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Context: At 30-day follow-up, patients with moderate- and high-risk acute coronary syndromes (ACS) undergoing early invasive treatment in the ACUITY trial with bivalirudin monotherapy vs heparin plus glycoprotein (GP) IIb/IIIa inhibitors had noninferior rates of adverse ischemic events with reduced rates of major bleeding. Deferred upstream use of GP IIb/IIIa inhibitors for selective administration to patients undergoing percutaneous coronary intervention (PCI) resulted in a significant reduction in major bleeding, although a small increase in composite ischemia could not be excluded.Objective: To determine 1-year ischemic outcomes for patients in the ACUITY trial.Design, Setting, and Patients: A prospective, randomized, open-label trial with 1-year clinical follow-up at 450 academic and community-based institutions in 17 countries. A total of 13,819 patients with moderate- and high-risk ACS undergoing invasive treatment were enrolled between August 23, 2003, and December 5, 2005.Interventions: Patients were assigned to heparin plus GP IIb/IIIa inhibitors (n = 4603), bivalirudin plus GP IIb/IIIa inhibitors (n = 4604), or bivalirudin monotherapy (n = 4612). Of these patients, 4605 were assigned to routine upstream GP IIb/IIIa administration and 4602 were deferred to selective GP IIb/IIIa inhibitor administration.Main Outcome Measure: Composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) at 1 year.Results: Composite ischemia at 1 year occurred in 15.4% of patients assigned to heparin plus GP IIb/IIIa inhibitors and 16.0% assigned to bivalirudin plus GP IIb/IIIa inhibitors (compared with heparin plus GP IIb/IIIa inhibitors, HR, 1.05; 95% CI, 0.95-1.16; P = .35), and 16.2% assigned to bivalirudin monotherapy (HR, 1.06; 95% CI, 0.95-1.17; P = .29). Mortality at 1 year occurred in an estimated 3.9% of patients assigned to heparin plus GP IIb/IIIa inhibitors, 3.9% assigned to bivalirudin plus GP IIb/IIIa inhibitors (HR, 0.99; 95% CI, 0.80-1.22; P = .92), and 3.8% assigned to bivalirudin monotherapy (HR, 0.96; 95% CI, 0.77-1.18; P = .67). Composite ischemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (HR, 1.08; 95% CI, 0.97-1.20; P = .15).Conclusions: At 1 year, no statistically significant difference in rates of composite ischemia or mortality among patients with moderate- and high-risk ACS undergoing invasive treatment with the 3 therapies was found. There was no statistically significant difference in the rates of composite ischemia between patients receiving routine upstream administration of GP IIb/IIIa inhibitors vs deferring their use for patients undergoing PCI.Trial Registration: clinicaltrials.gov Identifier: NCT00093158. [ABSTRACT FROM AUTHOR]

Context: In patients with moderate- and high-risk acute coronary syndromes (ACS) who undergo an early, invasive treatment strategy, current guidelines recommend administration of platelet glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors, either upstream to all patients prior to angiography or deferred for selective use in the catheterization laboratory just prior to angioplasty. The preferred approach is undetermined.Objective: To determine the optimal strategy for the use of Gp IIb/IIIa inhibitors in patients with moderate- and high-risk ACS undergoing an early, invasive treatment strategy.Design: Prospective, randomized, open-label trial with 30-day clinical follow-up.Setting: Four hundred fifty academic and community-based institutions in 17 countries.Patients: A total of 9207 patients with moderate- and high-risk ACS undergoing an invasive treatment strategy.Interventions: Patients were randomly assigned to receive either routine upstream (n=4605) or deferred selective (n=4602) Gp IIb/IIIa inhibitor administration, respectively.Main Outcome Measures: The primary outcome was assessment of noninferiority of deferred Gp IIb/IIIa inhibitor use compared with upstream administration for the prevention of composite ischemic events (death, myocardial infarction, or unplanned revascularization for ischemia) at 30 days, using a 1-sided alpha level of .025. Major secondary end points included noninferiority or superiority of major bleeding and net clinical outcomes (composite ischemia or major bleeding).Results: Glycoprotein IIb/IIIa inhibitors were used more frequently (98.3% vs 55.7%, respectively) and for a significantly longer duration (median, 18.3 vs 13.1 hours; P<.001) in patients in the upstream group compared with the deferred group. Composite ischemia at 30 days occurred in 7.9% of patients assigned to deferred use compared with 7.1% of patients assigned to upstream administration (relative risk, 1.12; 95% confidence interval, 0.97-1.29; P = .044 for noninferiority; P = .13 for superiority); as such, the criterion for noninferiority was not met. Deferred use compared with upstream use resulted in reduced 30-day rates of major bleeding (4.9% vs 6.1%, respectively; P<.001 for noninferiority; P = .009 for superiority) and similar rates of net clinical outcomes (11.7% vs 11.7%; P<.001 for noninferiority; P = .93 for superiority).Conclusions: Among patients with moderate- and high-risk ACS undergoing an invasive treatment strategy, deferring the routine upstream use of Gp IIb/IIIa inhibitors for selective administration in the cardiac catheterization laboratory only to patients undergoing percutaneous coronary intervention resulted in a numerical increase in composite ischemia that, while not statistically significant, did not meet the criterion for noninferiority. This finding was offset by a significant reduction in major bleeding.Trial Registration: ClinicalTrials.gov Identifier: NCT00093158. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The authors sought to determine whether integrated mental health services or enhanced referral to specialty mental health clinics results in greater engagement in mental health/substance abuse services by older primary care patients. METHOD: This multisite randomized trial included 10 sites consisting of primary care and specialty mental health/substance abuse clinics. Primary care patients 65 years old or older (N=24,930) were screened. The final study group consisted of 2,022 patients (mean age=73.5 years; 26% female; 48% ethnic minority) with depression (N=1,390), anxiety (N=70), at-risk alcohol use (N=414), or dual diagnosis (N=148) who were randomly assigned to integrated care (mental health and substance abuse providers co-located in primary care; N=999) or enhanced referral to specialty mental health/substance abuse clinics (i.e., facilitated scheduling, transportation, payment; N=1,023). RESULTS: Seventy-one percent of patients engaged in treatment in the integrated model compared with 49% in the enhanced referral model. Integrated care was associated with more mental health and substance abuse visits per patient (mean=3.04) relative to enhanced referral (mean=1.91). Overall, greater engagement was predicted by integrated care and higher mental distress. For depression, greater engagement was predicted by integrated care and more severe depression. For at-risk alcohol users, greater engagement was predicted by integrated care and more severe problem drinking. For all conditions, greater engagement was associated with closer proximity of mental health/substance abuse services to primary care. CONCLUSIONS: Older primary care patients are more likely to accept collaborative mental health treatment within primary care than in mental health/substance abuse clinics. These results suggest that integrated service arrangements improve access to mental health and substance abuse services for older adults who underuse these services. [ABSTRACT FROM AUTHOR]

