|Year : 2022 | Volume
| Issue : 1 | Page : 7
Effects and Prospects of the Integration of Traditional Chinese Medicine with Western Biomedical Approach for Premature Ejaculation
Elena Colonnello1, Fu Wang2, Juo Guo2, Emmanuele A Jannini3
1 Department of Systems Medicine, University of Rome Tor Vergata; Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
2 Department of Andrology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
3 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
|Date of Submission||01-Dec-2021|
|Date of Decision||15-Mar-2022|
|Date of Acceptance||03-Apr-2022|
|Date of Web Publication||30-Jun-2022|
Prof. Emmanuele A Jannini
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Via Montpellier, 1 – 00133 Rome
Source of Support: None, Conflict of Interest: None
Premature ejaculation (PE) is a frequently reported sexual dysfunction that has received considerable clinical attention in China. Being intrinsically related to cultural aspects, PE in the Chinese scientific environment is often treated using a combination of traditional Chinese medicine (TCM) techniques and a Western biomedical approach. In this perspective article, we highlight the most recent effects of the use of acupuncture, herbal medicine, and Fangzhongshu techniques, each alone and in combination with Western medicine, for delaying ejaculation; however, the efficacy of such therapies is not always supported by high-quality randomized control trials. To bridge the traditional holistic, individual-targeted perspective of TCM with Western biomedical approaches, we present the paradigm of the new Systems Sexology, derived from the well-known systems medicine, which may fill this gap by perfectly blending the most advanced technologies for an innovative, integrative, and interdisciplinary approach.
Keywords: Acupuncture, andrology, premature ejaculation, sexology, sexual medicine, traditional Chinese medicines
|How to cite this article:|
Colonnello E, Wang F, Guo J, Jannini EA. Effects and Prospects of the Integration of Traditional Chinese Medicine with Western Biomedical Approach for Premature Ejaculation. Integr Med Nephrol Androl 2022;9:7
|How to cite this URL:|
Colonnello E, Wang F, Guo J, Jannini EA. Effects and Prospects of the Integration of Traditional Chinese Medicine with Western Biomedical Approach for Premature Ejaculation. Integr Med Nephrol Androl [serial online] 2022 [cited 2022 Dec 3];9:7. Available from: https://journal-imna.com//text.asp?2022/9/1/7/349533
| Introduction|| |
Premature ejaculation (PE) or ejaculatio praecox ıs a multidimensional sexual disorder characterized by the inability to control ejaculation, a short intravaginal ejaculatory latency time (IELT), and distress. The prevalence of PE ranges from 8% to 38% and differs between countries, as confirmed by various surveys,[3-5] suggesting that variation in geographical locations may be related to cultural factors. For example, the popularity of circumcision in some countries may affect the perceived incidence of PE. In addition, it has been suggested that the rates of PE tend to be greater when sex is of special importance and female sexuality is foregrounded,, as is the case in East Asia and Central America. As PE is the only male symptom to be considered partner oriented, these regional variations reflect the importance of mutual sexual pleasure in a relationship. In China, for instance, PE (not considering complaints about ejaculatory control or subclinical PE) has a reported prevalence of 15%–19% and receives special attention for several reasons. First, it is generally regarded as a unique partner-oriented symptom, reflecting the notable importance given to the partner and the couple. The first psychometric instrument for PE to consider the sexual satisfaction of the partner was, indeed, the Chinese Index of PE. Second, PE is regarded as a true health concern, being related not only to the ancient Taoist doctrine for which losing semen is losing Yang energy but also to the intrinsic and holistic perspective of Chinese medicine. Currently, Chinese medicine seamlessly blends traditional and modern-day techniques into a thorough, systematic approach.,,, This is also seen in the treatment of PE, which employs traditional techniques (herbal medicine and acupuncture) followed by a modern approach. The aim of this review was to provide examples of the effects of combining some of the most common techniques of traditional Chinese medicine (TCM) (acupuncture, herbal remedies, and Fangzhongshu) with a Western biomedical approach for treating PE and to shed light on the possible perspectives of such integration for the future treatment of this sexual dysfunction.
