retrospective and prospective events.

BACKGROUND: A "frequent exacerbator phenotype" has been described, mostly in the population of patients with severe asthma. Further data are needed on such exacerbation-prone patients in milder asthma. AIM: To compare the characteristics of frequent and nonfrequent exacerbators in asthma of different severities and to assess the stability of the exacerbator status. METHODS: This was an observational study comparing baseline data from frequent (≥2 exacerbations in the past year) and nonfrequent (<2 exacerbations in the past year) exacerbators. Patients were also followed up for one year. Information regarding clinical, physiologic, and inflammatory characteristics was collected at baseline and one-year follow-up. RESULTS: Forty-seven frequent and 53 nonfrequent exacerbators were recruited. No specific clinical, physiologic, or inflammatory characteristic was observed in the frequent as compared to the nonfrequent exacerbators at baseline. Fifty-eight percent of patients reporting frequent exacerbations at baseline remained in this group after one year of follow-up. Forty-two and 62% of patients with, respectively, mild-to-moderate asthma and severe asthma had frequent exacerbations. In a post hoc analysis according to asthma severity, frequent exacerbators with severe asthma had a higher body mass index and poorer asthma control, although they reported higher adherence to medication, in comparison to frequent exacerbators with mild-to-moderate asthma. No specific characteristics could discriminate between frequent and nonfrequent exacerbators of the same asthma severity. CONCLUSIONS: Frequent exacerbators with severe asthma present some specific characteristics not observed in frequent exacerbators with mild-to-moderate disease. However, the latter group should be identified to reassess treatment needs and potential contributing factors.

Comparative Clinical, Physiological, and Inflammatory Characteristics of Elderly Subjects With or Without Asthma and Young Subjects With Asthma.

BACKGROUND: Asthma seems to present in the elderly as a specific phenotype that remains to be further described. In this prospective observational study, we aimed to assess the multidimensional aspects of asthma in the elderly. METHODS: In young (18 to 35 years old) subjects with mild to moderate asthma and elderly subjects (aged ≥60 years) either with or without mild to moderate asthma, we compared asthma control, health care and medication use, lung function, markers of airway and systemic inflammation, and adherence to therapy. RESULTS: Fifty subjects were recruited in each group. Elderly people with asthma showed more marked airway obstruction compared with young people with asthma and elderly people without asthma. They also had poorer asthma control, mainly associated with a lower FEV1, compared with young people with asthma, although airway responsiveness, health care use, prescribed doses of inhaled corticosteroids, and adherence to treatment were similar in both groups. Elderly subjects had an increase in some markers of systemic inflammation and bronchial epithelial dysfunction compared with young people with asthma. Blood eosinophils were higher in both asthma groups, particularly in elderly people with asthma. Sputum neutrophils were increased in both groups of elderly subjects and sputum eosinophils were increased in elderly people with asthma compared with the other two groups. CONCLUSIONS: Asthma in the elderly presents as a specific phenotype associated with increased airway obstruction and mixed airway inflammation in addition to signs of systemic inflammation.

Athletes Do Not Condition Inspired Air More Effectively than Nonathletes during Hyperpnea.

Endurance athletes have a high prevalence of airway diseases, some possibly representing adaptive mechanisms to the need of conditioning large volumes of inspired air during high ventilation in specific environments. The aim of this study is to assess the ability to condition (warm and humidify) inspired air in athletes by measuring the difference between inhaled and exhaled air temperature (ΔT) during and after eucapnic voluntary hyperpnea (EVH) test. METHODS: Twenty-three endurance athletes from various sports, 12 with airway hyperresponsiveness (AHR) and/or exercise-induced bronchoconstriction (EIB) (A+), 11 without AHR and/or EIB (A-), 12 nonathletes with AHR and/or EIB (C+), and 11 nonathletes without AHR and/or EIB (C-) were recruited. All subjects attended the laboratory on three occasions, twice for baseline characterization, including questionnaires, pulmonary function, methacholine bronchoprovocation, allergy skin prick tests, exhaled nitric oxide measurement, and a standard EVH, and once to perform a modified EVH to assess ΔT. Inspired and expired air temperatures were measured with a high-precision probe during EVH and at regular intervals until 30 min after the end of the test. RESULTS: The global ΔT during the EVH was +5.8°C ± 1.5°C and +4.7°C ± 1.5°C during the 30 min after the EVH. No difference was found between groups for either the ΔT or the slope of ΔT, during and after the EVH. CONCLUSION: This study shows no evidence of improved capacity to condition inspired air in endurance athletes, which could have suggested an increased bronchial blood flow or another adaptive mechanism. The absence of an adaptive mechanism could therefore contribute to airway damage observed in athletes in allowing colder but mainly dryer air to penetrate deeper in the lung.

Comparison of everolimus-eluting and biolimus-eluting coronary stents with everolimus-eluting bioresorbable scaffold: study protocol of the randomized controlled EVERBIO II trial.

