Mepolizumab in Patients With Severe Asthma and Comorbidities: 1-Year REALITI-A Analysis.

BACKGROUND: Severe asthma is complex; comorbidities may influence disease outcomes. OBJECTIVE: To assess mepolizumab effectiveness in patients with severe asthma and comorbidities. METHODS: REALITI-A was a 2-year international, prospective study enrolling adults with asthma newly prescribed mepolizumab (100 mg subcutaneously) at physician's discretion. This post hoc analysis assessed 1-year outcomes stratified by comorbidities at enrollment: chronic rhinosinusitis with nasal polyps (CRSwNP), gastroesophageal reflux disease (GERD), depression/anxiety, and chronic obstructive pulmonary disease (COPD). Outcomes included the rate of clinically significant asthma exacerbations (CSEs; requiring systemic corticosteroids and/or hospital/emergency room admission) between the 12 months pre- and post-mepolizumab treatment and changes from baseline in daily maintenance oral corticosteroid dose (mo 12), Asthma Control Questionnaire-5 score (mo 12) and forced expiratory volume in 1 second (FEV1; mo 9-12). RESULTS: At enrollment (n = 822), 321 of 822 (39%), 309 of 801 (39%), 203 of 785 (26%), and 81 of 808 (10%) patients had comorbid CRSwNP, GERD, depression/anxiety, and COPD, respectively. Post- versus pre-treatment across all comorbidity subgroups: the rate of CSEs decreased by 63% or more; among 298 (39%) patients on maintenance oral corticosteroids at baseline, median dose decreased by 50% or more; Asthma Control Questionnaire-5 score decreased by 0.63 or more points; FEV1 increased by 74 mL or more. Patients with versus without CRSwNP had the greatest improvements (eg, rate of CSEs decreased by 75%). Patients without GERD, depression/anxiety, or COPD had greater improvements than those with the respective comorbidities, except for FEV1 in patients with COPD. CONCLUSIONS: Mepolizumab improved disease outcomes in patients with severe asthma irrespective of comorbidities, with additional benefit for patients with CRSwNP.

The association of varying treatment thresholds of mepolizumab on asthma exacerbations in adults.

Background: Asthma has a high healthcare burden globally, with up to 10% of the asthma population suffering from severe disease. Biologic agents are a newer class of asthma treatments for severe asthma, with good evidence for efficacy in clinical trials. Nevertheless, real-world studies of its impact on clinical outcomes are limited.Methods: This is an observational cohort study using administrative claims data. The study population consisted of patients aged ≥18 years who had a diagnosis of asthma and initiated mepolizumab after November 4, 2015 and had continuous medical and drug coverage in both the 365 days prior to and following mepolizumab initiation. In patients treated with mepolizumab, we described clinically significant asthma exacerbations by minimum continuous treatment thresholds following initiation of mepolizumab, medication switching patterns and chronic oral corticosteroid (≥28 days) use.Results: We identified 2,536 adults with asthma who initiated mepolizumab. There was an association toward reduction in severe asthma-related events over the first one year of exposure. We observed associations with reduced dispensings of oral corticosteroids over the first year after mepolizumab initiation. Very few patients switched to other biologics during the study period.Conclusions: Treatment with mepolizumab may be associated with fewer asthma-related events in the first year. Over the first one year after initiating mepolizumab, we found associations with decreased concomitant dispensings of oral corticosteroids and medium to high dose ICS/LABA. Additionally, most patients who initiated mepolizumab did not switch to other biologics.

An algorithm-based approach to ascertain patients with rare diseases in electronic health records using hypereosinophilic syndrome as an example.

PURPOSE: Improved hypereosinophilic syndrome (HES) ascertainment in electronic health record (EHR) databases may improve disease understanding and management. An algorithm to ascertain and characterize this rare condition was therefore developed and validated. METHODS: Using the UK clinical practice research datalink (CPRD)-Aurum database linked to the hospital episode statistics database (Admitted Patient Care data) from Jan 2012 to June 2019, this cross-sectional study ascertained patients with a specific HES code (index). Patients with HES were matched (age, sex and index date) 1:29 with a non-HES cohort. An algorithm was developed by identifying pre-defined variables differing between cohorts; model-fitting using Firth logistic regression and statistical determination of the top-five performing models; and internal validation using Leave-One-Out Cross Validation. Final model sensitivity and specificity were determined at an 80% probability threshold. RESULTS: The HES and non-HES cohorts included 88 and 2552 patients, respectively; 270 models with four variables each (treatment used for HES, asthma code, white blood cell condition code, and blood eosinophil count [BEC] code) plus age and sex variables were tested. Of the top five models, the sensitivity model performed best (sensitivity, 69% [95% CI: 59%, 79%]; specificity, >99%). The strongest predictors of HES versus non-HES cases (odds >1000 times greater) were an ICD-10 code for white blood cell disorders and a BEC ≥1500 cells/µL in the 24 months pre-index. CONCLUSIONS: Using a combination of medical codes, prescribed treatments data and laboratory results, the algorithm can help ascertain patients with HES from EHR databases; this approach may be useful for other rare diseases.

Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis.

Background: An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods: In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11-18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results: In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13-0.25), maintenance OCS use (OR 0.75, 95% CI 0.61-0.92) and dose (mean -3.93 mg·day-1, 95% CI -5.24-2.62 mg·day-1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions: By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.

Hypereosinophilic syndrome in Europe: Retrospective study of treatment patterns, clinical manifestations, and healthcare resource utilization.

BACKGROUND: The burden of hypereosinophilic syndrome (HES) in Europe is not well characterized. OBJECTIVE: To evaluate real-world patient characteristics, treatment patterns, clinical manifestations, and healthcare resource utilization for patients with HES from France, Germany, Italy, Spain, and the United Kingdom. METHODS: In this retrospective, noninterventional study, data for patients with a physician-confirmed diagnosis of HES were abstracted from medical chart reviews. Patients were aged 6 years or older at the time of HES diagnosis and had 1 or more years of follow-up from the index date (first clinic visit between January 2015 and December 2019). Data on treatment patterns, comorbidities, clinical manifestations, clinical outcomes, and healthcare resource utilization were collected from diagnosis or index date to end of follow-up. RESULTS: Data for 280 patients were abstracted from medical charts by 121 physicians treating HES, with multiple specialties. Most patients (55%) had idiopathic HES, and 24% had myeloid HES; the median number (interquartile range [IQR]) of diagnostic tests per patient was 10 (6-12). The most common comorbidities were asthma (45%) and anxiety or depression (36%). Most patients (89%) used oral corticosteroids; 64% used immunosuppressants or cytotoxic agents, and 44% used biologics. Patients had a median (IQR) of 3 clinical manifestations (1-5), most commonly constitutional (63%), lung (49%), and skin (48%). Twenty-three percent of patients experienced a flare, and 40% had a complete treatment response. Some patients (30%) were hospitalized with a median (IQR) stay of 9 days (5-15) for HES-related issues. CONCLUSION: Patients with HES across 5 European countries had a substantial disease burden despite extensive oral corticosteroids treatment, highlighting the need for additional targeted therapies.

Knowledge and Attitude Among Patients and Physicians on Allergic Rhinitis (KAPPA): An International Survey.

Purpose: Our study compared knowledge of, and attitudes towards, allergic rhinitis (AR) among patients and physicians in: Brazil, Japan, Korea, Mexico, Saudi Arabia, Spain, United Arab Emirates, and the United Kingdom. Patients and Methods: Patients with AR were recruited via probability-based sampling. Data were captured via telephone interview, personal interview, or self-administered online survey. Physicians were recruited from an online physician panel and interviewed by self-administered online survey. Results: In total, 1436 patients and 1637 physicians were surveyed. Most patients (76.9%) reported moderate-to-severe AR, whereas physicians reported more mild (mean cases ranging from 57.0-68.2) than moderate-to-severe AR (mean cases ranging from 31.8-43.0). Overall, most physicians (85.4%) and patients (77.5%) agreed AR could be controlled with treatment. Physicians preferred prescribing oral antihistamines (OAHs) for mild AR (from 45.3% of physicians in Brazil to 73.6% of physicians in Mexico). For moderate and severe AR, more physicians preferred prescribing intranasal corticosteroids (INCSs) and OAHs for moderate and severe AR than other available treatments (from 48.5% of physicians in the UK to 69.5% of physicians in Spain). Patients preferred OAHs to INCSs for treating AR (62.0%). Patients also reported a range of comorbidities: overall, sinus infections were the most common (24.7%), and comorbid asthma was present in 12.9% of patients. Per country, Saudi Arabia had the highest proportion (53.5%) and Mexico had the lowest proportion (8.0%) of patients with comorbid asthma. Conclusion: Patient and physician perceptions of AR mostly differed between and within countries, although there was generally agreement that AR could be controlled with treatment. Differing attitudes towards AR among patients and physicians suggests a need for improved education in and communication between these groups, with subsequent implications for optimizing disease management.

