RESUMO
BACKGROUND: Observational studies suggest that total testosterone (TT) and sex hormone-binding globulin (SHBG) may have beneficial effects on lung function, but these findings might be spurious due to confounding and reverse causation. We addressed these limitations by using multivariable Mendelian randomisation (MVMR) to investigate the independent causal effects of TT and SHBG on lung function. METHODS: We first identified genetic instruments by performing genome-wide association analyses of TT and SHBG in the large UK Biobank, separately in males and females. We then assessed the independent effects of TT and SHBG on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using one-sample MVMR. We addressed pleiotropy, which could bias MVMR, using several methods that account for it. We performed subgroup MVMR analyses by obesity, physical activity and menopausal status, and assessed associations between TT and SHBG with lung function decline. Finally, we compared the MVMR results with those of observational analyses in the UK Biobank. FINDINGS: In the MVMR analyses, there was evidence of pleiotropy, but results were consistent when accounting for it. We found a strong beneficial effect of TT on FVC and FEV1 in both males and females, but a moderate detrimental effect of SHBG on FEV1 and FEV1/FVC in males only. Subgroup analyses suggested stronger effects of TT among obese and older males. The observational analyses, in line with previous studies, agreed with MRMV for TT, but not for SHBG. INTERPRETATION: These findings suggest that testosterone improves lung function in males and females, while SHBG has an opposite independent effect in males.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Globulina de Ligação a Hormônio Sexual , Testosterona , Humanos , Masculino , Globulina de Ligação a Hormônio Sexual/análise , Globulina de Ligação a Hormônio Sexual/metabolismo , Feminino , Testosterona/sangue , Capacidade Vital , Volume Expiratório Forçado , Pessoa de Meia-Idade , Reino Unido , Pulmão/fisiopatologia , Testes de Função Respiratória , Idoso , ObesidadeRESUMO
BACKGROUND: We determined the effectiveness of an intervention to reduce cotton dust-related respiratory symptoms and improve lung function of textile workers. METHODS: We undertook a cluster randomised controlled trial at 38 textile mills in Karachi, Pakistan. The intervention comprised: training in occupational health for workers and managers, formation of workplace committees to promote a health and safety plan that included wet mopping and safe disposal of cotton dust, provision of simple face masks, and further publicity about the risks from cotton dust. Participating mills were randomised following baseline data collection. The impact of the intervention was measured through surveys at 3, 12 and 18â months using questionnaires, spirometry and dust measurements. The primary outcomes were 1) changes in prevalence of a composite respiratory symptom variable, 2) changes in post-bronchodilator percentage predicted forced expiratory volume in 1â s (FEV1) and 3) changes in cotton dust levels. These were assessed using two-level mixed effects linear and logistic regression. RESULTS: Of 2031 participants recruited at baseline, 807 (40%) were available at the third follow-up. At that point, workers in the intervention arm were more likely to report an improvement in respiratory symptoms (OR 1.58, 95% CI 1.06-2.36) and lung function (FEV1 % pred: ß 1.31%, 95% CI 0.04-2.57%). Personal dust levels decreased, more so in intervention mills, although we did not observe this in adjusted models due to the small number of samples. CONCLUSION: We found the intervention to be effective in improving the respiratory health of textile workers and recommend scaling-up of such simple and feasible interventions in low- and middle-income countries.
Assuntos
Pneumopatias , Exposição Ocupacional , Humanos , Poeira , Exposição Ocupacional/prevenção & controle , Têxteis , Volume Expiratório ForçadoRESUMO
OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy. METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS). RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event. CONCLUSION: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.
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We conducted a feasibility study to evaluate micronutrients and body mass index (BMI). Fat soluble vitamins A, D, E and trace elements copper (Cu), selenium (Se), and zinc (Zn) levels were evaluated. Weight, height, BMI, and Z-scores were recorded. Side effects or specific adverse events were documented. No patient had a Z-score for height, weight, or BMI of less than 2 SD or greater than 2 SD. Ninety percent of patients had one or more micronutrient levels below normal. These results suggest that micronutrient abnormalities are common despite no obvious evidence of malnutrition. Side effects of chemotherapy may be exacerbated by micronutrient depletion.
