Nonadherence to treatment protocol in published randomised controlled trials: a review

ABSTRACT: This review aimed to ascertain the extent to which nonadherence to treatment protocol is reported and addressed in a cohort of published analyses of randomised controlled trials (RCTs). One hundred publications of RCTs, randomly selected from those published in BMJ, New England Journal of Medicine, the Journal of the American Medical Association and The Lancet during 2008, were reviewed to determine the extent and nature of reported nonadherence to treatment protocol, and whether statistical methods were used to examine the effect of such nonadherence on both benefit and harms analyses. We also assessed the quality of trial reporting of treatment protocol nonadherence and the quality of reporting of the statistical analysis methods used to investigate such nonadherence. Nonadherence to treatment protocol was reported in 98 of the 100 trials, but reporting on such nonadherence was often vague or incomplete. Forty-two publications did not state how many participants started their randomised treatment. Reporting of treatment initiation and completeness was judged to be inadequate in 64% of trials with short-term interventions and 89% of trials with long-term interventions. More than half (51) of the 98 trials with treatment protocol nonadherence implemented some statistical method to address this issue, most commonly based on per protocol analysis (46) but often labelled as intention to treat (ITT) or modified ITT (23 analyses in 22 trials). The composition of analysis sets for their benefit outcomes were not explained in 57% of trials, and 62% of trials that presented harms analyses did not define harms analysis populations. The majority of defined harms analysis populations (18 out of 26 trials, 69%) were based on actual treatment received, while the majority of trials with undefined harms analysis populations (31 out of 43 trials, 72%) appeared to analyse harms using the ITT approach. Adherence to randomised intervention is poorly considered in the reporting and analysis of published RCTs. The majority of trials are subject to various forms of nonadherence to treatment protocol, and though trialists deal with this nonadherence using a variety of statistical methods and analysis populations, they rarely consider the potential for bias introduced. There is a need for increased awareness of more appropriate causal methods to adjust for departures from treatment protocol, as well as guidance on the appropriate analysis population to use for harms outcomes in the presence of such nonadherence.     

Accounting for sap flow from different parts of the root system improves the prediction of xylem ABA concentration in plants grown with heterogeneous soil moisture

When soil moisture is heterogeneous, sap flow from, and ABA status of, different parts of the root system impact on leaf xylem ABA concentration ([X-ABA]leaf). The robustness of a model for predicting [X-ABA]leaf was assessed. 'Two root-one shoot' grafted sunflower (Helianthus annuus L.) plants received either deficit irrigation (DI, each root system received the same irrigation volumes) or partial rootzone drying (PRD, only one root system was watered and the other dried the soil). Irrespective of whether relative sap flow was assessed using sap flow sensors in vivo or by pressurization of de-topped roots, each root system contributed similarly to total sap flow during DI, while sap flow from roots in drying soil declined linearly with soil water potential (Psisoil) during PRD. Although Psisoil of the irrigated pot determined the threshold Psisoil at which sap flow from roots in drying soil decreased, the slope of this decrease was independent of the wet pot Psisoil. Irrespective of whether sap was collected from the wet or dry root system of PRD plants, or a DI plant, root xylem ABA concentration increased as Psisoil declined. The model, which weighted ABA contributions of each root system according to the sap flow from each, almost perfectly explained [X-ABA] immediately above the graft union. That the model overestimated measured [X-ABA]leaf may result from changes in [X-ABA] along the transport pathway or an artefact of collecting xylem sap from detached leaves. The implications of declining sap flow through partially dry roots during PRD for the control of stomatal behaviour and irrigation scheduling are discussed.     

Development of microsatellite markers for the white mangrove (Laguncularia racemosa C.F. Gaertn., Combretaceae)

We developed nine new microsatellite markers for the white mangrove (Laguncularia racemosa C.F. Gaertn.), a mangrove species widely distributed in the Western Hemisphere. The loci were developed from a sample collected in Baja California Sur, Mexico, and were screened for polymorphism in 108 individuals from the Pacific Coast of Mexico and Costa Rica. The level of polymorphism was relatively low, from two to four alleles. These are the first set of polymorphic markers described for L. racemosa and should be of value in studying regional genetic differentiation among natural populations of this species.     

