Maximum Size Research Articles

A tutorial on value-based adaptive designs: Could a value-based sequential two-arm design have created more health economic value for the Big CACTUS trial?

Value-based trials aim to maximize the expected net benefit by balancing technology adoption decisions and clinical trial costs. Adaptive trials offer additional efficiency. This paper provides guidance on determining whether a value-based sequential design is the best option for an adaptive two-arm trial, illustrated through a case study. We outline four steps for the value-based sequential approach. The case study re-evaluates the Big CACTUS trial design using pilot trial data and a model-based health economic analysis. Expected net benefit is computed for (a) original fixed design, (b) value-based design with fixed sample size, and (c) optimal value-based sequential design with adaptive stopping. We compare pre-trial modelling with actual Big CACTUS trial results. Over ten years, the adoption decision would impact approximately 215,378 patients. Pre-trial modelling shows that the expected net benefit minus costs is (a) £102m for the original fixed design, (b) £107m (+5.3% higher) for the value-based design with optimal fixed sample size, and (c) £109m (+6.7% higher) for the optimal value-based sequential design with maximum sample size of 435 per arm. Post hoc analysis using actual Big CACTUS trial data indicates that the value-adaptive trial with a maximum sample size of 95 participant pairs wouldn't have stopped early. Bootstrap simulations reveal a 9.76% probability of early completion with n=95, compared to 31.50% with n=435. The four-step approach to value-based sequential two-arm design with adaptive stopping was successfully implemented. Further application of value-based adaptive approaches could be useful to assess efficiency of alternative study designs.

Reinforcing membranes with subgaskets in proton exchange membrane water electrolysis: A model-based analysis

Ensuring the long-term mechanical durability of perfluorosulfonic acid membranes in proton exchange membrane water electrolysis (PEMWE) is essential for long lifetimes. This study investigates the potential of reinforcing the membrane by incorporating a subgasket layer outside the active area. Thus, experimental tensile measurements with the subgasket material and with the subgasket-membrane composite are conducted to characterize their mechanical properties. The obtained data are used to identify suitable material models and parameterize them by applying a tensile test simulation based on the finite element method. By integrating subgaskets in a structural mechanics PEMWE cell model, the impact of the reinforcement on the membrane stability was investigated. The results indicate that even thin layers of subgaskets stabilize the membrane at the gap interface between the cell frame and the porous transport layer. The level of stabilization is further enhanced when using thicker subgaskets that cover the entire gap. However, one-sided subgaskets exhibit reduced mechanical stabilization. Furthermore, membrane buckling due to an increased gap size can be prevented using a subgasket up to a maximum gap size of 0.45 mm.

Morphologic and phylogenetic investigations revealed size-divergent clades in chelae morphotypes of freshwater prawn Macrobrachium vollenhovenii Herklots (Decapoda: Palaemonidae) in a lake and river system of Southwest Nigeria

BackgroundThe freshwater prawn Macrobrachium vollenhovenii is one of the largest Macrobrachium species, a biological agent against human schistosomiasis, and a cheap protein source in riverine communities in West Africa. However, its aquaculture development for sustainable utilization is challenged by cryptic identity amidst the presence of morphotypes of unknown size and genetic relatedness. This study aimed to investigate the maximum sizes and evolutionary links of chelae morphotypes in M. vollenhovenii for precise identification and utilization in a 3 × 2 randomized block experimental design. Ninety biggest encountered samples of M. vollenhovenii chelae morphotypes—those possessing equal left and right side chelae, longer left chelae, and shorter left chelae—were obtained from fisherfolks’ catches at each of Asejire Lake and Ogun River during peak seasons (July–September) bimonthly field survey, representing EAAL, LLAL, SLAL—GAALs, and EAOR, LLOR, SLOR—GAORs. These were analyzed for differences (p < 0.05) in size-linked parameters—length (L (cm)), weight (W (g)), and condition factor (K). Specimens’ 16S rRNA nucleotide sequences were utilized to infer phylogenetic linkages, single-nucleotide polymorphism (SNP), and amino acid translations alongside NCBI references (NCBIrefseq).ResultsWeight (W) and condition factor (K), among GAALs, for SLAL and LLAL were similar; EAAL was significantly lowest; among GAORs, SLOR and LLOR were similar; and EAOR was significantly lowest. In GAALs, EAAL, LLAL, and SLAL had higher L, W, and K than counterpart GAORs. Sequences formed two polyphyletic groups: EAOR branch from EAAL, in which 100.0%EA rooted 75.0% NCBIrefseqs, forming a clade; and GAOR-SLOR and LLOR branch form GAOR-LLAL rooted SLAL, in which 100.0%LL and SL rooted KJ463387.1 (Badagry), forming another clade. SNP Locus 91 separated 100.0%GAOR from 100.0%GAAL and 100.0%NCBIrefseqs translating to valine; SNP Locus 171 separated 100.0%EA and its co-rooted NCBIrefseqs from 100.0%LL, SL, and their co-rooted NCBIrefseq, translating to glycine/glutamic acid change.ConclusionThe equal left and right side chelae and the unequal left and right side chelae specimens are, respectively, small- and robust-sized, irrespective of habitat. They are divergent size-linked clades having protein translate differences, delineable at 16S rRNA SNP Locus 171; their size variant habitat strains are delineable at SNP Locus 91. These SNP markers will be useful for precision identification and selection of the size variant chelae morph strains for sustainable utilization.

