Adjustment for Renal Function Improves the Prognostic Performance of Urinary Thromboxane Metabolites.

BACKGROUND: Systemic thromboxane A2 generation, assessed by quantifying the concentration of stable thromboxane B2 metabolites (TXB2-M) in the urine adjusted for urinary creatinine, is strongly associated with mortality risk. We sought to define optimal TXB2-M cutpoints for aspirin users and nonusers and determine if adjusting TXB2-M for estimated glomerular filtration rate (eGFR) in addition to urinary creatinine improved mortality risk assessment. METHODS: Urinary TXB2-M were measured by competitive ELISA in 1363 aspirin users and 1681 nonusers participating in the Framingham Heart Study. Cutpoints were determined for TXB2-M and TXB2-M/eGFR using log-rank statistics and used to assess mortality risk by Cox proportional hazard modeling and restricted mean survival time. Multivariable models were compared using the Akaike Information Criterion (AIC). A cohort of 105 aspirin users with heart failure was used for external validation. RESULTS: Optimized cutpoints of TXB2-M were 1291 and 5609 pg/mg creatinine and of TXB2-M/eGFR were 16.6 and 62.1 filtered prostanoid units (defined as pg·min/creatinine·mL·1.73 m2), for aspirin users and nonusers, respectively. TXB2-M/eGFR cutpoints provided more robust all-cause mortality risk discrimination than TXB2-M cutpoints, with a larger unadjusted hazard ratio (2.88 vs 2.16, AIC P < 0.0001) and greater differences in restricted mean survival time between exposure groups (1.46 vs 1.10 years), findings that were confirmed in the external validation cohort of aspirin users. TXB2-M/eGFR cutpoints also provided better cardiovascular/stroke mortality risk discrimination than TXB2-M cutpoints (unadjusted hazard ratio 3.31 vs 2.13, AIC P < 0.0001). CONCLUSION: Adjustment for eGFR strengthens the association of urinary TXB2-M with long-term mortality risk irrespective of aspirin use.

Association of Thromboxane Generation With Survival in Aspirin Users and Nonusers.

BACKGROUND: Persistent systemic thromboxane generation, predominantly from nonplatelet sources, in aspirin (ASA) users with cardiovascular disease (CVD) is a mortality risk factor. OBJECTIVES: This study sought to determine the mortality risk associated with systemic thromboxane generation in an unselected population irrespective of ASA use. METHODS: Stable thromboxane B2 metabolites (TXB2-M) were measured by enzyme-linked immunosorbent assay in banked urine from 3,044 participants (mean age 66 ± 9 years, 53.8% women) in the Framingham Heart Study. The association of TXB2-M to survival over a median observation period of 11.9 years (IQR: 10.6-12.7 years) was determined by multivariable modeling. RESULTS: In 1,363 (44.8%) participants taking ASA at the index examination, median TXB2-M were lower than in ASA nonusers (1,147 pg/mg creatinine vs 4,179 pg/mg creatinine; P < 0.0001). TXB2-M were significantly associated with all-cause and cardiovascular mortality irrespective of ASA use (HR: 1.96 and 2.41, respectively; P < 0.0001 for both) for TXB2-M in the highest quartile based on ASA use compared with lower quartiles, and remained significant after adjustment for mortality risk factors for similarly aged individuals (HR: 1.49 and 1.82, respectively; P ≤ 0.005 for both). In 2,353 participants without CVD, TXB2-M were associated with cardiovascular mortality in ASA nonusers (adjusted HR: 3.04; 95% CI: 1.29-7.16) but not in ASA users, while ASA use was associated with all-cause mortality in those with low (adjusted HR: 1.46; 95% CI: 1.14-1.87) but not elevated TXB2-M. CONCLUSIONS: Systemic thromboxane generation is an independent risk factor for all-cause and cardiovascular mortality irrespective of ASA use, and its measurement may be useful for therapy modification, particularly in those without CVD.