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PURPOSE: Musculoskeletal strength can be impaired in pediatric solid organ transplant recipients. Exercise training programs can be beneficial but in-person delivery can be challenging; virtual exercise programs can alleviate some of these challenges. This feasibility study aimed to deliver an 8-week virtual exercise program in pediatric solid organ transplant recipients. METHOD: Program delivery occurred 3 times per week for 30 minutes. An exercise stress test was completed prior to program start. The Bruininks-Oseretsky Test of Motor Proficiency strength subtest and self-report surveys were used to assess musculoskeletal strength, quality of life, fatigue, and physical activity. Contact was maintained through a text messaging platform. Z scores were calculated using standardized normative data. Medians (interquartile range) are reported for all other data. RESULTS: Eleven participants completed the program (2 liver, 5 kidney, 4 heart; 58% females; median age = 11.5 [10.3-13.8] y). Six participants attended ≥60% of classes, 5 participants attended <50% of classes. After 8 weeks, strength scores improved (Z score, Pre: -1.0 [-1.65 to -0.60] to Post: -0.2 [-1.30 to 0.40]; P = .007) with no change in other outcome measures. CONCLUSION: The virtual exercise program was delivered without technical issues and received positive participant feedback. Engagement and costs need to be considered.
Assuntos
Terapia por Exercício , Estudos de Viabilidade , Transplante de Órgãos , Qualidade de Vida , Humanos , Feminino , Masculino , Criança , Adolescente , Terapia por Exercício/métodos , Força Muscular , Transplantados , Fadiga/prevenção & controle , Exercício Físico/fisiologiaRESUMO
Objectives: Access to early phase trials for children with relapsed, refractory or progressive (RRPD) cancer is limited in Canada. Patients and families face barriers to access trials, which are poorly understood. The aims of this study were to assess availability of early phase trials and examine the impact of distance from home to study centre on trial enrolment among paediatric oncology patients with RRPD. Methods: Oncology patients ≤18 years at diagnosis who later had RRPD were identified retrospectively via registry at the only quaternary paediatric oncology centre in British Columbia (BC). We determined if distance to home, as calculated using geocoding software, was predictive of trial offer or enrolment. Results: Between January 2015 and July 2021, 266 patients experienced 396 RRPD events. Seventy-five patients (28.2%) were eligible for an early phase trial at least once. At first eligible event, 61 patients (22.9%) were offered trial (median age 11.8 years; 69.0% male; 46.0% with CNS tumour) and thirty patients (11.3%) enrolled. Distance was not associated with odds of offer (OR 1.01, CI 0.98 to 1.05) or enrolment (OR 0.99, CI 0.95 to 1.03) on univariate or multivariable analysis adjusted for sex and disease (OR 0.93, CI 0.86 to 1.00). For offered patients, 2-year event-free survival (EFS) and overall survival (OS) were 39.1% (CI 28.0% to 54.8%) and 51.8% (CI 39.9% to 67.2%), respectively. EFS/OS did not differ with distance or enrolment, but varied by disease (EFS P = 0.002, OS P < 0.0001). Conclusions: Children in BC with cancer and RRPD have limited access to early phase trials. Distance was not predictive of enrolment, suggesting that families travel to access therapy.
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BACKGROUND: Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. METHODS: Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN). RESULTS: Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77-2.70), chronic cough (OR = 2.56, 95% CI 2.08-3.15), chronic phlegm (OR = 2.29, 95% CI 1.77-4.05), wheeze (OR = 2.87, 95% CI 2.50-3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11-1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease. CONCLUSION: Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.
Assuntos
Obstrução das Vias Respiratórias , Doenças Cardiovasculares , Pneumopatias Obstrutivas , Humanos , Qualidade de Vida , Efeitos Psicossociais da Doença , EspirometriaRESUMO
The ductus arteriosus is important to fetal circulation. Failure to close at birth is a common event. In this educational pictorial essay, we illustrate the association of the ductus arteriosus with a variety of congenital cardiac, vascular and pulmonary lesions. These lesions can impact the systemic circulation, the pulmonary circulation or the airway and include coarctation of the aorta, ductal origin of the pulmonary artery and vascular rings.
