Unresolved Grief in a National Sample of Bereaved Parents: Impaired Mental and Physical Health 4 to 9 Years Later

PURPOSE: To assess unresolved parental grief, the associated long-term impact on mental and physical health, and health service use. PATIENTS AND METHODS: This anonymous, mail-in questionnaire study was performed as a population-based investigation in Sweden between August 2001 and October 2001. Four hundred forty-nine parents who lost a child as a result of cancer 4 to 9 years earlier completed the survey (response rate, 80%). One hundred ninety-one (43%) of the bereaved parents were fathers, and 251 (56%) were mothers. Bereaved parents were asked whether or not, and to what extent, they had worked through their grief. They were also asked about their physical and psychological well-being. For outcomes of interest, we report relative risk (RR) with 95% CIs as well as unadjusted odds ratios and adjusted odds ratios. RESULTS: Parents with unresolved grief reported significantly worsening psychological health (fathers: RR, 3.6; 95% CI, 2.0 to 6.4; mothers: RR, 2.9; 95% CI, 1.9 to 4.4) and physical health (fathers: RR, 2.8; 95% CI, 1.8 to 4.4; mothers: RR, 2.3; 95% CI, 1.6 to 3.3) compared with those who had worked through their grief. Fathers with unresolved grief also displayed a significantly higher risk of sleep difficulties (RR, 6.7; 95% CI, 2.5 to 17.8). Mothers, however, reported increased visits with physicians during the previous 5 years (RR, 1.7; 95% CI, 1.1 to 2.6) as well as a greater likelihood of taking sick leave when they had not worked through their grief (RR, 2.1; 95% CI, 1.2 to 3.5). CONCLUSION: Parents who have not worked through their grief are at increased risk of long-term mental and physical morbidity, increased health service use, and increased sick leave.

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data

BACKGROUND The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING None.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Comparison of co-located independent ground-based middle atmospheric wind and temperature measurements with numerical weather prediction models

High-resolution, ground-based and independent observations including co-located wind radiometer, lidar stations, and infrasound instruments are used to evaluate the accuracy of general circulation models and data-constrained assimilation systems in the middle atmosphere at northern hemisphere midlatitudes. Systematic comparisons between observations, the European Centre for Medium-Range Weather Forecasts (ECMWF) operational analyses including the recent Integrated Forecast System cycles 38r1 and 38r2, the NASA’s Modern-Era Retrospective Analysis for Research and Applications (MERRA) reanalyses, and the free-running climate Max Planck Institute–Earth System Model–Low Resolution (MPI-ESM-LR) are carried out in both temporal and spectral dom ains. We find that ECMWF and MERRA are broadly consistent with lidar and wind radiometer measurements up to ~40 km. For both temperature and horizontal wind components, deviations increase with altitude as the assimilated observations become sparser. Between 40 and 60 km altitude, the standard deviation of the mean difference exceeds 5 K for the temperature and 20 m/s for the zonal wind. The largest deviations are observed in winter when the variability from large-scale planetary waves dominates. Between lidar data and MPI-ESM-LR, there is an overall agreement in spectral amplitude down to 15–20 days. At shorter time scales, the variability is lacking in the model by ~10 dB. Infrasound observations indicate a general good agreement with ECWMF wind and temperature products. As such, this study demonstrates the potential of the infrastructure of the Atmospheric Dynamics Research Infrastructure in Europe project that integrates various measurements and provides a quantitative understanding of stratosphere-troposphere dynamical coupling for numerical weather prediction applications.

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. INTRODUCTION This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. METHODS Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. RESULTS For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). CONCLUSIONS Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Efficacy and safety of calcium channel blocker/diuretics combination therapy in hypertensive patients: a meta-analysis.

