Outcomes to measure the effects of pharmacological interventions for pain management for women during labour and birth: a review of systematic reviews and randomised trials.

BACKGROUND: Pharmacological pain management options can relieve women's pain during labour and birth. Trials of these interventions have used a wide variety of outcomes, complicating meaningful comparisons of their effects. To facilitate better assessment of the effectiveness of labour pain management in trials and meta-analyses, consensus about key outcomes and the development of a core outcome set is essential. OBJECTIVE: To identify all outcomes used in studies of pharmacological pain management interventions during labour and birth. DESIGN: A review of systematic reviews and their included randomised controlled trials was undertaken. SEARCH STRATEGY: Cochrane CENTRAL was searched to identify all Cochrane systematic reviews describing pharmacological pain management options for labour and birth. Search terms included 'pain management', 'labour' and variants, with no limits on year of publication or language. SELECTION CRITERIA: Cochrane reviews and randomised controlled trials contained within these reviews were included, provided they compared a pharmacological intervention with other pain management options, placebo or no treatment. DATA COLLECTION AND ANALYSIS: All outcomes reported by reviews or trials were extracted and tabulated, with frequencies of individual outcomes reported. MAIN RESULTS: Nine Cochrane reviews and 227 unique trials were included. In total, 146 unique outcomes were identified and categorised into maternal, fetal, neonatal, child, health service, provider's perspective or economic outcome domains. CONCLUSIONS: Outcomes of pharmacological pain management interventions during labour and birth vary widely between trials. The standardisation of trial outcomes would permit the assessment of meta-analyses for best clinical practice. TWEETABLE ABSTRACT: Outcomes to measure pharmacological pain management options during labour are highly variable and require standardisation.

Uptake of Noninvasive Prenatal Testing in Chinese Women following Positive Down Syndrome Screening.

OBJECTIVES: To investigate how the introduction of noninvasive prenatal testing (NIPT) influenced women's testing choices following a positive Down syndrome screening. METHODS: A retrospective study was conducted to compare differences in the uptake rates of invasive prenatal diagnosis (IPD) or no testing in one public hospital 1 year before (pre-NIPT) and 1 and 2 years after the introduction of NIPT in private in August 2011 using descriptive analysis and a χ² test. Conventional screening was funded publicly, but NIPT was not. Multivariable binary logistic regression was used to determine factors affecting choices. RESULTS: In pre-NIPT and in years 1 and 2 after the introduction of NIPT, 306, 362 and 401 women who screened positive were seen, respectively. In year 1 and year 2, 12.6 and 26.7% of them underwent NIPT while IPD was decreased by 16.3 and 25.6%, respectively (p < 0.001). Both chorionic villus sampling and amniocentesis decreased in year 1, but only the former in year 2. However, the rate of declining further testing was similar before and after NIPT (p = 0.213). In multivariable analysis, first trimester screening, nulliparity and working women were significant predictors of accepting NIPT, while only nulliparity was a predictor of declining IPD (OR = 0.61). CONCLUSIONS: Introduction of NIPT resulted in a significant decrease in IPD for 2 consecutive years..

Trend of sex ratio at birth in a public hospital in Hong Kong from 2001 to 2010.

