Roger B. Davis

Intensive Postremission Chemotherapy in Adults with Acute Myeloid Leukemia

BACKGROUND About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.

Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome

Objective To investigate whether placebo effects can experimentally be separated into the response to three components—assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship—and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components. Design A six week single blind three arm randomised controlled trial. Setting Academic medical centre. Participants 262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale. Interventions For three weeks either waiting list (observation), placebo acupuncture alone (“limited”), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence (“augmented”). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks. Main outcome measures Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life. Results At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus “limited” versus “augmented,” respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01).Results were similar at six week follow-up. Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component. Trial registration Clinical Trials NCT00065403.

Long-Term Trends in the Use of Complementary and Alternative Medical Therapies in the United States

Community surveys done over the past decade have documented that a substantial proportion of Americans use complementary and alternative medical (CAM) therapies (14), which have been defined as interventions neither taught widely in medical schools nor generally available in U.S. hospitals (1). Many managed care organizations have responded to this evidence by providing insurance coverage for some CAM therapies (5). Furthermore, most U.S. medical schools have begun offering courses on CAM therapies (6). These responses imply that CAM therapies are perceived to be a force to be reckoned with for some time to come. Yet, little is known about the likelihood that this will be the case. The prevailing assumption is that CAM therapies were used by a fairly narrow segment of the population until the 1970s, at which time the ideology associated with the youth counterculture led to a rapid dissemination and use of CAM therapies that has persisted through the present (7). However, lack of rigorous trend data from epidemiologic surveys have precluded evaluating this assumption rigorously or projecting the future growth of CAM therapies on the basis of evidence of past trends. In the current report, we present nationally representative trend data of this sort from a prevalence study. The data came from retrospective self-reports of a nationally representative sample of the U.S. general population in a 19971998 telephone survey (4) about age at first use of 20 representative CAM therapies. In our analysis, we studied trends by examining between-cohort differences in rates of initiation of CAM therapy use (8). In the absence of prospective data, which do not exist, our results represent, to our knowledge, the most accurate information currently available on U.S. trends in CAM therapy use over the past half-century. Methods Sample The telephone survey was conducted between November 1997 and February 1998 in a nationally representative household sample. Random-digit dialing was used to select households, and a random-selection method was used to select one respondent 18 years of age or older for interview in each sample household. Eligibility was limited to English speakers without cognitive or physical impairment that would prevent interview completion. The average administration time was 30 minutes. A

Impact of Unrecognized Myocardial Scar Detected by Cardiac Magnetic Resonance Imaging on Event-Free Survival in Patients Presenting With Signs or Symptoms of Coronary Artery Disease

20 financial incentive for participation was offered. The Beth Israel Deaconess Committee on Clinical Investigations, Boston, Massachusetts, approved the survey methods. Of the initial sample of 9750 telephone numbers, 26% did not work, 17% were not assigned to households, and 9% were unavailable despite six attempted follow-up contacts. Of the remaining households, 481 were ineligible because of language barrier or cognitive or physical incapacity. Of the 4167 total eligible respondents, 1720 (41.3%) completed the interview on initial request. Of a random subsample of 1066 persons who initially declined and were offered an increased stipend (

