Bayesian enrichment strategies for randomized discontinuation trials

We propose optimal choice of the design parameters for random discontinuation designs (RDD) using a Bayesian decision-theoretic approach. We consider applications of RDDs to oncology phase II studies evaluating activity of cytostatic agents. The design consists of two stages. The preliminary open-label stage treats all patients with the new agent and identifies a possibly sensitive subpopulation. The subsequent second stage randomizes, treats, follows, and compares outcomes among patients in the identified subgroup, with randomization to either the new or a control treatment. Several tuning parameters characterize the design: the number of patients in the trial, the duration of the preliminary stage, and the duration of follow-up after randomization. We define a probability model for tumor growth, specify a suitable utility function, and develop a computational procedure for selecting the optimal tuning parameters.     

CART trials are going ahead

正For a long time,unresectable tumors were mainly controlled by chemotherapy,radiation therapy or kinase inhibitors,with which complete and durable remission was infrequent despite great advances achieved.Until recently,together with checkpoint inhibitors,chimeric antigen receptor modified T(CART)therapies have made immunotherapy percolated into the mainstream of cancer treatment due to astonishing clinical results.     

Nonregistration,discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis

BackgroundWe previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs.Methods and findingsWe included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment.Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%).The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations.ConclusionsWe have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

Benjamin Speich and colleagues investigate whether rates of trial completion and publication have increased over the past decade, the extent to which non-published trials can be identified in registries, and the association between reporting quality of protocols and premature discontinuation or non-publication of trials.     

Incomplete polypeptides are formed in vitro by premature chain termination

The mechanism of incomplete polypeptides formation during protein synthesis was studied in the wheat germ cell-free system programmed with brome mosaic virus RNA 4. The synthesis of coat protein, the complete product of RNA 4 translation, was accompanied by the appearance of polypeptides of lower molecular mass. It was shown that incomplete products are formed by translation of different lengths of RNA 4, always from the first 5' AUG codon, and were due neither to proteolysis of coat protein nor to the translation of nucleolytic fragments of mRNA. The molecular masses of incomplete products were determined and the nucleotide sequence of RNA 4 was examined in the regions where wheat germ ribosomes stop translating. It was found that they contained, on average, a slightly higher guanosine content than the total coding part of RNA 4. Translation of RNA 4 in the reticulocyte lysate resulted in a marked diminution of incomplete polypeptides. Addition of high-speed supernatant from reticulocyte lysate prevented the formation of incomplete products during translation of RNA 4 in the wheat germ system. This suggests that reticulocyte lysate contains some factor(s) which facilitate the movement of ribosomes beyond the regions where the elongation is retarded.     

Cavity-nesting birds are limited by nesting habitat in Neotropical agricultural landscapes

Most studies comparing biodiversity between natural and human-modified landscapes focus on patterns in species occurrence or abundance, but do not consider how different habitat types meet species' breeding requirements. Organisms that use or nest in tree cavities may be especially threatened by habitat conversion due to the loss of their nesting sites. Although cavity-nesting bird diversity is highest in the tropics, little is known about how tropical birds use cavities, how agriculture affects their reproductive biology, and how effective nest boxes could be as a conservation strategy in tropical agriculture. Here, we explored how habitat conversion from tropical forests to pasture affects the abundance, nesting habitat availability, and nest success of cavity-nesting birds in Northwest Ecuador. We conducted bird surveys and measured natural cavity availability and use in forest and agriculture. We also added artificial nest boxes to forest and agriculture to see whether cavity limitation in agriculture would elicit higher use of artificial nest boxes. We found evidence of cavity limitation in agriculture—there were many more natural cavities in forest than in agriculture, as well as more avian use of nest boxes placed in agriculture as compared to forest. Our results suggest that it is important to retain remnant trees in tropical agriculture to provide critical nesting habitat for birds. In addition, adding nest boxes to tropical agricultural systems could be a good conservation strategy for certain species, including insectivores that could provide pest-control services to farmers. Abstract in Spanish is available with online material.     

Ceruloplasmin receptors in liver cell suspensions are limited to the endothelium

The interaction of ceruloplasmin (CP) with isolated liver cell suspensions was studied using 125I-labeled and latex minibead-derivatized CP. Fractionation of liver cell suspensions was done using metrizamide gradient centrifugation. In crude liver cell suspensions only endothelial cells, but not hepatocytes and Kupffer cells bound the minibead probe. The binding was specific and inhibited by excess native CP. These results were confirmed using 125I-CP combined with cell fractionation technique. Kinetic data, obtained from the latter system, indicated a dissociation constant (Kd) of 1 X 10(-7) M and the number of receptors to be 5.7 X 10(5) per endothelial cell. The exclusive binding of CP to liver endothelium suggests that this cell may mediate the hepatocytes uptake of CP and is, therefore, a crucial element of the tissue-blood barrier.     

Microbial communities in terrestrial surface soils are not widely limited by carbon

Microbial communities in soils are generally considered to be limited by carbon (C), which could be a crucial control for basic soil functions and responses of microbial heterotrophic metabolism to climate change. However, global soil microbial C limitation (MCL) has rarely been estimated and is poorly understood. Here, we predicted MCL, defined as limited availability of substrate C relative to nitrogen and/or phosphorus to meet microbial metabolic requirements, based on the thresholds of extracellular enzyme activity across 847 sites (2476 observations) representing global natural ecosystems. Results showed that only about 22% of global sites in terrestrial surface soils show relative C limitation in microbial community. This finding challenges the conventional hypothesis of ubiquitous C limitation for soil microbial metabolism. The limited geographic extent of C limitation in our study was mainly attributed to plant litter, rather than soil organic matter that has been processed by microbes, serving as the dominant C source for microbial acquisition. We also identified a significant latitudinal pattern of predicted MCL with larger C limitation at mid- to high latitudes, whereas this limitation was generally absent in the tropics. Moreover, MCL significantly constrained the rates of soil heterotrophic respiration, suggesting a potentially larger relative increase in respiration at mid- to high latitudes than low latitudes, if climate change increases primary productivity that alleviates MCL at higher latitudes. Our study provides the first global estimates of MCL, advancing our understanding of terrestrial C cycling and microbial metabolic feedback under global climate change.     

Evolution towards self‐compatibility when mates are limited

Theory of plant mating system evolution predicts the spread of self‐compatibility (SC) in a predominantly self‐incompatible population when inbreeding depression (ID; the decline in fitness because of selfing) is small and when compatible mates are limited. I tested these two predictions by measuring the occurrence of SC in 13 natural populations of Ranunculus reptans L. that varied in ID and frequency of cross‐incompatible mates. Enforced selfing experiments were conducted in 2 years. In the first year, self‐pollination was applied at two flower ages to investigate the occurrence of delayed SC. I found that SC was not uncommon across all populations, but self‐compatible plants usually produced few seeds. There was no evidence for delayed SC. The occurrence of SC was not associated with population‐level ID, but populations with more limited availability of compatible mates had a significantly higher frequency of plants that were at least partially self‐compatible. The results indicate that, in R. reptans, a shortage of available mates in small populations may cause the evolution of partial SC and mixed mating.