Airflow limitation and survival after surgery for non-small cell lung cancer: Results from a systematic review and lung cancer screening trial (NLST-ACRIN sub-study).

OBJECTIVE: Lung cancer remains the single greatest cause of cancer mortality where surgery for early stage non-small cell lung cancer achieves the greatest survival. While there is growing optimism for better outcomes with screening using annual computed tomography, the impact of co-existing airflow limitation on survival remains unknown. To compare survival in non-small cell lung cancer patients undergoing surgery stratified according to the presence or absence of pre-surgery airflow limitation. MATERIALS AND METHODS: We undertook a systematic literature search of non-screen lung cancer that encompassed studies reported between January 1946 and January 2017. Full-text articles were identified following eligibility scoring, with data extracted and analysed using a standardised analytical method (PRISMA). The results of this systematic review in non-screen lung cancers were compared to real-world results from a lung cancer screening cohort (N = 10,054), where outcomes following surgery could be compared after stratification according to pre-surgery airflow limitation. RESULTS: In the systematic review, 6899 subjects were included from 10 studies; 7 were retrospective, 3 were prospective. Overall survival was 950 (44%) in 2144 people with COPD and 2597 (55%) from 4755 controls (unadjusted P value <0.001). However, the overall meta-analysed random effects odds ratio for overall survival (N = 10) and 5-year survival (N = 4) comparing those with and without COPD was 0.91 (95% CI = 0.84-1.00) and 0.99 (95% CI = 0.79-1.24) respectively. There were no signs of significant heterogeneity (I2 = 19.1%, P = 0.27) nor publication bias as assessed by funnel plot and Egger's test (P = 0.19). In the lung cancer screening sub-study of 10,054 screening participants we found no difference in 5-year survival in those with and without airflow limitation (84% and 81% respectively, P = 0.64). CONCLUSION: Survival after surgery for non-small cell lung cancer is comparable between those with and without spirometry evidence of airflow limitation. This finding was replicated in lung cancer diagnosed during screening.

Anti-fracture efficacy of zoledronate in subgroups of osteopenic postmenopausal women: secondary analysis of a randomized controlled trial.

BACKGROUND: We recently reported that the administration of zoledronate every 18 months to osteopenic older women reduces the incidence of fractures. OBJECTIVE: Here, we present a more detailed analysis of that trial to determine whether baseline clinical characteristics impact on the anti-fracture efficacy of this intervention. METHODS: This is a prospective, randomized, placebo-controlled, double-blind trial in osteopenic postmenopausal women aged ≥ 65 years, to determine the anti-fracture efficacy of zoledronate. 2000 women were recruited using electoral rolls and randomized to receive 4 infusions of either zoledronate 5 mg or normal saline, at 18-month intervals. Each participant was followed for 6 years. Calcium supplements were not supplied. RESULTS: Fragility fractures (either vertebral or nonvertebral) occurred in 190 women in the placebo group (227 fractures) and in 122 women in the zoledronate group (131 fractures), odds ratio (OR) 0.59 (95%CI 0.46, 0.76; P < 0.0001). There were no significant interactions between baseline variables (age, anthropometry, BMI, dietary calcium intake, baseline fracture status, recent falls history, bone mineral density, calculated fracture risk) and the treatment effect. In particular, the reduction in fractures appeared to be independent of baseline fracture risk, and numbers needed to treat (NNT) to prevent one woman fracturing were not significantly different across baseline fracture risk tertiles. CONCLUSIONS: The present analyses indicate that the decrease in fracture numbers is broadly consistent across this cohort. The lack of relationship between NNTs and baseline fracture risk calls into question the need for BMD measurement and precise fracture risk assessment before initiating treatment in older postmenopausal women.

Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial.