Surgeons' Perspectives of Contralateral Prophylactic Mastectomy.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) is commonly performed for the treatment of breast cancer, despite its limited oncologic benefit. Little is known about surgeons' perceptions of performing CPM. We hypothesized that a proportion of surgeons would report discomfort with performing CPM, particularly when there is discordance between patients' perceived benefit from CPM and the expected oncologic benefit. METHODS: A survey was sent to members of the American Society of Breast Surgeons seeking self-reports of surgeons' practice patterns, perceptions, and comfort levels with CPM. RESULTS: Of the 2436 members surveyed, 601 responded (response rate = 24.7 %). The median age of respondents was 52 years, and 59 % of responders were women. The majority (58 %) reported that 80 % of their practice was devoted to the treatment of breast disease. Fifty-seven percent (n = 326) of respondents reported discomfort with performing CPM at some point in their practice. While most surgeons (95 %) were comfortable with CPM on a patient with a deleterious BRCA mutation, only 34 % were comfortable performing CPM on an average-risk patient. The most common reasons reported for surgeon discomfort with CPM were a concern for overtreatment, an unfavorable risk/benefit ratio, and inadequate patient understanding of the anticipated risks and benefits of CPM. CONCLUSIONS: Despite the increasing use of CPM for the treatment of breast cancer, many surgeons report discomfort with CPM. Concerns with performing CPM predominantly focus on ambiguities surrounding the oncologic benefit and relative risk of this procedure. Further research is needed to define optimal shared decision-making practices in this area.

NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma.

Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 10(9) engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1-LAGE-1 TCR-engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.

Ex vivo antibody-dependent cellular cytotoxicity inducibility predicts efficacy of cetuximab.

We conducted in vitro studies and a clinical trial for patients with squamous cell carcinoma of the head and neck (SCCHN) to study the relationship between FcγRIIIa polymorphisms and antibody-dependent cellular cytotoxicity (ADCC). In vitro, FcγRIIIa genotype was correlated with ADCC and innate cytotoxicity using natural killer (NK) cells harvested from healthy donors. In the phase II study, patients with recurrent or metastatic SCCHN were treated with cetuximab (500 mg/m(2) i.v. every 2 weeks) and lenalidomide (25 mg daily). FcγRIIIa genotype and ex vivo ADCC were correlated with clinical response, progression-free survival (PFS), and overall survival (OS). In vitro, healthy donors with a FcγRIIIa 158-V allele demonstrated more effective ADCC against two colon cancer cell lines HT29 and SW480, mean cytotoxicity: FF 16.1%, VF/VV 24.3% (P = 0.015) and FF 11.7%, VF/VV 21.0% (P = 0.008), respectively. We observed a linear relationship between ADCC response and innate cytotoxicity. In the phase II trial, 40 patients received cetuximab and lenalidomide with median PFS of 7.2 weeks and OS of 16.4 weeks. Thirty-six patients had FcγRIIIa genotype: VV (2), VF (20), and FF (14), and 25 patients had sufficient NK-cell yield to perform ex vivo ADCC. FcγRIIIa genotype was not associated with any clinical outcomes. Patients mounting ex vivo ADCC response had a higher likelihood of stable disease (P = 0.01) and showed a trend toward increased PFS: 14 weeks versus 6.8 weeks, respectively (P = 0.13). Enhanced ex vivo ADCC and innate immunity responses were more predictive of clinical response than FcγRIIIa and may offer a functional assay to select patients suitable for cetuximab therapy.

Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer.

INTRODUCTION: Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. METHODS: In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERα, HER2, and HIF-1α (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERα to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1α to determine its importance. RESULTS: Basal HIF-1α protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1α expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1α affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. CONCLUSIONS: One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.

Myocardial perfusion grade after late infarct artery recanalization is associated with global and regional left ventricular function at one year: analysis from the Total Occlusion Study of Canada-2.