Although recent guidelines recommend the combination of calcium channel blockers (CCBs) and thiazide (-like) diuretics, this combination is not widely used in clinical practice. The aim of this meta-analysis was to assess the efficacy and safety of this combination regarding the following endpoints: all-cause and cardiovascular mortality, myocardial infarction, and stroke. Four studies with a total of 30,791 of patients met the inclusion criteria. The combination CCB/thiazide (-like) diuretic was associated with a significant risk reduction for myocardial infarction (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.73-0.95) and stroke (RR, 0.77; CI, 0.64-0.92) compared with other combinations, whereas it was similarly effective compared with other combinations in reducing the risk of all-cause (RR, 0.89; CI, 0.75-1.06) and cardiovascular (RR, 0.89; CI 0.71-1.10) mortality. Elderly patients with isolated systolic hypertension may particularly benefit from such a combination, since both drug classes have been shown to confer cerebrovascular protection.

Diagnostic and Prognostic Impact of pc-ASPECTS Applied to Perfusion CT in the Basilar Artery International Cooperation Study

BACKGROUND AND PURPOSE The posterior circulation Acute Stroke Prognosis Early CT Score (pc-APECTS) applied to CT angiography source images (CTA-SI) predicts the functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS). We assessed the diagnostic and prognostic impact of pc-ASPECTS applied to perfusion CT (CTP) in the BASICS registry population. METHODS We applied pc-ASPECTS to CTA-SI and cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) parameter maps of BASICS patients with CTA and CTP studies performed. Hypoattenuation on CTA-SI, relative reduction in CBV or CBF, or relative increase in MTT were rated as abnormal. RESULTS CTA and CTP were available in 27/592 BASICS patients (4.6%). The proportion of patients with any perfusion abnormality was highest for MTT (93%; 95% confidence interval [CI], 76%-99%), compared with 78% (58%-91%) for CTA-SI and CBF, and 46% (27%-67%) for CBV (P < .001). All 3 patients with a CBV pc-ASPECTS < 8 compared to 6/23 patients with a CBV pc-ASPECTS ≥ 8 had died at 1 month (RR 3.8; 95% CI, 1.9-7.6). CONCLUSION CTP was performed in a minority of the BASICS registry population. Perfusion disturbances in the posterior circulation were most pronounced on MTT parameter maps. CBV pc-ASPECTS < 8 may indicate patients with high case fatality.

Discrepancies in Outcome Reporting Exist Between Protocols and Published Oral Health Cochrane Systematic Reviews

OBJECTIVES To assess discrepancies in the analyzed outcomes between protocols and published reviews within Cochrane oral health systematic reviews (COHG) on the Cochrane Database of Systematic Reviews (CDSR). STUDY DESIGN AND SETTING All COHG systematic reviews on the CDSR and the corresponding protocols were retrieved in November 2014 and information on the reported outcomes was recorded. Data was collected at the systematic review level by two reviewers independently. RESULTS One hundred and fifty two reviews were included. In relation to primary outcomes, 11.2% were downgraded to secondary outcomes, 9.9% were omitted altogether in the final publication and new primary outcomes were identified in 18.4% of publications. For secondary outcomes, 2% were upgraded to primary, 12.5% were omitted and 30.9% were newly introduced in the publication. Overall, 45.4% of reviews had at least one discrepancy when compared to the protocol; these were reported in 14.5% reviews. The number of review updates appears to be associated with discrepancies between final review and protocol (OR: 3.18, 95% CI: 1.77, 5.74, p<0.001). The risk of reporting significant results was lower for both downgraded outcomes [RR: 0.52, 95% CI: 0.17, 1.58, p = 0.24] and upgraded or newly introduced outcomes [RR: 0.77, 95% CI: 0.36, 1.64, p = 0.50] compared to outcomes with no discrepancies. The risk of reporting significant results was higher for upgraded or newly introduced outcomes compared to downgraded outcomes (RR = 1.19, 95% CI: 0.65, 2.16, p = 0.57). None of the comparisons reached statistical significance. CONCLUSION While no evidence of selective outcome reporting was found in this study, based on the present analysis of SRs published within COHG systematic reviews, discrepancies between outcomes in pre-published protocols and final reviews continue to be common. Solutions such as the use of standardized outcomes to reduce the prevalence of this issue may need to be explored.