Sham device v inert pill: randomised controlled trial of two placebo treatments

50), 335 agreed to participate. In all, 2055 interviews were completed. After we extrapolated the conversion rate to all persons who had initially declined and weighted the data for the undersampling of those who participated after initially declining, the weighted overall response rate among eligible respondents was 60%. The data were weighted for three factors: 1) probability of selection within household as well as geographic variation in cooperation (by region of the country and urbanicity [local population density]], 2) nonresponse, and 3) post-stratification for aggregate discrepancies between the sample distributions and Census population distributions on a variety of sociodemographic variables (9, 10). More details on the sample design have been presented elsewhere (4). Age data were missing for 6 respondents; our analyses are limited to the remaining 2049 respondents. Measures The interview was described to respondents as a survey by investigators from Harvard Medical School about the health care practices of Americans. Interviewers made no mention of CAM therapies. The first substantive questions concerned perceived health, functional impairment due to health problems, interactions with physicians, and history of chronic medical conditions. Interviewers then queried respondents about their lifetime and recent use of 20 CAM therapiesacupuncture, aromatherapy, biofeedback, chiropractic care, commercial diet programs, energy healing (for example, laying on of hands), folk remedy, herbal medicine, homeopathy, hypnosis, imagery, lifestyle diet (such as vegetarianism or macrobiotics), massage, megavitamin therapy, naturopathy, osteopathy, relaxation techniques, self-help group, spiritual healing by others, and yoga. Users of each therapy were asked their age at first use as well as details about the conditions for which the therapy was initiated. The final set of questions dealt with sociodemographic issues. Cohorts were aggregated into three subsamples: prebaby boom (respondents 54 years of age at interview, born before 1945); baby boom (34 to 53 years of age at interview, born 19451964); and postbaby boom (18 to 33 years of age at interview, born 19651979). For sociodemographic variables, we used two categories for sex (male or female), four for race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, or other), four for education (less than high school, high school graduate, some college, or college graduate), four for U.S. region (northeast, midwest, south, or west), and four for urbanicity (residence in a large city, small city, suburb, town/rural). Statistical Analysis All analyses were performed with weighted data by using SAS statistical software (11). To assess differences in trends among cohorts, the KaplanMeier (12) method was used to generate a graphic representation of the cumulative lifetime prevalences of CAM therapy use according to cohort. The significance of historical changes in lifetime use was estimated by using discrete-time survival analysis (13), a method of survival analysis appropriate for data in which events are recorded only at discrete time points (for example, in yearly increments). Discrete-time survival analysis was operationalized as a logistic regression with person-year as the unit of analysis and first use of CAM therapy as the outcome variable. The predictors of primary interest were a series of dummy variables for decades of historical time, and covariates included sociodemographic and dummy variables adjusted for the baseline hazard rate of each year of a persons life. This model results in an intercept for each time period, and the odds ratios (ORs) can be interpreted as the relative risk for the annual risk for use of alternative therapy. Subsample models were estimated to study sociodemographic variation in trends. Disaggregated models were estimated to study trends in the use of particular CAM therapies. To adjust for the design effects introduced by weighting of the data, the method of jackknife repeated replications (14) was used to estimate standard errors (SEs). For this method, we used user-written macros in SAS statistical software. For this process, 50 random primary sampling units were created with two random half-samples in each unit for a total of 100 random replicates. Jackknife repeated replication is a method that uses simulations of coefficient distributions in subsamples to generate empirical estimates of SEs and significance tests. The ratios of the coefficients to these adjusted SEs are used to compute the 95% CIs of the ORs. Tests for the significance of sets of predictors taken together were computed by using the Wald chi-square test from coefficient variancecovariance matrices based on the jackknife repeated replications simulations. Results Differences in Aggregate Use Trends among Cohorts At the time of interview, 67.6% of all respondents had used at least one CAM therapy at some time in their lives. The Figure presents KaplanMeier age-of-onset curves showing trends in each cohort in the cumulative probabilities of use according to age. Of note are the dramatic differences in use among cohorts. This is seen most clearly by focusing on cumulative probabilities of use for age 33 years, the oldest age represented in all three cohorts. Approximately 3 of every 10 respondents in the prebaby boom cohort used some type of CAM therapy by the age of 33 years compared with 5 of 10 in the baby boom cohort and 7 of 10 in the postbaby boom cohort. Figure. Weighted KaplanMeier estimates of age of first use of any complementary and alternative medical (CAM) therapy among lifetime users according to cohort. Historical Trends in Aggregate Use The aggregate data in the Figure are presented in a different format in the bottom row of Table 1, where the risk ratios are shown from a discrete-time survival model that estimated the effects of historical time in predicting age at first use of CAM therapy among respondents after adjustment for person-year and sociodemographic variables. The contrast category is first use before 1960. Consistent with the pattern in the Figure, the results of the model for the outcome of any therapy show monotonically increasing risk ratios in each decade from the 1960s through the 1990s. Table 1. Trends in Relative Risk for First Use of 20 Specific Complementary and Alternative Medical Therapies, according to Decade Possible demographic subsample differences in time trends were examined by estimating separate subsample models that were identical to the discrete-time survival model for any therapy and by evaluating the statistical significance of differences in trends across subsamples. No statistically significant (0.05 level in two-sided tests) differences in trends were found for sex, race/ethnicity, education level, region of the country, or urbanicity. Trends in the Use of Specific Therapies Table 1 also shows the risk ratios to estimate first use of each of the 20 CAM therapies assessed. All tre

