Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.

IMPORTANCE: Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE: To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS: International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION: Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES: The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS: By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE: Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294671.

Relationship between sleep position and risk of extreme cardiorespiratory events.

OBJECTIVE: To determine whether infants at sleep in the prone side positions are at higher risk for an extreme cardiorespiratory event compared with infants at sleep in the supine position. STUDY DESIGN: We used a case-control study to compare sleep position, determined with an accelerometer, in 116 infants during an extreme cardiorespiratory event with that in 231 matched control subjects (2 per case) who did not experience any extreme events during monitoring. RESULTS: From calculation of adjusted ORs and 95% CIs, infants placed in the prone or side position were no more likely to experience an extreme cardiorespiratory event compared with infants at sleep in the supine position. We used conditional logistic regression to account for the matched design of the study and to adjust for potential confounders or effect-modifiers. CONCLUSION: These findings, coupled with our earlier observation that the peak incidence of severe cardiorespiratory events occurred before the peak incidence of sudden infant death syndrome, strongly suggest that the supine sleeping position decreases the risk of sudden infant death syndrome by mechanisms other than by decreasing extreme cardiorespiratory events detected by monitoring.

Adverse health outcomes in women exposed in utero to diethylstilbestrol.

BACKGROUND: Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood. METHODS: We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero. RESULTS: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes. CONCLUSIONS: In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

Maternal assessment of physician qualification to give advice on AAP-recommended infant sleep practices related to SIDS.

OBJECTIVE: The American Academy of Pediatrics (AAP) strongly recommends the supine-only sleep position for infants and issued 2 more sudden infant death syndrome (SIDS) reduction recommendations: avoid bed sharing and use pacifiers during sleep. In this study, we investigated the following: 1) if mothers from at risk populations rate physicians as qualified to give advice about sleep practices and 2) if these ratings were associated with reports of recommended practice. METHODS: A cross-sectional survey of mothers (N=2355) of infants aged <8 months was conducted at Women, Infants, and Children (WIC) Program centers in 6 cities from 2006 to 2008. The predictor measures were maternal rating of physician qualification to give advice about 3 recommended sleep practices and reported nature of physician advice. The dependent measures were maternal report of usage of recommended behavior: 1) "infant usually placed supine for sleep," 2) "infant usually does not share a bed with an adult during sleep," and 3) "infant usually uses a pacifier during sleep." RESULTS: Physician qualification ratings varied by topic: sleep position (80%), bed sharing (69%), and pacifier use (60%). High ratings of physician qualification were associated with maternal reports of recommended behavior: supine sleep (adjusted odds ratio [AOR] 2.1, 95% confidence interval [CI], 1.6-2.6); usually no bed sharing (AOR 1.5, 95% CI, 1.2-1.9), and usually use a pacifier during sleep (AOR 1.2, 95% CI, 1.0-1.5). CONCLUSIONS: High maternal ratings of physician qualification to give advice on 2 of the 3 recommended sleep practices targeted to reduce the risk of SIDS were significantly associated with maternal report of using these behaviors. Lower ratings of physician qualification to give advice about these sleep practices may undermine physician effectiveness in promoting the recommended behavior.

Trends and factors associated with infant sleeping position: the national infant sleep position study, 1993-2007.

OBJECTIVE: To determine trends and factors associated with choice of infant sleeping position. DESIGN: Annual nationally representative telephone surveys from 1993 through 2007. SETTING: Forty-eight contiguous states of the United States. PARTICIPANTS: Nighttime caregivers of infants born within the last 7 months; approximately 1000 interviews were given each year. Main Outcome Measure Whether infant is usually placed supine to sleep. RESULTS: For the 15-year period, supine sleep increased (P < .001) and prone sleep decreased (P < .001) for all infants, with no significant difference in trend by race. Since 2001, a plateau has been reached for all races. Factors associated with increased supine sleep between 1993 and 2007 included time, maternal race other than African American, higher maternal educational level, not living in Southern states, first-born infant, and full-term infant. The effect of these variables was reduced when variables related to maternal concerns about infant comfort, choking, and advice from physicians were taken into account. Between 2003 and 2007, there was no significant yearly increase in supine sleep. Choice of sleep position could be explained almost entirely by caregiver concern about comfort, choking, and advice. Race no longer was a significant predictor. CONCLUSIONS: Since 2001, supine sleep has reached a plateau, and there continue to be racial disparities. There have been changes in factors associated with sleep position, and maternal attitudes about issues such as comfort and choking may account for much of the racial disparity in practice. To decrease sudden infant death syndrome rates, we must ensure that public health measures reach the populations at risk and include messages that address concerns about infant comfort and choking.