REALITI-A Study: Real-World Oral Corticosteroid-Sparing Effect of Mepolizumab in Severe Asthma.

BACKGROUND: Patients with severe asthma may require maintenance oral corticosteroids (mOCS) for disease control as well as systemic corticosteroid (SCS) bursts for clinically significant exacerbations. However, mOCS and SCS use are associated with adverse effects, which increases patient disease burden. OBJECTIVE: To assess the real-world corticosteroid-sparing effect of mepolizumab in patients with severe asthma. METHODS: REALITI-A was a 24-month international, prospective, observational cohort study involving 84 centers across Europe, Canada, and the United States, with a 1-year pre-post mepolizumab treatment preplanned interim analysis. A total of 822 adults with a clinical diagnosis of asthma and a physician decision to initiate mepolizumab treatment (100 mg subcutaneously) were included. End points included daily mOCS dose at baseline (penultimate 28 days of pretreatment) and 1 year after treatment; percent reduction from baseline in mOCS dose; patients discontinuing mOCS 1 year after treatment; and the rate of clinically significant exacerbations (those requiring OCS for 3 days or more [or parenteral administration], emergency room visit, and/or hospital admission) before and after treatment. RESULTS: A total of 319 patients received mOCS at baseline (median [interquartile range]: 10.0 [5.0-15.0] mg/d). At 1 year after treatment, median mOCS dose was reduced by 75% (2.5 [0.0-5.0] mg/d); 64% of patients had a reduction in mOCS dose of 50% or greater compared with baseline and 43% discontinued mOCS. Clinically significant exacerbations decreased between pretreatment and posttreatment (rate ratio [95% confidence interval] 0.29 [0.26-0.32]; P < .001). CONCLUSION: This 1-year analysis demonstrates that real-world mepolizumab treatment is clinically effective in patients with severe asthma, providing disease control while reducing the need for mOCS and SCS bursts.

Burden of illness associated with eosinophilic granulomatosis with polyangiitis: a systematic literature review and meta-analysis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease associated with vascular inflammation and multisystem organ damage. The literature reporting EGPA incidence or prevalence is limited. We performed a systematic literature review and meta-analysis to describe the incidence, prevalence, and disease burden associated with EGPA. Real-world, observational, English-language studies in MEDLINE, MEDLINE In-Process, and Embase up to 6 June, 2019, were included. A single investigator screened all identified titles/abstracts and extracted data; an additional, independent investigator repeated the screening and validated the extracted data. A random-effects meta-analysis was conducted to generate pooled estimates for EGPA incidence and prevalence. Data from 100 eligible publications were extracted (32 with incidence/prevalence data, 65 with morbidity/healthcare resource data; 3 with both types of data). Significant evidence of between-study heterogeneity for reported incidence (p = 0.0013-0.0016) and prevalence (p = 0.0001-0.0006) estimates was observed. Global and European pooled estimates (95% confidence interval) of EGPA incidence were 1.22 (0.93, 1.60) and 1.07 (0.94, 1.35) cases per million person-years, respectively; global and European pooled estimates (95% confidence interval) for EGPA prevalence were 15.27 (11.89, 19.61) and 12.13 (6.98, 21.06) cases per million individuals, respectively. The proportions of patients experiencing relapses, or who had nasal polyps or severe asthma, varied considerably across studies. EGPA healthcare resource use was high, with inpatient admissions and emergency department visits reported for 17-42% and 25-42% of patients, respectively. Our results indicate that although global and European EGPA incidence and prevalence is low, the associated disease burden is substantial. Key points • We performed a systematic literature review and meta-analysis of real-world, observational studies describing the incidence, prevalence, and disease burden associated with eosinophilic granulomatosis with polyangiitis (EGPA). • Based on meta-analysis data from 35 eligible studies reporting incidence and prevalence, the incidence and prevalence of EGPA were low (globally 1.22 cases per million person-years and 15.27 cases per million individuals, respectively). • Among the 49 studies with morbidity and/or healthcare resource data, most reported a large proportion of patients with EGPA relapses and comorbidities of nasal polyps and severe asthma. • Healthcare resource use was also high among patients with EGPA in these studies, with inpatient admissions and emergency department visits reported for 17-42% and 25-42% of patients, respectively. Taken together, these data indicate the substantial disease burden associated with EGPA.