BACKGROUND: Whether myocardial perfusion grade (MPG) following late recanalization of infarct-related arteries (IRAs) predicts left ventricular (LV) function recovery beyond the acute phase of myocardial infarction (MI) is unknown. METHODS AND RESULTS: The Total Occlusion Study of Canada-2 enrolled stable patients with a persistently occluded IRA beyond 24 hours and up to 28 days post-MI. We studied the relationship between the initial MPG and changes in LV function and volume as well as the change in MPG from immediate post-percutaneous coronary intervention (PCI) to 1 year in 139 PCI patients with thrombolysis in myocardial infarction grade 3 epicardial flow post-PCI and with paired values grouped into impaired or good MPG groups (MPG 0/1 or MPG 2/3). MPG 0/1 patients were more likely to have received thrombolytic therapy and to have a left anterior descending IRA. They had lower blood pressure and LV ejection fraction (LVEF) and a higher heart rate and systolic sphericity index at baseline. Changes in the MPG 0/1 and MPG 2/3 groups from baseline to 1 year were LVEF, 3.3±9.0% and 4.8±8.9% (P=0.42); LV end-systolic volume index (LVESVI), -1.1±9.2 and -4.7±12.3 mL/m(2) (P=0.25); LV end-diastolic volume index (LVEDVI), 0.08±19.1 and -2.4±22.2 mL/m(2) (P=0.67); and SDs/chord for infarct zone wall motion index (WMI), 0.38±0.70 and 0.84±1.11 (P=0.01). By covariate-adjusted analysis, post-PCI MPG 0/1 predicted lower WMI (P<0.001), lower LVEF (P<0.001), and higher LVESVI (P<0.01) but not LVEDVI at 1 year. Of the MPG 0/1 patients, 60% were MPG 2 or 3 at 1 year. CONCLUSIONS: Preserved MPG is present in a high proportion of patients following late PCI of occluded IRAs post-MI. Poor MPG post-PCI frequently improves MPG over 1 year. MPG graded after IRA recanalization undertaken days to weeks post MI is associated with LV recovery, indicating that MPG determined in the subacute post-MI period remains a marker of viability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00025766.

Renal impairment and heart failure with preserved ejection fraction early post-myocardial infarction.

AIM: To study if impaired renal function is associated with increased risk of peri-infarct heart failure (HF) in patients with preserved ejection fraction (EF). METHODS: Patients with occluded infarct-related arteries (IRAs) between 1 to 28 d after myocardial infarction (MI) were grouped into chronic kidney disease (CKD) stages based on estimated glomerular filtration rate (eGFR). Rates of early post-MI HF were compared among eGFR groups. Logistic regression was used to explore independent predictors of HF. RESULTS: Reduced eGFR was present in 71.1% of 2160 patients, with significant renal impairment (eGFR < 60 mL/min every 1.73 m(2)) in 14.8%. The prevalence of HF was higher with worsening renal function: 15.5%, 17.8% and 29.4% in patients with CKD stages 1, 2 and 3 or 4, respectively (P < 0.0001), despite a small absolute difference in mean EF across eGFR groups: 48.2 ± 10.0, 47.9 ± 11.3 and 46.2 ± 12.1, respectively (P = 0.02). The prevalence of HF was again higher with worsening renal function among patients with preserved EF: 10.1%, 13.6% and 23.6% (P < 0.0001), but this relationship was not significant among patients with depressed EF: 27.1%, 26.2% and 37.9% (P = 0.071). Moreover, eGFR was an independent correlate of HF in patients with preserved EF (P = 0.003) but not in patients with depressed EF (P = 0.181). CONCLUSION: A significant proportion of post-MI patients with occluded IRAs have impaired renal function. Impaired renal function was associated with an increased rate of early post-MI HF, the association being strongest in patients with preserved EF. These findings have implications for management of peri-infarct HF.

Adherence to hip protectors and implications for U.S. long-term care settings.

OBJECTIVES: Determine nursing home characteristics related to adherence to use of a hip protector (HP) to prevent fracture; also describe adherence and related resident characteristics. DESIGN: A multicenter, randomized controlled trial of a HP in which adherence to wearing the HP was monitored by research staff 3 times a week for up to 21 months; data were collected by interviews and chart review. SETTING: Thirty-five nursing homes in Boston, St. Louis, and Baltimore. PARTICIPANTS: A total of 797 eligible residents, 633 (79%) of whom passed the run-in period, 397 (63%) of whom remained in the study until the end of follow-up. INTERVENTION: Residents wore a single HP on their right or left side. MEASUREMENTS: In addition to regular monitoring of adherence, data were collected regarding facility characteristics, staffing, policies and procedures, perception of HPs and related experience, and research staff ratings of environmental and overall quality; and also resident demographic characteristics, and function, health, and psychosocial status. RESULTS: Facility characteristics related to more adherence were not being chain-affiliated; less Medicaid case-mix; fewer residents wearing HPs; more paraprofessional staff training; more rotating workers; and having administrators who were less involved in meetings. CONCLUSION: Efforts to increase adherence to the use of HPs should focus on facilities with more Medicaid case-mix to reduce disparities in care, and those that have less of a culture of training. Staff may need support to increase adherence, and when adherence cannot be maintained, HP use should be targeted to those who remain adherent.

Distribution and determinants of myocardial perfusion grade following late mechanical recanalization of occluded infarct-related arteries postmyocardial infarction: a report from the occluded artery trial.