BACKGROUND: Severe vitamin D deficiency causes osteomalacia, yet trials of vitamin D supplementation in the community have not on average demonstrated benefit to bone mineral density (BMD) or fracture risk in adults. OBJECTIVE: To determine whether monthly high-dose vitamin D supplementation influences BMD in the general population and in those with low 25-hydroxyvitamin D levels. METHODS: Two-year substudy of a trial in older community-resident adults. A total of 452 participants were randomized to receive monthly doses of vitamin D3 100 000 IU, or placebo. The primary end-point was change in lumbar spine BMD. Exploratory analyses to identify thresholds of baseline 25-hydroxyvitamin D for vitamin D effects on BMD were prespecified. RESULTS: Intention-to-treat analyses showed no significant treatment effect in the lumbar spine (between-groups difference 0.0071 g cm-2 , 95%CI: -0.0012, 0.0154) or total body but BMD loss at both hip sites was significantly attenuated by ~1/2% over 2 years. There was a significant interaction between baseline 25-hydroxyvitamin D and treatment effect (P = 0.04). With baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 (n = 46), there were between-groups BMD changes at the spine and femoral sites of ~2%, significant in the spine and femoral neck, but there was no effect on total body BMD. When baseline 25-hydroxyvitamin D was >30 nmol L-1 , differences were ~1/2% and significant only at the total hip. CONCLUSIONS: This substudy finds no clinically important benefit to BMD from untargeted vitamin D supplementation of older, community-dwelling adults. Exploratory analyses suggest meaningful benefit in those with baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 . This represents a significant step towards a trial-based definition of vitamin D deficiency for bone health in older adults.

Effect of single-dose dexamethasone on acute phase response following zoledronic acid: a randomized controlled trial.

Zoledronic acid provokes an inflammatory reaction, or acute phase response, in some individuals. We examined whether treatment with dexamethasone could prevent this response. A single dose of dexamethasone 4 mg, given at the time of zoledronic acid infusion, did not influence the incidence or severity of the acute phase response. INTRODUCTION: The potent bisphosphonate zoledronic acid (ZOL) is used to treat osteoporosis, Paget's disease, and hypercalcemia of malignancy. This medication can provoke an inflammatory reaction, known as the acute phase response (APR). We examined whether glucocorticoid treatment at the time of first exposure to ZOL prevents the development of APR. METHODS: This double-blind, randomized, controlled trial assessed 40 adults receiving ZOL 5 mg intravenously for the first time. Participants received oral dexamethasone 4 mg (n = 20) or placebo (n = 20) at the time of ZOL infusion. Oral temperature was measured at baseline and three times a day for 3 days following infusion. Symptoms of APR were assessed via questionnaire at baseline then daily for 3 days and again at day 15 post-infusion. Use of rescue medications (paracetamol or ibuprofen) in the 3 days following infusion was evaluated. Primary outcome was between-group difference in temperature change from baseline. RESULTS: There was no significant difference in temperature change (p = 0.95) or symptom score (p = 0.42) in the 3 days following ZOL between dexamethasone and placebo recipients. Eleven (55%) in the dexamethasone group and 10 (50%) placebo recipients experienced a temperature increase of ≥1 °C (p = 0.99). Seven (35%) in the dexamethasone group and 9 (45%) in the placebo group experienced an increase in symptom score of ≥3 points (p = 0.75). Thirteen (65%) dexamethasone recipients and 12 (60%) in the placebo group required rescue medications (p = 0.99). Dexamethasone was well-tolerated. CONCLUSIONS: A single dose of dexamethasone 4 mg does not influence the incidence or severity of APR following first exposure to ZOL. TRIAL REGISTRATION: ACTRN12615000794505.

Acute effects of calcium supplements on blood pressure: randomised, crossover trial in postmenopausal women.

Calcium supplements appear to increase cardiovascular risk, but the mechanism is unknown. We investigated the acute effects of calcium supplements on blood pressure in postmenopausal women. The reduction in systolic blood pressure was smaller after calcium compared with the placebo in the hours following dosing. INTRODUCTION: Calcium supplements appear to be associated with increased cardiovascular risk; however, the mechanism of this is uncertain. We previously reported that blood pressure declined over a day in older women, and that this reduction was smaller following a calcium supplement. To confirm this finding, we investigated the acute effects of calcium supplements on blood pressure. METHODS: This was a randomised controlled crossover trial in 40 healthy postmenopausal women (mean age 71 years and BMI 27.2 kg/m2). Women attended on two occasions, with visits separated by ≥7 days. At each visit, they received either 1 g of calcium as citrate, or placebo. Blood pressure and serum calcium concentrations were measured immediately before, and 2, 4 and 6 h after each intervention. RESULTS: Ionised and total calcium concentrations increased after calcium (p < 0.0001 versus placebo). Systolic blood pressure decreased after both calcium and placebo, but significantly less so after calcium (p = 0.02). The reduction in systolic blood pressure from baseline was smaller after calcium compared with placebo by 6 mmHg at 4 h (p = 0.036) and by 9 mmHg at 6 h (p = 0.002). The reduction in diastolic blood pressure was similar after calcium and placebo. CONCLUSIONS: These findings are consistent with those of our previous trial and indicate that the use of calcium supplements in postmenopausal women attenuates the post-breakfast reduction in systolic blood pressure by around 6-9 mmHg. Whether these changes in blood pressure influence cardiovascular risk requires further study.

