Airflow limitation and mortality during cancer screening in the National Lung Screening Trial: why quantifying airflow limitation matters.

IMPORTANCE: Current eligibility criteria for lung cancer (LC) screening are derived from randomised controlled trials and primarily based on age and smoking history. However, the individual benefits of screening are highly variable and potentially attenuated by co-morbidities such as advanced airflow limitation (AL). OBJECTIVE: To examine the relationship between the presence and severity of AL and screening outcomes. METHODS: This was a secondary analysis of 18 463 high-risk smokers, a substudy from the National Lung Screening Trial, who underwent pre-bronchodilator spirometry at baseline and median follow-up of 6.1 years. We used descriptive statistics and a competing risk proportional hazards model to examine differences in screening outcomes by chronic obstructive pulmonary disease severity group. RESULTS: The risk of developing LC increased with worsening AL (effect size=0.34, p<0.0001), as did the risk of dying of LC (effect size=0.35, p<0.0001). While those with severe AL (Global Initiative for Obstructive Lung Disease, GOLD grade 3-4) had the highest risk of LC and the highest LC mortality, they also had fewer adenocarcinomas (effect size=-0.20, p=0.008) and a lower surgery rate (effect size=-0.16, p=0.014) despite comparable staging, and greater non-LC mortality relative to LC mortality (effect size=0.30, p<0.0001). In participants with no AL, screening with CT was associated with a significant reduction in LC deaths relative to chest X-ray (30.3%, 95% CI 4.5% to 49.2%, p<0.05). The clinically relevant but attenuated reduction in those with AL (18.5%, 95% CI -8.4% to 38.7%, p>0.05) could be attributed to GOLD 3-4, where no appreciable mortality reduction was observed. CONCLUSION: Despite a greater risk of LC, severe AL was not associated with any apparent reduction in LC mortality following screening.

Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure.

AIMS: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). METHODS AND RESULTS: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. CONCLUSIONS: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Impact of Bariatric Surgery on Unplanned Hospital Admissions for Infection.

PURPOSE: Both obesity and type 2 diabetes are associated with an increased risk of skin and soft tissue (SSTI), urinary tract, and lower respiratory tract infections but it is not clear whether the incidence of such infections is reduced after bariatric surgery. MATERIALS AND METHODS: In people accepted onto our publicly funded bariatric program, we recorded unplanned admissions to public hospitals over a median follow-up of 4.5 years in those successfully undergoing surgery and in those who withdrew from the program. Rates of admission for the composite outcome (SSTI, urinary tract, or lower respiratory infection) were compared. RESULTS: Of 774 people accepted onto the program, 49% underwent surgery. Infections accounted for 27% of unplanned admissions in those not completing surgery and 13% of those who underwent surgery (p < 0.001). The rate of admission was 60% lower in people who underwent surgery than those who did not: 4.3 vs 12.2 per 100 patient-years (P < 0.002), a difference maintained across 8 years' follow-up. The impact of surgery was independent of enrolment age, BMI, or diabetes and smoking status. Of the three types of infection in the composite outcome, SSTI were the most prevalent and showed the greatest reduction (p < 0.0001). The median day stay for infection was 0.5 day less in those who underwent surgery (p < 0.01). CONCLUSIONS: Hospitalization for these three infectious diseases in people undergoing bariatric surgery was lower than that in people enrolled in the bariatric program but not completing surgery. The effect was greatest for SSTI, and sustained to at least 8 years.

Prophylactic Oral Dextrose Gel and Neurosensory Impairment at 2-Year Follow-up of Participants in the hPOD Randomized Trial.