Six-month follow-up of a brief intervention on self-reported safety belt use among emergency department patients.

OBJECTIVES: Safety belt use (SBU) reduces motor vehicle deaths by 45%. We previously reported that a brief intervention improved self-reported SBU among emergency department (ED) patients at 3 months. We sought to determine if these effects were sustained at 6 months postenrollment. METHODS: This was a prospective, randomized controlled trial of adult patients (age > or = 21 years) at an academic medical center ED from February 2006 to May 2006. Patients were systematically sampled for self-reported SBU. Those with self-reported SBU less than "always" were asked to participate. Subjects were surveyed at baseline with a nine-item series of situational SBU questions scored on a five-point Likert scale (e.g., 5 = always, 1 = never). This nine-item average comprised the mean SBU score. Subjects were randomized to a control group (CG) and an intervention group (IG). The CG received an injury prevention brochure; the IG received a brief motivation interview by a trained interventionist and the brochure. Subjects were phoned at 3 and 6 months to determine interval change in SBU scores via a standard script. Repeated-measures analysis of covariance and t-tests were used to analyze trends in mean SBU scores between groups, as well as to test mean changes in SBU scores from the 3- to 6-month intervals. RESULTS: Of 432 eligible patients, 292 enrolled (mean age = 35 years, SD +/- 11.2 years; 61% male). At baseline, there were no significant demographic differences; the IG (n = 147) and CG (n = 145) had similar mean SBU scores (2.8 vs. 2.6, p = 0.31), and 66% (n = 96 in each) completed both 3- and 6-month follow-up. The mean SBU score at 6 months in the IG was greater than in the CG group (3.6 vs. 2.9, p < 0.001), as were the mean SBU score differences from baseline (IG = 0.84 vs. CG = 0.29, p < 0.001). These differences were sustained from the 3-month interval (IG = -0.02 vs. CG = -0.06, p > 0.05). CONCLUSIONS: The previously reported finding that ED patients who received a brief motivation interview reported higher SBU scores at 3 months compared to a CG was sustained at 6-month follow-up. Although limited by self-report, a brief intervention may enhance lasting SBU behavior among high-risk ED patients.

Barriers to following the supine sleep recommendation among mothers at four centers for the Women, Infants, and Children Program.

OBJECTIVES: The risk for sudden infant death syndrome in black infants is twice that of white infants, and their parents are less likely to place them in the supine position for sleep. We previously identified barriers for parents to follow recommendations for sleep position. Our objective with this study was to quantify these barriers, particularly among low-income, primarily black mothers. DESIGN/METHODS: We conducted face-to-face interviews with 671 mothers, 64% of whom were black, who attended Women, Infants, and Children Program centers in Boston, Massachusetts, Dallas, Texas, Los Angeles, California, and New Haven, Connecticut. We used univariate analyses to quantify factors that were associated with choice of sleeping position and multivariate logistic regression to calculate adjusted odds ratios for the 2 outcome variables: "ever" (meaning usually, sometimes, or last night) put infant in the prone position for sleep and "usually" put infant in the supine position to sleep. RESULTS: Fifty-nine percent of mothers reported supine, 25% side, 15% prone, and 1% other as the usual position. Thirty-four percent reported that they ever placed infants in the prone position. Seventy-two percent said that a nurse, 53% a doctor, and 38% a female friend or relative provided source of advice. Only 42% reported that a nurse, only 36% a doctor, and only 15% a female friend or relative recommended the supine position for sleep. When a female friend or relative recommended the prone position, mothers were more likely ever to place their infants in the prone position and less likely usually to choose supine compared with those who received no advice from friends or relatives. When a doctor or a nurse recommended a nonsupine position, the mothers were less likely to choose supine compared with those who received no advice from a doctor or a nurse. Mothers who trusted the opinion of a doctor or a nurse about infant sleeping position were more likely to place their infants in the supine position. Half of the mothers believed that infants were more likely to choke when supine, and they were less likely to place their infants supine. Mothers who believed that infants are more comfortable in the prone position (36%) were more likely to place their infants prone. Twenty-nine percent believed that having their infants sleep with an adult helps prevent sudden infant death syndrome, and only 43% believed that sudden infant death syndrome is related to sleeping position. CONCLUSIONS: We identified specific barriers to placing infants in the supine position for sleep (lack of or wrong advice, lack of trust in providers, knowledge and concerns about safety and comfort) in low-income, primarily black mothers that should be considered when designing interventions to get more infants onto their back for sleep.