Circulating calcium concentrations, vascular disease and mortality: a systematic review.

Associations between serum calcium and vascular disease have been reported, but the consistency of these findings is unknown. We conducted a systematic review to determine whether circulating calcium concentrations are associated with risks of cardiovascular disease and death in normocalcaemic populations. We conducted PubMed searches up to 18 December 2014 and scrutinized reference lists of papers. Eligible studies related serum calcium to mortality or cardiovascular events in humans. A follow-up of at least one year was required for longitudinal studies. Studies in populations selected on the basis of renal disease or abnormal serum calcium were excluded. Two investigators performed independent data extraction. The results were tabulated and, where possible, meta-analysed. Five of 11 studies reported a statistically significant positive association between serum calcium and mortality. Meta-analysis of eight of these studies showed a hazard ratio of death of 1.13 (1.09, 1.18) per standard deviation of serum calcium. Eight of 13 studies reported a statistically significant positive association between serum calcium and cardiovascular disease. Meta-analysis of eight studies showed a hazard ratio of cardiovascular disease of 1.08 (1.04, 1.13) per standard deviation of serum calcium. For two studies reporting odds ratios, the pooled odds ratio per standard deviation was 1.22 (1.11, 1.32). When hazard ratios adjusted for cardiovascular risk factors were meta-analysed, the pooled hazard ratio was 1.04 (1.01, 1.08). Other studies demonstrated associations between serum calcium and stroke and between serum calcium and direct measurements of arterial disease and calcification. These observational data indicate that serum calcium is associated with vascular disease and death, but they cannot determine causality.

Acute and 3-month effects of calcium carbonate on the calcification propensity of serum and regulators of vascular calcification: secondary analysis of a randomized controlled trial.

SUMMARY: Calcium supplements have been associated with increased cardiovascular risk, but the mechanism is unknown. We investigated the effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50). Changes in serum calcium were related to changes in T50. INTRODUCTION: Calcium supplements have been associated with increased cardiovascular risk; however, it is unknown whether this is related to an increase in vascular calcification. METHODS: We investigated the acute and 3-month effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50), and on three possible regulators of calcification: fetuin-A, pyrophosphate and fibroblast growth factor-23 (FGF23). We randomized 41 postmenopausal women to 1 g/day of calcium as carbonate, or to a placebo containing no calcium. Measurements were performed at baseline and then 4 and 8 h after their first dose, and after 3 months of supplementation. Fetuin-A, pyrophosphate and FGF23 were measured in the first 10 participants allocated to calcium carbonate and placebo who completed the study. RESULTS: T50 declined in both groups, the changes tending to be greater in the calcium group. Pyrophosphate declined from baseline in the placebo group at 4 h and was different from the calcium group at this time point (p = 0.04). There were no other significant between-groups differences. The changes in serum total calcium from baseline were significantly related to changes in T50 at 4 h (r = -0.32, p = 0.05) and 8 h (r = -0.39, p = 0.01), to fetuin-A at 3 months (r = 0.57, p = 0.01) and to pyrophosphate at 4 h (r = 0.61, p = 0.02). CONCLUSIONS: These correlative findings suggest that serum calcium concentrations modulate the propensity of serum to calcify (T50), and possibly produce counter-regulatory changes in pyrophosphate and fetuin-A. This provides a possible mechanism by which calcium supplements might influence vascular calcification.

Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.

BACKGROUND: Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. AIM: We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). DESIGN: Individual person data meta-analysis. METHODS: Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. RESULTS: Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. CONCLUSIONS: Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.

Bone density in healthy men after cessation of calcium supplements: 20-month follow-up of a randomized controlled trial.