The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor with anticarcinogenic activities. BBI, in the form of BBI concentrate (BBIC), is currently being evaluated in clinical trials as a human cancer-preventive agent. In the present study, an enzyme-linked immunosorbent assay was used to measure BBI concentrations in serum samples collected from human subjects and animals treated with BBIC. The results demonstrate that the serum BBI concentration was higher than the baseline level for the patients after treatment with BBIC at 100-800 chymotrypsin-inhibitor units/day for 0.5, 1, 2, 4, and 6 mo. The increase in serum BBI concentration was also observed in dogs treated with BBIC at 100-1,000 mg/kg/day for 52 wk, and the increase was dose dependent. The results also indicate that anti-BBI antibodies were present in animals and the serum levels of anti-BBI antibodies increased significantly in mice treated with BBIC at 100-1,000 mg/kg/day for 15 and 26 wk. The increase in the serum level of anti-BBI antibodies in dogs treated with BBIC was not statistically significant, and no increase in the serum level of anti-BBI antibodies was observed in human subjects after BBIC treatment. These results suggest that orally ingested BBI is absorbed by human subjects and animals and that some animals develop antibodies to BBI in response to treatment with BBIC. [ABSTRACT FROM AUTHOR]

Bowman-Birk inhibitor (BBI) is a soybean-derived anticarcinogenic protease inhibitor previously shown to potentiate cisplatin-induced cytoxicity in human lung and ovarian cancer cells. To further assess the potential of BBI as a sensitizing agent for cancer radiotherapy and chemotherapy, we evaluated the effects of BBI and a soybean concentrate enriched in BBI known as BBI concentrate (BBIC) on clonogenic survival and radiation- or cisplatin-induced cell killing in MCF7 human breast carcinoma cells, SCC61 and SQ20B human head and neck carcinoma cells, HeLa, HeLa-R1, and HeLa-R3 human cervical carcinoma cells, MCF10 nontumorigenic human epithelial cells, HTori-3 nontumorigenic human thyroid epithelial cells, and C3H10T1/2 mouse fibroblast cells. BBI and BBIC significantly suppressed the clonogenic survival of MCF7 and SCC61 cells. BBIC also suppressed the survival of SQ20B cells and enhanced radiation-induced cell killing in SCC61 and SQ20B cells and cisplatin-induced cell killing in HeLa, HeLa-R1, and HeLa-R3 cells. In contrast, BBI and/or BBIC did not enhance radiation-induced cell killing in MCF10 cells or cisplatin-induced cell killing in C3H10T1/2 cells. BBI did not significantly affect the survival of SQ20B cells or enhance radiation-induced cell killing in SCC61 and SQ20B cells. The clonogenic survivals of MCF10 and C3H10T1/2 cells were not adversely affected by treatment with BBI or BBIC. The clonogenic survival of HTori-3 cells was only moderately suppressed by treatment with BBIC at > or = 80 micrograms/ml. These results suggest that BBIC could be a useful agent for the potentiation of radiation- and cisplatin-mediated cancer treatment without significant adverse effects on surrounding normal tissues. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess anticoagulation with the direct thrombin inhibitor bivalirudin during percutaneous coronary intervention in individuals with moderate and high-risk acute coronary syndromes.Methods: 13,819 individuals in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial were prospectively randomly assigned to receive heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibitors, bivalirudin plus glycoprotein IIb/IIIa inhibitors, or bivalirudin alone. Of these individuals, 7789 underwent percutaneous coronary intervention after angiography. The effect of the three regimens on the primary 30-day endpoints of composite ischaemia (death, myocardial infarction, or unplanned revascularisation for ischaemia), major bleeding, and net clinical outcomes (composite ischaemia or major bleeding) was assessed in this subgroup. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00093158.Findings: Of the individuals who underwent percutaneous coronary intervention, 2561 received heparin plus glycoprotein IIb/IIIa inhibitors, 2609 received bivalirudin plus glycoprotein IIb/IIIa inhibitors, and 2619 received bivalirudin alone. 26 (0.3%) individuals dropped out or were lost to follow-up. There was no significant difference in the proportion of individuals with composite ischaemia, major bleeding, or net clinical outcomes at 30 days between those who received bivalirudin plus glycoprotein IIb/IIIa inhibitors and those who received heparin plus glycoprotein IIb/IIIa inhibitors (composite ischaemia: 243 [9%] patients vs 210 [8%] patients, p=0.16; major bleeding: 196 [8%] patients vs 174 [7%] patients, p=0.32; net clinical outcomes: 389 [15%] patients vs 341 [13%] patients, p=0.1). Rates of composite ischaemia were much the same in those who received bivalirudin alone and those who received heparin plus glycoprotein IIb/IIIa inhibitors (230 [9%] patients vs 210 [8%] patients, p=0.45); however, there were significantly fewer individuals who experienced major bleeding among those who received bivalirudin alone than among those who received heparin plus glycoprotein IIb/IIIa inhibitors (92 [4%] patients vs 174 [7%] patients, p<0.0001, relative risk 0.52, 95% CI 0.40-0.66), resulting in a trend towards better 30-day net clinical outcomes (303 [12%] patients vs 341 [13%] patients, p=0.057; 0.87, 0.75-1.00).Interpretation: Substitution of unfractionated heparin or enoxaparin with bivalirudin results in comparable clinical outcomes in patients with moderate and high-risk acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors in whom percutaneous coronary intervention is done. Anticoagulation with bivalirudin alone suppresses adverse ischaemic events to a similar extent as does heparin plus glycoprotein IIb/IIIa inhibitors, while significantly lowering the risk of major haemorrhagic complications. [ABSTRACT FROM AUTHOR]