Importance: Prophylactic oral dextrose gel reduces neonatal hypoglycemia, but later benefits or harms remain unclear. Objective: To assess the effects on later development of prophylactic dextrose gel for infants born at risk of neonatal hypoglycemia. Design, Setting, and Participants: Prospective follow-up of a multicenter randomized clinical trial conducted in 18 Australian and New Zealand hospitals from January 2015 to May 2019. Participants were late preterm or term at-risk infants; those randomized in 9 New Zealand centers (n = 1359) were included and followed up between January 2017 and July 2021. Interventions: Infants were randomized to prophylactic 40% dextrose (n = 681) or placebo (n = 678) gel, 0.5 mL/kg, massaged into the buccal mucosa 1 hour after birth. Main Outcomes and Measures: The primary outcome of this follow-up study was neurosensory impairment at 2 years' corrected age. There were 44 secondary outcomes, including cognitive, language, and motor composite Bayley-III scores (mean [SD], 100 [15]; higher scores indicate better performance). Results: Of eligible infants, 1197 (91%) were assessed (581 females [49%]). Neurosensory impairment was not significantly different between the dextrose and placebo gel groups (20.8% vs 18.7%; unadjusted risk difference [RD], 2.09% [95% CI, -2.43% to 6.60%]; adjusted risk ratio [aRR], 1.13 [95% CI, 0.90 to 1.41]). The risk of cognitive and language delay was not significantly different between the dextrose and placebo groups (cognitive: 7.6% vs 5.3%; RD, 2.32% [95% CI, -0.46% to 5.11%]; aRR, 1.40 [95% CI, 0.91 to 2.17]; language: 17.0% vs 14.7%; RD, 2.35% [95% CI, -1.80% to 6.50%]; aRR, 1.19 [95% CI, 0.92 to 1.54]). However, the dextrose gel group had a significantly higher risk of motor delay (2.5% vs 0.7%; RD, 1.81% [95% CI, 0.40% to 3.23%]; aRR, 3.79 [95% CI, 1.27 to 11.32]) and significantly lower composite scores for cognitive (adjusted mean difference [aMD], -1.30 [95% CI, -2.55 to -0.05]), language (aMD, -2.16 [95% CI, -3.86 to -0.46]), and motor (aMD, -1.40 [95% CI, -2.60 to -0.20]) performance. There were no significant differences between groups in the other 27 secondary outcomes. Conclusions and Relevance: Among late preterm and term infants born at risk of neonatal hypoglycemia, prophylactic oral 40% dextrose gel at 1 hour of age, compared with placebo, resulted in no significant difference in the risk of neurosensory impairment at 2 years' corrected age. However, the study may have been underpowered to detect a small but potentially clinically important increase in risk, and further research including longer-term follow-up is required. Trial Registration: anzctr.org.au Identifier: ACTRN12614001263684.

Intensive Serum Urate Lowering With Oral Urate-Lowering Therapy for Erosive Gout: A Randomized Double-Blind Controlled Trial.

OBJECTIVE: To determine whether a therapeutic approach of intensive serum urate lowering results in improved bone erosion scores in patients with erosive gout. METHODS: We undertook a 2-year, double-blind randomized controlled trial of 104 participants with erosive gout who were receiving serum urate-lowering therapy orally and who had serum urate levels of ≥0.30 mmoles/liter at baseline. Participants were randomly assigned to either an intensive serum urate target of <0.20 mmoles/liter or a standard target of <0.30 mmoles/liter (considered the standard according to rheumatology guidelines). Oral serum urate-lowering therapy was titrated to target using a standardized protocol (with the maximum approved doses of allopurinol, probenecid, febuxostat, and benzbromarone). The primary end point was the total computed tomography (CT) bone erosion score. Outcome Measures in Rheumatology (OMERACT) gout core outcome domains were secondary end points. RESULTS: Although the serum urate levels were significantly lower in the intensive target group compared to the standard target group over the study period (P = 0.002), fewer participants in the intensive target group achieved the randomized serum urate target level by year 2 (62% versus 83% of patients in the standard target group; P < 0.05). The intensive target group required higher doses of allopurinol (mean ± SD 746 ± 210 mg/day versus 497 ± 186 mg/day; P < 0.001) and received more combination therapy (P = 0.0004) compared to the standard target group. We observed small increases in CT bone erosion scores in both serum urate target groups over 2 years, with no between-group difference (P = 0.20). OMERACT core outcome domains (gout flares, tophi, pain, patient's global assessment of disease activity, health-related quality of life, and activity limitation) improved in both groups over 2 years, with no between-group differences. Adverse event and serious adverse event rates were similar between the groups. CONCLUSION: Compared to a serum urate target of <0.30 mmoles/liter, more intensive serum urate lowering is difficult to achieve with an oral urate-lowering therapy. Intensive serum urate lowering leads to a high medication burden and does not improve bone erosion scores in patients with erosive gout.

Cardiac biomarkers retain prognostic significance in patients with heart failure and chronic obstructive pulmonary disease.