Assuntos
Permeabilidade do Canal Arterial , Canal Arterial , Canal Arterial/diagnóstico por imagem , Permeabilidade do Canal Arterial/diagnóstico por imagem , Coração , Humanos , Recém-Nascido , Artéria Pulmonar/diagnóstico por imagem , Circulação PulmonarRESUMO
BACKGROUND: EAACI guidelines emphasize the importance of patient history in diagnosing food allergy (FA) and the need for studies investigating its value using standardized allergy-focused questionnaires. OBJECTIVE: To determine the contribution of reaction characteristics, allergic comorbidities and demographics to prediction of FA in individuals experiencing food-related adverse reactions. METHODS: Adult and school-age participants in the standardized EuroPrevall population surveys, with self-reported FA, were included. Penalized multivariable regression was used to assess the association of patient history determinants with "probable" FA, defined as a food-specific case history supported by relevant IgE sensitization. RESULTS: In adults (N = 844), reproducibility of reaction (OR 1.35 [95% CI 1.29-1.41]), oral allergy symptoms (OAS) (4.46 [4.19-4.75]), allergic rhinitis (AR) comorbidity (2.82 [2.68-2.95]), asthma comorbidity (1.38 [1.30-1.46]) and male sex (1.50 [1.41-1.59]) were positively associated with probable FA. Gastrointestinal symptoms (0.88 [0.85-0.91]) made probable FA less likely. The AUC of a model combining all selected predictors was 0.85 after cross-validation. In children (N = 670), OAS (2.26 [2.09-2.44]) and AR comorbidity (1.47 [CI 1.39-1.55]) contributed most to prediction of probable FA, with a combined cross-validation-based AUC of 0.73. When focusing on plant foods, the dominant source of FA in adults, the pediatric model also included gastrointestinal symptoms (inverse association), and the AUC increased to 0.81. CONCLUSIONS: In both adults and school-age children from the general population, reporting of OAS and of AR comorbidity appear to be the strongest predictors of probable FA. Patient history particularly allows for good discrimination between presence and absence of probable plant FA.
Assuntos
Asma , Hipersensibilidade Alimentar , Adulto , Alérgenos , Criança , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/epidemiologia , Humanos , Masculino , Prevalência , Reprodutibilidade dos TestesRESUMO
The objective of this study was to describe hypersensitivity reactions with and without the use of in-line filters during intravenous etoposide therapy in pediatric oncology patients. This was a retrospective review of all patients treated in the Division of Oncology/Hematology/Bone Marrow Transplant at British Columbia Children's Hospital with intravenous etoposide between December 1, 2013 and February 1, 2018. Hypersensitivity reactions and anaphylaxis associated with etoposide infusions were compared over time, including 12 months prior to, 27 months during the use of, and for 12 months after the discontinuation of in-line filtration. There were 192 patients (median age 6.0 (IQR 2.8-13.0) years treated with etoposide and 486 etoposide infusions including 137 (28%) before, 261 (54%) during and 88 (18%) after use of in-line filters at our center. Twenty-six of 486 (5%) and 13/486 (3%) of infusions resulted in a type I hypersensitivity reaction and anaphylaxis, respectively. There were 2/137 (1%), 36/261 (14%) and 1/88 (1%) infusion reactions prior to, during and after in-line filter use, respectively. Infusion reactions during the in-line filter period were higher than during the pre-filter (Z = 3.978; p < 0.001) and post-filter (Z = 3.335; p < 0.001) periods of the study. These data suggest that the use of in-line filtration may be associated with increased frequency of hypersensitivity reactions to etoposide in pediatric cancer patients.