UNLABELLED: Bone density has been followed up for 20 months following completion of a trial which compared calcium 1,200 mg/day with placebo, in normal older men. Following cessation of calcium supplements, there is a small residual benefit in total body bone density, but not at the hip or spine. INTRODUCTION: Calcium supplements, or supplements of calcium-rich foods, have a positive effect on bone mineral density (BMD). However, it is uncertain whether there are any residual benefits of calcium on BMD following cessation of supplementation. METHODS: In a previously published study, 323 healthy men were randomized to receive elemental calcium 600 mg/day (n = 108), calcium 1,200 mg/day (n = 108), or placebo (n = 107) over 2 years. Consenting men from the placebo and calcium 1,200 mg/day groups (85 and 87, respectively) were followed over the next 1-2 years (mean 20 months), off trial medication. RESULTS: In the core trial, BMD increased at all sites by 1.0-1.5% at 2 years in the group receiving calcium 1,200 mg/day, compared to the group receiving placebo. In post-trial follow-up, the calcium group has some residual benefit at the total body (0.41% above placebo; P = 0.04) but there was no significant between-group differences at other sites. CONCLUSION: Following cessation of calcium supplements in healthy men, there is a small residual benefit in total body BMD, but not at the hip or spine. This is unlikely to confer a clinically significant dividend in terms of ongoing fracture prevention.

Bone density is normal and does not change over 2 years in sarcoidosis.

SUMMARY: Small studies have previously suggested that sarcoidosis may be associated with low bone mineral density. In this observational study of 64 patients with sarcoidosis, bone mineral density was within the normal range at baseline, and there was no evidence of accelerated bone loss over 1-2 years. INTRODUCTION: Several small studies have suggested that sarcoidosis may be associated with low bone mineral density (BMD). METHODS: We undertook a cross-sectional study of BMD in 64 patients with sarcoidosis. Of these, 27 with 25-hydroxyvitamin D<50 nmol/L entered a 1-year intervention study of vitamin D supplements, and 37 entered a 2-year longitudinal study of BMD, with the primary endpoint of the change in lumbar spine BMD. RESULTS: The mean age of participants was 58 years, 68% were female, and 8% were currently using oral glucocorticoids. At baseline, BMD for the entire cohort was greater than the expected values for the population at the lumbar spine (mean Z-score 0.7, P<0.001) and total body (0.5, P<0.001) and similar to expected values at the femoral neck (0.2, P=0.14) and total hip (0.2, P=0.14). BMD did not change at any of these four sites (P>0.19) over 2 years in the longitudinal study. In the intervention study, vitamin D supplements had no effect on BMD, and therefore we pooled the data from all participants. BMD did not change over 1 year at the spine, total hip, or femoral neck (P>0.3), but decreased by 0.7% (95% confidence interval 0.3-1.1) at the total body (P=0.019). CONCLUSIONS: BMD was normal at baseline, and there was no consistent evidence of accelerated bone loss over 1-2 years, regardless of baseline vitamin D status. Patients with sarcoidosis not using oral glucocorticoids do not need routine monitoring of BMD.

The Auckland calcium study: 5-year post-trial follow-up.

UNLABELLED: Five years after completion of a randomised placebo-controlled trial of calcium supplements, there was no effect of calcium on total fracture incidence, a significant reduction in vertebral and forearm fractures and, in a subset, no effect on bone density. There was no increased risk of cardiovascular events after discontinuation of calcium. INTRODUCTION: The Auckland calcium study was a 5-year randomised controlled trial of 1 g/day calcium citrate in 1,471 postmenopausal women. Calcium did not reduce total, vertebral or forearm fracture incidence, increased hip fracture incidence and had beneficial effects on bone mineral density (BMD). A secondary analysis raised concerns about the cardiovascular safety of calcium. The purpose of this study was to determine whether the effects of calcium on fracture incidence, BMD and cardiovascular endpoints persisted after supplement discontinuation. METHODS: Approximately 5-years post-trial, we collected information on the 1,408 participants alive at trial completion from the national databases of hospital admissions and deaths. We contacted 1,174 women by phone, and from these we obtained information on medical events and post-trial calcium use. We undertook BMD measurements at 10 years in a selected subset of 194 women who took study medication for 5 years in the original trial, and did not take bone-active medications post-trial. RESULTS: Over the 10-year period, there was no effect on total fracture (HR 0.90, 95% CI 0.75-1.07) or hip fracture incidence (1.40, 0.89-2.21), but significant reductions in forearm (0.62, 0.43-0.89) and vertebral fractures (0.52, 0.32-0.85) in those assigned to calcium. There were no between-group differences in BMD at 10 years at any site. The adverse cardiovascular outcomes observed in the 5-year trial did not persist post-trial. CONCLUSION: Calcium supplementation for 5 years had no effect on total fracture incidence at 10 years. The positive benefits on BMD and the adverse cardiovascular effects did not persist once supplements were stopped.

