Correspondence

HR adjusted for age, Further adjusted for biological mediators* sex, and smoking (95% CI) (95% CI)

PERM (%, 95% CI)

Baseline levels

1·32 (1·24–1·41)

1·12 (1·06–1·18)

63% (39–77%)

Usual levels

1·32 (1·24–1·41)

1·08 (1·02–1·14)

75% (47–92%)

Baseline levels

1·22 (1·13–1·31)

1·07 (0·99–1·14)

68% (50–76%)

Usual levels

1·20 (1·11–1·31)

1·01 (0·94–1·08)

95% (79–101%)

Baseline levels

1·26 (1·19–1·33)

1·08 (1·03–1·12)

69% (41–86%)

Usual levels

1·26 (1·19–1·34)

1·03 (0·99–1·08)

88% (57–106%)

2

Coronary heart disease

Ischaemic stroke

3

4

Cardiovascular disease

5 HR=hazard ratio. BMI=body-mass index. *Biological mediators= systolic blood pressure, markers of glycaemia, total cholesterol and HDL-cholesterol.

Table: HRs and excess risks per 5 kg/m² higher BMI mediated by baseline and usual levels of biological mediators

blood pressure is a valuable addition to the data on the mediated effects of BMI. Because their table did not provide uncertainty intervals for PERMs, we calculated uncertainty intervals using a correlation coefficient of 0·95 between the age-sex-smokingadjusted and fully-adjusted relative risks; this correlation coefficient was obtained by bootstrapping of the two sets of relative risks in our paper.1 The resulting uncertainty intervals are presented in the table, and show that the estimated PERMs for usual levels of risk factors for coronary heart disease and cardiovascular disease are not significantly different from those for baseline levels in the ERFC. This conclusion would hold even for an unusually low correlation of 0·50 between the two sets of relative risks. Further, even despite the differences in the cohorts included (eg, more Asian cohorts in our study) and with slightly different mediators (eg, HDLcholesterol was not included in our analyses) the PERMs are statistically indistinguishable between the two pooling studies. Nonetheless, incorporating time-varying measures of mediators is an important direction in research, which deserves more attention, as is the case for time-varying confounding by common determinants of mediators and cardiovascular disease such as diet and physical activity. Conventional regression-based 2044

methods can not handle this type of analysis and more advanced methods such as inverse-probability weighting of marginal structural models or use of the parametric g-formula should be explored in future research. In summary, this additional discussion and valuable evidence supports our original conclusions, and their public health implications: controlling metabolic mediators such as blood pressure and lipids would lead to substantial reductions in cardiovascular risk in overweight and obese people, but to fully reduce the harmful effect of overweight and obesity we must prevent weight gain itself. This is especially important in view of the rising levels of BMI and diabetes worldwide.4, 5 We declare no competing interests.

*Goodarz Danaei, Yuan Lu, Kaveh Hajifathalian, Eric B Rimm, Mark Woodward, Majid Ezzati [email protected] Department of Global Health and Population, Harvard School of Public Health, Boston, MA 02115, USA (GD, YK, KH); Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA (EBR); The George Institute for Global Health, Sydney, NSW, Australia (MW); and MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK (ME) 1

Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants. Lancet 2014; 383: 970–83.

Lloyd-Jones DM, Nam BH, D’Agostino RB, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA 2004; 291: 2204–11. VanderWeele TJ. Unmeasured confounding and hazard scales: sensitivity analysis for total, direct, and indirect effects. Eur J Epidemiol 2013; 28: 113–17. Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet 2011; 378: 31–40. Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377: 557–67.

Delirium in elderly people We have read with great interest the excellent Review on delirium in elderly people by Sharon Inouye and colleagues (March 8, p 911).1 We were surprised, however, by the lack of reference to epileptic disorders and nonconvulsive status epilepticus in the pathophysiology and potential causes of delirium. Almost all risk factors presented (table 2,1 risk factors for delirium from validated predictive models) are also classical risk factors for epilepsy. Delirium might be the manifestation of an ongoing seizure and can be protracted in case of lasting ictal activity.2,3 Manifestations of nonconvulsive status epilepticus can be subtle—with abnormal behaviour, mood changes, clouding of consciousness—reflecting almost all the criteria used to diagnose delirium in the confusion assessment method. Results from studies have shown that in all confounded causes of delirium in elderly people, epileptic discharges are commonly found and that non-convulsive status epilepticus is detected in 3–15% of patients.4 Some studies report that epileptic discharges might play a part in the pathophysiology of delirium considering that treating patients with www.thelancet.com Vol 383 June 14, 2014