Heights of posets associated with Green's relations on semigroups

Given a semigroup S, for each Green's relation K∈{L,R,J,H} on S, the K-height of S, denoted by HK(S), is the height of the poset of K-classes of S. More precisely, if there is a finite bound on the sizes of chains of K-classes of S, then HK(S) is defined as the maximum size of such a chain; otherwise, we say that S has infinite K-height. We discuss the relationships between these four K-heights. The main results concern the class of stable semigroups, which includes all finite semigroups. In particular, we prove that a stable semigroup has finite L-height if and only if it has finite R-height if and only if it has finite J-height. In fact, for a stable semigroup S, if HL(S)=n then HR(S)≤2n−1 and HJ(S)≤2n−1, and we exhibit a family of examples to prove that these bounds are sharp. Furthermore, we prove that if 2≤HL(S)<∞ and 2≤HR(S)<∞, then HJ(S)≤HL(S)+HR(S)−2. We also show that for each n∈N there exists a semigroup S such that HL(S)=HR(S)=2n+n−3 and HJ(S)=2n+1−4. By way of contrast, we prove that for a regular semigroup the L-, R- and H-heights coincide with each other, and are greater or equal to the J-height. Moreover, in a stable, regular semigroup the L-, R-, H- and J-heights are all equal.

P-144 Utilizing artificial intelligence to uncover Day 5 morphokinetic features associated with single blastocyst transfer implantation outcome

Abstract Study question Can AI aid in studing embryos’ continuous development in Day5 and identifying morphokinetic features (blastocyst growth and spontaneous collapse etc.), to improve implantation potential prediction? Summary answer The AI system utilized time-lapse images to measure newly identified morphokinetic features, establishing a significant correlation with clinical pregnancy outcomes. What is known already In Single Blastocyst Transfer (SBT), the conventional Gardner evaluation system may inadequately differentiate between embryos of comparable morphology scores in specific cases. To address this, integrating new morphokinetic features is essential for enhanced blastocyst evaluation. Spontaneous collapse (SC) during blastocyst expansion is a phenomenon that was revealed relatively recently following the clinical application of time-lapse monitoring in IVF laboratories. Previous studies link embryo size and SC to quality, yet these correlations require further validation. In the critical selection process utilizing time-lapse imaging (TLI) systems, AI technology is indispensable for developing automated and interpretable tools to ensure precise quantitative measurements. Study design, size, duration 255 patients underwent IVF with Day5 single blastocyst transfer in fresh cycles at the Center for Reproductive Medicine, Nanjing Drum Tower Hospital, from April 2021 to August 2022, and were analyzed in this retrospective study. Embryos were cultured in time-lapse incubators (CCM-iBIS, ASTEC). On Day 3 embryos were transferred to sequential media (G2, Vitrolife, Sweden) and cultured in the same incubator until Day5. In this cohort, there were 167 clinical pregnancies and 88 non-pregnant cases. Participants/materials, setting, methods An AI system was developed to calculate the development curves of areas in each part of the embryo (ZP,blastocel, ICM and TE) based on TLI images from 92 to 116 phi(±2). T-test and correlation analysis were used to select effective features. The dataset was divided into training and testing subset in an 80:20 ratio. The performance of different prediction models were compared by Delong test. Main results and the role of chance In this study, an AI system automatically generated blastocyst development curves, from which 35 morphokinetic features were extracted. These features were carefully defined to comprehensively capture the dynamics of embryo size development and spontaneous collapse (SC). Six parameters, including maximum size, max/min ratio of blastocyst area (with and without ZP region), speed of expansion after tSB, and number of minor SC, exhibited statistical correlation with clinical pregnancy outcomes. Using these parameters, an XGBoost model achieved an AUC of 0.71 for pregnancy prediction, surpassing (p = 0.0307, p &amp;lt; 0.05) the AUC of 0.48 from the model trained with manual Gardner evaluation. These findings underscore the potential of AI-generated morphokinetic features of D5 in enhancing blastocyst evaluation systems. Limitations, reasons for caution The limited sample size used in this retrospective experiment may lead to an underrepresentation of certain significant features. Wider implications of the findings In contrast to prior findings, most SC-based features in our study did not significantly correlate with clinical pregnancy outcome. Further research is needed to understand their causes and implications. Integrating AI with TLI offers promise for improving single blastocyst transfer outcomes, emphasizing quantifiability and interpretability in approach. Trial registration number NA

