Comparison of One‐Step and Two‐Step Meta‐Analysis Models Using Individual Patient Data

The problem of combining information from separate trials is a key consideration when performing a meta‐analysis or planning a multicentre trial. Although there is a considerable journal literature on meta‐analysis based on individual patient data (IPD), i.e. a one‐step IPD meta‐analysis, versus analysis based on summary data, i.e. a two‐step IPD meta‐analysis, recent articles in the medical literature indicate that there is still confusion and uncertainty as to the validity of an analysis based on aggregate data. In this study, we address one of the central statistical issues by considering the estimation of a linear function of the mean, based on linear models for summary data and for IPD. The summary data from a trial is assumed to comprise the best linear unbiased estimator, or maximum likelihood estimator of the parameter, along with its covariance matrix. The setup, which allows for the presence of random effects and covariates in the model, is quite general and includes many of the commonly employed models, for example, linear models with fixed treatment effects and fixed or random trial effects. For this general model, we derive a condition under which the one‐step and two‐step IPD meta‐analysis estimators coincide, extending earlier work considerably. The implications of this result for the specific models mentioned above are illustrated in detail, both theoretically and in terms of two real data sets, and the roles of balance and heterogeneity are highlighted. Our analysis also shows that when covariates are present, which is typically the case, the two estimators coincide only under extra simplifying assumptions, which are somewhat unrealistic in practice.     

An Extended ANOVA F‐Test with Applications to the Heterogeneity Problem in Meta‐Analysis

The classical F‐test in the one‐way random effects ANOVA model is extended to solve the long outstanding problem of testing the between‐group variance on values also different from zero. This is done first for homoscedastic and heteroscedastic cases in not necessarily balanced models and secondly for balanced homoscedastic models. By simulation, the tests are shown to attain acceptable significance levels and high power even in data that do not follow the usual ANOVA model. An important application of the tests is given by the heterogeneity questions concerning the treatment effects across studies in meta‐analysis.     

Assessing the frequency and drivers of early‐greening in broad‐leaved woodlands along a latitudinal gradient in southern Africa

Savannas are the only deciduous system where new leaf flush pre‐empts the onset of suitable conditions for growth, a phenological phenomenon known as early‐greening. Limited understanding of the frequency and drivers of the occurrence of early‐greening in southern African savanna trees exists. We aimed to estimate the frequency of early‐greening events across southern Africa and investigated potential environmental drivers of green‐up. We selected and compared seven broad‐leaved woodland sites where Burkea africana was a dominant species using remotely sensed data along a latitudinal gradient from South Africa to Zambia. Normalized difference vegetation index (NDVI) values were extracted from the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite imagery at each site from January 2002 to June 2014. Using an austral year (July 1st–June 30th), early‐greening was recorded if the green‐up start date occurred prior to the onset date of seasonal rainfall. A latitudinal gradient of early‐green‐up was detected across southern Africa (R² = 0.74) with the two most northerly (Zambian) sites showing the earliest and most consistent green‐up start dates (3 October ± 5.34 days). A strong latitudinal gradient was observed between the variability in the amount of rainfall in the first 6 months of green‐up and the green‐up start dates across southern Africa (R² = 0.92). Photoperiod appeared to play a role in areas where the onset of rainfall commenced late into the austral year. Mean maximum temperatures recorded 10 days prior to green‐up start dates suggested a potential threshold of about 35°C, which could drive early‐greening in the absence of rainfall. Correlations between the proportion of early‐greening years and the above mentioned environmental factors indicated that rainfall variability had the strongest influence over the observed phenological gradient (R² = 0.96). Understanding early‐greening in complex savanna systems is a vital step in furthering predictive phenological models under changing climatic conditions.     