The Last Six Months of Life for Patients with Congestive Heart Failure

Background— Contrast-enhanced cardiac magnetic resonance imaging (CMR) can determine the extent of myocardial scar from infarction (MI). However, the prognostic significance of unrecognized myocardial scar by CMR in patients without a history of MI is unknown. Methods and Results— One hundred ninety-five patients without a known prior MI underwent CMR for assessment of left ventricular (LV) function and late gadolinium enhancement (LGE). We assessed the prognostic value of LGE and other CMR variables beyond the strongest clinical predictors and built the best overall models for major adverse cardiac events (MACE) and cardiac mortality. During a median follow-up of 16 months, 31 patients (18%) experienced MACE, including 17 deaths. LGE demonstrated the strongest unadjusted associations with MACE and cardiac mortality (hazard ratios of 8.29 and 10.9, respectively; both P<0.0001). Patients in the lowest tertile of LGE-involved myocardium (mean LV mass, 1.4%) experienced a >7-fold increased risk for MACE. By multivariable analyses, LGE was independently associated with MACE beyond the clinical model (P<0.0001) or the clinical model combined with angiographically significant coronary stenosis (P=0.0007), LV ejection fraction (P=0.001), LV end-systolic volume index (P=0.0006), or segmental WMA (P=0.002). LGE remained the strongest predictor selected in the best overall models for MACE and cardiac mortality. Conclusions— Among patients with a clinical suspicion of coronary artery disease but without a history of MI, LGE involving a small amount of myocardium carries a high cardiac risk. In addition, LGE provides incremental prognostic value to MACE and cardiac mortality beyond common clinical, angiographic, and functional predictors.

Racial and Ethnic Disparities in Cancer Screening: The Importance of Foreign Birth as a Barrier to Care

Abstract Objective To investigate whether a sham device (a validated sham acupuncture needle) has a greater placebo effect than an inert pill in patients with persistent arm pain. Design A single blind randomised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls. Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study. Setting Academic medical centre. Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale. Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks. Main outcomemeasures Arm pain measured on a 10 point pain scale. Secondary outcomes were symptoms measured by the Levine symptom severity scale, function measured by Pranskys upper extremity function scale, and grip strength. Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups, but changes were not different between the groups (−0.14, 95% confidence interval −0.52 to 0.25, P = 0.49). Changes in severity scores for arm symptoms and grip strength were similar between groups, but arm function improved more in the placebo pill group (2.0, 0.06 to 3.92, P = 0.04). Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group (−0.33 (−0.40 to −0.26) v −0.15 (−0.21 to −0.09), P = 0.0001) and on the symptom severity scale (−0.07 (−0.09 to −0.05) v −0.05 (−0.06 to −0.03), P = 0.02). Differences were not significant, however, on the function scale or for grip strength. Reported adverse effects were different in the two groups. Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in. Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals.

Linguistic and cultural barriers to care.

OBJECTIVE: To characterize the experiences of patients with congestive heart failure (CHF) during their last 6 months of life.