BACKGROUND: Second-generation everolimus-eluting stents (EES) and third generation biolimus-eluting stents (BES) have been shown to be superior to first-generation paclitaxel-eluting stents (PES) and second-generation sirolimus-eluting stents (SES). However, neointimal proliferation and very late stent thrombosis is still an unresolved issue of drug-eluting stent (DES) implantation overall. The Absorb™ (Abbott Vascular, Abbott Park, IL, USA) is the first CE approved DES with a bioresorbable vascular scaffold (BVS) thought to reduce long-term complication rates. The EVERBIO II trial was set up to compare the BVS safety and efficacy with both EES and BES in all patients viable for inclusion. METHODS/DESIGN: The EVERBIO II trial is a single-center, assessor-blinded, randomized trial. The study population consists of all patients aged≥18 years old undergoing percutaneous coronary intervention. Exclusion criterion is where the lesion cannot be treated with BVS (reference vessel diameter>4.0 mm). A total of 240 patients will be enrolled and randomly assigned into 3 groups of 80 with either BVS, EES or BES implantation. All patients will undergo a follow-up angiography study at 9 months. Clinical follow-up for up to 5 years will be conducted by telephone. The primary endpoint is in-segment late lumen loss at 9 months measured by quantitative coronary angiography. Secondary endpoints are patient-oriented major adverse cardiac event (MACE) (death, myocardial infarction and target-vessel revascularization), device-oriented MACE (cardiac death, myocardial infarction and target-lesion revascularization), stent thrombosis according to ARC and binary restenosis at follow-up 12 months angiography. DISCUSSION: EVERBIO II is an independent, randomized study, aiming to compare the clinical efficacy, angiographic outcomes and safety of BVS, EES and BES in all comer patients. TRIAL REGISTRATION: The trial listed in clinicaltrials.gov as NCT01711931.

Long-term comparison of everolimus-eluting and biolimus-eluting stents.

AIMS: Second-generation everolimus-eluting stents (EES) are safer and more efficient than first-generation paclitaxel-eluting stents (PES). Third-generation biolimus-eluting stents (BES) have been found to be non-inferior to PES. To date, there is no available comparative study between EES and BES. We aimed to investigate the safety and efficacy of BES with biodegradable polymer compared to EES with durable polymer at a follow-up of two years in an unselected population of consecutively enrolled patients. METHODS AND RESULTS: A group of 814 consecutive patients undergoing percutaneous coronary intervention (PCI) was enrolled between 2007 and 2010, of which 527 were treated with EES and 287 with BES implantation. Clinical outcome was compared in 200 pairs using propensity score matching. The primary endpoint was a composite of death, myocardial infarction (MI) and target vessel revascularisation (TVR) at two-year follow-up. Median follow-up was 22 months. The primary outcome occurred in 11.5% of EES and 10.5% of BES patients (HR 1.11, 95% CI: 0.61-2.00, p=0.74). At two years, there was no significant difference with regard to death (HR 0.49, 95% CI: 0.18-1.34, p=0.17), cardiac death (HR 0.14, 95% CI: 0.02-1.14, p=0.66) or MI (HR 6.10, 95% CI: 0.73-50.9, p=0.10). Stent thrombosis (ST) incidence was evenly distributed between EES (n=2) and BES (n=2) (p-value=1.0). CONCLUSIONS: This first clinical study failed to demonstrate any significant difference regarding safety or efficacy between these two types and generations of drug-eluting stents (DES).

Spontaneous ovarian hyperstimulation syndrome and pituitary hyperplasia mimicking macroadenoma associated with primary hypothyroidism.

We report an unusual case of spontaneous ovarian hyperstimulation syndrome and pituitary hyperplasia mimicking macroadenoma in an adult, non-pregnant woman. Her condition was triggered by unrecognized primary hypothyroidism, which regressed after thyroid hormone replacement therapy. This case highlights the need for clinicians and radiologists to familiarize themselves with the clinical and imaging features detected in case of these complications of primary hypothyroidism, which are not well known in the medical and radiological profession. Such improved knowledge will help avoid delays in diagnosis, progression to life-threatening complications, and unnecessary surgery.

Work-exacerbated asthma and occupational asthma: do they really differ?

BACKGROUND: Although work-exacerbated asthma (WEA) is a prevalent condition likely to have an important societal burden, there are limited data on this condition. OBJECTIVES: The aims of this study were (1) to compare the clinical, functional, and inflammatory characteristics of workers with WEA and occupational asthma (OA) and (2) compare health care use and related costs between workers with WEA and OA, as well as between workers with work-related asthma (WRA; ie, WEA plus OA) and those with non-work-related asthma (NWRA) in a prospective study. METHODS: We performed a prospective observational study of workers with and without WRA with a 2-year follow-up. The diagnosis of OA and WEA was based on the positivity and negativity of results on specific inhalation challenges, respectively. RESULTS: One hundred fifty-four subjects were enrolled: 53 with WEA, 68 with OA, and 33 control asthmatic subjects (NWRA). WEA was associated with more frequent prescriptions of inhaled corticosteroids (odds ratio [OR], 4.4; 95% CI, 1.4-13.6; P = .009), a noneosinophilic phenotype (OR, 0.3; 95% CI, 0.1-0.9; P = .04), a trend toward a lower FEV1 (OR, 0.9; 95% CI, 0.9-1.0; P = .06), and a higher proportion of smokers (OR, 2.5; 95% CI, 0.96-9.7; P = .06) than the diagnosis of OA. The health care use of WRA and related costs were 10-fold higher than those of NWRA. CONCLUSION: Workers with WEA appeared to have features of greater asthma severity than workers with OA. In contrast with OA, WEA was associated with a noneosinophilic phenotype. Both OA and WEA were associated with greater health care use and 10-fold higher direct costs than NWRA.