The

n e w e ng l a n d j o u r na l

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tribution to disease offer invaluable insights into the mechanisms of disease pathogenesis. Jayakrishna Ambati, M.D.
University of Kentucky Lexington, KY 40536

Nicholas Katsanis, Ph.D.

Johns Hopkins University Baltimore, MD 21205 nkatsan1@jhmi.edu

Kang Zhang, M.D., Ph.D.

University of California, San Diego La Jolla, CA 92093
1. Kleinman ME, Yamada K, Takeda A, et al. Sequence- and

target-independent angiogenesis suppression by siRNA via TLR3. Nature 2008;452:591-7. 2. Karik K, Bhuyan P, Capodici J, Weissman D. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol 2004;172:6545-9. 3. Pirher N, Ivicak K, Pohar J, Bencina M, Jerala R. A second binding site for double-stranded RNA in TLR3 and consequences for interferon activation. Nat Struct Mol Biol 2008;15:761-3. 4. Klein R, Klein BE, Tomany SC, Meuer SM, Huang GH. Tenyear incidence and progression of age-related maculopathy: the Beaver Dam eye study. Ophthalmology 2002;109:1767-79. 5. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for agerelated macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417-36. [Erratum, Arch Ophthalmol 2008;126:1251.]

Weight Loss for Urinary Incontinence in Overweight and Obese Women

To the Editor: Subak et al. (Jan. 29 issue)1 report that weight loss among overweight and obese women with urinary incontinence decreased the frequency of incontinence. The mechanism is unclear. It is commonly assumed that reduced intraabdominal pressure is responsible. However, dietary changes independent of weight loss may be overlooked. Sodium intake is particularly important. We estimate that the sodium intake of participants at baseline was 3840 mg per day (167 mmol), on the basis of a sodium intake, adjusted for sex and age, of 1.63 mg per kilocalorie,2 multiplied by the energy requirement for low-activity women. The energy requirement was calculated according to the mean height, weight, and age of the study subjects.3 The reduction of the energy intake at baseline (2357 kcal per day) to that with the reduced-calorie diet (mean, 1350 kcal per day) represents a difference of 1640 mg of sodium (71 mmol) per day, assuming the ratio of sodium to kcal remained similar. A reduction of 2299 mg (100 mmol) in sodium per day predicts a decrease in the 24-hour urinary volume of 399 ml.4 Thus, the sodium reduction alone may have decreased the urinary volume by 285 ml per day, thus reducing the frequency of incontinence. Caleb J. Kelly, M.S., R.D.
University of Colorado Denver, CO 80045 caleb.kelly@ucdenver.edu

Piyagarnt E. Vichayavilas, M.S., R.D.

Childrens Hospital of Denver Denver, CO 80045
1. Subak LL, Wing R, West DS, et al. Weight loss to treat uri-

nary incontinence in overweight and obese women. N Engl J Med 2009;360:481-90. 2. Briefel RR, Johnson CL. Secular trends in dietary intake in the United States. Annu Rev Nutr 2004;24:401-31. 3. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. 5th ed. Washington, DC: National Academy Press, 2002. 4. He FJ, Markandu ND, Sagnella GA, MacGregor GA. Effect of salt intake on renal excretion of water in humans. Hypertension 2001;38:317-20.

To the Editor: Subak and colleagues present data suggesting an association between weight loss and reduction in the frequency of urinary incontinence episodes in obese and overweight women as compared with a control group. However, to prove the effect of weight loss adequately, one must consider all other conditions that may affect continence.1 We know that many drugs (e.g., 1-adrenoceptor antagonists, antipsychotic agents, benzodiazepines, diuretics, and anti depressants, as well as hormone-replacement therapy in postmenopausal women) have been suggested to induce incontinence.2 There is no information about concurrent drug use by the patients in the trial by Subak et al. We think that Subak et al. should have matched the two groups with regard to medication use to assess

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correspondence

the net effect of weight loss in the management of incontinence. Zekeriya Ulger, M.D. Mustafa Cankurtaran, M.D. Servet Arogul, M.D.
Hacettepe University 06100 Ankara, Turkey zulger@hacettepe.edu.tr
1. Rogers RG. Urinary stress incontinence in women. N Engl J

Med 2008;358:1029-36. 2. Tsakiris P, Oelke M, Michel MC. Drug-induced urinary incontinence. Drugs Aging 2008;25:541-9.

The authors reply: Kelly and Vichayavilas suggest that changes in sodium intake rather than weight loss may mediate the effect of the Program to Reduce Incontinence by Diet and Exercise (PRIDE) weight loss intervention on frequency of urinary incontinence. To test this hypothesis, we added weight loss and changes in sodium intake to the generalized estimating equation negative binomial model we used to assess the effect of treatment on the frequency of urinary incontinence. We assessed the relative difference between the overall effect of treatment, as estimated in the unadjusted model, and its direct effect through other pathways, as estimated in models controlling for post-randomization changes in weight and sodium intake. Sodium intake was quantified using the Block Food Frequency Questionnaire, a 110-item self-administered questionnaire validated to estimate the intake of nutrients and foods in the various food groups.1 Completed questionnaires were sent to Berkeley Nutrition Services (Berkeley, CA) for a complete nutrient analysis including macronutrients and micronutrients.2 The overall effect of assignment to the weightloss intervention was an estimated 21.7% reduction in the frequency of urinary incontinence over 6 months. This overall estimate is based on a complete case analysis and cannot be computed from the within-group percent reductions in frequency that are based on multiple imputation and shown in Table 2 of our article.

Analyses adjusting for change in weight only indicated that change in weight explained 74% of the overall effect of treatment. In contrast, adjustment for change in sodium intake explained, at most, 9% of the treatment effect. Thus, change in weight appears to be a much more important mediator than change in sodium intake in the present study. Ulger et al. suggest that we should have matched the two study groups with respect to medication use to avoid the confounding of an effect of weight loss. Drugs proposed to have an effect on urinary incontinence include 1-adreno ceptor antagonists, antipsychotic agents, benzodiazepines, diuretics, and antidepressants, as well as hormone-replacement therapy in postmenopausal women. Because this was a randomized study, the use of these medications is expected to be balanced at baseline. To verify the balance, we examined medication logs collected for each woman and found that among all medications reported at baseline, there was no difference in medication use among the noted drug categories (12.9% in the weight-loss group and 12.8% in the control group). However, there is no way for us to control the potential influence of study group on post-randomization changes in use. Leslee L. Subak, M.D.
University of California, San Francisco San Francisco, CA 64115 subakl@obgyn.ucsf.edu

Rena Wing, Ph.D.

Warren Alpert Medical School at Brown University Providence, RI 02912

Eric Vittinghoff, Ph.D.

University of California, San Francisco San Francisco, CA 64115

for the PRIDE Investigators

1. Boucher B, Cotterchio M, Kreiger N, Nadalin V, Block T,

Block G. Validity and reliability of the Block98 food-frequency questionnaire in a sample of Canadian women. Public Health Nutr 2006;9:84-93. 2. Block G, Sinha R, Gridley G. Collection of dietary-supplement data and implications for analysis. Am J Clin Nutr 1994;59: Suppl:232S-239S.

Preemption and Malpractice Liability

To the Editor: In their Perspective article about suggest that preemption will not result in more the Supreme Court, preemption, and malpractice malpractice claims against physicians for failure liability (Feb. 5 issue),1 Kesselheim and Studdert to warn, which they say are uncommon and finan-

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