A 6-year safety surveillance of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in South Korea.

In 2010, Korea introduced 10-valent pneumococcal conjugate vaccine for children aged 6 weeks to 5 years against invasive disease caused by Streptococcus pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F and cross-reactive 19A. The aim of this 6-year real-world study of 646 healthy Korean children from 16 centers vaccinated in routine practice is to monitor vaccine safety, as per Ministry of Food and Drug Safety regulations. Around 50% had a past or existing medical condition, 19.3% an existing condition and 7.6% received concomitant medication). Total of 489 recorded adverse events (AEs) were reported in 274 infants; 86% were mild and the rest moderate, only three were reported as serious. Most AEs (97.8%) were not related to vaccination; one case of injection-site swelling and of fever was related, two cases of fever were probably related, five cases of fever and one case each of diarrhea and coughing were possibly related. None of the serious AEs were related to vaccination. Of 11 adverse drug reactions (ADRs) in 10 subjects, none were serious. Overall, 263 subjects (40.7%) received medication (mainly antibiotics or antipyretics) for the treatment of an AE, of which 6 subjects were treated for an ADR. There was no difference in the incidence of AEs according to age, sex or concomitant vaccination. Subjects with an existing medical condition had significantly more AEs than those without any conditions (p = 0.03), but no differences regarding ADRs. Four-dose vaccination with PHiD-CV appears to have a clinically-acceptable safety profile for Korean children. ClinicalTrials.gov identifier: NCT01248988.

Community-Acquired Pneumonia Case Validation in an Anonymized Electronic Medical Record-Linked Expert System.

An electronic anonymized patient portal analysis using radiographic reports and admission and discharge diagnoses had sensitivity, specificity, positive predictive value, and negative predictive value of 84.7%, 78.2%, 75%, and 87%, respectively, for community-acquired pneumonia validated against a blinded expert medical review. This approach can help to track antimicrobial use and resistance.

Parental knowledge, attitudes and perception of pneumococcal disease and pneumococcal conjugate vaccines in Singapore: a questionnaire-based assessment.

BACKGROUND: Under the National Childhood Immunisation Schedule (NCIS) in Singapore most vaccines are provided free while some, including pneumococcal conjugate vaccines (PCV), added to the NCIS in October 2009, are not free. In contrast to ≥95 % coverage achieved for recommended childhood vaccines that are free, 2013 coverage of the PCV booster dose was 58.9 % (for unclear reasons). To date, no population impact on pneumococcal disease (PD) has been observed. We conducted a questionnaire-based study of parents of young children to assess the value of PCV to parents, and to quantify the extent to which vaccine cost is a barrier to PCV uptake in Singapore. METHODS: A single, trained interviewer administered a questionnaire to 200 parents ≥21 years of age with young children attending the Singapore Sengkang Polyclinic. The questionnaire asked closed-ended questions on parents' knowledge about PD and PCV. A 5-point Likert scale measured perceived benefits and barriers to PCV vaccination. RESULTS: There were 162 parents whose children were either PCV-vaccinated or who intended to vaccinate their child with PCV (Vaccinated group), and 38 whose children were non-PCV vaccinated or who did not intend to vaccinate (Unvaccinated group). The odds ratio for PCV vaccination among parents who perceived cost as a barrier was 0.16 (95%CI 0.02-1.23). Compared to the Vaccinated group, parents in the Unvaccinated group were less willing to pay for PCV (50.0 %/94.4 %). Compared to the Vaccinated group, fewer parents in the Unvaccinated group had heard about PD (34.2 %/82.1 %) or PCV (36.8 %/69.1 %), or perceived that PD was a threat to their child. Fewer parents in the Unvaccinated group knew that vaccination could prevent PD (28.9 %/77.8 %), or reported that PCV vaccination was recommended to them by any source (63.2 % had no PCV recommendation, versus 20.4 %). When informed that PCV is included in the NCIS only 65.8 % of parents in the Unvaccinated group, versus 98.8 % in the Vaccinated group, indicated that they would be willing to vaccinate their child. CONCLUSIONS: Cost considerations, not having vaccination recommended to parents and a lack of knowledge among parents of the benefits of PCV to the child may adversely impact PCV uptake in Singapore.