Unconditional optimal [formula omitted]-norm error estimate and superconvergence analysis of a linearized nonconforming finite element variable-time-step BDF2 method for the nonlinear complex Ginzburg–Landau equation

In this paper, a linearized fully discrete scheme combining the variable-time-step two-step backward differentiation formula (VSBDF2) in time and the nonconforming finite element methods (FEMs) in space is constructed and analyzed for the nonlinear complex Ginzburg–Landau equation. A novel convergence analysis approach is proposed, which shows that the H1-norm error of this scheme can reach optimal order in space and sharp second-order convergence in time. The key ingredients of our analysis are temporal-spatial error splitting approach, a new positive definiteness property of discrete orthogonal convolution (DOC) kernels with respect to complex sequences, an energy projection operator and a discrete Laplace operator Δh related to the nonconforming element space, and a relationship between Δh and classical L2 projection operator in complex space. Furthermore, through a specific treatment of the error equation and the combination technique of interpolating operator and projection operator, we prove that the proposed scheme has the global superconvergence result of order O(τ2+h2) in H1-norm for the first time, which further improves the efficiency of numerical computation. Here τ and h are the maximum time and spatial step sizes, respectively. It should be pointed out that all these error results are rigorously established under mild assumptions of the time step, and get rid of the usual grid ratio constraints between temporal and spatial step sizes in linearized scheme. At last, numerical experiments are provided to verify the theoretical analysis.

Stability of bubble-particle hetero-coagulates accessed by atomic force microscopy to understand the froth flotation of agglomerating hydrophobic fines

The key microprocesses, which determine the efficiency in froth flotation are the formation and breakage of particle-bubble hetero-coagulates. Agglomeration can be used to increase the recovery of fine particles < 20 µm. Here the stability of hetero-coagulates consisting of agglomerates and gas bubble determines the process performance. Therefore, the stability of agglomerate-bubble hetero-coagulates was accessed by atomic force microscopy (AFM) on particle-laden gas bubbles, agglomerates and pristine gas bubbles without particles in the interface. The force and work of adhesion from AFM measurements were compared to the detaching force and the detaching energy that act on agglomerate-bubble and particle-bubble hetero-coagulates under turbulent conditions, similar to those in a flotation cell. This comparison provides the maximum size of agglomerates and single particles that can remain attached to the gas bubbles at a given energy dissipation rate. The results suggest that the size of agglomerates attached to gas bubbles can grow beyond the Kolmogorov length, which limits the size of agglomerates under turbulent conditions. The findings are supported by in-line probe images of agglomerate-bubble hetero-coagulates that were captured in an aerated stirred tank under turbulent conditions. It was further shown that the particle detachment from particle-laden bubbles is governed by the deformation of the underlying gas bubble and the local particle coverage.