Assuntos
Anafilaxia/induzido quimicamente , Antineoplásicos Fitogênicos/efeitos adversos , Etoposídeo/efeitos adversos , Hipersensibilidade Imediata/induzido quimicamente , Inibidores da Topoisomerase II/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Criança , Pré-Escolar , Etoposídeo/administração & dosagem , Feminino , Filtração/instrumentação , Humanos , Infusões Intravenosas/instrumentação , Masculino , Estudos Retrospectivos , Inibidores da Topoisomerase II/administração & dosagemRESUMO
OBJECTIVES: Radiographic survey of the entire aerodigestive tract (nares to anus) is common practice in children presenting to the emergency department following coin ingestion. The purpose of our study was to determine the optimal protocol for radiographic survey post-coin ingestion. We hypothesized that for children presenting with a clear history of coin ingestion a frontal chest radiograph including the entire esophagus is adequate to guide treatment. METHODS: We reviewed the clinical history and radiographic surveys of 134 patients presenting with suspected or witnessed coin ingestion to the emergency department of a tertiary care pediatric hospital between January 2012 and June 2016. Patient demographics, presenting symptoms, anatomic coverage of survey, type, number and location of radiopaque foreign bodies, intervention, and follow-up were recorded. RESULTS: Coins were identified on radiographic surveys in 109 of 134 patients; 25 of 134 patients had no coin. Of those with coins, none of 109 had coin(s) in the airway, 42 of 109 had coin(s) in the esophagus, and 67 of 109 had coin(s) distal to the esophagus. Of those with esophageal coins, 35 of 42 reported symptoms, 7 of 42 were asymptomatic, 40 of 42 underwent endoscopic coin removal, and 2 of 42 had no intervention. Of 92 of 134 surveyed patients with no coin or coin distal to the esophagus, 30 of 92 reported symptoms, 62 of 92 were asymptomatic, 90 of 92 had no further intervention, and 2 of 92 eventually underwent endoscopic coin removal for specific indications (abdominal pain, delayed passage). When there was no coin found in the esophagus, the negative predictive value for intervention was 97.8%. CONCLUSIONS: Following a clear history of coin ingestion, a frontal chest radiograph including the entire length of the esophagus provides sufficient information to direct patient management.
Assuntos
Corpos Estranhos , Numismática , Criança , Ingestão de Alimentos , Serviço Hospitalar de Emergência , Esôfago/diagnóstico por imagem , Corpos Estranhos/diagnóstico por imagem , Corpos Estranhos/cirurgia , Humanos , LactenteRESUMO
OBJECTIVE: To evaluate the relative incidence of cardiogenic and septic shock in term neonates and identify findings that help differentiate the two entities. STUDY DESIGN: We conducted a retrospective chart review of term neonates presenting to British Columbia Children's Hospital (BCCH) with decompensated shock of an undiagnosed etiology between January 1, 2008 and January 1, 2013. Charts were reviewed to determine the underlying diagnoses of all neonates meeting our inclusion criteria. Patients were categorized as having septic, cardiogenic, or other etiologies of shock. We then evaluated potential demographic, clinical, and biochemical parameters that could help differentiate between septic and cardiogenic shock. RESULTS: Cardiogenic shock was more common than septic shock (relative risk=1.53). A history of cyanosis was suggestive of cardiogenic shock (positive likelihood ratio, LR+=3.2 and negative likelihood ratio, LR-=0.4). Presence of a murmur or gallop (LR+=5.4, LR-=0.3), or decreased femoral pulses (LR+=5.1, LR-=0.5) on physical exam were also suggestive of cardiogenic shock as was cardiomegaly on chest x-ray (LR+=4.9, LR-=0.5). Notably, temperature instability (LR+=0.7, LR-=1.8) and white blood cell count elevation or depression (LR+=0.8, LR-=1.1) were all poor predictors of septic shock. CONCLUSION: Cardiogenic shock is a more common cause of decompensated shock than septic shock. A history of cyanosis, murmur or gallop, or decreased femoral pulses on exam and cardiomegaly on chest x-ray are useful indicators of cardiogenic shock. In evaluating the neonate with decompensated shock, early consideration for Cardiology consultation and interventions to treat the underlying condition is warranted.
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BACKGROUND: Historical data suggest 15% of laboratory animal workers develop IgE sensitisation and 10% symptoms of laboratory animal allergy (LAA), including occupational asthma. Individually ventilated cages (IVCs) are replacing conventional open cages; we sought to evaluate their impact on the development of LAA. METHODS: We surveyed 750 laboratory animal workers and measured airborne Mus m 1 (mouse allergen) levels in seven UK institutions. We compared the prevalence of sensitisation to mouse proteins (by specific IgE assay or skin prick test) and of work-related allergic symptoms in IVC-only and open cage units. RESULTS: Full-shift Mus m 1 levels were lower in IVC than open cage units (geometric mean 1.00 (95% CI 0.73-1.36) versus 8.35 (95% CI 6.97-9.95) ng·m-3; p<0.001), but varied eight-fold across the IVC units (geometric mean range 0.33-4.12â ng·m-3). Primary analyses on data from 216 participants with ≤3â years exposure to mice revealed a lower prevalence of sensitisation in those working in IVC units compared with conventional cage units (2.4% (n=2) versus 9.8% (n=13); p=0.052). Sensitisation in IVC units varied from 0% to 12.5%; the use of fitted respiratory protection was less common in IVC units where prevalence of sensitisation was higher. Work-related allergy symptoms were more frequently reported by mouse-sensitised individuals (46.7% versus 10.9%; p<0.001) and only by those working in open cage units. CONCLUSION: In contemporary practice, LAA is now largely preventable with the use of IVC systems and the judicious use of appropriate respiratory protection.