Bone density in heart or lung transplant recipients--a longitudinal study.

BACKGROUND: Osteoporosis is prevalent among heart or lung transplant (HLT) candidates. Bone loss is common posttransplant, with an associated increase in fracture risk. There is a lack of consensus regarding optimal management of bone health in HLT recipients. We report bone health data in a cohort of HLT recipients before and after transplantation and make recommendations for management. METHODS: Patients over the age of 20 who had a heart or lung transplant between 2000 and 2011 were identified from the New Zealand HLT Service database, and demographic data, immunosuppressive regimens, bisphosphonate use, and serial bone mineral density (BMD) data were extracted. RESULTS: Pretransplant BMD was available in 52 heart and 72 lung transplant recipients; 30 and 42, respectively, also had posttransplant BMD data. Pretransplant osteopenia or osteoporosis prevalence were 23% and 8% for heart candidates and 36% and 31% for lung candidates. Posttransplant, BMD decreased significantly at the femoral neck but not at the lumbar spine in the first year, with subsequent stabilization particularly in the presence of bisphosphonate use. Pretransplant BMD was the major predictor for developing osteopenia or osteoporosis after transplantation. CONCLUSION: A significant proportion of HLT recipients have osteopenia or osteoporosis pretransplant, and this persists posttransplant. Pretransplant BMD is an important predictor of subsequent osteopenia or osteoporosis development, allowing risk stratification and targeted intervention.

The impact of dietary calcium intake and vitamin D status on the effects of zoledronate.

UNLABELLED: We investigated whether baseline dietary calcium intake or vitamin D status modified the effects of zoledronate. Neither variable influenced the effect of zoledronate on bone mineral density, bone turnover, or risk of acute phase reaction, suggesting that co-administration of calcium and vitamin D supplements with zoledronate may not always be necessary. INTRODUCTION: Calcium and vitamin D supplements are often co-administered with bisphosphonates, but it is unclear whether they are necessary for therapeutic efficacy or minimizing side effects of bisphosphonates. We investigated whether baseline dietary calcium intake or vitamin D status modified the effect of zoledronate on bone mineral density (BMD) or bone turnover at 1 year, or the risk of acute phase reactions (APR). METHODS: Data were pooled from two trials of zoledronate in postmenopausal women without vitamin D deficiency in which calcium and vitamin D were not routinely administered. The cohort (zoledronate n = 154, placebo n = 68) was divided into subgroups by baseline dietary calcium intake (<800 vs. ≥800 mg/day) and vitamin D status [25-hydroxyvitamin D (25OHD) <50 vs. ≥50 nmol/L, and <75 nmol/L vs. ≥75 nmol/L] and treatment × subgroup interactions tested. RESULTS: There were 52, 86, and 36 % of the zoledronate group and 64, 94, and 46 % of the placebo group that had dietary calcium intake ≥800 mg/day, 25OHD ≥50 nmol/L, and 25OHD ≥75 nmol/L, respectively. There were no significant interactions between treatment and either baseline dietary calcium or baseline vitamin D status for lumbar spine BMD, total hip BMD, the bone turnover markers P1NP and ß-CTx, or the risk of an APR. There was also no three-way interaction between baseline dietary calcium intake, baseline vitamin D status, and treatment for any of these variables. CONCLUSIONS: Baseline dietary calcium intake and vitamin D status did not alter the effects of zoledronate, suggesting that co-administration of calcium and vitamin D with zoledronate may not be necessary for individuals not at risk of marked vitamin D deficiency.

Clinical applications of gene-based risk prediction for lung cancer and the central role of chronic obstructive pulmonary disease.

Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case-control study, where smokers with normal lungs were compared to smokers who had spirometry-defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions.

The larger exercise stroke volume in endurance-trained men does not result from increased left ventricular early or late inflow or tissue velocities.