The prevalence and patient characteristics of chronic obstructive pulmonary disease in non-smokers in Vietnam and Indonesia: An observational survey.

BACKGROUND AND OBJECTIVE: An estimated 25-40% of patients with chronic obstructive pulmonary disease (COPD) have never smoked. We investigated the prevalence and patient characteristics of COPD in non-smokers from Vietnam and Indonesia. METHODS: This population-based cross-sectional survey of participants from urban and rural Vietnam and Indonesia used a stratified multistage cluster sampling design, with sample and population weights applied to ensure representativeness. Participants were female or male (recruited in the ratio 2:1) non-smokers, 40 years or older and able to perform a spirometry test. Spirometry was performed at a single study visit. Other clinical information was collected via standardized questionnaires. RESULTS: The 1506 evaluable participants were approximately equally distributed between Vietnam and Indonesia, and rural and urban areas. Overall prevalence of COPD was found to be 6.9% (95% confidence interval (CI): 5.7-8.3), with almost three times higher prevalence in men than women (12.9% (95% CI: 9.1-18.0) vs 4.4% (95% CI: 3.0-6.5)). We found higher rates of COPD in Vietnam than Indonesia (8.1% (95% CI: 5.8-11.3) vs 6.3% (95% CI: 4.8-8.3)), with a particularly high prevalence in urban Vietnam (11.1% (95% CI: 8.1-15.1)). Very few participants (6%) diagnosed to have COPD during the study had been previously diagnosed with COPD. Respiratory symptoms and lower health-related quality of life were more common in participants with COPD. CONCLUSIONS: The prevalence of COPD in non-smoking individuals from rural and urban Vietnam and Indonesia was 6.9%, of which a significant proportion (94%) were previously undiagnosed.

Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality.

OBJECTIVE: Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease with a wide spectrum of manifestations, shows considerable variation across the globe, although there is little evidence to indicate its relative prevalence in Asia. This review describes its prevalence, severity, and outcome across countries in the Asia-Pacific region. METHODS: We conducted a systematic literature search using 3 groups of terms (SLE, epidemiology, and Asia-Pacific countries) of EMBase and PubMed databases and non-English language resources, including Chinese Wanfang, Korean KMbase, Korean College of Rheumatology, Japana Centra Revuo Medicina, Taiwan National Digital Library of Theses and Dissertations, and Taiwanese, Thai, and Vietnamese journals. RESULTS: The review showed considerable variation in SLE burden and survival rates across Asia-Pacific countries. Overall crude incidence rates (per 100,000 per year) ranged from 0.9-3.1, while crude prevalence rates ranged from 4.3-45.3 (per 100,000). Higher rates of renal involvement, one of the main systems involved at death, were observed for Asians (21-65% at diagnosis and 40-82% over time) than for whites. While infections and active SLE were leading causes of death, a substantial proportion (6-40%) of deaths was due to cardiovascular involvement. The correlation between the Human Development Index and 5-year survival was 0.83. CONCLUSION: This review highlights the need to closely monitor Asian SLE patients in Asian countries for renal and cardiovascular involvement, especially those who may not receive proper treatment and are therefore at greater risk of severe disease. We hope this will encourage further research specific to this region and lead to improved clinical management.

Estimating physical activity energy expenditure, sedentary time, and physical activity intensity by self-report in adults.

BACKGROUND: Few questionnaires that assess usual physical activity have been reported to be valid for all different subdimensions of physical activity. OBJECTIVE: The objective was to assess the validity and reliability of the Recent Physical Activity Questionnaire (RPAQ), which assesses usual physical activity (PA) in 4 domains (work, travel, recreation, and domestic life). DESIGN: Total energy expenditure (TEE) was measured for 14 d by using the doubly labeled water technique combined with a measure of resting metabolic rate to yield PA energy expenditure (PAEE) in 25 men and 25 women. Simultaneously, intensity of activity was measured by using combined heart rate and movement sensing for 11 d. Repeatability of the RPAQ was assessed in an independent sample of 71 women and 60 men aged 31-57 y. RESULTS: Estimated TEE and PAEE were significantly associated with criterion measures (TEE: r = 0.67; PAEE: r = 0.39) with mean (+/-SD) biases of -3452 +/- 2025 kJ/d and -13 +/- 24 kJ d(-1) kg(-1). The correlation between self-reported and measured time spent was significant for vigorous PA (r = 0.70) and marginally insignificant for sedentary time (r = 0.27, P = 0.06). The mean biases were relatively small for sedentary time and vigorous PA: 0.7 +/- 2.8 h/d and -12 +/- 24 min/d, respectively. The intraclass correlation coefficient for repeatability of total PAEE (kJ/d) was 0.76 (P < 0.0001). CONCLUSION: The RPAQ is the first questionnaire with demonstrated validity for ranking individuals according to their time spent at vigorous-intensity activity and overall energy expenditure.