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Poluição do Ar em Ambientes Fechados/prevenção & controle , Criação de Animais Domésticos/instrumentação , Animais de Laboratório , Abrigo para Animais , Hipersensibilidade/prevenção & controle , Adolescente , Adulto , Alérgenos/efeitos adversos , Alérgenos/urina , Técnicos em Manejo de Animais , Animais , Feminino , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Imunoglobulina E/análise , Masculino , Camundongos/urina , Pessoa de Meia-Idade , Saúde Ocupacional , Ratos , Segurança , Testes Cutâneos , Reino Unido , Ventilação , Adulto JovemRESUMO
In observational studies, early menopause is associated with lower forced vital capacity (FVC) and a higher risk of spirometric restriction, but not airflow obstruction. It is, however, unclear if this association is causal. We therefore used a Mendelian randomisation (MR) approach, which is not affected by classical confounding, to assess the effect of age at natural menopause on lung function.We included 94â742 naturally post-menopausal women from the UK Biobank and performed MR analyses on the effect of age at menopause on forced expiratory volume in 1â
s (FEV1), FVC, FEV1/FVC, spirometric restriction (FVCAssuntos
Pulmão/fisiopatologia
, Menopausa Precoce/genética
, Idoso
, Feminino
, Volume Expiratório Forçado
, Humanos
, Análise da Randomização Mendeliana
, Menopausa/genética
, Pessoa de Meia-Idade
, Polimorfismo de Nucleotídeo Único
, Fatores de Proteção
, Doença Pulmonar Obstrutiva Crônica/epidemiologia
, Doença Pulmonar Obstrutiva Crônica/fisiopatologia
, Capacidade Vital
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BACKGROUND: Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males. METHODS AND FINDINGS: MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10(-5)) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10(-4)), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking. CONCLUSIONS: This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.
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Asma/epidemiologia , Puberdade , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Menarca , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Obesidade Infantil/epidemiologia , Autorrelato , Reino Unido/epidemiologiaRESUMO
Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.
Assuntos
Calsequestrina/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Adolescente , Criança , Análise Mutacional de DNA , Morte Súbita Cardíaca/epidemiologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Prognóstico , Conformação Proteica , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Relação Estrutura-Atividade , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/fisiopatologiaRESUMO
BACKGROUND: Patients with anorexia nervosa exhibit abnormal myocardial repolarization and are susceptible to sudden cardiac death. Exercise testing is useful in unmasking QT prolongation in disorders associated with abnormal repolarization. We characterized QT adaptation during exercise in anorexia. METHODS AND RESULTS: Sixty-one adolescent female patients with anorexia nervosa and 45 age- and sex-matched healthy volunteers performed symptom-limited cycle ergometry during 12-lead ECG monitoring. Changes in the QT interval during exercise were measured, and QT/RR-interval slopes were determined by using mixed-effects regression modeling. Patients had significantly lower body mass index than controls; however, resting heart rates and QT/QTc intervals were similar at baseline. Patients had shorter exercise times (13.7±4.5 versus 20.6±4.5 minutes; P<0.001) and lower peak heart rates (159±20 versus 184±9 beats/min; P<0.001). The mean QTc intervals were longer at peak exercise in patients (442±29 versus 422±19 ms; P<0.001). During submaximal exertion at comparable heart rates (114±6 versus 115±11 beats/min; P=0.54), the QTc interval had prolonged significantly more in patients than controls (37±28 versus 24±25 ms; P<0.016). The RR/QT slope, best described by a curvilinear relationship, was more gradual in patients than in controls (13.4; 95% confidence interval, 12.8-13.9 versus 15.8; 95% confidence interval, 15.3-16.4 ms QT change per 10% change in RR interval; P<0.001) and steepest in patients within the highest body mass index tertile versus the lowest (13.9; 95% confidence interval, 12.9-14.9 versus 12.3; 95% confidence interval, 11.3-13.3; P=0.026). CONCLUSIONS: Despite the absence of manifest QT prolongation, adolescent anorexic females have impaired repolarization reserve in comparison with healthy controls. Further study may identify impaired QT dynamics as a risk factor for arrhythmias in anorexia nervosa.