Commutative nilpotent transformation semigroups

AbstractCameron et al. determined the maximum size of a null subsemigroup of the full transformation semigroup $$\mathcal {T}(X)$$ T ( X ) on a finite set X and provided a description of the null semigroups that achieve that size. In this paper we extend the results on null semigroups (which are commutative) to commutative nilpotent semigroups. Using a mixture of algebraic and combinatorial techniques, we show that, when X is finite, the maximum order of a commutative nilpotent subsemigroup of $$\mathcal {T}(X)$$ T ( X ) is equal to the maximum order of a null subsemigroup of $$\mathcal {T}(X)$$ T ( X ) and we prove that the largest commutative nilpotent subsemigroups of $$\mathcal {T}(X)$$ T ( X ) are the null semigroups previously characterized by Cameron et al.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov (NCT04217551, 2019-12-30).

Histological predictors of the unfavorable outcome of anorectal melanoma

AIM: to find histological prognostic factors for survival in patients with anorectal melanoma.PATIENTS AND METHODS: single center retrospective study of histological specimens of patients with anorectal melanoma (2005-2023). A revision of histological specimens was carried out, using the following criteria: multifocal growth, maximum tumor size, maximum thickness by Breslow, ulceration, perineural and lymphovascular invasion, as well as depth of invasion. Statistical processing was carried out using the Cox regression.RESULTS: twenty-one patients were included in the study. In all patients, treatment started with surgery: 13 (61.9%) — abdominoperineal excision (APE); 8 (28.1%) — local excision). The sample contained patients with the following initial stages of the process: IB–IIB — 12 (57.1%); III — 9 (42.9%). Nine (42.9%) patients developed local recurrence, and 8 (38.1%) — distant metastases. On univariate analysis, DFS was significantly affected by ulceration RR 0.061 (CI 95.0%; 0.004–0.097, p = 0.048), there was a trend towards the role of neurotropism RR 3.654 (CI 95.0%; 0.934–14.297, p = 0.063) and pigmentation RR 2.485 (CI 95.0%; 0.832–7.424, p = 0.103). In multivariate analysis, none of the criteria had a significant effect on DFS. On OS in univariate analysis was a trend towards an effect of Breslow invasion depth of more than 2 cm HR 1.028 (CI 95.0%; 0.998–1.060, p = 0.070) and depth of tumor invasion HR 2.117 (CI 95.0%; 0.990–4.525, p = 0.053). In multivariate analysis, none of the criteria had a significant effect on OS.CONCLUSION: evaluation of the effectiveness by histological features of skin melanoma showed the potential use of neurotropism, Breslow invasion of more than 2 cm and depth of tumor invasion as factors of unfavorable impact on DFS and OS in ARM. More trials are needed.

Collision energy dependence of source sizes for primary and secondary pions at energies available at the JINR nuclotron-based ion collider facility from Lévy fits

We study the evolution of the two-pion correlation function parameters with collision energy in the context of relativistic heavy-ion collisions within the NICA energy range. To this end, we perform UrQMD simulations in the cascade mode to produce samples of pions from 5×106\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$5\ imes 10^6$$\\end{document} Bi+Bi collisions for each of the studied energies. The effects of the quantum-statistical correlations are introduced using the correlation afterburner code CRAB. We fit the correlation function using Gaussian, exponential and symmetric Lévy shapes and show that for all collision energies the latter provides the best fit. We separate the sample into pions coming from primary processes and pions originating from the decay of long-lived resonances, and show that the source size for the latter is significantly larger than for the former. The source size for the secondaries, is similar but in general larger than the size for the whole pion sample. To further characterize the pion source, we also simulate the effects of a non-ideal detector introducing a momentum smearing parameter, representing the minimum pair momentum and thus a maximum source size that can be resolved. The values of the correlation function intercept parameter are therefore modified from the values they attain for the perfect detector case. Using the core-halo picture of the source, we show that the values of the intercept parameter are influenced by the presence of a significant fraction of core pions coming from the decay of long-lived but slow-moving resonances. These findings serve as a benchmark to compare with future Monte Carlo studies that consider an Equation of State and thus allow for a phase transition within the studied energy domain.