Acupuncture, the practice of inserting various types of needles into the subcutaneous tissue at definite points along special lines of the body called “meridians,” has a long history in China. It is also the best-studied TCM therapy in the English language. In 2002, the World Health Organization published a list of 28 conditions for which acupuncture was “proven – through controlled trials – to be an effective treatment,” and another 63 conditions for which acupuncture was shown to have a therapeutic effect, although more evidence is needed. Acupuncture has also been used for the treatment of sexual dysfunctions. Since the first 2011 placebo-controlled clinical trial of acupuncture, the potential use of this remedy for delaying IELT in PE has been suggested. Indeed, by comparing the utility of acupuncture with that of paroxetine (20 mg daily) in men with PE, Sunay et al. demonstrated that although less effective than daily paroxetine, acupuncture had a significantly stronger effect on delaying ejaculation than the placebo treatment. These findings were confirmed in another study in 2016 by Sahin et al., using 30 mg and 60 mg dapoxetine and sham acupuncture as controls. Several hypotheses have been proposed to explain the potential benefits of acupuncture. First, there may be a central effect on neurotransmitters such as neurotrophins, serotonin, or endorphins, which are involved in sexual behavior, particularly in PE. Second, it is possible that acupuncture affects peripheral neurogenic mechanisms regulating ejaculation, an interaction that is unlikely to occur with sham acupuncture. Moreover, a recent article by Liu et al. illustrated the molecular mechanism through which electroacupuncture can interfere with the vagal–adrenal axis, an interesting result that should prompt further studies. Overall, acupuncture appears to be a promising strategy for the treatment of PE, and more randomized clinical trials should be encouraged in this field.
The use of herbal remedies is a cornerstone of TCM, with many compounds existing since the earliest Chinese medical book Huangdi Neijing (Canon of Internal Medicine, 770 BC–22’ BC). Although often not evidence-based according to Western standards, these treatments have gained popularity among patients of all ages across China and other countries. Even in the andrological field, several hospitals in China often treat patients using Chinese herbal decoctions in combination with other conventional drug treatments. A systematic review of complementary and alternative medicine for treating PE lists a series of randomized control trials (RCTs), all conducted in China, that assessed a 2–8-week course of oral Chinese herbal medicine compared to selective serotonin reuptake inhibitors (SSRI), such as fluoxetine or sertraline, as well as combination treatment against SSRI alone. The compounds used were the popular Qilin pills (a combination of herbs) at a dose of 6 g twice daily, mycelium of Cordyceps sinensis C4, Yimusake at 50 mg/d, and Uighur twice daily. In summary, these studies favored SSRI treatment over Chinese medicine, but the use of combination treatment seems to show promising results. Indeed, for IELT, combining Qilin pills or Yimusake with SSRI showed better results than SSRI alone (stopwatch-measured IELT; pooled mean differences [MD] = 1.92 min, 95% confidence interval [CI] = 1.5–-2.32, P < 0.00001) or Chinese medicine alone (stopwatch-measured IELT; pooled MD = 2.52, 95% CI = 2.13–2.91, P < 0.00001)., Interesting results have been reported by studies on a relatively recent but largely popular treatment based on the Qiaoshao formula (QSF). A previous RCT showed that QSF alone, compared to dapoxetine, was effective and safe in lifelong PE (LPE) patients. A more recent retrospective trial of 905 patients with both LPE and acquired PE showed that combining 30 mg dapoxetine on-demand and QSF resulted in a better delay of perceived-IELT than that with dapoxetine alone after the first dose and at all of the following time points (P < 0.05). Therefore, although the lack of a double-blind RCT design and a QSF alone group (which was included in the earlier study) constitutes a great limitation of the study, investigating the therapeutic potential of the QSF formula alone and in a combination treatment may be of great interest in the andrological field. Indeed, while the rich tradition of herbal medicine is not devoid of human errors or bias due to clinical methodology, it contains invaluable biomedical information waiting to be uncovered using modern, demystifying scientific approaches.