Interventions for hirsutism (excluding laser and photoepilation therapy alone)

BACKGROUND Hirsutism occurs in 5% to 10% of women of reproductive age when there is excessive terminal hair growth in androgen-sensitive areas (male pattern). It is a distressing disorder with a major impact on quality of life. The most common cause is polycystic ovary syndrome. There are many treatment options, but it is not clear which are most effective. OBJECTIVES To assess the effects of interventions (except laser and light-based therapies alone) for hirsutism. SEARCH METHODS We searched the Cochrane Skin Group Specialised Register, CENTRAL (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974), and five trials registers, and checked reference lists of included studies for additional trials. The last search was in June 2014. SELECTION CRITERIA Randomised controlled trials (RCTs) in hirsute women with polycystic ovary syndrome, idiopathic hirsutism, or idiopathic hyperandrogenism. DATA COLLECTION AND ANALYSIS Two independent authors carried out study selection, data extraction, 'Risk of bias' assessment, and analyses. MAIN RESULTS We included 157 studies (sample size 30 to 80) comprising 10,550 women (mean age 25 years). The majority of studies (123/157) were 'high', 30 'unclear', and four 'low' risk of bias. Lack of blinding was the most frequent source of bias. Treatment duration was six to 12 months. Forty-eight studies provided no usable or retrievable data, i.e. lack of separate data for hirsute women, conference proceedings, and losses to follow-up above 40%.Primary outcomes, 'participant-reported improvement of hirsutism' and 'change in health-related quality of life', were addressed in few studies, and adverse events in only half. In most comparisons there was insufficient evidence to determine if the number of reported adverse events differed. These included known adverse events: gastrointestinal discomfort, breast tenderness, reduced libido, dry skin (flutamide and finasteride); irregular bleeding (spironolactone); nausea, diarrhoea, bloating (metformin); hot flushes, decreased libido, vaginal dryness, headaches (gonadotropin-releasing hormone (GnRH) analogues)).Clinician's evaluation of hirsutism and change in androgen levels were addressed in most comparisons, change in body mass index (BMI) and improvement of other clinical signs of hyperandrogenism in one-third of studies.The quality of evidence was moderate to very low for most outcomes.There was low quality evidence for the effect of two oral contraceptive pills (OCPs) (ethinyl estradiol + cyproterone acetate versus ethinyl estradiol + desogestrel) on change from baseline of Ferriman-Gallwey scores. The mean difference (MD) was -1.84 (95% confidence interval (CI) -3.86 to 0.18).There was very low quality evidence that flutamide 250 mg, twice daily, reduced Ferriman-Gallwey scores more effectively than placebo (MD -7.60, 95% CI -10.53 to -4.67 and MD -7.20, 95% CI -10.15 to -4.25). Participants' evaluations in one study with 20 participants confirmed these results (risk ratio (RR) 17.00, 95% CI 1.11 to 259.87).Spironolactone 100 mg daily was more effective than placebo in reducing Ferriman-Gallwey scores (MD -7.69, 95% CI -10.12 to -5.26) (low quality evidence). It showed similar effectiveness to flutamide in two studies (MD -1.90, 95% CI -5.01 to 1.21 and MD 0.49, 95% CI -1.99 to 2.97) (very low quality evidence), as well as to finasteride in two studies (MD 1.49, 95% CI -0.58 to 3.56 and MD 0.40, 95% CI -1.18 to 1.98) (low quality evidence).Although there was very low quality evidence of a difference in reduction of Ferriman-Gallwey scores for finasteride 5 mg to 7.5 mg daily versus placebo (MD -5.73, 95% CI -6.87 to -4.58), it was unlikely it was clinically meaningful. These results were reinforced by participants' assessments (RR 2.06, 95% CI 0.99 to 4.29 and RR 11.00, 95% CI 0.69 to 175.86). However, finasteride showed inconsistent results in comparisons with other treatments, and no firm conclusions could be reached.Metformin demonstrated no benefit over placebo in reduction of Ferriman-Gallwey scores (MD 0.05, 95% CI -1.02 to 1.12), but the quality of evidence was low. Results regarding the effectiveness of GnRH analogues were inconsistent, varying from minimal to important improvements.We were unable to pool data for OCPs with cyproterone acetate 20 mg to 100 mg due to clinical and methodological heterogeneity between studies. However, addition of cyproterone acetate to OCPs provided greater reductions in Ferriman-Gallwey scores.Two studies, comparing finasteride 5 mg and spironolactone 100 mg, did not show differences in participant assessments and reduction of Ferriman-Gallwey scores (low quality evidence). Ferriman-Gallwey scores from three studies comparing flutamide versus metformin could not be pooled (I² = 62%). One study comparing flutamide 250 mg twice daily with metformin 850 mg twice daily for 12 months, which reached a higher cumulative dosage than two other studies evaluating this comparison, showed flutamide to be more effective (MD -6.30, 95% CI -9.83 to -2.77) (very low quality evidence). Data showing reductions in Ferriman-Gallwey scores could not be pooled for four studies comparing finasteride with flutamide as the results were inconsistent (I² = 67%).Studies examining effects of hypocaloric diets reported reductions in BMI, but which did not result in reductions in Ferriman-Gallwey scores. Although certain cosmetic measures are commonly used, we did not identify any relevant RCTs. AUTHORS' CONCLUSIONS Treatments may need to incorporate pharmacological therapies, cosmetic procedures, and psychological support. For mild hirsutism there is evidence of limited quality that OCPs are effective. Flutamide 250 mg twice daily and spironolactone 100 mg daily appeared to be effective and safe, albeit the evidence was low to very low quality. Finasteride 5 mg daily showed inconsistent results in different comparisons, therefore no firm conclusions can be made. As the side effects of antiandrogens and finasteride are well known, these should be accounted for in any clinical decision-making. There was low quality evidence that metformin was ineffective for hirsutism and although GnRH analogues showed inconsistent results in reducing hirsutism they do have significant side effects.Further research should consist of well-designed, rigorously reported, head-to-head trials examining OCPs combined with antiandrogens or 5α-reductase inhibitor against OCP monotherapy, as well as the different antiandrogens and 5α-reductase inhibitors against each other. Outcomes should be based on standardised scales of participants' assessment of treatment efficacy, with a greater emphasis on change in quality of life as a result of treatment.