Coolability of a Corium Pool in a Debris Bed: Impact of Debris Size, Steam, and Liquid Flow Rate; Tilting Angle; and Pressure on Critical Heat Flux—First Numerical Evaluations

In case of a severe accident in a light water reactor, a debris bed may form in the core and possibly melt, as happened in Three Mile Island Unit 2. Knowledge about the coolability of such a molten pool surrounded by debris is crucial to investigate the possibility of stabilizing a part of the fuel inside the vessel. In particular, it is of primary interest to determine the maximum size of a molten pool surrounded by debris that may be stabilized under water. A key parameter is the maximum heat flux [critical heat flux (CHF)] that may be extracted from the pool boundary by water flowing within the debris bed. A facility was built at IRSN to determine the CHF under various conditions. A heated copper surface simulates the boundary of the pool and is placed in contact with a debris bed (monodisperse steel balls), under water. In this article, we first complete previous experimental work with steam and liquid flow rates, ball diameter, tilting angle of the heated surface, and pressure up to 2.5 bar absolute. A general CHF correlation depending on the tilting angle and the steam flow rate is derived, and an example of the use of this correlation to evaluate the maximum mass of the corium pool that can be stabilized under water is given, for some typical reactor conditions. In the last part of the article, the accuracy of the ASTEC code is evaluated based on first calculations intending to reproduce the experimental impact of liquid and steam flow rates.

Prospective Spatiotemporal Cluster Detection Using SaTScan: Tutorial for Designing and Fine-Tuning a System to Detect Reportable Communicable Disease Outbreaks.

Staff at public health departments have few training materials to learn how to design and fine-tune systems to quickly detect acute, localized, community-acquired outbreaks of infectious diseases. Since 2014, the Bureau of Communicable Disease at the New York City Department of Health and Mental Hygiene has analyzed reportable communicable diseases daily using SaTScan. SaTScan is a free software that analyzes data using scan statistics, which can detect increasing disease activity without a priori specification of temporal period, geographic location, or size. The Bureau of Communicable Disease's systems have quickly detected outbreaks of salmonellosis, legionellosis, shigellosis, and COVID-19. This tutorial details system design considerations, including geographic and temporal data aggregation, study period length, inclusion criteria, whether to account for population size, network location file setup to account for natural boundaries, probability model (eg, space-time permutation), day-of-week effects, minimum and maximum spatial and temporal cluster sizes, secondary cluster reporting criteria, signaling criteria, and distinguishing new clusters versus ongoing clusters with additional events. We illustrate how to support health equity by minimizing analytic exclusions of patients with reportable diseases (eg, persons experiencing homelessness who are unsheltered) and accounting for purely spatial patterns, such as adjusting nonparametrically for areas with lower access to care and testing for reportable diseases. We describe how to fine-tune the system when the detected clusters are too large to be of interest or when signals of clusters are delayed, missed, too numerous, or false. We demonstrate low-code techniques for automating analyses and interpreting results through built-in features on the user interface (eg, patient line lists, temporal graphs, and dynamic maps), which became newly available with the July 2022 release of SaTScan version 10.1. This tutorial is the first comprehensive resource for health department staff to design and maintain a reportable communicable disease outbreak detection system using SaTScan to catalyze field investigations as well as develop intuition for interpreting results and fine-tuning the system. While our practical experience is limited to monitoring certain reportable diseases in a dense, urban area, we believe that most recommendations are generalizable to other jurisdictions in the United States and internationally. Additional analytic technical support for detecting outbreaks would benefit state, tribal, local, and territorial public health departments and the populations they serve.

Updated endometrial cancer FIGO staging: the role of MRI in determining newly included histopathological criteria.