OBJECTIVE: To evaluate the distribution and determinants of myocardial perfusion grade (MPG) following late recanalization of persistently occluded infarct-related arteries (IRA). BACKGROUND: MPG reflects microvascular integrity. It is an independent prognostic factor following myocardial infarction, but has been studied mainly in the setting of early reperfusion. The occluded artery trial (OAT) enrolled stable patients with persistently occluded IRAs beyond 24 hr and up to 28 days post-MI. METHODS: Myocardial blush was assessed using TIMI MPG grading in 261 patients with TIMI 3 epicardial flow following IRA PCI. Patients demonstrating impaired (0-1) versus preserved (2-3) MPG were compared with regard to baseline clinical and pre-PCI angiographic characteristics. RESULTS: Impaired MPG was observed in 60 of 261 patients (23%). By univariate analysis, impaired MPG was associated with failed fibrinolytic therapy, higher heart rate, lower systolic blood pressure, lower ejection fraction, LAD occlusion, absence of collaterals (P < 0.01) and ST elevation MI, lower diastolic blood pressure, and higher systolic sphericity index (P < 0.05). By multivariable analysis, higher heart rate, LAD occlusion, absence of collaterals and higher systolic sphericity index (P < 0.01), and lower systolic blood pressure (P < 0.05) were independently associated with impaired MPG. CONCLUSION: Preserved microvascular integrity was present in a high proportion of patients following late recanalization of occluded IRAs post-MI. Presence of collaterals was independently associated with preserved MPG and likely accounted for the high frequency of preserved myocardial perfusion in this clinical setting. Impaired MPG was associated with baseline clinical and angiographic features consistent with larger infarct size.

Neurobehavior of preterm infants at 36 weeks postconception as a function of morphine analgesia.

This study evaluated early neurobehavioral outcomes in ventilated preterm infants randomized to receive morphine analgesia or placebo in the Neurological Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial. Eight hundred and ninety-eight infants between 23 and 32 weeks of gestation were randomized to receive preemptive morphine analgesia (morphine) or placebo. Infants also received additional analgesia (AA) with open-label morphine. The Neurobehavioral Assessment of the Preterm Infant (NAPI) was used to evaluate 572 of 793 survivors (72.1%) at 36 weeks of postconceptual age. The Neonatal Medical Index (NMI) was used to evaluate the severity of medical complications. Regression analyses were used to determine the effect of covariates. Infants were equally distributed in morphine and placebo groups with similar neonatal and demographic characteristics. Infants assessed with the NAPI were more likely to have sepsis ( P = 0.03), bronchopulmonary dysplasia ( P = 0.02), and longer length of stay ( P = 0.008). Infants randomized to the morphine group had higher NMI scores (odds ratio [OR]; 95% confidence interval [CI]: 1.75; 1.23 to 2.50; P = 0.002). Use of AA was associated with higher NMI scores (OR; 95% CI: 4.5; 2.9 to 5.9; P < 0.001). Of the NAPI subscales, the (mean +/- standard deviation [SD]) popliteal angle cluster scores were significantly higher in the morphine group compared with placebo (51.2 +/- 33.2 versus 45.0 +/- 33.5; P = 0.03). AA use was associated with lower (mean +/- SD) MOTOR scores in the morphine group (48.2 +/- 16.1 versus 52.7 +/- 19.1; P = 0.03) and with lower POPLITEAL ANGLE cluster scores in both the morphine group (41.5 +/- 34.0 versus 59.5 +/- 30.1; P < 0.0001) and the placebo group (40.8 +/- 36.8 versus 49.4 +/- 28.0; P = 0.004). No differences were noted in the other NAPI subscales cluster scores in either subgroup. We conclude that morphine analgesia may result in subtle neurobehavioral differences in premature infants.

Morphine administration and short-term pulmonary outcomes among ventilated preterm infants.