AIMS: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2). METHODS: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values. RESULTS: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P < 0.001), but not sST2 (P = 0.165). Over a median 2.0-year follow-up (1.5-2.5), 1717 patients (21%) died, and 1298 (16%) died from cardiovascular causes; 2255 patients (28%) were hospitalized for HF over 1.8 years (0.9-2.1). NT-proBNP, hs-TnT and sST2 predicted the three end points regardless of COPD status. The best cut-offs from receiver-operating characteristics analysis were higher in patients with COPD than in those without. Patients with all three biomarkers higher than or equal to end-point- and COPD-status-specific cut-offs were also those with the worst prognosis. CONCLUSIONS: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status.

Chr15q25 genetic variant (rs16969968) independently confers risk of lung cancer, COPD and smoking intensity in a prospective study of high-risk smokers.

IMPORTANCE: While cholinergic receptor nicotinic alpha 5 (CHRNA5) variants have been linked to lung cancer, chronic obstructive pulmonary disease (COPD) and smoking addiction in case-controls studies, their corelationship is not well understood and requires retesting in a cohort study. OBJECTIVE: To re-examine the association between the CHRNA5 variant (rs16969968 AA genotype) and the development of lung cancer, relative to its association with COPD and smoking. METHODS: In 9270 Non-Hispanic white subjects from the National Lung Screening Trial, a substudy of high-risk smokers were followed for an average of 6.4 years. We compared CHRNA5 genotype according to baseline smoking exposure, lung function and COPD status. We also compared the lung cancer incidence rate, and used multiple logistic regression and mediation analysis to examine the role of the AA genotype of the CHRNA5 variant in smoking exposure, COPD and lung cancer. RESULTS: As previously reported, we found the AA high-risk genotype was associated with lower lung function (p=0.005), greater smoking intensity (p<0.001), the presence of COPD (OR 1.28 (95% CI 1.10 to 1.49) p=0.0015) and the development of lung cancer (HR 1.41, (95% CI 1.03 to 1.93) p=0.03). In a mediation analyses, the AA genotype was independently associated with smoking intensity (OR 1.42 (95% CI 1.25 to 1.60, p<0.0001), COPD (OR 1.25, (95% CI 1.66 to 2.53), p=0.0015) and developing lung cancer (OR 1.37, (95% CI 1.03 to 1.82) p=0.03). CONCLUSION: In this large-prospective study, we found the CHRNA5 rs 16 969 968 AA genotype to be independently associated with smoking exposure, COPD and lung cancer (triple whammy effect).

Circulating levels and prognostic value of soluble ST2 in heart failure are less influenced by age than N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T.

AIMS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. METHODS AND RESULTS: Individual data from 5301 patients with chronic HF and NT-proBNP, hs-TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60-69 years (n = 1628, 31%), 70-79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT-proBNP 1564 ng/L, hs-TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT-proBNP and hs-TnT, but not sST2. The best NT-proBNP and hs-TnT cut-offs for 1-year and 5-year all-cause and cardiovascular mortality and 1- to 12-month HF hospitalization increased with age, while the best sST2 cut-offs did not. When stratifying patients according to age- and outcome-specific cut-offs, this stratification yielded independent prognostic significance over NT-proBNP levels only, or the composite of NT-proBNP and hs-TnT, and improved risk prediction for most endpoints. Finally, absolute NT-proBNP, hs-TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables. CONCLUSIONS: Soluble ST2 is less influenced by age than NT-proBNP or hs-TnT; all these biomarkers predict outcome regardless of age. The use of age- and outcome-specific cut-offs of NT-proBNP, hs-TnT and sST2 allows more accurate risk stratification than NT-proBNP alone or the combination of NT-proBNP and hs-TnT.

The SIARI Score: A Novel Decision Support Tool Outperforms LRINEC Score in Necrotizing Fasciitis.