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

The RNA binding proteins RBM binding motif protein 38 (RBM38) and DEAD END 1 (DND1) selectively stabilize mRNAs by attenuating RNAse activity or protecting them from micro(mi)RNA-mediated cleavage. Furthermore, both proteins can efficiently stabilize the mRNA of the cell cycle inhibitor p21(CIP1). Since acute myeloid leukemia (AML) differentiation requires cell cycle arrest and RBM38 as well as DND1 have antiproliferative functions, we hypothesized that decreased RBM38 and DND1 expression may contribute to the differentiation block seen in this disease. We first quantified RBM38 and DND1 mRNA expression in clinical AML patient samples and CD34(+) progenitor cells and mature granulocytes from healthy donors. We found significantly lower RBM38 and DND1 mRNA levels in AML blasts and CD34(+) progenitor cells as compared to mature neutrophils from healthy donors. Furthermore, the lowest expression of both RBM38 and DND1 mRNA correlated with t(8;21). In addition, neutrophil differentiation of CD34(+) cells in vitro with G-CSF (granulocyte colony stimulating factor) resulted in a significant increase of RBM38 and DND1 mRNA levels. Similarly, neutrophil differentiation of NB4 acute promyelocytic leukemia (APL) cells was associated with a significant induction of RBM38 and DND1 expression. To address the function of RBM38 and DND1 in neutrophil differentiation, we generated two independent NB4RBM38 as well as DND1 knockdown cell lines. Inhibition of both RBM38 and DND1 mRNA significantly attenuated NB4 differentiation and resulted in decreased p21(CIP1) mRNA expression. Our results clearly indicate that expression of the RNA binding proteins RBM38 and DND1 is repressed in primary AML patients, that neutrophil differentiation is dependent on increased expression of both proteins, and that these proteins have a critical role in regulating p21(CIP1) expression during APL differentiation.

