The

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

cial penalties under the FDAAA. Herein, we use data from ClinicalTrials.gov (www.clinicaltrials .gov) to estimate the proportion of trials sponsored by nonprofits, mostly academic medical centers (AMCs), that would be subject to one or both of the recently proposed reporting requirements. We chose this subset because rates of results reporting for trials sponsored by AMCs are currently low and lag behind rates for industrysponsored trials.3 Of 6099 registered trials initiated in 2014 with at least one facility in the United States and with information available from ClinicalTrials.gov on April 22, 2015, a total of 3495 trials (57.3%) listed 786 AMCs or other nonprofit organizations as the lead sponsor. Of these trials, an estimated 59.1% (2065 of 3495 trials) would be subject to one or both proposals, 83.9% (1733 of 2065 trials) would be subject to the FDAAA NPRM, and 29.6% (611 of 2065 trials) would be subject to the draft NIH policy. For the 80 organizations (mostly AMCs) listed as the lead sponsor of 10 or more registered trials (2185 of 3495 trials [62.5%]), the percentage of trials per organization covered by either proposal ranged from 0% to 100% (median, 58.6; interquartile range, 47.6 to 66.8) (Fig. 1). Of these 80 organizations, 57 (71%) had at least half of their registered trials subject to at least one proposal. We anticipate that AMCs will have an incentive to offer more support and oversight of their research endeavors as they are held legally accountable (with substantial fines for noncompliance) for results reporting for increasing proportions of their sponsored trials. Our analysis probably underestimates the effect on

of

m e dic i n e

AMCs because some AMC-sponsored trials are subject to requirements from other funders (e.g., the Department of Veterans Affairs and the Patient-Centered Outcomes Research Institute). Our analysis may be limited by miscategorization of trials, owing to mislabeling of record content during self-reporting by sponsors, and by undercounting, because NIH funding may not have been described and not all AMC-sponsored trials are registered on ClinicalTrials.gov. Deborah A. Zarin, M.D. Tony Tse, Ph.D. National Library of Medicine Bethesda, MD

[email protected]

Joseph S. Ross, M.D., M.H.S. Yale University School of Medicine New Haven, CT Supported in part by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on May 20, 2015, at NEJM.org. 1. Chan AW, Song F, Vickers A, et al. Increasing value and re-

ducing waste: addressing inaccessible research. Lancet 2014;383: 257-66. 2. Food and Drug Administration Amendments Act of 2007: Public Law 110-85 (http://www.fda.gov/RegulatoryInformation/ Legislation/FederalFoodDrugandCosmeticActFDCAct/Significant AmendmentstotheFDCAct/FoodandDrugAdministration AmendmentsActof2007/FullTextofFDAAALaw/default.htm). 3. Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, Califf RM. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med 2015;372:1031-9. 4. Zarin DA, Tse T, Sheehan J. The proposed rule for U.S. clinical trial registration and results submission. N Engl J Med 2015; 372:174-80. 5. Hudson KL, Collins FS. Sharing and reporting the results of clinical trials. JAMA 2015;313:355-6. DOI: 10.1056/NEJMc1505965

Sterile Pyuria To the Editor: In their review, Wise and Schlegel (March 12 issue)1 describe a number of causes of sterile pyuria, along with approaches to facilitate clinical evaluation. The authors did not mention pregnancy as a confounder in otherwise normal sterile pyuria. Some older studies showed rather conclusively that urinary leukocyte excretion increases during pregnancy and rises to levels that would be considered abnormal in nonpregnant persons.2-4 Indeed, Kincaid-Smith and Bullen4 spe-

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cifically showed that findings of pyuria did not correlate with culture-proven urinary infection. These findings should dissuade clinicians from treating pregnant women who have pyuria for a urinary or sexually transmitted infection without confirmatory culture or nucleic acid amplification testing. David B. Nelson, M.D. F. Gary Cunningham, M.D. University of Texas Southwestern Medical Center Dallas, TX

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correspondence 3. Nunkoo DH, Mahomoodally MF. Ethnopharmacological

Marshall D. Lindheimer, M.D. University of Chicago Medical School Chicago, IL No potential conflict of interest relevant to this letter was reported. 1. Wise GJ, Schlegel PN. Sterile pyuria. N Engl J Med 2015;372:

1048-54. 2. Gallery EDM, Györy AZ. Urinary concentration, white blood cell excretion, acid excretion, and acid-base status in normal pregnancy: alterations in pregnancy-associated hypertension. Am J Obstet Gynecol 1979;135:27-36. 3. Chadd MA, Humphreys DM, Leather HM, Wills SA. Urinary leucocyte excretion in hypertension in pregnancy. Br Med J 1967; 4:655-6. 4. Kincaid-Smith P, Bullen M. Bacteriuria in pregnancy. Lancet 1965;1:395-9. DOI: 10.1056/NEJMc1504516

To the Editor: In the review by Wise and Schlegel, we were surprised that prior antibiotic treatment1 was not mentioned as a cause of sterile pyuria. It is routine practice in our laboratory to use the filter-paper disk technique to screen all urine specimens showing sterile pyuria for antibacterial activity against a known antibiotic-susceptible strain of Escherichia coli (American Type Culture Collection number 25922).2 In 2014, we detected sterile pyuria in 544 of 21,366 urine specimens (2.5%) processed for microscopy and culture, and antibacterial activity was detected in 400 of these 544 specimens (73.5%). The antibacterial activity detected probably reflects prior antibiotic use, since self-medication and consulting more than one doctor for the same ailment are not uncommon practices in Mauritius. However, it may also have been due to treatment with traditional medicines, some of which have antibacterial properties.3,4 It is important to rule out treatment with antibiotics or other products with antibacterial activity as the cause of sterile pyuria before embarking on potentially unnecessary and costly investigations. Mohammad I. Issack, M.B., Ch.B. Dan Jinerdeb, M.Sc. Central Health Laboratory Quatre Bornes, Mauritius [email protected] No potential conflict of interest relevant to this letter was reported. 1. Public Health England. UK standards for microbiology in-

vestigations: investigation of urine. July 2014 (https://www .gov.uk/government/uploads/system/uploads/attachment_data/ file/343969/B_41i7.2.pdf). 2. Liu YC, Huang WK, Huang TS, Kunin CM. Detection of antimicrobial activity in urine for epidemiologic studies of antibiotic use. J Clin Epidemiol 1999;52:539-45.

survey of native remedies commonly used against infectious diseases in the tropical island of Mauritius. J Ethnopharmacol 2012;143:548-64. 4. Mahomoodally MF, Gurib-Fakim A, Subratty AH. Screening for alternative antibiotics: an investigation into the antimicrobial activities of medicinal food plants of Mauritius. J Food Sci 2010;75:M173-M177. DOI: 10.1056/NEJMc1504516

The Authors Reply: We appreciate the comments of Nelson et al. In our article, Table 1 listed gynecologic infection as a potential source of sterile pyuria, but it did not list pregnancy. They cite Chadd et al.,1 who reported elevated leukocyte excretion in 29 of 35 hypertensive pregnant women who did not receive treatment for urinary infections and in 31 of 54 normotensive pregnant women. In the latter group, 15 women had elevated leukocyte excretion after stimulation with prednisolone, and 6 of the 15 women had urinary infection (>100,000 organisms per milliliter). It is worthwhile to note that in that study, urinary leukocytes were measured in cells per hour, not in the more commonly reported white cells per high-power field. It is quite likely that what Chadd and colleagues described as elevated leukocyte excretion would not be considered to be pyuria with more than 5 white cells per high-power field. Pyuria in pregnancy should result in a search for infection, irrespective of colony count. In response to Issack and Jinerdeb: Table 1 of our article listed “current use of antibiotics” and “recently treated urinary tract infection.” Their reference2 on the treatment of urinary infections with natural remedies provided an interesting observation, but data are lacking on the effect of such treatment on pyuria. Gilbert J. Wise, M.D. Peter N. Schlegel, M.D. Weill Cornell Medical College New York, NY [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Chadd MA, Humphreys DM, Leather HM, Wills SA. Urinary

leucocyte excretion in hypertension in pregnancy. Br Med J 1967; 4:655-6. 2. Nunkoo DH, Mahomoodally MF. Ethnopharmacological survey of native remedies commonly used against infectious diseases in the tropical island of Mauritius. J Ethnopharmacol 2012;143:548-64. DOI: 10.1056/NEJMc1504516 Correspondence Copyright © 2015 Massachusetts Medical Society.

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