OBJECTIVES: To identify factors affecting the sex ratio at birth. DESIGN: Cross-sectional study. SETTING: Obstetric department of a public hospital in Hong Kong. PARTICIPANTS: All pregnant women delivered between 2001 and 2010. MAIN OUTCOME MEASURES: Sex ratio at birth versus women's eligibility status, age, parity, number of miscarriages or terminations of pregnancy, and number of fetuses were analysed using the Chi squared test. Multivariate regression was used to determine the effects of multiple factors on the sex of the newborn. RESULTS: A total of 54 039 cases were reviewed. The sex ratio at birth changed since 2003, and became unbalanced (>107 males per 100 females) since 2006 revealed by a significant increase in males per 100 females, from 106.6 in 2001-2005 to 111.4 in 2006-2010. From 2001 to 2010, the sex ratio at birth increased from being balanced to becoming unbalanced in eligible persons, and became more unbalanced in non-eligible persons. The ratio increased in eligible persons after having two children, but in non-eligible persons after having one child. The sex ratio at birth was unbalanced (1.095) in singleton pregnancies, but balanced (1.019) in multiple pregnancies. Based on logistic regression, the chance of a male baby being born increased with parity of 2 or above (odds ratio=1.1; P<0.001), non-eligible person status (odds ratio=1.05; P=0.034), and delivery in the period 2006-2010 (odds ratio=1.04; P=0.019). The ratio was not increased with advanced maternal age, the number of miscarriages/terminations of pregnancy, and number of fetuses. CONCLUSION: Compared with 2001-2005, the sex ratio at birth became unbalanced in 2006-2010. An unbalanced ratio ensued in the latter period in both eligible and non-eligible persons, but to a greater extent and even after having one child in the latter group.

Thiazole orange as the fluorescent intercalator in a high resolution fid assay for determining DNA binding affinity and sequence selectivity of small molecules.

The viability of using thiazole orange as an alternative to ethidium bromide in a fluorescent intercalator displacement (FID) assay is explored by profiling the DNA binding affinity and sequence selectivity of netropsin. Utilizing a library of hairpin deoxyoligonucleotides containing all possible four base-pair sequences, the method provides a high resolution profile of the DNA binding properties of small molecules in a high throughput format.

Total syntheses of thiocoraline and BE-22179 and assessment of their DNA binding and biological properties.

Full details of the total syntheses of thiocoraline (1) and BE-22179 (2), C(2) symmetric bicyclic octadepsipeptides possessing two pendant 3-hydroxyquinoline chromophores, are described in which their relative and absolute stereochemistry were established. Key elements of the approach include the late-stage introduction of the chromophore, symmetrical tetrapeptide coupling, macrocyclization of the 26-membered octadepsipeptide conducted at the single secondary amide site following disulfide formation, and a convergent assemblage of the tetradepsipeptide with introduction of the labile thiol ester linkage in the final coupling reaction under near racemization free conditions. By virtue of the late-stage introduction of the chromophore and despite the challenges this imposes on the synthesis, this approach provides ready access to a range of key chromophore analogues. Thiocoraline and BE-22179 were shown to bind to DNA by high-affinity bisintercalation analogous to echinomycin, but with little or no perceptible sequence selectivity. Both 1 and 2 were found to exhibit exceptional cytotoxic activity (IC(50) = 200 and 400 pM, respectively, L1210 cell line) comparable to echinomycin and one analogue, which bears the luzopeptin chromophore, was also found to be a potent cytotoxic agent.

A simple, high-resolution method for establishing DNA binding affinity and sequence selectivity.

Full details of the development of a simple, nondestructive, and high-throughput method for establishing DNA binding affinity and sequence selectivity are described. The method is based on the loss of fluorescence derived from the displacement of ethidium bromide or thiazole orange from the DNA of interest or, in selected instances, the change in intrinsic fluorescence of a DNA binding agent itself and is applicable for assessing relative or absolute DNA binding affinities. Enlisting a library of hairpin deoxyoligonucleotides containing all five base pair (512 hairpins) or four base pair (136 hairpins) sequences displayed in a 96-well format, a compound's rank order binding to all possible sequences is generated, resulting in a high-resolution definition of its sequence selectivity using this fluorescent intercalator displacement (FID) assay. As such, the technique complements the use of footprinting or affinity cleavage for the establishment of DNA binding selectivity and provides the information at a higher resolution. The merged bar graphs generated by this rank order binding provide a qualitative way to compare, or profile, DNA binding affinity and selectivity. The 96-well format assay (512 hairpins) can be conducted at a minimal cost (presently ca. $100 for hairpin deoxyoligonucleotides/assay with ethiduim bromide or less with thiazole orange), with a rapid readout using a fluorescent plate reader (15 min), and is adaptable to automation (Tecan Genesis Workstation 100 robotic system). Its use in generating a profile of DNA binding selectivity for several agents including distamycin A, netropsin, DAPI, Hoechst 33258, and berenil is described. Techniques for establishing binding constants from quantitative titrations are compared, and recommendations are made for use of a Scatchard or curve fitting analysis of the titration binding curves as a reliable means to quantitate the binding affinity.