BACKGROUND: The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) scoring system was developed to aid the diagnosis of necrotizing fasciitis and guide management [1]. AIM: To validate the LRINEC score and identify clinical predictors to develop a refined diagnostic scoring tool for the diagnosis of necrotizing fasciitis at Middlemore Hospital, New Zealand. METHODS: This was a retrospective case-control study of patients admitted to Middlemore Hospital with necrotizing fasciitis and severe cellulitis between January 2000 and December 2010. The LRINEC scores at admission were evaluated for performance in discriminating between cases of necrotizing fasciitis and severe cellulitis. Cases and controls were randomized into developmental and validation cohorts. Univariate and multivariate logistic regression analysis of demographic, clinical, and laboratory variables for the diagnosis of necrotizing fasciitis was performed. The identified independent predictors were used to develop a new diagnostic scoring tool. RESULTS: The area under the receiver operating characteristic curve (C-statistic) of a LRINEC score ≥6 for the diagnosis of necrotizing fasciitis was 0.679. The newly developed SIARI score [Site other than the lower limb, Immunosuppression, Age < 60 years, Renal impairment (creatinine > 141), and Inflammatory markers (CRP ≥ 150, WCC > 25] demonstrated superior diagnostic ability compared with the LRINEC score in both the developmental (C-statistic: 0.832 vs. 0.691, p < 0.001) and validation cohorts (C-statistic: 0.847 vs. 0.667, p < 0.001). CONCLUSION: The LRINEC score exhibited only modest discriminative performance in this cohort, while the SIARI score is a simplified tool that demonstrates superior diagnostic ability for detecting necrotizing fasciitis. Future external validation studies are required to confirm the trends observed in this study.

Fibroblast growth factor 23 levels decline following sleeve gastrectomy.

OBJECTIVE: Levels of fibroblast growth factor 23 (FGF23) have been positively associated with measures of adiposity, cardiovascular disease and mortality. It is unclear whether the relationship of FGF23 with cardiovascular disease and mortality is confounded by obesity. We aimed to determine whether FGF23 concentrations decline following a reduction in adiposity after sleeve gastrectomy (SG). DESIGN: The effect of SG on FGF23 was evaluated in 22 obese adults (59% male) with type 2 diabetes. Fat mass, weight, BMI, plasma intact FGF23, parathyroid hormone (PTH) and leptin were determined at baseline and at 12 months following SG. RESULTS: At baseline, median (IQR) age was 51 (43-54) years, fat mass 47.8 (41.0-59.4) kg, BMI 40.9 (36.9-46.9) kg/m2 and FGF23 66.2 (55.3-82.9) pg/mL. Significant changes in median BMI (-10.8 kg/m2 , 95% CI: -12.9 to -7.2, P < 0.0001), fat mass (-20.0 kg, 95% CI: -26.7 to -12.4, P < 0.0001) and weight (-34.7 kg, 95% CI -40.0 to -23.1, P < 0.0001) were observed after SG. FGF23 (-12.4 pg/mL, 95% CI: -19.5 to 2.0, P = 0.005), PTH (-1.1 pmol/L, 95% CI: -1.7 to 0.2, P = 0.009) and leptin (-1687 pg/mL, 95% CI -4524 to -563, P = 0.01) declined following SG. Change in FGF23 was not significantly associated with change in measures of adiposity, PTH or leptin. CONCLUSIONS: FGF23 concentrations decline in the setting of significant weight loss following SG, implying that increased FGF23 concentrations are a downstream consequence of obesity, which may confound its association with cardiometabolic dysfunction. Mediators of the relationship between adiposity and FGF23 require further elucidation.

Effects of Intravenous Zoledronate on Bone Turnover and Bone Density Persist for at Least 11 Years in HIV-Infected Men.

Previously we reported the results of a 4-year extension of a 2-year randomized placebo-controlled trial showing that the antiresorptive effects of two annual 4-mg doses of zoledronate in HIV-infected men persisted for at least 5 years after the second dose. We set out to determine whether the effects on BMD and bone turnover persist beyond 10 years. We invited all participants in the original trial known to be alive and living in New Zealand to attend an additional visit approximately 12 years after trial entry and 11 years after their second dose of study medication. The outcome measures were BMD at the lumbar spine, proximal femur, and total body, and markers of bone turnover. Twenty-five of the 43 men originally enrolled in the trial attended the final visit, representing 25 of 31 (81%) participants alive and residing in New Zealand at the time. The average duration of follow-up was 12.4 years. At the final visit, BMD remained higher in the zoledronate group than the placebo group (lumbar spine 3.7%, 95% CI, 0.1 to 7.3; total hip 3.7%, 95% CI, 1.2 to 6.2; femoral neck 5.0%, 95% CI, 2.1 to 7.9; total body 2.4%, 95% CI, 0.7 to 4.0), and the between-group differences in BMD remained stable between 6 and 12 years. Serum CTx remained lower in the zoledronate group than the placebo group between 6 and 12 years and, at the final visit, was 45% lower (95% CI, 25 to 64) than the placebo group. P1NP was 26% (95% CI, 4 to 48) lower in the zoledronate group than the placebo group at the final visit. In summary, two annual 4-mg doses of zoledronate have effects on bone turnover and BMD in men that persist for at least 11 years after the second dose. © 2019 American Society for Bone and Mineral Research.