BACKGROUND: The use of opioid therapy for sedation and analgesia among ventilated infants varies among care providers. The impact of opioid therapy early in the neonatal course of respiratory distress syndrome (RDS) on pulmonary outcomes is not known. OBJECTIVE: We tested the hypothesis that preterm neonates randomized to the morphine infusion group would have improved ventilatory outcomes, measured as shorter durations of ventilator or oxygen therapy, fewer air leaks, and lower incidence of bronchopulmonary dysplasia. METHODS: All 898 subjects (gestational age [GA] of > or =23 to < or =32 weeks) who were enrolled in the Neurologic Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial formed the study cohort (morphine: 449 patients; placebo: 449 patients). Subjects received the masked study drug until they were weaned from the ventilator or for 14 days, whichever occurred earlier. Outcome measures included air leaks, duration of ventilation or oxygen therapy, hospitalization, bronchopulmonary dysplasia, and death. RESULTS: Subjects in the 2 groups had similar baseline characteristics (mean +/- SD, morphine versus placebo: GA: 27.3 +/- 2.3 vs 27.4 +/- 2.3 weeks; birth weight: 1037 +/- 340 vs 1054 +/- 354 g). Infants in the morphine group required ventilator therapy significantly longer, compared with the placebo group (median [interquartile range]: 7 days [4-20 days] vs 6 days [3-19 days]). This difference in ventilation duration was significant for infants with GA of 27 to 29 weeks (6 days [4-12 days] vs 5 days [2-9 days]) and 30 to 32 weeks (4 days [3-6 days] vs 3 days [2-5 days]). Infants who received additional analgesia with intermittent morphine doses in both groups were sicker than those who were not given open-label morphine. After adjustment for birth weight, Clinical Risk Index for Babies scores, maternal chorioamnionitis, RDS requiring surfactant, and patent ductus arteriosus in a logistic regression model, the use of additional analgesia with morphine was associated independently with increased air leaks and longer durations of high-frequency ventilation, nasal continuous positive airway pressure, and oxygen therapy. CONCLUSIONS: Morphine infusions do not improve short-term pulmonary outcomes among ventilated preterm neonates. Additional morphine doses were associated with worsening respiratory outcomes among preterm neonates with RDS.

Fast-food intake and diet quality in black and white girls: the National Heart, Lung, and Blood Institute Growth and Health Study.

OBJECTIVE: To examine trends in fast-food consumption and its relationship to calorie, fat, and sodium intake in black and white adolescent girls. DESIGN: A longitudinal multicenter cohort study of the development of obesity and cardiovascular risk factors in black and white female adolescents. Data collection occurred annually using a validated 3-day food record and a food-patterns questionnaire. SUBJECTS AND SETTINGS: A biracial and socioeconomically diverse group of 2379 black and white girls recruited from 3 centers. MAIN OUTCOME MEASURE: Three-day food records and a food-patterns questionnaire were examined for intake of fast food and its association with nutrient intake. We compared patterns of exposure to fast food and its impact on intake of calories, fat, and sodium. RESULTS: Fast-food intake was positively associated with intake of energy and sodium as well as total fat and saturated fat as a percentage of calories. Fast-food intake increased with increasing age in both races. With increasing consumption of fast food, energy intake increased with an adjusted mean of 1837 kcal for the low fast-food frequency group vs 1966 kcal for the highest fast-food frequency group (P<.05). Total fat in the low fast-food frequency group was 34.3% as opposed to 35.8% in the highest fast-food frequency group (P<.05). Saturated fat went from 12.5% to 13% and sodium increased from 3085 mg to 3236 mg in the lowest vs the highest fast-food frequency group (P<.001). CONCLUSIONS: Dietary intake of fast food is a determinant of diet quality in adolescent girls. Efforts to reduce fast-food consumption may be useful in improving diet and risk for future cardiovascular disease.

Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial.

OBJECTIVES: Hypotension occurs commonly among preterm neonates, but its cause and consequences remain unclear. Secondary data analyses from the NEOPAIN trial identified the clinical factors associated with hypotension and examined the contributions of morphine treatment or hypotension to severe intraventricular hemorrhage (IVH) (grades 3 and 4), any IVH (grades 1-4), or death. METHODS: In the NEOPAIN trial, 898 ventilated neonates between 23 and 32 weeks of gestation were enrolled, with equal numbers randomized to receive masked morphine or placebo infusions. Additional doses of open-label morphine were administered as necessary by medical staff members. IVH was diagnosed with centralized readings of early and late cranial ultrasonograms. Hypotension was assessed before study drug infusion, during the loading dose, and at 24 and 72 hours during study drug infusion. Logistic regression analyses with stepdown elimination identified the predictor factors associated with the hypotension, severe IVH, any IVH, or death outcomes at each time point. RESULTS: Hypotension was associated with 23 to 26 weeks of gestation, morphine infusions, severity of illness, additional morphine doses, and prior hypotension. Severe IVH was associated with shorter gestation, higher Clinical Risk Index for Babies scores, no prenatal steroids, pulmonary hemorrhage, hypotension before the loading dose, and morphine doses before intubation and at 25 to 72 hours. Neonatal deaths were associated with 23 to 26 weeks of gestation, higher Clinical Risk Index for Babies scores, pulmonary hemorrhage, patent ductus arteriosus, thrombocytopenia, and hypotension before the loading dose. Morphine infusions were not a significant factor in logistic models for severe IVH, any IVH, or death. CONCLUSIONS: Preemptive morphine infusions, additional morphine, and lower gestational age were associated with hypotension among preterm neonates. Severe IVH, any IVH, and death were associated with preexisting hypotension, but morphine therapy did not contribute to these outcomes. Morphine infusions, although they cause hypotension, can be used safely for most preterm neonates but should be used cautiously for 23- to 26-week neonates and those with preexisting hypotension.