Background: Current guidelines for patients with moderate- or high-risk acute coronary syndromes recommend an early invasive approach with concomitant antithrombotic therapy, including aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors. We evaluated the role of thrombin-specific anticoagulation with bivalirudin in such patients.Methods: We assigned 13,819 patients with acute coronary syndromes to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. The primary end points were a composite ischemia end point (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding.Results: Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point (7.7% and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point (7.8% and 7.3%, respectively; P=0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%; P=0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97).Conclusions: In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown., Methods: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D 3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508., Results: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups., Conclusions: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D 3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.)., (Copyright © 2019 Massachusetts Medical Society.)

Study Objectives: The long-term effect of continuous positive airway pressure (CPAP) on health-related quality of life (HRQOL) in patients with high cardiovascular disease risk and obstructive sleep apnea (OSA) without severe sleepiness is uncertain. We aimed to determine the effect of CPAP treatment on HRQOL in individuals with moderate or severe OSA and cardiovascular disease (CVD) or multiple CVD risk factors without severe sleepiness., Methods: In this randomized, controlled, parallel group study, 169 participants were assigned to treatment with CPAP or the control group (conservative medical therapy [CMT] or CMT with sham CPAP). Analyses were based on an intention-to-treat approach. Linear mixed effect models were fitted to compare the changes in the Medical Outcomes Study Short Form-36 (SF-36) and in subjective sleepiness (Epworth Sleepiness Scale [ESS]) between groups from baseline to the average of 6- and 12-month measurements., Results: CPAP improved several domains of HRQOL including bodily pain (treatment effect 9.7 [95% confidence interval, CI 3.9 to 15.4]; p = .001), vitality (5.7 [95% CI 1.5 to 9.9]; p = .008), general health (8.2 [95% CI 3.7 to 12.7]; p < .001), physical functioning (5.5 [95% CI 1.1 to 10.0]; p = .016), and the physical health summary score (3.3 [95% CI 1.4 to 5.3]; p = .001). CPAP also resulted in less daytime sleepiness (mean change in ESS -1.0 point [95% CI -2.0 to -0.0]; p = .040)., Conclusions: In patients with moderate-severe OSA at high risk of cardiovascular events and without severe sleepiness, CPAP improved daytime sleepiness and multiple domains of HRQOL over 6 to 12 months of follow-up, with the largest improvement observed for bodily pain., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

We evaluate properties of sample size re-estimation (SSR) designs similar to the promising zone design considered by Mehta and Pocock (2011). We evaluate these designs under the assumption of a true effect size of 1.1 down to 0.4 of the protocol-specified effect size by six measures: 1. The probability of a sample size increase, 2. The mean proportional increase in sample size given an increase; 3 and 4. The mean true conditional power with and without a sample size increase; 5 and 6. The expected increase in sample size and power due to the SSR procedure. These measures show the probability of a sample size increase and the cost/benefit for given true effect sizes, particularly when the SSR may either be pursuing a small effect size of little clinical importance or be unnecessary when the true effect size is close to the protocol-specified effect size. The results show the clear superiority of conducting the SSR late in the study and the inefficiency of a mid-study SSR. The results indicate that waiting until late in the study for the SSR yields a smaller, better targeted set of studies with a greater increase in overall power than a mid-study SSR.