Fangzhongshu: behavioral therapy and psychotherapy
Before the development of effective pharmacological treatments, behavioral therapy had long been a mainstay of treatment for PE, and it remains a common approach presently as well. The aim of behavioral therapy is to gradually make the owner learn to recognize his level of excitement and “control” it. The same goal is addressed by psychotherapy, which can be effective in some men in learning to modulate the psychosexual response to sexual stimulation and gain some conscious control of the ejaculatory reflex. Nowadays, psychotherapy for PE most often represents an integration of behavioral (i.e., start-stop, squeeze, and Kegel exercises) and cognitive approaches within a short-term psychotherapy model (cognitive-behavioral therapy [CBT]). Quite similar to the concepts of behavioral therapy and psychotherapy that are employed in modern medicine is ancient Chinese Fangzhongshu (literally, sexual skills, and methods). Fangzhongshu contains many treatments for erectile dysfunction, PE, anejaculation, and other types of sexual dysfunction that are based on the Taoist thoughts that sexual harmony, flirting, and foreplay before sexual intercourse are important in sex. Zhu et al. provided a description of several techniques described in ancient texts such as the Sheshengzongyao (Summary of Nourishing of Life), which was written during the Ming dynasty. The following are the core ideas of this ancient practice for approaching PE: (i) idea transferring, i.e., methods to relieve mental stress and anxiety, which are known risk factors for PE,,, such as holding a pill of tianwanbuxin dan (a tranquilizer compound much used in TCM although with yet unconfirmed efficacy, as evidenced by a recent metanalysis) in the right hand, stimulating in this way the hand acupoint Laogong (PC8) that has the function of sedation; (ii) suppressing yin and raising qi by “pressing the meridian behind the scrotum,” which means pressing the Huiyin meridian, a sort of modified “stop and squeeze” technique that aims to raise the ejaculation threshold to delay ejaculation; (iii) interruptions or intermissions in sex, which resembles the popular stop–start technique invented by Semans, requiring the man to pause sexual intercourse when feeling impending ejaculation, allowing him to acclimatize to the sensation and eventually to learn control over the ejaculatory response; (iv) adopting special posture, since changing sexual positions or body posture can allow for better control of ejaculation; (v) “touching three peaks and foreplay,” which means stimulating the tongue, breasts, and vaginal orifice so that sexual intercourse is performed only after a high degree of sexual desire is attained. This last point resembles behavioral therapy exercises wherein men gain more control of the ejaculation reflex through a series of graduated exercises that begin with self-stimulation, moving on to partner-hand stimulation, then intercourse without movement, and finally stop/start thrusting. Despite the lack of evidence-based efficacy, Fangzhongshu techniques might raise true scientific interest in the field of PE due to their similarity to existing modern behavioral techniques, such as the aforementioned stop-start, squeeze technique, or CBT. Therefore, more studies incorporating such traditional techniques in a scientific rationale should be encouraged.
| Discussion|| |
PE is a frequently reported condition that is often combined with other sexual dysfunctions but more frequently occurs alone. An interesting perspective of its diagnosis and treatment is given by the Chinese andrological milieu that typically combines Western-style urology and its TCM equivalent, Nánkē, owing to the intrinsic cultural meaning that the condition still has at the present day. In fact, much space has been devoted to TCM in the approach, and treatment of this condition demonstrates promising results. However, one of the flaws that impedes the recognition of TCM in Western andrology is the peculiar nature of TCM, which relies on the individualization of therapy. Indeed, in traditional Chinese clinical practice, patients with the same disorder may be treated with different acupoints or herbal compounds depending on the overall presentation. The use of RCTs, which employ a single standardized treatment for all patients in the study, may severely hamper the efficacy of traditional therapies. For these reasons, some authors have encouraged other strategies, such as the use of case reports, rather than RCTs, or a different research framework for assessing the efficacy of TCM; however, this contrasts with the evidence-based medicine levels normally employed by Western studies and regulatory agencies. Moreover, much of the efficacy of TCM is due to the holistic approach based on the patient’s overall health and patient-therapist interactions, an aspect that RCTs cannot evaluate but should be taken into account.