Correspondence

antiepileptic drugs improves delirium symptoms.5 We did a prospective study, in which all elderly people with delirium had electroencephalographic monitoring for 24 h. Preliminary results, in more than 60 patients, show non-convulsive status epilepticus in 28% of elderly people with delirium. Such findings lead us to propose that epileptic activities might play an important part in elderly people delirium and that non-convulsive status epilepticus might explain a substantial proportion of delirium symptoms in many patients.

determined because they are based on referral samples (ie, patients receiving electroencephalography or neurology consultation), small sample sizes, retrospective studies, and case reports. Moreover, the diagnostic criteria remain unclear, without accepted consensus.2,3 In view of these considerations, it would be premature to recommend that electroencephalography be done routinely for delirium. We agree that further evidence is needed to clarify the inter-relations of occult seizures and delirium.

We declare no competing interests.

We declare no competing interests.

*Gilles Naeije, Thierry Pepersack

*Sharon K Inouye, Rudi GJ Westendorp, Jane S Saczynski, Eyal Y Kimchi, Alycia A Cleinman

1 2

3

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5

Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014; 383: 911–22. Beyenburg S, Elger CE, Reuber M. Acute confusion or altered mental state: consider nonconvulsive status epilepticus. Gerontology 2007; 53: 388–96. Sheth RD, Drazkowski JF, Sirven JI, Gidal BE, Hermann BP. Protracted ictal confusion in elderly patients. Arch Neurol 2006; 63: 529–32. Naeije G, Bachir I, Gaspard N, Legros B, Pepersack T. Epileptic activities are common in older people with delirium. Geriatr Gerontol Int 2014; 14: 447–51. Kaplan PW, Duckworth J. Confusion and SIRPIDs regress with parenteral lorazepam. Epileptic Disord 2011; 13: 291–94.

[email protected] Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, MA 02131, USA (SKI); Leiden University Medical Center, Leiden, Netherlands (RGJW); Division of Geriatric Medicine and Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester, MA, USA (JSS); Department of Neurology, Massachusetts General Hospital, Boston, MA, USA (EYK); and Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA (AAC) 1

Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014; 383: 911–22. Zehtabchi S, Baki SGA, Malhotra S, Grant AC. Nonconvulsive seizures in patients presenting with altered mental status: an evidence-based review. Epilepsy Behav 2011; 22: 139–43. Sutter R, Kaplan PW. Electroencephalographic criteria for nonconvulsive status epilepticus: synopsis and comprehensive survey. Epilepsia 2012; 53 (suppl 3): 1–51.

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Authors’reply

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We are pleased to clarify important aspects about our Review.1 We agree with Gilles Naeije and Thierry Pepersack that delirium can be a manifestation of occult seizures and heightened awareness is needed. Our Review stresses that electroencephalography is useful for difficult-to-diagnose cases and can help to identify patients with occult seizures. It is useful to emphasize, however, that non-convulsive status epilepticus remains controversial, including both its frequency and diagnostic criteria. 2,3 In 14 recent articles identified by our PubMed search, the true frequency of nonconvulsive status epilepticus in patients with delirium could not be

For more on China State Tobacco Monopoly Administration see http://www.tobacco.gov.cn/

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Hopital Erasme, Université Libre de Bruxelles, Brussels 1070, Belgium

The recent Editorial (April 19, p 1360)1 on cigarette packaging in China not only highlighted China’s failure to comply with Article 11 of the WHO Framework Convention on Tobacco Control (FCTC)’s requirement for health warnings on tobacco packaging, but also correctly pointed out the main cause for this failure, which is the serious conflict of interest presented by the State Tobacco Monopoly Administration, a government agency responsible for maintaining country’s tobacco industry and also responsible for leading national tobacco control efforts. Tobacco production and sales are strictly controlled by the state, largely through China National Tobacco Corporation, founded in 1982. In 1983, China’s State Council issued the Tobacco Monopoly Regulations to formally establish a national tobacco monopoly system. In the following year, the State Tobacco Monopoly Administration was created, embedded within China National Tobacco Corporation, to provide centralised management of the national tobacco industry, including finance, people, material, production, supply, marketing, and internal and external trade. The integration of government administrative power with strong financial resources into tobacco

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Tobacco in China

Year

Figure: Production of cigarettes in China, 1952–2012 Data are from China National Bureau of Statistics.

For China National Bureau of Statistics data see http://data.stats.gov.cn

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Delirium in elderly people.

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