Background: Motivational enhancement (ME) shows promise as a means of increasing adherence to CPAP for OSA., Methods: We performed an open-label, parallel-arm, randomized controlled trial of CPAP only or CPAP + ME, recruiting individuals 45 to 75 years with moderate or severe OSA without marked sleepiness and with either established cardiovascular disease (CVD) or at risk for CVD. All participants received standardized CPAP support from a sleep technologist; those randomly assigned to CPAP + ME also received standardized ME delivered by a psychologist during two appointments and six phone calls over 32 weeks. Mixed-effect models with subject-specific intercepts and slopes were fitted to compare objective CPAP adherence between arms, adjusting for follow-up duration, randomization factors, and device manufacturer. All analyses were intention-to-treat., Results: Overall, 83 participants (n = 42 CPAP only; n = 41 CPAP + ME) contributed 14,273 nights of data for 6 months. Participants were predominantly male (67%) and had a mean ± SD age of 63.9 ± 7.4 years, a BMI of 31.1 ± 5.2 kg/m(2), and an apnea-hypopnea index of 26.2 ± 12.9 events/h. In our fully adjusted model, average nightly adherence for 6 months was 99.0 min/night higher with CPAP + ME compared with CPAP only (P = .003; primary analysis). A subset of 52 participants remained in the study for 12 months; modeling these data yielded a consistent difference in adherence between arms of 97 min/night (P = .006) favoring CPAP + ME., Conclusions: ME delivered during brief appointments and phone calls resulted in a clinically significant increase in CPAP adherence. This strategy may represent a feasible approach for optimizing management of OSA., Trial Registry: ClinicalTrials.gov; No.: NCT01261390; URL: www.clinicaltrials.gov., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The challenges of drug development, including increasing costs, late-stage drug failures, and the decline in the number of drugs being approved by the US Food and Drug Administration over time, have generated interest in adaptive study designs that have the potential to address these problems. Adaptive trial designs use interim data analysis to amend trials, and have been recognized for more than a decade as a way to increase trial efficiency, partly by the increased probability of demonstrating a drug effect if one exists. In this article, we define adaptive trials; give examples of the most common types; highlight the pros, cons, and ethical considerations of these designs; and illustrate how these tools can be applied to drug development in dermatology., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Under-five mortality is declining in Ghana and many other countries. Very few studies have measured under-five mortality-and its social and environmental risk factors-at fine spatial resolutions, which is relevant for policy purposes. Our aim was to estimate under-five mortality and its social and environmental risk factors at the district level in Ghana., Methods and Findings: We used 10% random samples of Ghana's 2000 and 2010 National Population and Housing Censuses. We applied indirect demographic methods and a Bayesian spatial model to the information on total number of children ever born and children surviving to estimate under-five mortality (probability of dying by 5 y of age, 5q0) for each of Ghana's 110 districts. We also used the census data to estimate the distributions of households or persons in each district in terms of fuel used for cooking, sanitation facility, drinking water source, and parental education. Median district 5q0 declined from 99 deaths per 1,000 live births in 2000 to 70 in 2010. The decline ranged from <5% in some northern districts, where 5q0 had been higher in 2000, to >40% in southern districts, where it had been lower in 2000, exacerbating existing inequalities. Primary education increased in men and women, and more households had access to improved water and sanitation and cleaner cooking fuels. Higher use of liquefied petroleum gas for cooking was associated with lower 5q0 in multivariate analysis., Conclusions: Under-five mortality has declined in all of Ghana's districts, but the cross-district inequality in mortality has increased. There is a need for additional data, including on healthcare, and additional environmental and socioeconomic measurements, to understand the reasons for the variations in mortality levels and trends.

Aims: A recent study demonstrated that intracoronary near-infrared spectroscopy (NIRS) findings in non-target vessels are associated with major adverse cardiovascular and cerebrovascular events (MACCE). It is unknown whether NIRS findings at non-stented sites in target vessels are similarly associated with future MACCE. This study evaluated the association between large lipid-rich plaques (LRP) detected by NIRS at non-stented sites in a target artery and subsequent MACCE., Methods and Results: This study evaluated 121 consecutive registry patients undergoing NIRS imaging in a target artery. After excluding stented segments, target arteries were evaluated for a large LRP, defined as a maximum lipid core burden index in 4 mm (maxLCBI4 mm) ≥400. Excluding events in stented segments, Cox regression analysis was performed to evaluate for an association between a maxLCBI4 mm ≥400 and future MACCE, defined as all-cause mortality, non-fatal acute coronary syndrome, and cerebrovascular events. NIRS detected a maxLCBI4 mm ≥400 in a non-stented segment of the target artery in 17.4% of patients. The only baseline clinical variable marginally associated with MACCE was ejection fraction (HR 0.96, 95% CI 0.93-1.00, P = 0.054). A maxLCBI4 mm ≥400 in a non-stented segment at baseline was significantly associated with MACCE during follow-up (HR 10.2, 95% CI 3.4-30.6, P < 0.001)., Conclusion: Detection of large LRP by NIRS at non-stented sites in a target artery was associated with an increased risk of future MACCE. These findings support ongoing prospective studies to further evaluate the ability of NIRS to identify vulnerable patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Multiple classifications have been developed that classify the medical literature into different levels of evidence to facilitate the evaluation of study results and practice of evidence-based medicine. The suggested hierarchies of evidence are generally based on the type of study design; randomized, controlled clinical trials constitute the top level of evidence while case reports rank the lowest among epidemiologic study designs. However, little is known about the frequency with which different study designs appear in the medical literature overall. The purpose of this study was to describe trends in the frequency of reports of randomized control trials (RCTs) as compared to other study designs in the medical literature over two decades., Methods: Data about the prevalence of various types of study designs in the medical literature over the last two decades (years 1990 - 2009) were abstracted from PubMed, validated and subjected to cross-sectional and longitudinal analysis., Results: In the last 20 years, the annual rate of publication of journal articles has more than doubled. During this period, the percentage of observational studies increased from 29.9% to 40.5%, the percentage of reports of RCTs increased minimally, and there was a striking decline in the percentage of case reports (from 49.8% to 33.6%) in the medical literature overall. In contrast, in three selected, highly cited medical journals, the percentage of reports of RCTs increased by almost 10%. Surprisingly, the percentage of articles classified as case reports also increased (from 36.3% to 43.8%) in these three journals, while the percentage of reports of cohort and case-control studies decreased., Conclusion: Though the relative frequency of reports from RCTs has not changed substantially in the last 20 years, cohort studies and case-control studies have largely supplanted simple case reports. In contrast, in high impact journals, the representation of RCTs and case reports has increased, with corresponding declines in reports based on other study designs. Further research will be needed to determine whether those trends in publication have resulted in more robust evidence and faster advancement of medical knowledge.