Application of NMR spectroscopy for assignment of the absolute configuration of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one

In order to assign the absolute configurations of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one ( 2a , 2b ), their esters ( 5a , 5b , 5c , 5d ) with (R)‐ or (S)‐2‐methoxyphenylacetic acid ( 4a , 4b ) have been synthesized. The absolute configurations of these compounds have been determined on the basis of NOESY correlations between the protons of the tert‐butyl group and the cyclopentane fragment of the molecules. The crucial part of this analysis was assignment of the absolute configuration at C‐5. Additionally, by calculation of the chemical shift anisotropy, δ^RS, for the relevant protons, it was also possible to confirm the absolute configurations at the C‐2 centres of compounds 2a , 2b and 5a , 5b , 5c , 5d . Chirality, 25:422–426, 2013.© 2013 Wiley Periodicals, Inc.     

All‐Manganese‐Based Binder‐Free Stretchable Lithium‐Ion Batteries

Advanced electrode materials with bendability and stretchability are critical for the rapid development of fully flexible/stretchable lithium‐ion batteries. However, the sufficiently stretchable lithium‐ion battery is still underdeveloped that is one of the biggest challenges preventing from realizing fully deformable power sources. Here, a low‐temperature hydrothermal synthesis of a cathode material for stretchable lithium‐ion battery is reported by the in situ growth of LiMn₂O₄ (LMO) nanocrystals inside 3D carbon nanotube (CNT) film networks. The LMO/CNT film composite has demonstrated the chemical bonding between the LMO active materials and CNT scaffolds, which is the most important characteristic of the stretchable electrodes. When coupled with a wrinkled MnO_x /CNT film anode, a binder‐free, all‐manganese‐based stretchable full battery cell is assembled which delivers a high average specific capacity of ≈97 mA h g^?1 and stabilizes after over 300 cycles with an enormous strain of 100%. Furthermore, combining with other merits such as low cost, natural abundance, and environmentally friendly, the all‐manganese design is expected to accelerate the practical applications of stretchable lithium‐ion batteries for fully flexible and biomedical electronics.     

Reduced‐oxidized difference spectral analysis and chemiluminescence‐based Scatchard analysis demonstrate selective binding of myeloperoxidase to microbes

Myeloperoxidase (MPO), a microbicidal haloperoxidase of neutrophil leukocytes, was observed to selectively bind to bacteria. Binding was quantified by dithionite‐reduced minus oxidized (R? O) difference spectral analysis. Escherichia coli and Pseudomonas aeruginosa showed large MPO binding by R? O difference spectral analysis, whereas Streptococcus sanguinis did not. For increased sensitivity, free and microbe‐bound MPO and chloroperoxidase (CPO) activities were quantified by acid‐optimum haloperoxidase‐dependent chemiluminescence (CL) measurements, and these data were used for Scatchard analysis. The MPO bound/free (B/F) CL ratio was 49.5 for P. aeruginosa, 14.6 for Staphylococcus aureus, 2.8 for E. coli, 0.7 for Candida albicans and 0.4 for S. sanguinis. By comparison, the CPO B/F CL ratio was 0.03 for P. aeruginosa, 0.09 for S. aureus, 0.31 for E. coli, 0.18 for C. albicans and 0.16 for S. sanguinis. As a member of the lactic acid family of bacteria and a viridans streptococcus, S. sanguinis does not synthesize cytochromes and is catalase‐negative. The metabolic products of S. sanguinis, i.e. lactic acid and hydrogen peroxide, provide optimal acidity and substrate for MPO oxidation of chloride to hypochlorite. Hypochlorite can react with organic substrates to yield dehydrogenated or chlorinated products, but when peroxide is not limiting, hypochlorite reacts with peroxide yielding singlet oxygen. The reactivity of hypochlorite is dependent on substrate availability. The microsecond half‐life of electronically excited singlet oxygen restricts reactivity to within a radius of <0.25 µm; i.e. the reactivity of singlet oxygen is both substrate and half‐life dependent. Poor MPO binding provides protection and possibly competitive advantage to viridans streptococci. Copyright © 2010 John Wiley & Sons, Ltd.     