AIM: To determine whether the larger exercise stroke volume in senior endurance-trained athletes results from an attenuation of age-related alterations in left ventricular (LV) early diastolic filling or a more vigorous late filling. METHODS: Body composition (DEXA), VO(2)peak, stroke volume (CO(2) rebreathing) and Doppler measures of early and late mitral inflow and mitral annular velocities were collected at seated upright rest and heart rate-matched exercise (100 and 120 bpm) in trained and untrained younger (18-30 years) men and trained and untrained older (60-80 years) healthy men. RESULTS: Ageing had a greater effect than training status on seated rest mitral inflow and tissue Doppler imaging parameters, as shown by a lower peak early-to-late mitral inflow velocity ratio (E/A ratio) and slower peak early mitral annular velocity (Em) in older compared with younger men. Exercise stroke volume was unaffected by healthy ageing; however, Em, an index of early LV lengthening rate and relaxation, was slower (P < 0.001), while measures of atrial systole were increased (P < 0.001) during exercise in older men. Stroke volume during exercise was larger in the trained men (P < 0.001); however, early and late mitral inflow and tissue velocities were not different between trained and untrained men. CONCLUSION: The larger exercise stroke volume in trained older male athletes does not seem to be related to faster filling or lengthening velocities during early or late filling. Thus, a larger, more compliant left ventricle in combination with an increased blood volume may explain the larger LV filling volumes in trained seniors.

Chromosome 4q31 locus in COPD is also associated with lung cancer.

Chronic obstructive pulmonary disease (COPD) is the single greatest risk factor for lung cancer in smokers and is found in 50-90% of lung cancer cases. The link between COPD and lung cancer may stem in part from the matrix remodelling and repair processes underlying COPD, and the development of epithelial-mesenchymal transition (EMT) that underlies lung carcinogenesis. The Hedgehog-interacting protein (HHIP), which mediates the epithelial response (EMT) to smoking, has been implicated in COPD and lung cancer. Recent genome-wide and candidate gene studies of COPD implicate genetic variants on the chromosomal 4q31 (HHIP/glycophorin A (GYPA)) locus. In a case-control study of smokers with normal lung function, COPD and lung cancer (subphenotyped for COPD), we show the GG genotype of the rs 1489759 HHIP single-nucleotide polymorphism (SNP) and the CC genotype of the rs 2202507 GYPA SNP confers a "protective" effect on COPD (OR 0.59, p = 0.006 for HHIP and OR = 0.65, p = 0.006 for GYPA) and lung cancer (OR = 0.70 (p = 0.05) for HHIP and OR 0.70 (p = 0.02) for GYPA). This study suggests that, in smokers, genetic variants of the 4q31 locus conferring a protective effect for COPD are also protective in lung cancer. We conclude that genetic susceptibility to lung cancer includes COPD-related gene variants.

Characterization of and risk factors for the acute-phase response after zoledronic acid.

CONTEXT: Intravenous aminobisphosphonates often cause an acute-phase response (APR), but the precise components of this, its frequency, and the risk factors for its development have not been systematically studied. OBJECTIVE: The objective of the study was to characterize the APR and determine its frequency and the risk factors for its development. DESIGN: The study was an analysis of adverse events from a large randomized trial. SETTING: This was a multicenter international trial. PATIENTS: Patients included 7765 postmenopausal women with osteoporosis. INTERVENTION: Zoledronic acid 5 mg annually or placebo was the intervention. MAIN OUTCOME MEASURE: Adverse events occurring within 3 d of zoledronic acid infusion were measured. RESULTS: More than 30 adverse events were significantly more common in the zoledronic acid group and were regarded collectively as constituting an APR. These were clustered into five groups: fever; musculoskeletal (pain and joint swelling); gastrointestinal (abdominal pain, vomiting, diarrhea); eye inflammation; and general (including fatigue, nasopharyngitis, edema). A total of 42.4% of the zoledronic acid group had an APR after the first infusion, compared with 11.7% of the placebo group. All APR components had their peak onset within 1 d, the median duration of the APR was 3 d, and severity was rated as mild or moderate in 90%. Stepwise regression showed that APR was more common in non-Japanese Asians, younger subjects, and nonsteroidal antiinflammatory drug users and was less common in smokers, patients with diabetes, previous users of oral bisphosphonates, and Latin Americans (P < 0.05 for all). CONCLUSION: This analysis identifies new components of the APR and provides the first assessment of risk factors for it. Despite its frequency, APR rarely resulted in treatment discontinuation in this study.