Objective: Observational studies suggest that vitamin D may lower the risk of type 2 diabetes. However, data from long-term trials are lacking. The Vitamin D and Type 2 Diabetes (D2d) study is a randomized clinical trial designed to examine whether a causal relationship exists between vitamin D supplementation and the development of diabetes in people at high risk for type 2 diabetes., Research Design and Methods: D2d was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The final protocol was approved by the D2d Research Group, the data and safety monitoring board, and NIDDK. Key eligibility criteria are age ≥30 years, BMI of 24 (22.5 for Asian Americans) to 42 kg/m(2), increased risk for diabetes (defined as meeting two of three glycemic criteria for prediabetes established by the American Diabetes Association [fasting glucose 100-125 mg/dL (5.5-6.9 mmol/L), 2-h postload glucose after 75-g glucose load 140-199 mg/dL (7.7-11.0 mmol/L), hemoglobin A₁c 5.7-6.4% (39-46 mmol/mol)]), and no hyperparathyroidism, nephrolithiasis, or hypercalcemia. D2d participants are randomized to once-daily vitamin D₃ (cholecalciferol 4,000 IU) or placebo and followed for an average of 3 years. The primary end point is time to incident diabetes as assessed by laboratory criteria during the study or by adjudication if diagnosed outside of D2d. Recruitment was initiated at the end of 2013., Conclusions: D2d will test whether vitamin D supplementation is safe and effective at lowering the risk of progression to diabetes in people at high risk for type 2 diabetes., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Study Objectives: A challenge in conducting randomized controlled trials of sleep apnea is the timely recruitment of participants to active and control arms. This study assesses the costs and efficiencies of alternative recruitment methods., Design: Analysis of recruitment data from the Best Apnea Intervention in Research planning study., Setting: Sleep clinics and cardiology practices., Participants: One hundred forty-eight individuals with an apnea-hypopnea index > 15 and cardiovascular (CV) risk factors randomized from a pool of more than 30,000 potentially eligible patients., Interventions: Comparisons: (1) modes of recruitment: face-to-face (F2F) recruitment versus mail-based recruitment (MBR); (2) recruitment source (sleep versus cardiology clinics)., Measurements and Results: Recruitment yield was defined as the ratio of the number of subjects randomized to the number of screened records. Recruitment costs were estimated based on staff time. Of the 148 randomized subjects, 25 were recruited from sleep clinics using F2F recruitment and 123 were recruited from cardiology using a F2F (n = 35) or MBR (n = 88) strategy. F2F recruitment yields were 0.17% and 0.30% for sleep versus cardiology sources, respectively (P = 0.04). A comparison of F2F to MBR showed recruitment yields of 1.11% and 0.90% and costs per randomized subject of $2,139 and $647, respectively., Conclusions: Large resources may be needed to meet the recruitment goals of sleep apnea intervention trials. Recruitment source and mode influence efficiencies. For a trial comparing active versus sham continuous positive airway pressure in patients with CV risk factors, recruiting from cardiology was more efficient than from sleep clinics. MBR was three times less costly than F2F recruitment., (© 2014 Associated Professional Sleep Societies, LLC.)

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2-4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79-4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: -0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91-3.34, P = 0.10; risk difference, 0.010; 95% CI: -0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.

Biostatistics--the application of statistics to understanding health and biology-provides powerful tools for developing research questions, designing studies, refining measurements, analyzing data, and interpreting findings. Biostatistics plays an important role in health-related research, yet biostatistics resources are often fragmented, ad hoc, or oversubscribed within academic health centers (AHCs). Given the increasing complexity and quantity of health-related data, the emphasis on accelerating clinical and translational science, and the importance of conducting reproducible research, the need for the thoughtful development of biostatistics resources within AHCs is growing.In this article, the authors identify strategies for developing biostatistics resources in three areas: (1) recruiting and retaining biostatisticians, (2) efficiently using biostatistics resources, and (3) improving biostatistical contributions to science. AHCs should consider these three domains in building strong biostatistics resources, which they can leverage to support a broad spectrum of research. For each of the three domains, the authors describe the advantages and disadvantages of AHCs creating centralized biostatistics units rather than dispersing such resources across clinical departments or other research units. They also address the challenges that biostatisticians face in contributing to research without sacrificing their individual professional growth or the trajectory of their research teams. The authors ultimately recommend that AHCs create centralized biostatistics units because this approach offers distinct advantages both to investigators who collaborate with biostatisticians as well as to the biostatisticians themselves, and it is better suited to accomplish the research and education missions of AHCs.