Dietary Calcium Intake and Bone Loss Over 6 Years in Osteopenic Postmenopausal Women.

CONTEXT: Calcium intakes are commonly lower than the recommended levels, and increasing calcium intake is often recommended for bone health. OBJECTIVE: To determine the relationship between dietary calcium intake and rate of bone loss in older postmenopausal women. PARTICIPANTS: Analysis of observational data collected from a randomized controlled trial. Participants were osteopenic (hip T-scores between -1.0 and -2.5) women, aged >65 years, not receiving therapy for osteoporosis nor taking calcium supplements. Women from the total cohort (n = 1994) contributed data to the analysis of calcium intake and bone mineral density (BMD) at baseline, and women from the placebo group (n = 698) contributed data to the analysis of calcium intake and change in BMD. BMD and bone mineral content (BMC) of the spine, total hip, femoral neck, and total body were measured three times over 6 years. RESULTS: Mean calcium intake was 886 mg/day. Baseline BMDs were not related to quintile of calcium intake at any site, before or after adjustment for baseline age, height, weight, physical activity, alcohol intake, smoking status, and past hormone replacement use. There was no relationship between bone loss and quintile of calcium intake at any site, with or without adjustment for covariables. Total body bone balance (i.e., change in BMC) was unrelated to an individuals' calcium intake (P = 0.99). CONCLUSIONS: Postmenopausal bone loss is unrelated to dietary calcium intake. This suggests that strategies to increase calcium intake are unlikely to impact the prevalence of and morbidity from postmenopausal osteoporosis.

Performance of contemporary surgical risk scores for mitral valve surgery.

BACKGROUND: Risk stratification for mitral valve repair or replacement (MVR) is important in the decision-making for treating several mitral valve disease but is rarely studied. We compared the prognostic utility of EuroSCORE, EuroSCORE II, and Society of Thoracic Surgeons (STS) Score for MVR. METHODS: The three scores were retrospectively calculated for consecutive patients undergoing isolated MVR at Auckland City Hospital during 2005-2012 and their discrimination and calibration for mortality and morbidities assessed. RESULTS: There were 408 patients (mitral valve repair 48.1% and replacement 51.9%) followed-up for 6.0 ± 2.6 years. The operative mortality was 2.5%. Mean EuroSCORE, EuroSCORE II, and STS Score were 7.6%, 3.4%, and 3.5%. C-statistics were 0.844, 0.817, and 0.850 for operative mortality. Hosmer-Lemeshow test p values were 0.076, 0.541, and 0.306, and Brier scores 0.0246, 0.0035, and 0.0075, respectively, for operative mortality. The numerically highest c-statistic for predicting complications include EuroSCORE for return to the operating room (c = 0.673); EuroSCORE II for stroke (c = 0.669) and mediastinitis (c = 0.801); and STS for renal failure (c = 0.828), ventilation >24 hours (c = 0.789), and composite morbidity (c = 0.732). The individual STS complication models for MVR had a numerically higher c-statistic only for stroke (c = 0.737). CONCLUSIONS: All scores discriminated mortality and most morbidities after MVR, although EuroSCORE over-estimated operative mortality. The STS Score was the best overall predictor of mortality and morbidity in the MVR cohort.

Reduced Expiratory Flow Rate among Heavy Smokers Increases Lung Cancer Risk. Results from the National Lung Screening Trial-American College of Radiology Imaging Network Cohort.