Hence, the integration of TCM with Western medicine requires higher-quality RCTs to confirm its efficacy. On the other hand, holistic, individualized approaches and systematic biomedical research often tend to remain separate. One solution to bridge this gap is to look in the direction of new Systems Sexology (SS) [Figure 1], a part of the well-recognized systems medicine (SM),, which considers the systems of the human body as part of an integrated whole, incorporating genomic, biochemical, physiological, behavioral, sociocultural, political, economic, and environmental interactions. Through the SS-SM approach, diseases should be studied using a life course approach to identify modifiable and nonmodifiable lifestyle risk factors, link data from experimental sources to better understand the complex molecular interactions that influence the course of medical conditions, and identify clinically important molecular targets for diagnostic and therapeutic interventions. Therefore, in our opinion, a precision medicine that looks at the individual, as with the SS-SM approach, may represent the golden bridge between Western medicine and traditional Chinese holistic medical approaches for the diagnosis and treatment of sexual dysfunctions, including PE.
|Figure 1: Perspective of the TCM and western medicine approaches for PE integrated into the new Systems Sexology paradigm. TCM, Traditional Chinese medicine;|
PE, Premature ejaculation.
Click here to view
| Conclusion|| |
This review aimed to describe the most recent effects of the use of TCM in the modern andrological field of PE. By analyzing the progress that such integration has gained thus far, we shed light on the future of such an integrated approach. More and higher-quality RCTs in this field are required, although such levels of evidence need to be adapted to the context of TCM, which targets individuals; it might not benefit from standardized studies. However, new research frameworks may be offered by the SS-SM paradigm, which perfectly blends advanced technologies and scientific rationales for targeting the unicity of an individual’s health.
Conflicts of interest
Emmanuele A. Jannini is an Associate-Editor-in-Chief of the journal. The article was subject to the journal’s standard procedures, and peer review was handled independently of this editor and his research groups. Emmanuele A. Jannini has also been a speaker and or paid consultant for Bayer, Ibsa, Lundbeck, Menarini, Otsuka, Pfizer, Shionogi, and Viatris. All others declare not to have any conflicts of interest for the present manuscript.
| References|| |
Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG, et al
. An update of the International Society of Sexual Medicine’s guidelines for the diagnosis and treatment of premature ejaculation (PE). J Sex Med 2014;11:1392-422.
Burgio G, Giammusso B, Calogero AE, Mollaioli D, Condorelli RA, Jannini EA, et al
. Evaluation of the mistakes in self-diagnosis of sexual dysfunctions in 11,000 male outpatients: A real-life study in an andrology clinic. J Clin Med 2019;8:E1679.
Nicolosi A, Laumann EO, Glasser DB, Moreira ED Jr, Paik A, Gingell C, et al
. Sexual behavior and sexual dysfunctions after age 40: The global study of sexual attitudes and behaviors. Urology 2004;64:991-7.
Waldinger MD, Quinn P, Dilleen M, Mundayat R, Schweitzer DH, Boolell M. A multinational population survey of intravaginal ejaculation latency time. J Sex Med 2005;2:492-7.
Nolazco C, Bellora O, López M, Surur D, Vázquez J, Rosenfeld C, et al
. Prevalence of sexual dysfunctions in Argentina. Int J Impot Res 2004;16:69-72.
Kim D, Pang MG. The effect of male circumcision on sexuality. BJU Int 2007;99:619-22.
Colonnello E, Ciocca G, Limoncin E, Sansone A, Jannini EA. Redefining a sexual medicine paradigm: Subclinical premature ejaculation as a new taxonomic entity. Nat Rev Urol 2021;18:115-27.
Jannini EA, Ciocca G, Limoncin E, Mollaioli D, Di Sante S, Gianfrilli D, et al
. Premature ejaculation: Old story, new insights. Fertil Steril 2015;104:1061-73.
Gao J, Zhang X, Su P, Shi K, Tang D, Hao Z, et al
. Prevalence and impact of premature ejaculation in outpatients complaining of ejaculating prematurely: Using the instruments of intravaginal ejaculatory latency time and patient-reported outcome measures. Int J Impot Res 2014;26:94-9.
Ruan FF. Sex in China: Studies in Sexology in Chinese Culture. New York: Springer Science & Business Media; 2013.
Yuan YM, Xin ZC, Jiang H, Guo YJ, Liu WJ, Tian L, et al
. Sexual function of premature ejaculation patients assayed with Chinese Index of Premature Ejaculation. Asian J Androl 2004;6:121-6.