Endometrial cancer (EC) is among the prevalent malignancies in gynecology, showing an increasing occurrence and mortality rate. The updated 2023 FIGO staging integrates both histopathological and molecular analyses, which significantly impact the prognosis and treatment approaches. This research aims to examine the effectiveness of MRI in identifying essential histopathological tumor features, including histological subtype, grade, and lymphovascular space invasion. A total of 106 patients diagnosed with EC from February 2018 to December 2023 underwent preoperative pelvic MRI. Surgical procedures followed ESMO guidelines, with histopathological assessments using FIGO 2009 criteria. Two radiologists independently evaluated MRI images, measuring maximum tumor size, minimum tumor ADC value (using a free-hand ROI technique), and ADC tumor/myometrium ratio. MRI findings were compared with histopathological data. Peritoneal implant presence and tumor size exhibited significant differences between endometrioid adenocarcinoma (EAC) and non-endometrioid endometrial carcinoma (NEEC), with p values of < 0.001 and 0.003, respectively. Significant differences in age, tumor size, ADC tumor, and ADC tumor/myometrium between low-grade and high-grade tumors were observed, with p values of < 0.001, 0.004, 0.006, and 0.011, respectively. Increased tumor size, reduced ADC tumor, ADC tumor/myometrium, and pelvic peritoneal implant presence were significantly associated with LVSI, with p values of < 0.001, 0.001, 0.002, and 0.001, respectively. The AUC values for tumor size, ADC tumor, and ADC tumor/myometrium were 0.842, 0.781 and 0.747, respectively, in distinguishing between low and high-grade endometrial tumors. Similarly, obtained AUC values for predicting LVSI were 0.836, 0.719, and 0.696, respectively. Our study emphasizes MRI's role in predicting tumor characteristics such as histological subtype, grade, and LVSI based on updated FIGO criteria. By highlighting the potential of MRI, this research contributes to our comprehension of improving diagnostic and clinical management for EC. Further multicenter studies are warranted to validate these findings and establish MRI's role in EC management.

Multi-arm multi-stage (MAMS) randomised selection designs: impact of treatment selection rules on the operating characteristics

BackgroundMulti-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage. In these cases, an additional treatment selection rule can be applied at the early stages of the trial to restrict the maximum number of research arms that can progress to the subsequent stage(s).This article provides guidelines on how to implement treatment selection within the MAMS framework. It explores the impact of treatment selection rules, interim lack-of-benefit stopping boundaries and the timing of treatment selection on the operating characteristics of the MAMS selection design.MethodsWe outline the steps to design a MAMS selection trial. Extensive simulation studies are used to explore the maximum/expected sample sizes, familywise type I error rate (FWER), and overall power of the design under both binding and non-binding interim stopping boundaries for lack-of-benefit.ResultsPre-specification of a treatment selection rule reduces the maximum sample size by approximately 25% in our simulations. The familywise type I error rate of a MAMS selection design is smaller than that of the standard MAMS design with similar design specifications without the additional treatment selection rule. In designs with strict selection rules - for example, when only one research arm is selected from 7 arms - the final stage significance levels can be relaxed for the primary analyses to ensure that the overall type I error for the trial is not underspent. When conducting treatment selection from several treatment arms, it is important to select a large enough subset of research arms (that is, more than one research arm) at early stages to maintain the overall power at the pre-specified level.ConclusionsMulti-arm multi-stage selection designs gain efficiency over the standard MAMS design by reducing the overall sample size. Diligent pre-specification of the treatment selection rule, final stage significance level and interim stopping boundaries for lack-of-benefit are key to controlling the operating characteristics of a MAMS selection design. We provide guidance on these design features to ensure control of the operating characteristics.

Disturbance history, neighborhood crowding and soil conditions jointly shape tree growth in temperate forests.

Understanding how different mechanisms act and interact in shaping communities and ecosystems is essential to better predict their future with global change. Disturbance legacy, abiotic conditions, and biotic interactions can simultaneously influence tree growth, but it remains unclear what are their relative contributions and whether they have additive or interactive effects. We examined the separate and joint effects of disturbance intensity, soil conditions, and neighborhood crowding on tree growth in 10 temperate forests in northeast China. We found that disturbance was the strongest driver of tree growth, followed by neighbors and soil. Specifically, trees grew slower with decreasing initial disturbance intensity, but with increasing neighborhood crowding, soil pH and soil total phosphorus. Interestingly, the decrease in tree growth with increasing soil pH and soil phosphorus was steeper with high initial disturbance intensity. Testing the role of species traits, we showed that fast-growing species exhibited greater maximum tree size, but lower wood density and specific leaf area. Species with lower wood density grew faster with increasing initial disturbance intensity, while species with higher specific leaf area suffered less from neighbors in areas with high initial disturbance intensity. Our study suggests that accounting for both individual and interactive effects of multiple drivers is crucial to better predict forest dynamics.

Navigating uncertainty in maximum body size in marine metazoans.