Mortality rates among augmentation mammoplasty patients: an update.

BACKGROUND: A large follow-up study of cosmetic breast implant patients previously suggested an overall decrease in mortality but increased risks of brain and respiratory cancers and of suicides. METHODS: This cohort of 12,144 implant patients and 3614 patients with other types of plastic surgeries was followed for 5 additional years, enabling derivations of standardized mortality ratios (SMRs) based on population rates and relative risks (RRs) based on comparisons with the other patients. RESULTS: A total of 443 implant and 221 other plastic surgery patients were identified as deceased (SMR = 0.65 [95% confidence interval (CI) = 0.6-0.7] and 0.56 [0.5-0.6], respectively). Despite evidence that implants can interfere with mammographic visualization, there was no evidence that implant patients had a higher risk of death from breast cancer as compared with either the general population or other plastic surgery patients. The previous excess risk of brain cancer deaths among implant patients was attenuated by follow-up (as the result of no additional deaths; SMR = 1.43, 0.8-2.5; RR = 2.07, 0.5-8.9). A previously observed excess risk of respiratory cancer deaths persisted in comparisons with other plastic surgery patients (RR = 1.63; 1.0-2.7), but there was no evidence of a trend of risk with follow-up time. Implant patients also showed an elevated risk of suicide (SMR = 1.63, 1.1-2.3; RR = 2.58, 0.9-7.8) and of deaths caused by motor vehicle accidents (RR = 1.73; 0.6-5.4). CONCLUSIONS: Although several elevations in cause-specific mortality were attenuated by additional follow-up, the excess risk of suicide among the implant patients remains of concern.

Barriers to following the back-to-sleep recommendations: insights from focus groups with inner-city caregivers.

BACKGROUND: African American infants have a higher incidence of SIDS and increased risk of being placed in the prone position for sleep. OBJECTIVE: To determine new barriers and more information about previously identified barriers that interfere with adherence to the Back-to-Sleep recommendations among inner-city, primarily African Americans. DESIGN/METHODS: We conducted 9 focus groups with caregivers of infants and young children from women, infants, and children centers and clinics in New Haven and Boston. Themes were identified using standard qualitative techniques. RESULTS: Forty-nine caregivers participated, of whom 86% were African American, 6% were Hispanic, 4% were white, and 4% were other. Four themes were identified: 1) SAFETY: Participants chose the position for their infants based on which position they believed to be the safest. Some participants did not choose to put their infants in the supine position for sleep because they feared their infants would choke; 2) Advice: Participants relied on the advice of more experienced female family members. Health care providers were not uniformly a trusted source of advice; 3) Comfort: Participants made choices about their infants sleeping positions based on their perceptions of whether the infants appeared comfortable. Participants thought that their infants appeared more comfortable in the prone position; 4) Knowledge: Some participants had either limited or erroneous knowledge about the Back-to-Sleep recommendations. CONCLUSIONS: We identified multiple barriers to adherence to recommendations regarding infant sleep position. Data obtained from these focus groups could be used to design educational interventions aimed at improving communication about and adherence to the Back-to-Sleep recommendations.

Risk of connective tissue disorders among breast implant patients.

In a US retrospective cohort study (1960-1996), 351 (4.8%) of 7,234 patients with breast implants and 62 (2.9%) of 2,138 patients who had undergone other types of plastic surgery reported subsequent rheumatoid arthritis (RA), scleroderma, systemic lupus erythematosus, or Sjögren's syndrome (relative risk = 2.0, 95% confidence interval (CI): 1.5, 2.8). Risks of RA, scleroderma, and Sjögren's syndrome were elevated both before and after 1992, when the Food and Drug Administration changed the status of breast implants to investigational. When records for these diseases were retrieved (35-40% retrieval rate) and blindly reviewed, two expert rheumatologists assessed only a minority of the cases as being "likely" (e.g., regarding RA, 16.5% for implant patients and 23.5% for comparison patients). Recalculation of incidence rates using "likely" diagnoses found relative risks of 2.5 (95% CI: 0.8, 7.8) for RA, scleroderma, and Sjögren's syndrome combined and 1.9 (95% CI: 0.6, 6.2) for RA only. When the proportions deemed "likely" were applied to all self-reports, the estimated relative risks were 2.0 (95% CI: 0.7, 5.4) for the three disorders combined and 1.3 (95% CI: 0.5, 3.8) for RA. These results indicate that self-reports of connective tissue disorders are influenced by reporting and surveillance biases. Given the diagnostic complexities of these diseases, excess risks, if they exist, may be beyond detection even in a study of this size.

Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial.

CONTEXT: Anemia is common in critically ill patients and results in a large number of red blood cell (RBC) transfusions. Recent data have raised the concern that RBC transfusions may be associated with worse clinical outcomes in some patients. OBJECTIVE: To assess the efficacy in critically ill patients of a weekly dosing schedule of recombinant human erythropoietin (rHuEPO) to decrease the occurrence of RBC transfusion. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter trial conducted between December 1998 and June 2001. SETTING: A medical, surgical, or a medical/surgical intensive care unit (ICU) in each of 65 participating institutions in the United States. PATIENTS: A total of 1302 patients who had been in the ICU for 2 days and were expected to be in the ICU at least 2 more days and who met eligibility criteria were enrolled in the study; 650 patients were randomized to rHuEPO and 652 to placebo. INTERVENTION: Study drug (40 000 units of rHuEPO) or placebo was administered by subcutaneous injection on ICU day 3 and continued weekly for patients who remained in the hospital, for a total of 3 doses. Patients in the ICU on study day 21 received a fourth dose. MAIN OUTCOME MEASURES: The primary efficacy end point was transfusion independence, assessed by comparing the percentage of patients in each treatment group who received any RBC transfusion between study days 1 and 28. Secondary efficacy end points identified prospectively included cumulative RBC units transfused per patient through study day 28; cumulative mortality through study day 28; change in hemoglobin from baseline; and time to first transfusion or death. RESULTS: Patients receiving rHuEPO were less likely to undergo transfusion (60.4% placebo vs 50.5% rHuEPO; P<.001; odds ratio, 0.67; 95% confidence interval [CI], 0.54-0.83). There was a 19% reduction in the total units of RBCs transfused in the rHuEPO group (1963 units for placebo vs 1590 units for rHuEPO) and reduction in RBC units transfused per day alive (ratio of transfusion rates, 0.81; 95% CI, 0.79-0.83; P =.04). Increase in hemoglobin from baseline to study end was greater in the rHuEPO group (mean [SD], 1.32 [2] g/dL vs 0.94 [1.9] g/dL; P<.001). Mortality (14% for rHuEPO and 15% for placebo) and adverse clinical events were not significantly different. CONCLUSIONS: In critically ill patients, weekly administration of 40 000 units of rHuEPO reduces allogeneic RBC transfusion and increases hemoglobin. Further study is needed to determine whether this reduction in RBC transfusion results in improved clinical outcomes.

Risk of breast cancer in women exposed to diethylstilbestrol in utero: prelimiinary results (United States).

BACKGROUND: A synthetic estrogen, diethylstilbestrol (DES), was widely prescribed to pregnant women during the 1950s and 1960s but was later discovered to be associated with an increased risk of clear-cell carcinoma of the vagina and cervix in female offspring. DES has not been linked to other cancers in female offspring, but studies of other prenatal factors such as twin gestation and pre-eclampsia have indicated that in-utero estrogen levels may influence breast cancer risk. We evaluated the relation of in-utero DES exposure to the risk of adult breast cancer. METHODS: A cohort of 4821 exposed women and 2095 unexposed women, most of whom were first identified in the mid-1970s, were followed by mailed questionnaires for an average of 19 years. Reported cancer outcomes were validated by medical record review. Breast cancer incidence in DES-exposed daughters was compared with cancer incidence in unexposed daughters with use of Poisson regression analysis, adjusting for year of birth, age at menarche, age at first birth, and number of births. FINDINGS: The rate ratio for incidence of invasive breast cancer in exposed versus unexposed women was 1.4 (95% confidence interval (CI) = 0.7-2.6). DES exposure was not associated with an increased risk of breast cancer in women under 40 years, but among women aged 40 and older the rate ratio was 2.5 (95% CI = 1.0-6.3). The rate ratio for the association of DES exposure with estrogen receptor-positive tumors was 1.9 (95% CI = 0.8-4.5). INTERPRETATION: While not statistically significant, the overall 40% excess risk, arising exclusively from the subset of estrogen receptor-positive cases, raises a concern calling for continued investigation.