Predictors of timing of pregnancy discovery

Objective

Earlier pregnancy discovery is important in the context of prenatal and abortion care. We evaluated characteristics associated with later pregnancy discovery among women seeking abortion care.

Modeling a Predictive Energy Equation Specific for Maintenance Hemodialysis

Background: Hypermetabolism is theorized in patients diagnosed with chronic kidney disease who are receiving maintenance hemodialysis (MHD). We aimed to distinguish key disease‐specific determinants of resting energy expenditure to create a predictive energy equation that more precisely establishes energy needs with the intent of preventing protein‐energy wasting. Materials and Methods: For this 3‐year multisite cross‐sectional study (N = 116), eligible participants were diagnosed with chronic kidney disease and were receiving MHD for at least 3 months. Predictors for the model included weight, sex, age, C‐reactive protein (CRP), glycosylated hemoglobin, and serum creatinine. The outcome variable was measured resting energy expenditure (mREE). Regression modeling was used to generate predictive formulas and Bland‐Altman analyses to evaluate accuracy. Results: The majority were male (60.3%), black (81.0%), and non‐Hispanic (76.7%), and 23% were ≥65 years old. After screening for multicollinearity, the best predictive model of mREE (R² = 0.67) included weight, age, sex, and CRP. Two alternative models with acceptable predictability (R² = 0.66) were derived with glycosylated hemoglobin or serum creatinine. Based on Bland‐Altman analyses, the maintenance hemodialysis equation that included CRP had the best precision, with the highest proportion of participants’ predicted energy expenditure classified as accurate (61.2%) and with the lowest number of individuals with underestimation or overestimation. Conclusions: This study confirms disease‐specific factors as key determinants of mREE in patients on MHD and provides a preliminary predictive energy equation. Further prospective research is necessary to test the reliability and validity of this equation across diverse populations of patients who are receiving MHD.     

A systematic review and meta‐analysis of clinical variables used in Huntington disease research

Treatment effect in Huntington disease (HD) clinical trials has relied on primary outcome measures such as total motor score or functional rating scales. However, these measures have limited sensitivity, particularly in pre‐ to early stages of the disease. We performed a systematic review of HD clinical studies to identify endpoints that correlate with disease severity. Using standard HD keywords and terms, we identified 749 published studies from 1993 to 2011 based on the availability of demographic, biochemical, and clinical measures. The average and variability of each measure was abstracted and stratified according to pre‐far, pre‐close, early, mild, moderate, and severe HD stages. A fixed‐effect meta‐analysis on selected variables was conducted at various disease stages. A total of 1,801 different clinical variables and treatment outcomes were identified. Unified Huntington Disease Rating Scale (UHDRS) Motor, UHDRS Independence, and Trail B showed a trend toward separation between HD stages. Other measures, such as UHDRS Apathy, Verbal Fluency, and Symbol Digit, could only distinguish between pre‐ and early stages of disease and later stages, whereas other measures showed little correlation with increasing HD stages. Using cross‐sectional data from published HD clinical trials, we have identified potential endpoints that could be used to track HD disease progression and treatment effect. Longitudinal studies, such as TRACK‐HD, are critical for assessing the value of potential markers of disease progression for use in future HD therapeutic trials. A list of variables, references used in this meta‐analysis, and database is available at http://www.cmmt.ubc.ca/research/investigators/leavitt/publications . © 2013 International Parkinson and Movement Disorder Society     

Safety,pharmacokinetics, and activity of EZN‐2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies

BACKGROUND:

EZN‐2208 is a water‐soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN‐2208 in adult patients with advanced solid tumors.

METHODS:

Patients in sequential cohorts (3 + 3 design) received intravenous EZN‐2208 at doses between 1.25 mg/m² and 25 mg/m² once every 21 days.

RESULTS:

Thirty‐nine patients received EZN‐2208. The median number of prior therapies was 2 (range, 0‐10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN‐2208 with (16.5 mg/m²) and without (10 mg/m²) granulocyte‐colony–stimulating factor (G‐CSF). The dose‐limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m² with G‐CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m²). PK analysis indicated a mean terminal half‐life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short‐lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥4 months, 3 had received prior irinotecan, and 1 had KRAS‐positive colorectal cancer.

CONCLUSIONS:

EZN‐2208 was well tolerated and produced stable disease that lasted for ≥4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy. Cancer 2012. © 2012 American Cancer Society.     

Orchidectomy enhances the effects of phenylephrine in rat isolated portal vein

1. Orchidectomy results in long‐term testosterone deprivation similar to that observed in male clinical pathologies, such as hypogonadism and age‐related reductions in plasma testosterone concentrations. Although the vascular effects of these sorts of hormone deprivations are known in arteries, they have not been studied to the same extent in veins. 2. The aim of the present study was to determine the effect of orchidectomy, with or without subsequent testosterone replacement (started 23 days after orchidectomy; 10 mg/kg, i.m., testosterone propionate once every 5 days for 3 weeks), on responses of rat isolated portal veins and vena cavae to exogenous phenylephrine (PE). Isolated vessels were mounted in an organ bath and concentration–response curves constructed to PE (10^?10–10^?4 mol/L), endothelin (ET; 10^?10–10^?5 mol/L) and KCl (10^?2–1.2 × 10^?1 mol/L; as a control). 3. Orchidectomy had no effect on contractile responses of either the portal vein or vena cava to KCl. However, orchidectomy enhanced the maximum response (R_max) of the portal vein, but not the vena cava, to PE. Testosterone replacement had no effect on these responses. The effects of orchidectomy on the R_max to PE in portal veins were not altered by the nitric oxide synthase inhibitor N^G‐nitro‐l‐ arginine methyl ester (10^?4 mol/L) alone or combined with 10^?5 mol/L indomethacin (a non‐selective cyclo‐oxygenase inhibitor), but they were abolished following treatment of isolated vessels with the ET_A and ET_B receptor antagonists BQ‐123 and BQ‐788 (both at 10^?6 mol/L). Orchidectomy did not alter portal vein responses to the application of exogenous ET. 4. The results of the present study indicate that orchidectomy‐induced decreases in plasma testosterone can increase the venoconstrictor effects of PE on the portal vein and that this effect involves activation of both ET_A and ET_B receptors by locally produced ET.