Independent external validation of nomograms for predicting risk of low-trauma fracture and hip fracture

Background

A set of nomograms based on the Dubbo Osteoporosis Epidemiology Study predicts the five- and ten-year absolute risk of fracture using age, bone mineral density and history of falls and low-trauma fracture. We assessed the discrimination and calibration of these nomograms among participants in the Canadian Multicentre Osteoporosis Study.

Methods

We included participants aged 55–95 years for whom bone mineral density measurement data and at least one year of follow-up data were available. Self-reported incident fractures were identified by yearly postal questionnaire or interview (years 3, 5 and 10). We included low-trauma fractures before year 10, except those of the skull, face, hands, ankles and feet. We used a Cox proportional hazards model.

Results

Among 4152 women, there were 583 fractures, with a mean follow-up time of 8.6 years. Among 1606 men, there were 116 fractures, with a mean follow-up time of 8.3 years. Increasing age, lower bone mineral density, prior fracture and prior falls were associated with increased risk of fracture. For low-trauma fractures, the concordance between predicted risk and fracture events (Harrell C) was 0.69 among women and 0.70 among men. For hip fractures, the concordance was 0.80 among women and 0.85 among men. The observed fracture risk was similar to the predicted risk in all quintiles of risk except the highest quintile of women, where it was lower. The net reclassification index (19.2%, 95% confidence interval [CI] 6.3% to 32.2%), favours the Dubbo nomogram over the current Canadian guidelines for men.

Interpretation

The published nomograms provide good fracture-risk discrimination in a representative sample of the Canadian population.Current recommendations for the treatment of osteoporosis are in transition. The T-score-based definition of osteoporosis and osteopenia by the expert committee of the World Health Organization on bone mineral density has been used in many guidelines to set intervention thresholds for treatment. However, studies have consistently reported that the highest number of fractures in a given population occurs in those with osteopenic or normal bone mineral density.^1,2 In fact, the National Osteoporosis Foundation has singled out people with osteopenic bone mineral density as a population in which assessment for fracture risk is merited.³Nevertheless, appropriate prevention and treatment strategies for such people are uncertain.⁴ Recent developments include the assessment of absolute fracture risk based on bone mineral density and other risk factors. Current Canadian methodology determines categorical risk based on age, sex, T-score, fracture history and glucocorticoid use.⁵ These criteria were derived from Swedish data, but have been assessed and validated in a cohort of Manitoba women.⁶ Newer nomograms based on the Australian cohort of the Dubbo Osteoporosis Epidemiology Study⁷ are now available for the calculation of low-trauma hip fracture⁸ and any fracture.⁹ These nomograms provide continuous estimates for five- and 10-year absolute fracture risk in both men and women (available at http://fractureriskcalculator.com). The use of factors in addition to bone mineral density may provide a better assessment of fracture risk for people who are near the T-score thresholds and facilitate decisions regarding therapeutic intervention.A key step in the development of any prediction model is the assessment of its validity.¹⁰ The aim of our study was to assess the performance of the Australian-derived nomogram among community-dwelling Canadians aged 55–95 years old. The first part of this assessment was a comparison of the nomogram model using the same variables, but using data from a Canadian population — participants in the Canadian Multicentre Osteoporosis Study (www.camos.org). The second part involved computing the calibration and discrimination of the nomogram in a Canadian cohort. The final part was comparison of the new assessments with the existing Canadian risk classification system.     

Search for the possible role of ‘immunotherapy’ in operable bronchial non-small cell carcinoma (stage I and II): A phase I study with Corynebacterium parvum intrapleurally

Summary The possibility of giving C. parvum intrapleurally (i.p.) was investigated. C. parvum was given post-operatively either i.p. only or i.p. and intravenously (i.v.) simultaneously. The dose varied from 0.1–10 mg i.p. All patients had been operated for a bronchial carcinoma. Results: (1) Subjective complaints of either dyspnoea, thoracic pain, chills or nausea occured in 31 of 63 patients. No clear dose relation was found. A feeling of discomfort and fever could occur for another 3–4 days after the above more acute symptoms had disappeared. (2) Increased fever (0.5° C) occurred in 71% of the patients injected i.p. only. (3) No anaphylactic reaction was observed. (4) Increased total white blood cell counts (<20%) occurred in 38 patients. The WBC increase was mainly due to higher number of neutrocytes and granulocytes. Total lymphocyte, monocyte, eosinophilic, and basophilic granulocytes values per mm³ circulating blood remained unchanged, except at the dose of 7 mg C. parvum i.p. when monocyte values were increased significantly from 576±247 to 1100±578/mm³. (5) Moderate to severe effusions were observed radiologically in three patients after C. parvum intrapleurally.The study group is: M. Kaufmann, J. Stjernswärd (Ludwig Institut for Cancer Research, Lausanne Branch, Switzerland), M. Zelen, K. Stanley (Frontier Science and Technology Research Foundation, Inc. Amherst, New York, USA), D. S. Freestone, R. Bomford, M. T. Scott, T. Priestman (The Wellcome Research Laboratory, Beckenham, England), C. Mouritzen, G. Ahlbom (Dept. of Thoracic and Cardiovascular Surgery, Aarhus Kommunehospital, Aarhus, Denmark), N. Konietzko, D. Greschuchna (Ruhrland Klinic, Essen-Haidhausen, Germany), P. Hilgard (Innere Klinik und Poliklinik [Tumorforschung] Essen, Germany), J. Vogt-Moykopf, D. Zeidler, H. Toomes (Thoraxchirurgische Spezial-Klinik, Heidelberg-Rohrbach, Germany), F. Krause, R. Rios (Thoraxchirurgische Abt., Fachkrankenhaus für Lungen- und Bronchialerkrankungen, Löwenstein, Germany), J. Orel, M. Benedik, B. Hrabar (Clinical Center, Dept. of Thoracic Surgery, Ljubljana, Yugoslavia), S. Plesnicar (The Institute of Oncology, Ljubljana, Yugoslavia), H. A. Rostad, J. R. Vale (Rikshospital, Oslo, Norway), S. Hagen, S. Birkeland, (Ulleval Hospital, Oslo, Norway), T. Harbitz, R. Nissen-Meyer (Aker Hospital, Oslo, Norway), L. Rodriguez, V. O. Björk, K. Böök (Karolinska Sjukhuset, Thoracic Clinic, Stockholm, Sweden), E. Gradel, J. Hasse, P. Holbro (Kantonsspital, Thoraxchirurgische Klinik, Basel, Switzerland), L. Eckmann (Tiefenauspital, Chir. Univ.-Klinik, Bern, Switzerland), B. Nachbur, T. Liechti (Inselspital, Dept. of Thoracic and Cardiovascular Surgery, Bern, Switzerland), H. Cottier (Inst. of Pathology, Inselspital, Bern, Switzerland), W. Maurer, M. Kaufmann, P. Froelicher (Bürgerspital, Surgical Dept., Solothurn, Switzerland), H. Denck, N. Pridun (Krankenhaus der Stadt Wien-Lainz, Chir. Abt., Vienna, Austria), K. Karrer (Institute for Cancer Research, University of Vienna, Austria) Reprint requests should be addressed to any of the members listed above, or to the Ludwig Lung Cancer Trial, Operation Office, LICR, CH-1066 Epalinges, Switzerland. (For Current Contents, etc., please use above address)     