HS‐SPME‐GC‐FID method for detection and quantification of Bacillus cereus ATCC 10702 mediated 2‐acetyl‐1‐pyrroline

A rapid micro‐scale solid‐phase micro‐extraction (SPME) procedure coupled with gas‐chromatography with flame ionized detector (GC‐FID) was used to extract parts per billion levels of a principle basmati aroma compound “2‐acetyl‐1‐pyrroline” (2‐AP) from bacterial samples. In present investigation, optimization parameters of bacterial incubation period, sample weight, pre‐incubation time, adsorption time, and temperature, precursors and their concentrations has been studied. In the optimized conditions, detection of 2‐AP produced by Bacillus cereus ATCC10702 using only 0.5 g of sample volume was 85 μg/kg. Along with 2‐AP, 15 other compounds produced by B. cereus were also reported out of which 14 were reported for the first time consisting mainly of (E)?2‐hexenal, pentadecanal, 4‐hydroxy‐2‐butanone, n‐hexanal, 2–6‐nonadienal, 3‐methoxy‐2(5H) furanone and 2‐acetyl‐1‐pyridine and octanal. High recovery of 2‐AP (87 %) from very less amount of B. cereus samples was observed. The method is reproducible fast and can be used for detection of 2‐AP production by B. cereus. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:1356–1363, 2014     

Validated spectrofluorimetric method for the determination of carbamazepine in pharmaceutical dosage forms after reaction with 4‐chloro‐7‐‐nitrobenzo‐2‐oxa‐1,3‐diazole (NBD‐Cl)

A sensitive and simple spectrofluorimetric method has been developed and validated for the determination of the anti‐epileptic drug carbamazepine (CBZ) in its dosage forms. The method was based on a nucleophilic substitution reaction of CBZ with 4‐chloro‐7‐nitrobenzo‐2‐ oxa‐1,3‐diazole (NBD‐Cl) in borate buffer (pH 9) to form a highly fluorescent derivative that was measured at 530 nm after excitation at 460 nm. Factors affecting the formation of the reaction product were studied and optimized, and the reaction mechanism was postulated. The fluorescence–concentration plot is rectilinear over the range of 0.6–8 µg/mL with limit of detection of 0.06 µg/mL and limit of quantitation of 0.19 µg/mL. The method was applied to the analysis of commercial tablets and the results were in good agreement with those obtained using the reference method. Validation of the analytical procedures was evaluated according to ICH guidelines. Copyright © 2015 John Wiley & Sons, Ltd.     

Enantioselective resolution of 4‐chloromandelic acid by liquid–liquid extraction using 2‐chloro‐N‐carbobenzyloxy‐L‐amino acid

A liquid–liquid extraction resolution of 4‐chloro‐mandelic acid (4‐ClMA) was studied by using 2‐chloro‐N‐carbobenzyloxy‐L‐amino acid (2‐Cl‐Z‐AA) as a chiral extractant. Important factors affecting the extraction efficiency were investigated, including the type of chiral extractant, pH value of aqueous phase, initial concentration of chiral extractant in organic phase, initial concentration of 4‐ClMA in aqueous phase, and resolution temperature. It was observed that the concentration of (R)‐4‐ClMA was much higher than that of (S)‐4‐ClMA in organic phase due to a higher stability of the complex formed between (R)‐4‐ClMA and 2‐Cl‐Z‐AA. A separation factor (α) of 3.05 was obtained at 0.02 mol/L 2‐Cl‐Z‐Valine dissolved in dichloromethane, pH of 2.0, concentration of 4‐ClMA of 0.11 mmol/Land T of 296.7K.     