Colonnello E, Jannini EA. Impact of Chinese traditional culture and related social norms on current Chinese sexuality and on the future of Chinese sexual medicine. In: Cultural Differences and the Practice of Sexual Medicine. Cham: Springer; 2020. p. 95-113.
Ma WG, Jia JM. The effects and prospects of the integration of traditional Chinese medicine and Western medicine on andrology in China. Asian J Androl 2011;13:592-5.
Peng J, Yang L, Liu L, Zhou R, Liu J, Li N, et al
. Safety and effectiveness of dapoxetine on demand in Chinese men with premature ejaculation: Results of a multicenter, prospective, open-label phase IV study. Sex Med 2021;9:100296.
Hou G, Gao M, Zhang L, Dun X, Zheng Y, Wang F, et al
. An internally validated nomogram for predicting the likelihood of improvement of clinical global impression in patients with lifelong premature ejaculation treated with dapoxetine. J Sex Med 2020;17:2341-50.
Xi Y, Colonnello E, Ma G, Limoncin E, Ciocca G, Zhang H, et al
. Validity of erectile function assessment questionnaires in premature ejaculation patients: A comparative study between the abridged forms of the International Index of Erectile Function and Proposal for Optimal Cutoff Redefinition. J Sex Med 2021;18:440-7.
WHO. Acupuncture: Review and Analysis of Reports on Controlled Clinical Trials. Geneva: World Health Organization; 2002.
Chubak B, Doctor A. Traditional Chinese medicine for sexual dysfunction: Review of the evidence. Sex Med Rev 2018;6:410-8.
Sunay D, Sunay M, Aydoğmuş Y, Bağbancı S, Arslan H, Karabulut A, et al
. Acupuncture versus paroxetine for the treatment of premature ejaculation: A randomized, placebo-controlled clinical trial. Eur Urol 2011;59:765-71.
Sahin S, Bicer M, Yenice MG, Seker KG, Yavuzsan AH, Tugcu V, A prospective randomized controlled study to compare acupuncture and dapoxetine for the treatment of premature ejaculation. Urol Int 2016;97:104-11.
Manni L, Albanesi M, Guaragna M, Barbaro Paparo S, Aloe L. Neurotrophins and acupuncture. Auton Neurosci 2010;157:9-17.
Sansone A, Aversa A, Corona G, Fisher AD, Isidori AM, La Vignera S, et al
. Management of premature ejaculation: A clinical guideline from the Italian Society of Andrology and Sexual Medicine (SIAMS). J Endocrinol Invest 2021;44:1103-18.
Jannini EA, Lenzi A. Sexual dysfunction: Is acupuncture a therapeutic option for premature ejaculation? Nat Rev Urol 2011;8:235-6.
Maeda Y, Kim H, Kettner N, Kim J, Cina S, Malatesta C, et al
. Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture. Brain 2017;140:914-27.
Liu S, Wang Z, Su Y, Qi L, Yang W, Fu M, et al
. A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis. Nature 2021;598:641-5.
Hao YF, Jiang JG. Origin and evolution of China Pharmacopoeia and its implication for traditional medicines. Mini Rev Med Chem 2015;15:595-603.
Guo J, Wang F, Zhou Q, Geng Q, Gao Q, Zhang R, et al
. Safety and efficacy of traditional Chinese medicine, Qiaoshao formula, combined with dapoxetine in the treatment of premature ejaculation: An open-label, real-life, retrospective multicentre study in Chinese men. Andrologia 2021;53:e13915.
Cooper K, Martyn-St James M, Kaltenthaler E, Dickinson K, Cantrell A, Ren S, et al
. Complementary and alternative medicine for management of premature ejaculation: A systematic review. Sex Med 2017;5:e1-18.
Li JX, Lu QG. Efficacy of Qilin Pills combined with sertraline in the treatment of secondary non-consolidated kidney qi premature ejaculation. Zhonghua Nan Ke Xue 2015;21:443-6.
Xu G, Jiang HW, Fang J, Wen H, Gu B, Liu J, et al
. An improved dosage regimen of sertraline hydrochloride in the treatment for premature ejaculation: An 8-week, single-blind, randomized controlled study followed by a 4-week, open-label extension study. J Clin Pharm Ther 2014;39:84-90.