The Directional Distance Function and Measurement of Super-Efficiency: An Application to Airlines Data

Lovell and Rouse (LR) have recently proposed a modification of the standard DEA model that overcomes the infeasibility problem often encountered in computing super-efficiency. In the LR procedure one appropriately scales up the observed input vector (scale down the output vector) of the relevant super-efficient firm thereby usually creating its inefficient surrogate. An alternative procedure proposed in this paper uses the directional distance function introduced by Chambers, Chung, and Färe and the resulting Nerlove-Luenberger (NL) measure of super-efficiency. The fact that the directional distance function combines features of both an input-oriented and an output-oriented model, generally leads to a more complete ranking of the observations than either of the oriented models. An added advantage of this approach is that the NL super-efficiency measure is unique and does not depend on any arbitrary choice of a scaling parameter. A data set on international airlines from Coelli, Perelman, and Griffel-Tatje (2002) is utilized in an illustrative empirical application.

Optimal Test for Parameter Instability When the Unstable Process and the Error Distribution are Unknown

This paper proposes asymptotically optimal tests for unstable parameter process under the feasible circumstance that the researcher has little information about the unstable parameter process and the error distribution, and suggests conditions under which the knowledge of those processes does not provide asymptotic power gains. I first derive a test under known error distribution, which is asymptotically equivalent to LR tests for correctly identified unstable parameter processes under suitable conditions. The conditions are weak enough to cover a wide range of unstable processes such as various types of structural breaks and time varying parameter processes. The test is then extended to semiparametric models in which the underlying distribution in unknown but treated as unknown infinite dimensional nuisance parameter. The semiparametric test is adaptive in the sense that its asymptotic power function is equivalent to the power envelope under known error distribution.

The association between uterus shape and development of chronic conditions in a retrospective corhort of diethylstilbestrol-exposed women in Minnesota and Texas

Diethylstilbestrol (DES) exposed women are well known to be at increased risk of gynecologic cancers and infertility. Infertility may result from DES associated abnormalities in the shape of women's uteri, yet little research has addressed the effect of uterine abnormalities on risk of infertility and reproductive tract infection. Changes in uterine shape may also influence the risk of autoimmune disease and women's subsequent mental health. A sample of consenting women exposed in utero to hormone who were recruited into the DESAD project, underwent hysterosalpingogram (HSG) from 1978 to 1984. These women also completed a comprehensive health questionnaire in 1994 which included women's self-reports of chronic conditions. HSG data were used to categorize uterine shape abnormalities as arcuate shape, hypoplastic, wide lower segment, and constricted. Women were recruited from two of the four DESAD study sites in Houston (Baylor) and Minnesota (Mayo). All women were DES-exposed. Adjusted relative risk estimates were calculated comparing the range of abnormal uterine shaped to women with normal shaped uteri for each of the four outcomes: infertility, reproductive tract infection, autoimmune disease and depressive symptoms. Only the arcuate shape (n=80) was associated with a higher risk of infertility (relative risk [RR]= 1.53, 95% CI = 1.09, 2.15) as well as reproductive tract infection (RR= 1.74, 95% CI = 1.11, 2.73). In conclusion, DES-associated arcuate shaped uteri appeared to be associated with the higher risk of a reproductive tract infection and infertility while no other abnormal uterine shapes were associated with these two outcomes.^

Hazardous air pollutants and childhood lymphohematopoietic cancer in Southeast Texas, 1995--2004