In the analysis of prevention and intervention studies, it is often important to investigate whether treatment effects vary among subgroups of patients defined by individual characteristics. These "subgroup analyses" can provide information about how best to use a new prevention or intervention program. However, subgroup analyses can be misleading if they test data-driven hypotheses, employ inappropriate statistical methods, or fail to account for multiple testing. These problems have led to a general suspicion of findings from subgroup analyses. This article discusses sound methods for conducting subgroup analyses to detect moderators. Multiple authors have argued that, to assess whether a treatment effect varies across subgroups defined by patient characteristics, analyses should be based on tests for interaction rather than treatment comparisons within the subgroups. We discuss the concept of heterogeneity and its dependence on the metric used to describe treatment effects. We discuss issues of multiple comparisons related to subgroup analyses and the importance of considering multiplicity in the interpretation of results. We also discuss the types of questions that would lead to subgroup analyses and how different scientific goals may affect the study at the design stage. Finally, we discuss subgroup analyses based on post-baseline factors and the complexity associated with this type of subgroup analysis.

Objective: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities., Study Design: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities., Results: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1)., Conclusion: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis., (Copyright © 2011 Mosby, Inc. All rights reserved.)

In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses.

The present study was undertaken to characterize carbon and iron ion radiation-induced adverse biological effects in terms of toxicity and transformation in vitro. HTori-3 human thyroid epithelial cells were irradiated with 0.3-GeV/n (13.6 KeV/µm) carbon ions and 1-GeV/n (150 KeV/µm) iron ions, both of which represent high-mass, high atomic number (Z) and high-energy particles known as HZE particles, as well as γ-rays. The survival of the irradiated cells was determined by a clonogenic survival assay. The yield of colonies growing in soft agar was used as a surrogate endpoint biomarker for transformation in vitro. The results showed that HZE particles and γ-ray radiations are effective in increasing the yield of anchorage-independent colonies. Based on the relative biological effectiveness (RBE) values in the clonogenic survival assays, 0.3-GeV/n carbon ions and 1-GeV/n iron ions were 2.9 and 2.4 times, respectively, as effective as γ-rays at killing the irradiated HTori-3 cells. At a dose of 200 cGy, 0.3-GeV/n carbon ions and 1-GeV/n iron ions were found to be 3.5 and 7.3 times, respectively, as effective as γ-rays at inducing anchorage-independent growth. These results suggest that the carcinogenic potential of 0.3-GeV/n carbon ions, as represented by the ability to induce anchorage-independent growth, may be lower than that of 1-GeV/n iron ions.

In the coming decades human space exploration is expected to move beyond low-Earth orbit. This transition involves increasing mission time and therefore an increased risk of radiation exposure from solar particle event (SPE) radiation. Acute radiation effects after exposure to SPE radiation are of prime importance due to potential mission-threatening consequences. The major objective of this study was to characterize the dose-response relationship for proton and γ radiation delivered at doses up to 2 Gy at high (0.5 Gy/min) and low (0.5 Gy/h) dose rates using white blood cell (WBC) counts as a biological end point. The results demonstrate a dose-dependent decrease in WBC counts in mice exposed to high- and low-dose-rate proton and γ radiation, suggesting that astronauts exposed to SPE-like radiation may experience a significant decrease in circulating leukocytes.

Objectives: This nested case-crossover study examined the association between rushing, distraction and walking on a contaminated floor and the rate of slipping, and whether the effects varied according to weekly hours worked, job tenure and use of slip-resistant shoes., Methods: At baseline, workers from 30 limited-service restaurants in the USA reported average work hours, average weekly duration of exposure to each transient risk factor and job tenure at the current location. Use of slip-resistant shoes was determined. During the following 12 weeks, participants reported weekly their slip experience and exposures to the three transient exposures at the time of slipping. The case-crossover design was used to estimate the rate ratios using the Mantel-Haenszel estimator for person-time data., Results: Among 396 participants providing baseline information, 210 reported one or more slips with a total of 989 slips. Rate of slipping was 2.9 times higher when rushing as compared to working at a normal pace (95% CI 2.5 to 3.3). Rate of slipping was also significantly increased by distraction (rate ratio (RR) 1.7, 95% CI 1.5 to 2.0) and walking on a contaminated floor (RR 14.6, 95% CI 12.6 to 17.0). Use of slip-resistant shoes decreased the effects of rushing and walking on a contaminated floor. Rate ratios for all three transient factors decreased monotonically as job tenure increased., Conclusion: The results suggest the importance of these transient risk factors, particularly floor contamination, on rate of slipping in limited-service restaurant workers. Stable characteristics, such as slip-resistant shoes, reduced the effects of transient exposures.