Xu JX, Gao G, Xu N, Yang YY. Yimusake alone or combined with trazodone hydrochloride for primary premature ejaculation. Zhonghua Nan Ke Xue 2012;18:376-8.
Song GH, Halmurat-Upur, Geng JC, Feng LC, Yilihamujiang-shabi, Ma C, et al
. Clinical study on the treatment of premature ejaculation by Uighur medicine gu-jing-mai-si-ha tablet. Chin J Integr Med 2007;13:185-9.
Guo J, Gao QH, Wang F, Yu GJ, Zhang JW, Zeng Y, et al
. Efficacy and safety of Qiaoshao Formula () on patients with lifelong premature ejaculation of Gan (Liver) depression and Shen (Kidney) deficiency syndrome: A randomized controlled trial. Chin J Integr Med 2016;22:889-93.
Li FS, Weng JK. Demystifying traditional herbal medicine with modern approach. Nat Plants 2017;3:17109.
Cooper K, Martyn-St James M, Kaltenthaler E, Dickinson K, Cantrell A, Wylie K, et al
. Behavioral therapies for management of premature ejaculation: A systematic review. Sex Med 2015;3:174-88.
Rodríguez JE, Marzo JC, Piqueras JA. Efficacy of Sphincter Control Training (SCT) in the treatment of premature ejaculation, a new cognitive behavioral approach: A parallel-group randomized, controlled trial. PLoS One 2019;14:e0212274.
Zhu Y, Chen Q, Gu Y, Yue J, Zeng Q. Ancient Chinese Fangzhongshu (sexual skills and methods) therapy for premature ejaculation. World J Mens Health 2016;34:173-8.
Gao M, Geng B, Jannini TB, Wu J, Wang Y, Zhang Y, et al
. Thalamocortical dysconnectivity in lifelong premature ejaculation: A functional MRI study. Urology 2022;159:133-8.
McMahon CG, Jannini EA, Serefoglu EC, Hellstrom WJ. The pathophysiology of acquired premature ejaculation. Transl Androl Urol 2016;5:434-49.
Jannini TB, Lorenzo GD, Bianciardi E, Niolu C, Toscano M, Ciocca G, et al
. Off-label uses of selective serotonin reuptake inhibitors (SSRIs). Curr Neuropharmacol 2022;20:693-712.
Yang XQ, Liu L, Ming SP, Fang J, Wu DN. Tian Wang Bu Xin Dan for Insomnia: A systematic review of efficacy and safety. Evid Based Complement Alternat Med 2019;2019:4260801.
de Carufel F, Trudel G. Effects of a new functional-sexological reatment for premature ejaculation. J Sex Marital Ther 2006;32:97-114.
Perelman MA. Psychosexual therapy for delayed ejaculation based on the Sexual Tipping Point model. Transl Androl Urol 2016;5:563-75.
Limoncin E, Lotti F, Rossi M, Maseroli E, Gravina GL, Ciocca G, et al
. The impact of premature ejaculation on the subjective perception of orgasmic intensity: Validation and standardisation of the ‘Orgasmometer’. Andrology 2016;4:921-6.
Corona G, Rastrelli G, Limoncin E, Sforza A, Jannini EA, Maggi M. Interplay Between Premature Ejaculation and Erectile Dysfunction: A Systematic Review and Meta-Analysis. J Sex Med 2015;12:2291-300.
Rey T. Revisiting the Chinese Medical Case Statement and Its Publics. Melbourne: Cases and their Publics: Interdisciplinary and Transnational Perspectives on the Case Study Genre, 2011.
Fønnebø V Grimsgaard S, Walach H, Ritenbaugh C, Norheim AJ, MacPherson H, et al
. Researching complementary and alternative treatments – The gatekeepers are not at home. BMC Med Res Methodol 2007;7:7.
Jannini EA. SM=SM: The interface of systems medicine and sexual medicine for facing non-communicable diseases in a gender-dependent manner. Sex Med Rev 2017;5:349-64.
Kamada T. System biomedicine: A new paradigm in biomedical engineering. Front Med Biol Eng 1992;4:1-2.
Federoff HJ, Gostin LO. Evolving from reductionism to holism: Is there a future for systems medicine? JAMA 2009;302:994-6.