Effect of inborn versus outborn delivery on clinical outcomes in ventilated preterm neonates: secondary results from the NEOPAIN trial.

OBJECTIVE: The objective of this study was to evaluate the effect of birth center (inborn versus outborn) on morbidity and mortality for preterm neonates (23 to 32 weeks) using data collected prospectively within a uniform protocol. STUDY DESIGN: Secondary analyses of data from the NEurologic Outcomes and Pre-emptive Analgesia In Neonates (NEOPAIN) trial (n=898) were performed to evaluate the effect of inborn versus outborn delivery on neonatal outcomes, including the occurrence of severe intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), chronic lung disease (CLD), and mortality. RESULTS: Outborn babies were more likely to have severe IVH (p=0.0005); this increased risk persisted after controlling for severity of illness. When adjustments for antenatal steroids were added, the effect of birth center was no longer significant. Neither the occurrences of PVL or CLD nor mortality were significantly different between the inborn and outborn infants. CONCLUSION: Outborn babies are more likely to have severe IVH than inborn babies, perhaps because their mothers are less likely to receive antenatal steroids. Improvements in antenatal steroid administration to high-risk women may substantially reduce neonatal morbidity.

Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.

BACKGROUND: Opioid analgesia is commonly used during neonatal intensive care. We undertook the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial to investigate whether pre-emptive morphine analgesia decreases the rate of a composite primary outcome of neonatal death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL) in preterm neonates. METHODS: Ventilated preterm neonates (n=898) from 16 centres were randomly assigned masked placebo (n=449) or morphine (n=449) infusions. After a loading dose (100 microg/kg), morphine infusions (23-26 weeks of gestation 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); 30-32 weeks 30 microg kg(-1) h(-1)) were continued as long as clinically justified (maximum 14 days). Open-label morphine could be given on clinical judgment (placebo group 242/443 [54.6%], morphine group 202/446 [45.3%]). Analyses were by intention to treat. FINDINGS: Baseline variables were similar in the randomised groups. The placebo and morphine groups had similar rates of the composite outcome (105/408 [26%] vs 115/419 [27%]), neonatal death (47/449 [11%] vs 58/449 [13%]), severe IVH (46/429 [11%] vs 55/411 [13%]), and PVL (34/367 [9%] vs 27/367 [7%]). For neonates who were not given open-label morphine, rates of the composite outcome (53/225 [24%] vs 27/179 [15%], p=0.0338) and severe IVH (19/219 [9%] vs 6/189 [3%], p=0.0209) were higher in the morphine group than the placebo group. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine (78/228 [34%] vs 27/179 [15%], p<0.0001). Morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (36/190 [19%] vs 19/219 [9%], p=0.0024). INTERPRETATION: Pre-emptive morphine infusions did not reduce the frequency of severe IVH, PVL, or death in ventilated preterm neonates, but intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome. The morphine doses used in this study decrease clinical signs of pain but can cause significant adverse effects in ventilated preterm neonates.

Pubertal maturation in girls and the relationship to anthropometric changes: pathways through puberty.