We have previously reported data from a long-term carcinogenesis study indicating that dietary antioxidant supplements can suppress radiation-induced malignant lymphoma and harderian gland tumors induced by space radiations (specifically, 1 GeV/n iron ions or protons) in CBA/J mice. Two different antioxidant dietary supplements were used in these studies: a supplement containing a mixture of antioxidant agents [l-selenomethionine (SeM), N-acetyl cysteine (NAC), ascorbic acid, co-enzyme Q10, α-lipoic acid and vitamin E succinate], termed the AOX supplement, and another supplement known as Bowman-Birk Inhibitor Concentrate (BBIC). In the present report, the results from the earlier analysis of the harderian gland data from the published long-term animal study have been combined with new data derived from the same long-term animal study. In the earlier analysis, harderian glands were removed from animals exhibiting abnormalities (e.g. visibly swollen areas) around the eyes at the time of euthanasia or death in the long-term animal study. Abnormalities around the eyes were usually due to the development of tumors in the harderian glands of these mice. The new data presented here focused on the histopathological results obtained from analyses of the harderian glands of mice that did not have visible abnormalities around the eyes at the time of necropsy in the long-term animal study. In this paper, the original published data and the new data have been combined to provide a more complete evaluation of the harderian glands from animals in the long-term carcinogenesis study, with all available harderian glands from the animals processed and prepared for histopathological evaluation. The results indicate that, although dietary antioxidant supplements suppressed harderian gland tumors in a statistically significant fashion when all glands were analyzed, the antioxidant diets were less effective at suppressing the incidence of all harderian gland tumors than they were at suppressing the incidence of large harderian gland tumors (>2 mm) observed at animal necropsy. These results suggest that the dietary antioxidant formulations had major suppressive effects in the later stages of radiation-induced carcinogenesis in vivo. It is hypothesized that the dietary antioxidant formulations prevented the early-stage neoplastic growths from progressing to fully developed, malignant tumors. In addition, the antioxidant dietary formulations were very effective at preventing the development of proton- or iron-ion-induced malignant tumors, because, in contrast to irradiated controls, no malignant tumors were observed in the irradiated animals maintained on either of the dietary antioxidant diets.

Objectives: Slips and falls are a leading cause of injury at work. Few studies, however, have systematically examined risk factors of slipping outside the laboratory environment. This study examined the association between floor surface characteristics, slip-resistant shoes, floor cleaning frequency and the risk of slipping in limited-service restaurant workers., Methods: 475 workers from 36 limited-service restaurants from three major chains in six states in the USA were recruited to participate in a prospective cohort study of workplace slipping. Kitchen floor surface roughness and coefficient of friction (COF) were measured in eight working areas and then averaged within each restaurant. The use of slip-resistant shoes was determined by examining the participant's shoes and noting the presence of a 'slip-resistant' marking on the sole. Restaurant managers reported the frequency of daily kitchen floor cleaning. Participants reported their slip experience and work hours weekly for up to 12 weeks. The survey materials were made available in three languages: English, Spanish and Portuguese. The associations between rate of slipping and risk factors were assessed using a multivariable negative binomial generalised estimating equation model., Results: The mean of individual slipping rate varied among the restaurants from 0.02 to 2.49 slips per 40 work hours. After adjusting for age, gender, BMI, education, primary language, job tenure and restaurant chain, the use of slip-resistant shoes was associated with a 54% reduction in the reported rate of slipping (95% CI 37% to 64%), and the rate of slipping decreased by 21% (95% CI 5% to 34%) for each 0.1 increase in the mean kitchen COF. Increasing floor cleaning frequency was significantly associated with a decreasing rate of slipping when considered in isolation but not after statistical adjustment for other factors., Conclusion: These results provide support for the use of slip-resistant shoes and measures to increase COF as preventive interventions to reduce slips, falls and injuries.

The objectives of the present study were to characterize γ-ray, 1 GeV/n proton, and 1 GeV/n iron ion radiation-induced adverse biological effects in terms of toxicity and transformation of HTori-3 human thyroid epithelial cells; to evaluate the ability of L-selenomethionine (SeM) to protect against radiation-induced transformation when present at different times during the assay period; and to evaluate the tumorigenicity of HTori-3 cells derived from anchorage-independent colonies following iron ion radiation exposure. Cell survival was determined by a clonogenic assay, transformation was measured by a soft agar colony formation assay, and the tumorigenic potential of the cells was determined by injecting them subcutaneously into athymic nude mice and monitoring tumor formation. The results demonstrate that exposure of HTori-3 cells to γ-ray, proton, or iron ion radiation resulted in decreased clonogenic survival, which persisted for weeks after the radiation exposure. Treatment with SeM initiated up to 7 days after the radiation exposure conferred significant protection against radiation-induced anchorage-independent growth. HTori-3 cells derived from all evaluated anchorage-independent colonies formed tumors when injected into athymic nude mice, indicating that these cells are tumorigenic and that anchorage-independent colony growth is a reliable surrogate endpoint biomarker for the radiation-induced malignant transformation of HTori-3 cells.

The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.