A Controlled Trial Comparing Foscarnet with Vidarabine for Acyclovir-Resistant Mucocutaneous Herpes Simplex in the Acquired Immunodeficiency Syndrome

CONTEXT: Racial/ethnic groups comprised largely of foreign-born individuals have lower rates of cancer screening than white Americans. Little is known about whether these disparities are related primarily to their race/ethnicity or birthplace.OBJECTIVE: To determine whether foreign birthplace explains some racial/ethnic disparities in cancer screening.DESIGN, SETTING, AND SUBJECTS: Cross-sectional study using 1998 data from the National Health Interview Survey.MAIN OUTCOME MEASURES: Completion of cervical, breast, or colorectal cancer screening.RESULTS: Of respondents, 15% were foreign born. In analyses adjusted for sociodemographic characteristics and illness burden, black respondents were as or more likely to report cancer screening than white respondents; however, Hispanic and Asian-American and Pacific Islander (AAPI) respondents were significantly less likely to report screening for most cancers. When race/ethnicity and birthplace were considered together, U.S.-born Hispanic and AAPI respondents were as likely to report cancer screening as U.S.-born whites; however, foreign-born white (adjusted odds ratio [AOR], 0.58; 95% confidence interval [CI], 0.41 to 0.82), Hispanic (AOR, 0.65; 95% CI, 0.53 to 0.79), and AAPI respondents (AOR, 0.28; 95% CI, 0.19 to 0.39) were less likely than U.S.-born whites to report Pap smears. Foreign-born Hispanic and AAPI respondents were also less likely to report fecal occult blood testing (FOBT); AORs, 0.72; 95% CI, 0.53 to 0.98; and 0.61; 95% CI, 0.39 to 0.96, respectively); and sigmoidoscopy (AORs, 0.70; 95% CI, 0.51 to 0.97; and 0.63; 95% CI, 0.40 to 0.99, respectively). Furthermore, foreign-born AAPI respondents were less likely to report mammography (AOR, 0.49; 95% CI, 0.28 to 0.86). Adjusting for access to care partially attenuated disparities among foreign-born respondents.CONCLUSION: Foreign birthplace may explain some disparities previously attributed to race or ethnicity, and is an important barrier to cancer screening, even after adjustment for other factors. Increasing access to health care may improve disparities among foreign-born persons to some degree, but further study is needed to understand other barriers to screening among the foreign-born.

Lead, Mercury, and Arsenic in US- and Indian-Manufactured Ayurvedic Medicines Sold via the Internet

AbstractCONTEXT: Primarily because of immigration, Asian Americans are one of the fastest growing and most ethnically diverse minority groups in the United States. However, little is known about their perspectives on health care quality. OBJECTIVE: To examine factors contributing to quality of care from the perspective of Chinese- and Vietnamese-American patients with limited English language skills. DESIGN: Qualitative study using focus groups and content analysis to determine domains of quality of care. SETTING: Four community health centers in Massachusetts. PARTICIPANTS: A total of 122 Chinese- and Vietnamese-American patients were interviewed in focus groups by bilingual interviewers using a standardized, translated moderator guide. MAIN OUTCOME MEASURES: Domains of quality of care mentioned by patients in verbatim transcripts. RESULTS: In addition to dimensions of health care quality commonly expressed by Caucasian, English-speaking patients in the United States, Chinese- and Vietnamese-American patients with limited English proficiency wanted to discuss the use of non-Western medical practices with their providers, but encountered significant barriers. They viewed providers’ knowledge, inquiry, and nonjudgmental acceptance of traditional Asian medical beliefs and practices as part of quality care. Patients also considered the quality of interpreter services to be very important. They preferred using professional interpreters rather than family members, and preferred gender-concordant translators. Furthermore, they expressed the need for help in navigating health care systems and obtaining support services. CONCLUSIONS: Cultural and linguistically appropriate health care services may lead to improved health care quality for Asian-American patients who have limited English language skills. Important aspects of quality include providers’ respect for traditional health beliefs and practices, access to professional interpreters, and assistance in obtaining social services.