Bifunctional alkylating agents derived from duocarmycin SA: potent antitumor activity with altered sequence selectivity.

The series of four dimers derived from head to tail coupling of the two enantiomers of the duocarmycin SA alkylation subunit are described.

Yuehchukene, a bis-indole alkaloid, and cyclophosphamide are active in breast cancer in vitro.

Yuehchukene (YCK) is a novel bis-indole alkaloid with weak estrogenic activity. Biochemical studies showed that YCK could attenuate estrogenic action. In this study, the response of MCF-7, an estrogen-receptor-positive breast cancer cell line, under different combinations of estradiol, cyclophosphamide and YCK, was tested. From the dose-response curve, we discovered that 10(-2) M cyclophosphamide, even in its so-called 'bio-inert' form, could inhibit MCF-7 cell growth. However, the cytotoxic effect of cyclophosphamide was lost by reducing its concentration to approximately 1 x 10(-3) M. On the other hand, a low concentration ( approximately 10(-8)-10(-9) M) of YCK was found to potentiate the cytotoxic effect of cyclophosphamide on the MCF-7 cell line. Such an effect was absent in the estrogen-receptor-negative cell line MDA-MB-231. These findings, together with the dual role of a mixed estrogen and anti-estrogen effect, suggested that YCK and cyclophosphamide can be a potential combination in chemo-hormonal therapy for breast cancer.

Structural basis of inhibition of cysteine proteases by E-64 and its derivatives.

This paper focuses on the inhibitory mechanism of E-64 and its derivatives (epoxysuccinyl-based inhibitors) with some cysteine proteases, based on the binding modes observed in the x-ray crystal structures of their enzyme-inhibitor complexes. E-64 is a potent irreversible inhibitor against general cysteine proteases, and its binding modes with papain, actinidin, cathepsin L, and cathepsin K have been reviewed at the atomic level. E-64 interacts with the Sn subsites of cysteine proteases. Although the Sn-Pn (n = 1-3) interactions of the inhibitor with the main chains of the active site residues are similar in respective complexes, the significant difference is observed in the side-chain interactions of S2-P2 and S3-P3 pairs because of different residues constituting the respective subsites. E-64-c and CA074 are representative derivatives developed from E-64 as a clinical usable and a cathepsin B-specific inhibitors, respectively. In contrast with similar binding/inhibitory modes of E-64-c and E-64 for cysteine proteases, the inhibitory mechanism of cathepsin B-specific CA074 results from the binding to the Sn' subsite.

Evidence for the extended helical nature of polysaccharide epitopes. The 2.8 A resolution structure and thermodynamics of ligand binding of an antigen binding fragment specific for alpha-(2-->8)-polysialic acid.

The antigen binding fragment from an IgG2a kappa murine monoclonal antibody with specificity for alpha-(2-->8)-linked sialic acid polymers has been prepared and crystallized in the absence of hapten. Crystals were grown by vapor diffusion equilibrium with 16-18% polyethylene glycol 4000 solutions. The structure was solved by molecular replacement methods and refined to a conventional R factor of 0.164 for data to 2.8 A. The binding site is observed to display a shape and distribution of charges that is complementary to that of the predicted conformation of the oligosaccharide epitope. A thermodynamic description of ligand binding has been compiled for oligosaccharides ranging in length from 9 to 41 residues, and the data for the largest ligand has been used in a novel way to estimate the size of the antigen binding site. A model of antigen binding is presented that satisfies this thermodynamic data, as well as a previously reported requirement of conformational specificity of the oligosaccharide. X-ray crystallographic and thermodynamic evidence are consistent with a binding site that accommodates at least eight sialic acid residues.