High‐Performance Liquid Chromatographic Enantioseparation of Unusual Isoxazoline‐Fused 2‐Aminocyclopentanecarboxylic Acids on (+)‐(18‐Crown‐6)‐2,3,11,12‐Tetracarboxylic Acid‐Based Chiral Stationary Phases

The enantiomers of four unusual isoxazoline‐fused 2‐aminocyclopentanecarboxylic acids were directly separated on chiral stationary phases containing (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid as chiral selector. The nature of the alcoholic modifier (MeOH, EtOH, IPA) exerted a great effect on the retention, whereas the selectivity and resolution did not change substantially. Two types of dependence of retention on alcohol content were detected: k₁ increased continuously with increasing alcohol content or a U‐shaped retention curve was observed. A comparison of the chromatographic data obtained with HCOOH, AcOH, TFA, HClO₄, H₂SO₄, or H₃PO₄ as acidic modifier at a constant concentration demonstrated that in most cases, larger k values were obtained on the application of AcOH or HCOOH, and an increase of the acid content resulted in a decrease of retention. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes and selector. The sequence of elution of the enantiomers was determined in all cases. Chirality 24:817‐824, 2012. © 2012 Wiley Periodicals, Inc.     

Synthesis and Olfactory Characterization of Silicon‐Containing Derivatives of the Acyclic Lily‐of‐the‐Valley Odorant 5,7,7‐Trimethyl‐4‐methylideneoctanal

5‐Methyl‐4‐methylidene‐6‐(trimethylsilyl)hexanal ( 1b ), a sila analog of the acyclic lily‐of‐the‐valley odorant 5,7,7‐trimethyl‐4‐methylideneoctanal ( 1a ), and the Si‐containing derivatives 2 – 6 were prepared in multistep syntheses, starting from Cl₃SiH and Cl₂SiMe₂, respectively. Compounds 1b, 2 – 6 , and their new precursors were characterized by elemental analyses (C, H, N) and NMR spectroscopic studies (¹H, ¹³C, ¹⁵N, and ²⁹Si). To gain more information about the structure? odor correlation in the family of lily‐of‐the‐valley or ‘muguet’ odorants, C/Si analogs 1a / 1b and derivatives 2 – 6 were evaluated for their olfactory properties.     

2H‐Pyran‐2‐one and 2H‐Furan‐2‐one Derivatives from the Plant Endophytic Fungus Pestalotiopsis fici

Two new α‐pyrones (=2H‐pyran‐2‐ones), ficipyrones A and B ( 1 and 2 , resp.), and two new α‐furanones (=2H‐furan‐2‐ones), ficifuranones A and B ( 3 and 4 , resp.), together with three known metabolites, antibiotic F 0368 ( 5 ), hydroxyseiridin ( 6 ), and hydroxyisoseiridin ( 7 ), were isolated from solid cultures of the plant endophytic fungus Pestalotiopsis fici. Their structures were elucidated primarily by NMR spectroscopy, and the absolute configuration of 1 was deduced from the circular‐dichroism (CD) data. Compound 1 showed antifungal activity against the plant pathogen Gibberella zeae (CGMCC 3.2873) with an IC₅₀ value of 15.9 μM .     

Homo‐C‐nucleoside analogs IV. Synthesis of 4‐(2,5‐anhydro‐D‐altro‐pentitol‐1‐yl)‐2‐phenyl‐2H‐1,2,3‐triazole homo‐C‐nucleoside. CD assignment of the absolute configuration of the carbon bridge

Dehydrative cyclization of 4‐(D‐altro ‐pentitol‐1‐yl)2‐phenyl‐2H ‐1,2,3‐triazole in basic medium with one moler equivalent of p‐toluene sulfonyl chloride in pyridine solution gave the homo‐C‐ nucleoside 4‐(2,5‐anhydro‐D‐altro ‐1‐yl)‐2‐phenyl‐2H ‐1,2,3‐triazole. The structure and anomeric configuration was determined by acylation, nuclear magnetic resonance (NMR), and mass spectroscopy. The stereochemistry at the carbon bridge of homo‐C‐ nucleoside 2‐phenyl‐2H ‐1,2,3‐triazoles was determined by circular dichroism (CD) spectroscopy.     