Assuntos
Anorexia Nervosa/diagnóstico , Anorexia Nervosa/fisiopatologia , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatologia , Teste de Esforço/métodos , Adolescente , Anorexia Nervosa/epidemiologia , Síndrome de Brugada/epidemiologia , Doença do Sistema de Condução Cardíaco , Criança , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia/métodos , Feminino , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/epidemiologia , Síndrome do QT Longo/fisiopatologia , Adulto JovemRESUMO
The relationship between lung function decline and dietary antioxidants over 10â years in adults from three European countries was investigated.In 2002, adults from three participating countries of the European Community Respiratory Health Survey (ECRHS) answered a questionnaire and underwent spirometry (forced expiratory volume in 1â s (FEV1) and forced vital capacity (FVC)), which were repeated 10â years later. Dietary intake was estimated at baseline with food frequency questionnaires (FFQ). Associations between annual lung function decline (mL) and diet (tertiles) were examined with multivariable analyses. Simes' procedure was applied to control for multiple testing.A total of 680 individuals (baseline mean age 43.8±6.6â years) were included. A per-tertile increase in apple and banana intake was associated with a 3.59â mL·year-1 (95% CI 0.40, 7.68) and 3.69â mL·year-1 (95% CI 0.25, 7.14) slower decline in FEV1 and FVC, respectively. Tomato intake was also associated with a slower decline in FVC (4.5â mL·year-1; 95% CI 1.28, 8.02). Only the association with tomato intake remained statistically significant after the Simes' procedure was performed. Subgroup analyses showed that apple, banana and tomato intake were all associated with a slower decline in FVC in ex-smokers.Intake of fruits and tomatoes might delay lung function decline in adults, particularly in ex-smokers.
Assuntos
Antioxidantes/administração & dosagem , Dieta , Pneumopatias/fisiopatologia , Pulmão/fisiopatologia , Adulto , Europa (Continente) , Feminino , Volume Expiratório Forçado , Inquéritos Epidemiológicos , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fumar/fisiopatologia , Capacidade VitalRESUMO
BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. OBJECTIVE: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). METHODS: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. RESULTS: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1-5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. CONCLUSION: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.
Assuntos
Fumarato de Dimetilo/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: We investigated the net changes in prevalence of symptoms of asthma and rhinitis over 10 years in a cohort of young by baseline sensitization status. METHODS: One thousand one hundred ninety three Chilean adults subjects aged 22-28 living in a semi-rural area of central Chile answered a lifestyle and the European Community Respiratory Health Survey (ECRHS) questionnaires. Bronchial hyper-responsiveness (BHR) and skin prick test (SPT) to eight allergens were measured at baseline in 2001. Ten years later, 772 participants completed the questionnaires again. Estimates of adjusted net changes in prevalence of symptoms by sensitization status at baseline and association between sensitization status at baseline and respiratory symptoms ten years later were assessed. RESULTS: A quarter of the participants were sensitized to at least one allergen in 2001. Prevalence of wheeze had a net change per year of -0.37 % (95 % Confidence Interval -0.71 to 0.02 %; p = 0.067). Self-reported nasal allergies in the last 12 months increased by 0.83 % per year (95 % CI 0.49 to 1.17 %; p < 0.001). Those sensitized to either cat fur (OR 1.76; CI 1.01 to 3.05), cockroach, (OR 2.09; 1.13 to 3.86) blend of grass and pollens (1.78; 95 % CI 1.08 to 2.92), or weeds (OR 1.77; 95 % CI 1.01 to 3.12) in 2001 were more likely to have wheeze in the last 12 months 10 years later. CONCLUSION: Symptoms of asthma remained stable or slightly changed over 10 years in adults, whilst rhinitis and nasal allergies greatly increased. Being sensitized to at least one allergen is a risk factor for persistent symptoms of asthma and rhinitis, but not for determining net changes of symptoms over time. The underlying causes for the contrasting trends between asthma and nasal allergy are unknown.