There is controversy regarding the possibility that long-acting beta-agonists (LABA) may paradoxically contribute adversely to asthma mortality. While studies and meta-analyses indicate increased risk, epidemiological data indicate a slow fall in asthma mortality since the introduction of LABA. Advocates for LABA propose that mandatory simultaneous use of inhaled corticosteroids satisfactorily reduce any potential risk. In the face of lingering doubts, others propose that LABA should be withdrawn from use. In this pro-con article, Kazani et al. provide the rationale for a modified randomized controlled trial that would define the level of risk more clearly, and provide the basis for a clear judgment to be made. Sears argues that current knowledge about the risks associated with LABA, especially when prescribed as monotherapy, provides sufficient evidence for clinicians and licensing authorities alike, and that the logistics and likely outcomes for a large prospective study are unjustified.

Abciximab and eptifibatide have been shown to reduce ischemic complications compared with heparin alone in patients with acute coronary syndromes who undergo percutaneous coronary intervention. Whether 1 agent is safer and/or more effective has not been prospectively examined. The aim of this study was to assess the outcomes related to downstream glycoprotein IIb/IIIa inhibitor treatment selection during percutaneous coronary intervention in 2,211 patients with moderate and high-risk acute coronary syndromes in the prospective multicenter Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. The protocol permitted operator selection of abciximab (n = 835) or eptifibatide (n = 1,376) for routine use in the trial. Multivariate and propensity-based adjustments were used to assess the independent association of glycoprotein IIb/IIIa inhibitor treatment selection with prespecified study end points. Compared to patients receiving eptifibatide, those administered abciximab were older, more likely to be enrolled outside of North America, more frequently had biomarker elevations and ST-segment deviation, but had fewer baseline cardiac risk factors and previous revascularization procedures. After multivariate propensity-based adjustment, abciximab was independently associated with significantly fewer net clinical adverse events (odds ratio 0.61, 95% confidence interval 0.42 to 0.90, p = 0.01), mediated by composite ischemia (odds ratio 0.61, 95% confidence interval 0.38 to 0.98, p = 0.04) and major bleeding (odds ratio 0.58, 95% confidence interval 0.34 to 1.00, p = 0.051). In conclusion, in this prespecified but nonrandomized comparison in patients with acute coronary syndromes who underwent percutaneous coronary intervention with catheterization laboratory initiation of glycoprotein IIb/IIIa inhibitors, the use of abciximab rather than eptifibatide was associated with improved clinical outcomes at 30 days. These findings should be viewed as exploratory in light of the nonrandomized and heterogeneous nature of the comparator groups and significant potential for residual confounding., (Copyright (c) 2010. Published by Elsevier Inc.)

Abstract The present study was undertaken to investigate the ability of dietary supplements to reduce the formation and severity of cataracts in mice irradiated with high-energy protons or iron ions, which are important components of the radiation encountered by astronauts during space travel. The mice were exposed to proton or iron-ion radiation and fed with a control diet or diets supplemented with the soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), in the form of BBI Concentrate (BBIC) or an antioxidant formulation [containing l-selenomethionine (SeM), N-acetyl cysteine (NAC), ascorbic acid, co-enzyme Q10, alpha-lipoic acid and vitamin E succinate] both before and after the radiation exposure. At approximately 2 years after the radiation exposure, the animals were killed humanely and lenses were harvested and characterized using an established classification system that assigns discrete scores based on the severity of the lens opacifications. The results showed that exposure to 1 GeV/nucleon proton (3 Gy) or iron-ion (50 cGy) radiation significantly increased the cataract prevalence and severity in CBA/J mice to levels above the baseline levels of age-induced cataract formation in this mouse strain. Treatment with BBIC or the antioxidant formulation significantly reduced the prevalence and severity of the lens opacifications in the mice exposed to iron-ion radiation. Treatment with BBIC or the antioxidant formulation also decreased the severity of the lens opacifications in the mice exposed to proton radiation; however, the decrease did not reach statistical significance. These results indicate that BBIC and the antioxidant formulation evaluated in this study could be useful for protecting astronauts against space radiation-induced cataracts during or after long-term manned space missions.

Background: In animal models, there is evidence to suggest a causal link between maternal cortisol levels during pregnancy and offspring outcomes; however, evidence for this relationship in humans is inconclusive. We address important confounders of this association by estimating the relationship between maternal cortisol levels in late pregnancy and childhood IQ in a birth cohort and in a subsample of siblings., Methods: This study included 832 children who were members of the Collaborative Perinatal Project. Maternal serum collected between 1959 and 1966 during the third trimester of pregnancy was analysed for free cortisol. We investigated the relationship between maternal cortisol in quintiles and full, verbal and performance scale scores on the Wechsler Intelligence Scale for Children at age 7 years, adjusting for prenatal and family characteristics. We repeated this analysis among 74 discordant sibling pairs using a fixed effects approach, which adjusts for shared family characteristics., Results: Maternal cortisol levels were negatively related to full-scale IQ, an effect driven by verbal IQ scores. Compared with those in the lowest quintile of cortisol exposure, the verbal IQ of children in the highest quintile of exposure was 3.83 points lower [95% confidence interval (CI): -6.44 to -1.22]. Within sibling pairs, being in the highest quintile of exposure was associated with verbal IQ scores 5.5 points lower (95% CI: -11.24 to 0.31) compared with the other quintiles., Conclusion: These findings are consistent with prior human and animal studies, and suggest that exposure to high levels of maternal cortisol during pregnancy may be negatively related to offspring cognitive skills independently of family attributes that characterize the postnatal environment.

Abstract Dietary antioxidants have radioprotective effects after gamma-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of l-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve survival of mice after proton total-body irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD(50/30); for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFbeta1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.