Body size is a fundamental biological trait shaping ecological interactions, evolutionary processes, and our understanding of the structure and dynamics of marine communities on a global scale. Accurately defining a species' body size, despite the ease of measurement, poses significant challenges due to varied methodologies, tool usage, and subjectivity among researchers, resulting in multiple, often discrepant size estimates. These discrepancies, stemming from diverse measurement approaches and inherent variability, could substantially impact the reliability and precision of ecological and evolutionary studies reliant on body size data across extensive species datasets. This study examines the variation in reported maximum body sizes across 69,570 individual measurements of maximum size, ranging from <0.2 μm to >45 m, for 27,271 species of marine metazoans. The research aims to investigate how reported maximum size variations within species relate to organism size, taxonomy, habitat, and the presence of skeletal structures. The investigation particularly focuses on understanding why discrepancies in maximum size estimates arise and their potential implications for broader ecological and evolutionary studies relying on body size data. Variation in reported maximum sizes is zero for 38% of species, and low for most species, although it exceeds two orders of magnitude for some species. The likelihood of zero variation in maximum size decreased with more measurements and increased in larger species, though this varied across phyla and habitats. Pelagic organisms consistently had low maximum size range values, while small species with unspecified habitats had the highest variation. Variations in maximum size within a species were notably smaller than interspecific variation at higher taxonomic levels. Significant variation in maximum size estimates exists within marine species, and partially explained by organism size, taxonomic group, and habitat. Variation in maximum size could be reduced by standardized measurement protocols and improved meta-data. Despite the variation, egregious errors in published maximum size measurements are rare, and their impact on comparative macroecological and macroevolutionary research is likely minimal.

Stereotactic radiosurgery in patients with small cell lung cancer and 1-10 brain metastases: A multi-institutional, phase II, prospective clinical trial.

2020 Background: Stereotactic radiosurgery (SRS) as opposed to whole brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases. Brain metastases from small cell lung cancer (SCLC), however, represent an exception to this dogma, given that prior trials evaluating SRS in lieu of WBRT excluded patients with SCLC due to the historical role of prophylactic cranial irradiation (PCI) and concerns relating to neurologic decline and death when WBRT is omitted from upfront management. We conducted a prospective, multi-center, phase II trial of SRS in patients with SCLC and 1-10 brain metastases to determine how rates of neurologic death compared to historical controls managed with WBRT. Methods: Following approval from the Dana-Farber/Harvard Cancer Center IRB, we opened a single-arm, multi-center, phase II trial to investigate SRS in patients with SCLC and 1-10 brain metastases naïve to prior brain-directed radiation including PCI (NCT03391362). Prior resection of a brain metastasis was permitted. Patients with leptomeningeal disease were excluded. Metastases &lt;2cm in maximal size were generally managed with SRS to 20 Gy; larger tumors, or those near sensitive structures, were dose reduced to 16-19 Gy or managed with fractioned SRS (SRT) to 30 Gy in 5 fractions. Gross totally resected brain metastases received SRT to 25 Gy in 5 fractions. We sought to determine, as the primary endpoint, whether or not use of SRS in lieu of WBRT would lead to meaningfully higher rates of neurologic death (HR 1.61, corresponding to a 1-year event rate of 26.7% relative to a historical 1-year rate of 17.5% in patients previously managed with WBRT at our center), with 90% power and a one-sided alpha error of 5%. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression / systemic symptoms of a life-threatening nature and was assessed by a panel of 2-3 neuro-radiation oncologists. Results: Between 3/2018 – 4/2023, 100 patients were enrolled across 4 centers. The median age was 68 years (IQR 63 – 74 years). The median number of brain metastases was 2 (IQR 1 – 3); 16 (16%) of patients underwent prior neurosurgical resection. On study, 66 (66%) patients were treated with SRS alone while 32 (32%) were treated with SRT to at least 1 site; 2 patients died of systemic disease progression before study treatment. The median overall survival was 10.3 months. In total, 19 neurologic deaths were observed, relative to 62 systemic deaths. The neurologic death rate at 1 year was 11.0% (95% CI 4.8% – 17.2%). Conclusions: Our prospective, multi-institutional study demonstrated modest rates of neurologic death when SRS as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases and represents the largest prospective experience to date. Clinical trial information: NCT03391362 .