RATIONALE: Although epidemiological studies consistently show that chronic obstructive pulmonary disease is associated with an increased risk of lung cancer, debate exists as to whether there is a linear relationship between the severity of airflow limitation and lung cancer risk. OBJECTIVES: We examined this in a large, prospective study of older heavy smokers from the American College of Radiology Imaging Network subcohort of the National Lung Screening Trial (ACRIN). Airflow limitation was defined by prebronchodilator spirometry subgrouped according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1-4. METHODS: In the National Lung Screening Trial-ACRIN cohort of 18,473 screening participants, 6,436 had airflow limitation (35%) and 12,037 (65%) had no airflow limitation. From these groups, 758 lung cancer cases were prospectively identified. Participants with airflow limitation were stratified according to GOLD groups 1 (n = 1,607), 2 (n = 3,528), 3 (n = 1,083), and 4 (n = 211). Lung cancer incidence at study end (mean follow-up, 6.4 yr) was compared between the GOLD groups and those with no airflow limitation (referent group). MEASUREMENTS AND MAIN RESULTS: Compared with those with no airflow limitation, where lung cancer incidence was 3.78/1,000 person years, incidence rates increased in a simple linear relationship: GOLD 1 (6.27/1,000 person yr); GOLD 2 (7.86/1,000 person yr); GOLD 3 (10.71/1,000 person yr); and GOLD 4 (13.25/1,000 person yr). All relationships were significant versus the reference group at a P value of 0.0001 or less. CONCLUSIONS: In a large prospective study of high-risk cigarette smokers, we report a strong linear relationship between increasing severity of airflow limitation and risk of lung cancer.

Reduced Bone Density and Cortical Bone Indices in Female Adiponectin-Knockout Mice.

A positive association between fat and bone mass is maintained through a network of signaling molecules. Clinical studies found that the circulating levels of adiponectin, a peptide secreted from adipocytes, are inversely related to visceral fat mass and bone mineral density, and it has been suggested that adiponectin contributes to the coupling between fat and bone. Our study tested the hypothesis that adiponectin affects bone tissue by comparing the bone phenotype of wild-type and adiponectin-knockout (APN-KO) female mice between the ages of 8-37 weeks. Using a longitudinal study design, we determined body composition and bone density using dual energy x-ray absorptiometry. In parallel, groups of animals were killed at different ages and bone properties were analyzed by microcomputed tomography, dynamic histomorphometry, 3-point bending test, nanoindentation, and computational modelling. APN-KO mice had reduced body fat and decreased whole-skeleton bone mineral density. Microcomputed tomography analysis identified reduced cortical area fraction and average cortical thickness in APN-KO mice in all the age groups and reduced trabecular bone volume fraction only in young APN-KO mice. There were no major differences in bone strength and material properties between the 2 groups. Taken together, our results demonstrate a positive effect of adiponectin on bone geometry and density in our mouse model. Assuming adiponectin has similar effects in humans, the low circulating levels of adiponectin associated with increased fat mass are unlikely to contribute to the parallel increase in bone mass. Therefore, adiponectin does not appear to play a role in the coupling between fat and bone tissue.

Concordance of Results from Randomized and Observational Analyses within the Same Study: A Re-Analysis of the Women's Health Initiative Limited-Access Dataset.

BACKGROUND: Observational studies (OS) and randomized controlled trials (RCTs) often report discordant results. In the Women's Health Initiative Calcium and Vitamin D (WHI CaD) RCT, women were randomly assigned to CaD or placebo, but were permitted to use personal calcium and vitamin D supplements, creating a unique opportunity to compare results from randomized and observational analyses within the same study. METHODS: WHI CaD was a 7-year RCT of 1g calcium/400IU vitamin D daily in 36,282 post-menopausal women. We assessed the effects of CaD on cardiovascular events, death, cancer and fracture in a randomized design- comparing CaD with placebo in 43% of women not using personal calcium or vitamin D supplements- and in a observational design- comparing women in the placebo group (44%) using personal calcium and vitamin D supplements with non-users. Incidence was assessed using Cox proportional hazards models, and results from the two study designs deemed concordant if the absolute difference in hazard ratios was ≤0.15. We also compared results from WHI CaD to those from the WHI Observational Study(WHI OS), which used similar methodology for analyses and recruited from the same population. RESULTS: In WHI CaD, for myocardial infarction and stroke, results of unadjusted and 6/8 covariate-controlled observational analyses (age-adjusted, multivariate-adjusted, propensity-adjusted, propensity-matched) were not concordant with the randomized design results. For death, hip and total fracture, colorectal and total cancer, unadjusted and covariate-controlled observational results were concordant with randomized results. For breast cancer, unadjusted and age-adjusted observational results were concordant with randomized results, but only 1/3 other covariate-controlled observational results were concordant with randomized results. Multivariate-adjusted results from WHI OS were concordant with randomized WHI CaD results for only 4/8 endpoints. CONCLUSIONS: Results of randomized analyses in WHI CaD were concordant with observational analyses for 5/8 endpoints in WHI CaD and 4/8 endpoints in WHI OS.