北京山区封山育林试验研究效果

 本文报道了1984年在北京密云县古石峪进行的封山育林试验研究。五年中进行了三次复查,证明在植被盖度、灌木草本生物量、多样性指数方面都有增加。四类样地更新较好;两类阳坡干旱型样地更新不良,但引种栓皮栎获得成功。本研究还进行了山杨移根的试验。     

Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries

BackgroundTaller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke.Methods and findingsHeight-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations.ConclusionsThe findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke.

In a Mendelian randomization study, Andrew B. Linden and colleagues study the relationship between height and risk of stroke subtypes among individuals from the MEGASTROKE consortium, China Kadoorie Biobank, and UK Biobank.     

Amyloid-Related Memory Decline in Preclinical Alzheimer’s Disease Is Dependent on APOE ε4 and Is Detectable over 18-Months

High levels of β-amyloid (Aβ) in the brain and carriage of the APOE ε4 allele have each been linked to cognitive impairment in cognitively normal (CN) older adults. However, the relationship between these two biomarkers and cognitive decline is unclear. The aim of this study was to investigate the relationship between cerebral Aβ level, APOE ε4 carrier status, and cognitive decline over 18 months, in 317 cognitively healthy (CN) older adults (47.6% males, 52.4% females) aged between 60 and 89 years (Mean = 69.9, SD = 6.8). Cognition was assessed using the Cogstate Brief Battery (CBB) and the California Verbal Learning Test, Second Edition (CVLT-II). Planned comparisons indicated that CN older adults with high Aβ who were also APOE ε4 carriers demonstrated the most pronounced decline in learning and working memory. In CN older adults who were APOE ε4 non-carriers, high Aβ was unrelated to cognitive decline in learning and working memory. Carriage of APOE ε4 in CN older adults with low Aβ was associated with a significantly increased rate of decline in learning and unexpectedly, improved cognitive performance on measures of verbal episodic memory over 18 months. These results suggest that Aβ and APOE ε4 interact to increase the rate of cognitive decline in CN older adults and provide further support for the use of Aβ and APOE ε4 as biomarkers of early Alzheimer’s disease.     

The role of circulating serotonin in the development of chronic obstructive pulmonary disease

Background

Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD). The serotonin transporter (SERT) gene polymorphism has been reported to be associated with COPD, and the degree of cigarette smoking has been shown to be a significant mediator in this relationship. The interrelation between circulating serotonin (5-hydroxytyptamine, 5-HT), cigarette smoking and COPD is however largely unknown. The current study aimed at investigating the mediation effects of plasma 5-HT on cigarette smoking-induced COPD and the relation between plasma 5-HT levels and age.

Methods

The association between plasma 5-HT, age and COPD was analyzed in a total of 62 COPD patients (ever-smokers) and 117 control subjects (healthy non-smokers and ever-smokers). Plasma 5-HT levels were measured by enzyme-linked immuno assay (EIA).

Results

The elevated plasma 5-HT levels were significantly associated with increased odds for COPD (OR = 1.221, 95% CI = 1.123 to 1.319, p<0.0001). The effect remained significant after being adjusted for age and pack-years smoked (OR = 1.271, 95% CI = 1.134 to 1.408, p = 0.0003). Furthermore, plasma 5-HT was found to mediate the relation between pack-years smoked and COPD. A positive correlation (r = 0.303, p = 0.017) was found between plasma 5-HT levels and age in COPD, but not in the control subjects (r = −0.149, p = 0.108).

Conclusion

Our results suggest that cigarette smoke-induced COPD is partially mediated by the plasma levels of 5-HT, and that these become elevated with increased age in COPD. The elevated plasma 5-HT levels in COPD might contribute to the pathogenesis of this disease.     

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Background

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C₁₂U), in patients with debilitating CFS/ME.

Methods and Findings

A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.

Conclusions/Significance

Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00215800","term_id":"NCT00215800"}}NCT00215800