OBJECTIVE: Patterns of pubertal maturation may have an impact on several risk factors associated with adult morbidity and mortality, such as obesity. We examined the relationship of the initial manifestation of puberty in girls with anthropometric measures, as well as age at menarche. METHODS: White females (n = 1166, ages 9 and 10 at intake) were followed with annual visits for 10 years. Physical examinations included height, weight, skinfold thicknesses, and pubertal maturation assessment. RESULTS: During the course of the study, 443 of 859 eligible females (51.6%) were observed to have asynchronous maturation in the development of puberty, that is, initial areolar/breast (thelarche pathway) or pubic hair (adrenarche pathway) development, without development of the other characteristic. Using a longitudinal regression model, significant interactions were noted between initial pubertal manifestation and years since onset of puberty on the following outcomes: sum of skinfolds thickness, percent body fat, waist-to-hip ratio, and body mass index (BMI). However, age of onset of pubertal maturation was the same in the 2 groups (10.7 years). Females in the thelarche pathway had earlier menarche (12.6 vs 13.1 years) as well as greater skinfolds, body fat, and BMI at the time of menarche. Females in the thelarche pathway also had greater body fat and BMI 1 year before puberty and throughout puberty compared with those in the adrenarche pathway. CONCLUSIONS: Females who enter puberty through the thelarche pathway, as compared with the adrenarche pathway, had greater sum of skinfold thicknesses, BMI, and percent body fat 1 year before the onset, as well as throughout, puberty. Because larger body composition and earlier age of menarche of females in the thelarche pathway parallel the epidemiologic profiles of women who are obese or at risk for obesity, these females may be at greater risk for adult obesity.

Macronutrient intake of black and white adolescent girls over 10 years: the NHLBI Growth and Health Study.

OBJECTIVE: To compare age-related changes in macronutrient and cholesterol intake between black and white girls, compare intakes with National Cholesterol Education Program (NCEP) recommendations, and examine sociodemographic associations with macronutrient intake. DESIGN: Cohort study with 3-day food records collected over 10 years. SUBJECTS: 2,379 girls, 1,166 white and 1,213 black, age 9 to 10 years at baseline, recruited from three geographic locations. Statistical Analysis Longitudinal generalized estimating equation (GEE) regression models examined the relationships of age, ethnicity, and sociodemographic factors with macronutrient and cholesterol intake and with percentage of girls meeting NCEP recommendations. RESULTS: Total and saturated fat intakes decreased with age, more in white girls than black girls, from 35.1% and 13.6% kcal at age 9 to 29.3% and 10.4% at age 19 for white girls and from 36.5% and 13.4% kcal at age 9 to 35.1% and 11.7% kcal at age 19 for black girls. Dietary cholesterol decreased with age, but decreased more in white girls than black girls (range 95 to 119 mg/1,000 kcal for white girls and 119 to 132 mg/1,000 kcal for black girls). Depending on age, 7% to 51% of white girls and 8% to 26% of black girls met NCEP recommendations for total fat (

Obesity development during adolescence in a biracial cohort: the NHLBI Growth and Health Study.

OBJECTIVE: The National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) is a 10-year study to investigate the development of obesity in black and white girls during adolescence and its environmental and psychosocial correlates. The purpose of this report was to examine changes in the annual prevalence rates of overweight and obesity in the NGHS cohort from ages 9 to 19 years. PARTICIPANTS AND SETTING: A total of 2379 black and white girls, aged 9 to 10 years, were recruited from schools in Richmond, California, and Cincinnati, Ohio, and from families enrolled in a health maintenance organization in the Washington, DC area. Participant eligibility was limited to girls and their parents who declared themselves as being either black or white and who lived in racially concordant households. DESIGN AND STATISTICAL ANALYSIS: The NGHS is a multicenter prospective study of a biracial cohort followed annually from ages 9 to 10 years through 18 to 19 years. The prevalence of overweight and obesity was based on age-specific > or =85th and > or =95th percentile values, respectively, for body mass index based on the 1960-1965 National Health Examination Survey reference population. MAIN OUTCOME MEASURES: The main outcome measures were body mass index (weight in kilograms divided by height in meters, squared) and proportions of girls who were "overweight" and "obese" by age and race. RESULTS: The prevalence of overweight was 37% higher in blacks as compared with whites (30.6% vs 22.4%) even by age 9. The rate of overweight almost doubled in both groups during the 10-year period. By age 19, the rate of overweight was 56.9% in black and 41.3%, in white girls. The prevalence of obesity was 17.7% in black and 7.7% in white girls at 9 years old, and the rates also doubled during the study period. CONCLUSIONS: The doubling in the prevalence of overweight and obesity during adolescence in black and white NGHS girls was surprising. By age 19, more than half of black girls were overweight and more than one third were obese. Almost half of white girls were overweight and almost 1 of 5 girls were obese. These findings should sound an alarm for all primary care physicians and public health professionals to take heed of what is happening to our youth.