Effects of synthesis conditions on particle size and pore size of spherical mesoporous silica

The particle size and pore size of spherical mesoporous silica materials play significant roles in their application. However, relatively limited systematic research has been conducted on how preparation conditions influence these properties. In particular, the effects of some important factors have not been adequately studied, including reaction time, reaction temperature, and organic solvent type. In this work, octane and water were used as solvents, and tetraethyl orthosilicate was used as the silicon source to systematically study the effects of reaction time, reaction temperature, different organic solvents, octane/water mass ratio, styrene template concentration, and surfactant (cetyltrimethylammonium bromide, CTAB)/H2O mass ratio on the particle morphology, particle size, and pore size of silica. The results suggest that the above-mentioned neglected factors exert a substantial influence on both particle size and pore size. In the experimental temperature range, the pore diameter decreases and the particle size increases with increasing temperature. The maximum particle size and pore size are achieved after a reaction time of 3 h, and a further increase in reaction time leads to a smaller particle size and pore size. As the number of carbon atoms in the organic solvent decreases, the pore size also gradually increases. Styrene and organic solvents that dissolve in CTAB micelles are crucial factors in pore formation, while the aggregation of the swollen CTAB micelles influences the particle size. The changes in the pore structure stability and hydroxyl density of the synthesized samples in water were also studied. After undergoing water treatment at temperatures ranging from 20 to 60 °C for 72 h, both the pore structure and morphology remain relatively unchanged. When the temperature increases, the surface hydroxyl density exhibits a more pronounced increase in the presence of water. After water treatment for 5 h, the surface hydroxyl density reaches saturation.

Postoperative adjuvant hepatic arterial infusion chemotherapy combined with donafenib in hepatocellular carcinoma with solitary large tumor and microvascular invasion: A multicenter, prospective, single-arm, phase II trial.

e16227 Background: Hepatocellular carcinoma (HCC) with solitary large tumor (≥ 5 cm) and microvascular invasion (MVI) was associated with high 5-year recurrence rate and poor survival prognosis. Postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) was found to improve the recurrence-free survival (RFS) with acceptable safety profiles in HCC patients with MVI. However, the prognosis of HCC who received adjuvant HAIC after hepatectomy still remain far from satisfactory. Several studies have shown that the combination of HAIC and tyrosine kinase inhibitors (TKIs) could exhibit a synergistic anticancer effect and improve the survival outcomes of advanced HCC. Thus, the present study was conducted to explore the efficacy and safety of adjuvant HAIC plus the novel multikinase inhibitor donafenib in HCC with solitary tumor ≥ 5 cm and MVI. Methods: This prospective, single-arm phase II study was conducted in three medical centers in China. HCC patients with both solitary tumor ≥ 5 cm and MVI, no evidence of recurrence at radiological follow-up at 4-8 weeks after hepatectomy, no previous treatment for HCC other than hepatectomy, Child-Pugh score A or B7 were enrolled. Eligible patients received one cycle of HAIC with oxaliplatin, fluorouracil, and leucovorin (HAIC-FOLFOX4), and followed by donafenib (200 mg orally twice daily) for up to 1 year until disease recurrence or unacceptable toxicity. The primary endpoint was 1-year recurrence-free survival rate (1-year RFS rate). Secondary endpoints included RFS, overall survival (OS) and safety. Results: A total of 18 patients were included for analysis. The median age was 59 years (range, 28–75), the median maximum tumor size was 7.0 cm (interquartile range [IQR], 6.2–7.8), 88.9% had low-risk MVI, 61.1% had Edmondson-Steiner grade III-IV and 44.4% had incomplete tumour capsule. As of November 27, 2023, 4 of 18 patients (22.2%) recurrenced and no deaths occurred with a median follow-up of 15.0 months (95% confidence interval [CI], 5.1–19.1). The 1-year RFS rate was 64.9% (95%CI, 39.2%–100%), and current immature median RFS was 14.3 months (95%CI, not available [NA], 11.2–NA). The most common treatment-related adverse events (TRAEs) were hand-foot skin reaction (72.2%), diarrhea (38.9%), decreased platelet count (22.2%), hypoalbuminemia (22.2%), and alopecia (22.2%). Grade 3 TRAEs occurred in 6 patients (33.3%), and no grade 4 or 5 TRAEs occurred. Conclusions: In this prospective study, the preliminary data indicated that HAIC combined with donafenib is an encouraging adjuvant therapy with well-tolerated safety profiles for HCC patients with solitary tumor ≥ 5 cm and MVI. Clinical trial information: NCT04962958 .