Southeast Texas, including Houston, has a large presence of industrial facilities and has been documented to have poorer air quality and significantly higher cancer rates than the remainder of Texas. Given citizens’ concerns in this 4th largest city in the U.S., Mayor Bill White recently partnered with the UT School of Public Health to determine methods to evaluate the health risks of hazardous air pollutants (HAPs). Sexton et al. (2007) published a report that strongly encouraged analytic studies linking these pollutants with health outcomes. In response, we set out to complete the following aims: 1. determine the optimal exposure assessment strategy to assess the association between childhood cancer rates and increased ambient levels of benzene and 1,3-butadiene (in an ecologic setting) and 2. evaluate whether census tracts with the highest levels of benzene or 1,3-butadiene have higher incidence of childhood lymphohematopoietic cancer compared with census tracts with the lowest levels of benzene or 1,3-butadiene, using Poisson regression. The first aim was achieved by evaluating the usefulness of four data sources: geographic information systems (GIS) to identify proximity to point sources of industrial air pollution, industrial emission data from the U.S. EPA’s Toxic Release Inventory (TRI), routine monitoring data from the U.S. EPA Air Quality System (AQS) from 1999-2000 and modeled ambient air levels from the U.S. EPA’s 1999 National Air Toxic Assessment Project (NATA) ASPEN model. Further, once these four data sources were evaluated, we narrowed them down to two: the routine monitoring data from the AQS for the years 1998-2000 and the 1999 U.S. EPA NATA ASPEN modeled data. We applied kriging (spatial interpolation) methodology to the monitoring data and compared the kriged values to the ASPEN modeled data. Our results indicated poor agreement between the two methods. Relative to the U.S. EPA ASPEN modeled estimates, relying on kriging to classify census tracts into exposure groups would have caused a great deal of misclassification. To address the second aim, we additionally obtained childhood lymphohematopoietic cancer data for 1995-2004 from the Texas Cancer Registry. The U.S. EPA ASPEN modeled data were used to estimate ambient levels of benzene and 1,3-butadiene in separate Poisson regression analyses. All data were analyzed at the census tract level. We found that census tracts with the highest benzene levels had elevated rates of all leukemia (rate ratio (RR) = 1.37; 95% confidence interval (CI), 1.05-1.78). Among census tracts with the highest 1,3-butadiene levels, we observed RRs of 1.40 (95% CI, 1.07-1.81) for all leukemia. We detected no associations between benzene or 1,3-butadiene levels and childhood lymphoma incidence. This study is the first to examine this association in Harris and surrounding counties in Texas and is among the first to correlate monitored levels of HAPs with childhood lymphohematopoietic cancer incidence, evaluating several analytic methods in an effort to determine the most appropriate approach to test this association. Despite recognized weakness of ecologic analyses, our analysis suggests an association between childhood leukemia and hazardous air pollution.^

Enlarged tracheoesophageal puncture: A systematic review and retrospective analysis

Background. An enlarged tracheoesophageal puncture (TEP) results in aspiration around the voice prosthesis (VP) and may lead to pneumonia. The aims of this research were: (1) to conduct a systematic review and meta-analysis on enlarged TEP; (2) to analyze preoperative, perioperative, and postoperative risk factors for enlarged TEP; and (3) to evaluate control of leakage around the VP using conservative treatments and adverse events in patients with enlarged TEP.^ Methods. A systematic review was conducted (1978-2008). A summary risk estimate was calculated using a random-effects meta-analysis model. A retrospective cohort study was completed. Patients who underwent total laryngectomy and TEP at The University of Texas M. D. Anderson Cancer Center (MDACC) were included. Multiple logistic regression methods were used to assess risk factors for enlargement. Descriptive and bivariate statistics were calculated to evaluate outcomes and adverse events. Results: Twenty-seven manuscripts were included in the systematic review. The summary risk estimate of enlarged TEP/leakage around the VP was 7.2% (95% CI: 4.8%-9.6%). Temporary VP removal and TEP-site injections were the most commonly reported treatments. Neither prosthetic diameter (p=0.076) nor timing of TEP (p=0.297) significantly increased risk of enlargement per stratified analyses of published outcomes. The cumulative incidence of enlarged TEP was 18.6% (36/194, 95% CI: 13.0%-24.1%) in the MDACC cohort. Enlarged TEP occurred exclusively in irradiated patients. Adjusting for length of follow-up and timing of TEP, advanced nodal disease (ORadjusted: 4.3, 95% CI: 1.0-19.1), stricture (ORadjusted : 3.2, 95% CI: 1.2-8.6), and locoregional recurrence/distant metastasis after laryngectomy (ORadjusted: 6.2, 95% CI: 2.3-16.4) increased risk of enlarged TEP. At last follow-up, conservative methods controlled leakage around the VP in 81% (29/36) of patients. Unresolved leakage was associated with recurrent cancer (p=0.081) and TEP-site irregularity (p=0.003). Relative to those without enlargement, enlarged TEP patients had significantly higher risk of pneumonia (RR: 3.4, 95% CI: 1.9-6.2).^ Conclusions. These data establish that enlarged TEP poses serious health risks, and provide insight into medical and oncologic factors that may contribute to development of this complication. In addition, this research supports the use of conservative treatments to address leakage after enlarged TEP in lieu of complete TEP closure.^