State ranks of incident cancer burden due to overweight and obesity in the United States, 2003

Objective: Given links between obesity and cancer, we estimated incident cancer burden due to overweight and obesity at the state level in the United States. Methods and Procedures: Using state rankings by per capita burden of incident cancer cases diagnosed in 2003 that were related to overweight and obesity, we examined the frequency with which states ranked in the highest and lowest quintiles of weight‐related burden for cancers of the postmenopausal breast, endometrium, kidney, colon, and prostate. In this study, data from the Behavioral Risk Factor Surveillance System (BRFSS), US Census, US Mortality Public Use Data Tapes, and National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program were used. Results: Western states had the lowest weight‐related cancer burden for both sexes. Iowa, South Dakota, and West Virginia had the highest burden for all three types of male cancers. West Virginia is the only state that ranked in the quintile of highest weight‐related burden for all four cancers considered in women. Discussion: For certain cancers, including endometrial, postmenopausal breast, and colon cancers, states with high burdens clustered in geographic regions, warranting further inquiry. Although state ranks for the total cancer burden and the prevalence of overweight and obesity correlated with state ranks for weight‐related incident cancer burden, they often served poorly as its proxy. Such a finding cautions against simply targeting states with high overweight and obesity or high total burdens of cancers for which overweight and obesity are risk factors, as this approach may not reach areas of unrecognized burden.     

Predominant allylic hydroxylation at carbons 6 and 7 of 4 and 5-ene functionalized steroids by the thermophilic fungus Rhizomucor tauricus IMI23312

This paper demonstrates for the first time transformation of a series of steroids (progesterone, androst-4-en-3,17-dione, testosterone, pregnenolone and dehydroepiandrosterone) by the thermophilic fungus Rhizomucor tauricus. All transformations were found to be oxidative (monohydroxylation and dihydroxylation) with allylic hydroxylation the predominant route of attack functionalizing the steroidal skeleta. Timed experiments demonstrated that dihydroxylation of progesterone, androst-4-en-3,17-dione and pregnenolone all initiated with hydroxylation on ring-B followed by attack on ring-C. Similar patterns of steroidal transformation to those observed with R. tauricus have been observed with some species of thermophilic Bacilli and mesophilic fungi. All metabolites were isolated by column chromatography and were identified by (1)H, (13)C NMR, DEPT analysis and other spectroscopic data. The application of thermophilic fungi to steroid transformation may represent a potentially rich source for the generation of new steroidal compounds as well as for uncovering inter and intraspecies similarities and differences in steroid metabolism.     

Benzothiazole based inhibitors of p38alpha MAP kinase

Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.     

Bacterial Community Structure and Location in Stilton Cheese

The microbial diversity occurring in Stilton cheese was evaluated by 16S ribosomal DNA analysis with PCR-denaturing gradient gel electrophoresis. DNA templates for PCR experiments were directly extracted from the cheese as well as bulk cells harvested from a variety of viable-count media. The variable V3 and V4-V5 regions of the 16S genes were analyzed. Closest relatives of Lactococcus lactis, Enterococcus faecalis, Lactobacillus plantarum, Lactobacillus curvatus, Leuconostoc mesenteroides, Staphylococcus equorum, and Staphylococcus sp. were identified by sequencing of the DGGE fragments. Fluorescently labeled oligonucleotide probes were developed to detect Lactococcus lactis, Lactobacillus plantarum, and Leuconostoc mesenteroides in fluorescence in situ hybridization (FISH) experiments, and their specificity for the species occurring in the community of Stilton cheese was checked in FISH experiments carried out with reference cultures. The combined use of these probes and the bacterial probe Eub338 in FISH experiments on Stilton cheese sections allowed the assessment of the spatial distribution of the different microbial species in the dairy matrix. Microbial colonies of bacteria showed a differential location in the different parts of the cheese examined: the core, the veins, and the crust. Lactococci were found in the internal part of the veins as mixed colonies and as single colonies within the core. Lactobacillus plantarum was detected only underneath the surface, while Leuconostoc microcolonies were homogeneously distributed in all parts observed. The combined molecular approach is shown to be useful to simultaneously describe the structure and location of the bacterial flora in cheese. The differential distribution of species found suggests specific ecological reasons for the establishment of sites of actual microbial growth in the cheese, with implications of significance in understanding the ecology of food systems and with the aim of achieving optimization of the fermentation technologies as well as preservation of traditional products.