Asymmetrically simultaneous synthesis of L‐homophenylalanine and N6‐protected‐2‐oxo‐6‐amino‐hexanoic acid by engineered Escherichia coli aspartate aminotransferase

L ‐Homophenylalanine (L ‐HPA) and N⁶‐protected‐2‐oxo‐6‐amino‐hexanoic acid (N⁶‐protected‐OAHA) can be used as building blocks for the manufacture of angiotensin‐converting enzyme inhibitors. To synthesize L ‐HPA and N⁶‐protected‐OAHA simultaneously from 2‐oxo‐4‐phenylbutanoic acid (OPBA) and N⁶‐protected‐L ‐lysine, several variants of Escherichia coli aspartate aminotransferase (AAT) were developed by site‐directed mutagenesis and their catalytic activities were investigated. Three kinds of N⁶‐protected‐L ‐lysine were tested as potential amino donors for the bioconversion process. AAT variants of R292E/L18H and R292E/L18T exhibited specific activities of 0.70±0.01 U/mg protein and 0.67±0.02 U/mg protein to 2‐amino‐6‐tert‐butoxycarbonylamino‐hexanoic acid (BOC‐lysine) and 2‐amino‐6‐(2,2,2‐trifluoro‐acetylamino)‐hexanoic acid, respectively. E. coli cells expressing R292E/L18H variant were able to convert OPBA and BOC‐lysine to L ‐HPA and 2‐oxo‐6‐tert‐butoxycarbonylamino‐hexanoic acid (BOC‐OAHA) with 96.2% yield in 8 h. This is the first report demonstrating a process for the simultaneous production of two useful building blocks, L ‐HPA and BOC‐OAHA. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009     

The special optical properties and application of the heterocyclic compound diethyl 6‐anilino‐5H‐2,3‐dithia‐5,7‐diazacyclopenta(cd)indene‐1,4‐dicarboxylate

The heterocyclic compound diethyl 6‐anilino‐5H‐2,3‐dithia‐5,7‐diazacyclopenta(cd)indene‐1,4‐dicarboxylate (D1) was found to form highly emissive aggregates in polar solvents, and the aggregate emission can be tuned by the simple addition of water to a dimethylsulfoxide solution. A theoretical study based on Density functional theory (DFT) calculations, shows that intermolecular interactions of D1 with solvent may be potential factors in the fluorescence change. In addition, the phenyl ring in D1 plays an important role because of its response to solvent. In the non‐aggregated state, deprotonation of the N–H of D1 can proceed easily on the addition of base, and the deprotonated compound might interact with Ag⁺, resulting in a significant change in color and fluorescence quenching, which make it a potential chemosensor for the selective detection of trace amounts of Ag⁺. Copyright © 2013 John Wiley & Sons, Ltd.     

Resolution of 1‐n‐Butyl‐3‐Methyl‐3‐Phospholene 1‐Oxide With TADDOL Derivatives and Calcium Salts of O,O'‐Dibenzoyl‐(2R,3R)‐ or O,O'‐di‐p‐Toluoyl‐(2R,3R)‐tartaric Acid

The resolution methods applying (?)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane (“TADDOL”), (?)‐(2R,3R)‐α,α,α',α'‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol (“spiro‐TADDOL”), as well as the acidic and neutral Ca²⁺ salts of (?)‐O,O'‐dibenzoyl‐ and (?)‐O,O'‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid were extended for the preparation of 1‐n‐butyl‐3‐methyl‐3‐phospholene 1‐oxide in optically active form. In one case, the intermediate diastereomeric complex could be identified by single‐crystal X‐ray analysis. The absolute P‐configuration of the enantiomers of the phospholene oxide was also determined by comparing the experimentally obtained and calculated CD spectra. Chirality 26:174–182, 2014. © 2014 Wiley Periodicals, Inc.     

Expression and metabolic activity of flavin‐containing monooxygenase 1 in cynomolgus macaque kidney

Flavin‐containing monooxygenase 1 (FMO1) largely remains to be characterized in cynomolgus macaque kidney. Immunoblotting showed expression of cynomolgus FMO1 in kidneys where activities of FMO1 (benzydamine N‐oxygenation) were detected. No sex differences were observed in their contents or activities. These results suggest the functional role of cynomolgus FMO1 in kidney.