Airflow Limitation and Histology Shift in the National Lung Screening Trial. The NLST-ACRIN Cohort Substudy.

RATIONALE: Annual computed tomography (CT) is now widely recommended for lung cancer screening in the United States, although concerns remain regarding the potential harms, including those from overdiagnosis. OBJECTIVES: To examine the effect of airflow limitation on overdiagnosis by comparing lung cancer incidence, histology, and stage shift in a subgroup of the National Lung Screening Trial (NLST). METHODS: In an NLST subgroup (n = 18,714), screening participants were randomized to annual computed tomography (CT, n = 9,357) or chest radiograph (n = 9,357) screening and monitored for a mean of 6.1 years. After baseline prebronchodilator spirometry, to identify the presence of airflow limitation, 18,475 subjects (99%) were assigned as having chronic obstructive pulmonary disease (COPD) or no COPD. Lung cancer prevalence, incidence, histology, and stage shift were compared after stratification by COPD. MEASUREMENTS AND MAIN RESULTS: For screening participants with spirometric COPD (n = 6,436), there was a twofold increase in lung cancer incidence (incident rate ratio, 2.15; P < 0.001) and, when compared according to screening arm, no excess lung cancers and comparable histology. Compared with chest radiography, there was also a trend favoring reduced late-stage and increased early-stage cancers in the CT arm (P = 0.054). For those with normal baseline spirometry (n = 12,039), we found an excess of lung cancers during screening in the CT arm, almost exclusively early-stage adenocarcinoma-related cancers (histology shift and overdiagnosis). After correction for these excess cancers, stage shift was marginal (P = 0.077). CONCLUSIONS: In the CT arm of the NLST-ACRIN (American College of Radiology Imaging Network) cohort, COPD status was associated with a doubling of lung cancer incidence, no apparent overdiagnosis, and a more favorable stage shift.

Acute and 3-month effects of microcrystalline hydroxyapatite, calcium citrate and calcium carbonate on serum calcium and markers of bone turnover: a randomised controlled trial in postmenopausal women.

Ca supplements are used for bone health; however, they have been associated with increased cardiovascular risk, which may relate to their acute effects on serum Ca concentrations. Microcrystalline hydroxyapatite (MCH) could affect serum Ca concentrations less than conventional Ca supplements, but its effects on bone turnover are unclear. In the present study, we compared the acute and 3-month effects of MCH with conventional Ca supplements on concentrations of serum Ca, phosphate, parathyroid hormone and bone turnover markers. We randomised 100 women (mean age 71 years) to 1 g/d of Ca as citrate or carbonate (citrate-carbonate), one of two MCH preparations, or a placebo. Blood was sampled for 8 h after the first dose, and after 3 months of daily supplementation. To determine whether the acute effects changed over time, eight participants assigned to the citrate dose repeated 8 h of blood sampling at 3 months. There were no differences between the citrate and carbonate groups, or between the two MCH groups, so their results were pooled. The citrate-carbonate dose increased ionised and total Ca concentrations for up to 8 h, and this was not diminished after 3 months. MCH increased ionised Ca concentrations less than the citrate-carbonate dose; however, it raised the concentrations of phosphate and the Ca-phosphate product. The citrate-carbonate and MCH doses produced comparable decreases in bone resorption (measured as serum C-telopeptide (CTX)) over 8 h and bone turnover (CTX and procollagen type-I N-terminal propeptide) at 3 months. These findings suggest that Ca preparations, in general, produce repeated sustained increases in serum Ca concentrations after ingestion of each dose and that Ca supplements with smaller effects on serum Ca concentrations may have equivalent efficacy in suppressing bone turnover.