Adjusting for energy intake--what measure to use in nutritional epidemiological studies?

BACKGROUND: The measurement of energy intake in epidemiological studies is difficult. However, it is important that energy intake is assessed if epidemiological analyses are to correspond to isocaloric experiments. The aim of this study was to compare self-reported energy intake, physical activity, and body weight with energy expenditure measured by 4 days of heart rate monitoring with individual calibration of the relationship between heart rate and oxygen consumption. METHODS: Volunteer sub-study of 97 men and women (mean ages 54 and 51 years respectively) within the European Investigation into Cancer (EPIC) study in Norfolk (UK). Dietary assessment of energy intake and physical activity was by self-report and weight was measured using standard techniques. Energy expenditure was assessed objectively by recording heart rate for 4 days following a calibration of the relationship between heart rate and oxygen consumption. RESULTS: Self-reported energy intake by 7-day diary (mean 8.5 MJ/day) and food frequency questionnaire (FFQ) (mean 8.8 MJ/day) were significantly lower than objectively measured total energy expenditure (mean 11.2 MJ/day). The deattenuated partial correlations between total energy expenditure were 0.33 (7-day diary), 0.34 (FFQ), 0.50 (physical activity), and 0.56 (weight). Weight accounted for 31% (deattenuated) of the sum of squares about the mean of true energy intake after adjusting for age and sex. With the addition of self-reported physical activity, the model was significantly improved (R2 = 0.57). Adding energy either assessed by the diary or FFQ did not improve the model. CONCLUSIONS: The results presented here indicate that to adjust for energy intake, for the purpose of replicating an isocaloric experiment in an observational epidemiological study, one would do considerably better adjusting for weight and physical activity, than adjusting for energy intake estimated from an FFQ.

PGC-1alpha genotype modifies the association of volitional energy expenditure with [OV0312]O2max.

UNLABELLED: Sedentary lifestyles are increasingly common and result in low cardiorespiratory fitness ([OV0312]O2max), a well-established predictor of early mortality and coronary heart disease (CHD). Adaptation in [OV0312]O2max after exercise training varies considerably between people. Because there are hereditary components to fitness, it is likely that genetic factors explain some of this variability. PPARGC1 (PGC-1alpha) coactivates genes involved in energy transduction and mitochondrial biogenesis. Transgenic mouse data demonstrate that overexpression of PGC-1alpha mRNA increases endurance capacity by transformation of nonoxidative to oxidative skeletal muscle tissue. Other murine studies demonstrate that exercise increases PGC-1alpha mRNA expression. PURPOSE: To explore whether a candidate polymorphism in the PGC-1alpha gene modifies the association between physical activity energy expenditure (PAEE) and predicted [OV0312]O2max ([OV0312]O2max.pred). METHOD: We examined whether the Gly482Ser polymorphism of PGC-1alpha modified the relationship between objectively measured PAEE and [OV0312]O2max.pred in a population-based sample of 599 healthy middle-aged people. PAEE was assessed using individual calibration with 4 d of heart rate monitoring. [OV0312]O2max.pred was measured during a submaximal exercise stress test on a bicycle ergometer. RESULTS: Homozygosity at the Ser482 allele was found in 12.7% of the cohort, whereas 38.9% and 48.4% carried the Gly482Gly and Gly482Ser genotypes, respectively. The association between PAEE and [OV0312]O2max.pred (mL x kg(-1) x min(-1)) was strongest in people homozygous for the Ser482 allele (beta = 12.03; P < 0.00001) compared with carriers of the Gly allele (beta = 5.61; P < 0.00001). In a recessive model for the Ser482 allele, the interaction between PAEE and genotype on [OV0312]O2max.pred (L x min(-1)) was highly significant (P = 0.009). CONCLUSION: Our results indicate that Ser482 homozygotes may be most capable of improving cardiorespiratory fitness when physically active, and that Gly482Ser may explain some of the between-person variance previously reported in cardiorespiratory adaptation after exercise training.

Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action.

Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT) cohort in the United Kingdom. Polymorphisms in five of 15 genes (33%) encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor), KCNJ11 (KIR6.2), SLC2A2 (GLUT2), HNF4A (HNF4alpha), and INS (insulin)-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%)-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.

Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

OBJECTIVE: To assess the validity and repeatability of a simple index designed to rank participants according to their energy expenditure estimated by self-report, by comparison with objectively measured energy expenditure assessed by heart-rate monitoring with individual calibration. DESIGN: Energy expenditure was assessed over one year by four separate episodes of 4-day heart-rate monitoring, a method previously validated against whole-body calorimetry and doubly labelled water. Cardio-respiratory fitness was assessed by four repeated measures of sub-maximum oxygen uptake. At the end of the 12-month period, participants completed a physical activity questionnaire that assessed past-year activity. A simple four-level physical activity index was derived by combining occupational physical activity together with time participating in cycling and other physical exercise (such as keep fit, aerobics, swimming and jogging). SUBJECTS: One hundred and seventy-three randomly selected men and women aged 40 to 65 years. RESULTS: The repeatability of the physical activity index was high (weighted kappa=0.6, ). There were positive associations between the physical activity index from the questionnaire and the objective measures of the ratio of daytime energy expenditure to resting metabolic rate and cardio-respiratory fitness As an indirect test of validity, there was a positive association between the physical activity index and the ratio of energy intake, assessed by 7-day food diaries, to predicted basal metabolic rate. CONCLUSIONS: The summary index of physical activity derived from the questions used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study suggest it is useful for ranking participants in terms of their physical activity in large epidemiological studies. The index is simple and easy to comprehend, which may make it suitable for situations that require a concise, global index of activity.

Physical inactivity is associated with lower forced expiratory volume in 1 second : European Prospective Investigation into Cancer-Norfolk Prospective Population Study.

Forced expiratory volume in 1 second (FEV(1)) is a strong risk factor for cardiovascular disease, stroke, lung cancer, and all-cause mortality. One possible explanation for this association is that FEV(1) is a marker of other determinants of mortality risk, such as obesity and physical inactivity. In a population-based cohort study of 12,283 men and women aged 45-74 years from the European Prospective Investigation into Cancer-Norfolk Study recruited in 1993-1997, the cross-sectional association between physical activity and FEV(1) and that between physical activity and change in FEV(1) were analyzed. Indices of physical activity, including participation in vigorous recreational activity, stair climbing, and television viewing, were assessed with a validated questionnaire designed to assess activity in the previous year. Television viewing was negatively associated with FEV(1) in men and women (p < 0.001), whereas stair climbing and participation in vigorous leisure time activities were positively associated with FEV(1) in men and women (p < 0.001). The associations remained after adjustment for known confounders, including age, height, vitamin C, and smoking. Climbing more stairs and participating in vigorous leisure-time activity predicted a slower rate in annual percent decline in FEV(1) (p < 0.004 and p < 0.002, respectively). In conclusion, physical activity is associated with higher levels of FEV(1), whereas television viewing is associated with lower levels.

Mammographic parenchymal patterns and self-reported soy intake in Singapore Chinese women.

The study aimed to investigate whether self-reported dietary variables were associated with mammographic parenchymal patterns, which have been shown to predict risk of breast cancer. Among the 3,421 women, ages 45-74 years, common to two independent population-based cohorts, mammographic parenchymal patterns and current dietary habits were assessed for 406 randomly chosen participants. Logistic regression methods were used to compare dietary and other lifestyle profiles between subjects classified as displaying high (cases) and low risk (controls) parenchymal patterns. After adjustment for energy intake and other potential confounders, dietary soy protein intake was inversely related to risk of high-risk parenchymal pattern (odds ratio, 0.41; 95% confidence interval, 0.18-0.94, highest versus lowest quartile of intake). Similarly, the highest versus lowest quartile of dietary soy isoflavone intake was significantly related to low-risk parenchymal patterns (odds ratio, 0.44; 95% confidence interval, 0.20-0.98). The association between high soy intake and a reduced risk of mammographic parenchymal patterns that are associated with high breast cancer risk may have important implications in breast cancer prevention.