Interim Stage Research Articles

Cruciate-Retaining vs Posterior-Stabilized Antibiotic Cement Articulating Spacers for Two-Stage Revision of Prosthetic Knee Infection: A Retrospective Cohort Study

BackgroundAntibiotic cement articulating spacers are recommended during 2-stage revision for prosthetic knee infection because of increased range of motion (ROM) and improved function; however, spacer mechanical complications have been reported. We aimed to determine the association between different constraints of articulating spacers and the rate of complications and infection eradication, functional outcomes, and ROM. MethodsA retrospective study of prosthetic knee infection using cruciate-retaining (CR) or posterior-stabilized (PS) spacers was conducted between 2011 and 2018. The rate of spacer mechanical complications, infection eradication after reimplantation and reoperation, Hospital of Special Surgery (HSS) knee score, and ROM during the interim stage were analyzed. All patients were regularly followed up for 2 years. ResultsOne hundred forty-one patients were included, with 66 CR and 75 PS spacers. Overall mechanical complication rate was lower in PS (9.3%) than in CR spacers (45.5%) (P < .001), especially in joint dislocation (1.3% vs 30.3%, respectively, P < .001). Overall reoperation rate was lower in PS (16.0%) than in CR spacers (36.4%) (P < .001), especially for mechanical complications (1.3% vs 24.2%, respectively, P < .001). HSS knee score was higher in PS (72.3) than in CR spacers (63.8) (P < .001). ROM was greater in PS (90.3°) than in CR spacers (80.6°) (P = .005), especially at maximum flexion (102.4° vs 89.6°, respectively, P = .003). Infection eradication was comparable between the spacers. ConclusionBoth spacers can control infection; however, PS spacers had a lower rate of mechanical complications and reoperation, better HSS knee scores, and greater ROM than CR spacers.

Two-Stage Primary Arthroplasty in the Infected Native Knee: A Systematic Review and Pooled Analysis.

The knee is the commonest native joint to develop an infection. A two-stage primary knee replacement, with an interim stage of debridement and cement spacer application, modelled after two-stage revision for periprosthetic joint infections (PJI) has been reported for the management of chronic infections. To systematically review the literature to find the infection-free survival and outcomes of this operation and explore its indications. PRISMA guidelines were followed for this review. A systematic search of 4 online databases was conducted on 9/8/2020. After reviewing 226 abstracts and applying our selection criteria, 10 papers were selected for full-text review, and 9 included in the final synthesis. On pooled analysis, an infection-free survival of 95.6% (CI 94.7-96.4) was found at 2years in 139 knees, which was unchanged over the remainder of the follow-up (Mean 3.9years). The complication rate after final implantation was 6% in those that did not develop reinfection. The mean pooled Knee Society Score (KSS) and KSS Function score among 70 patients (4 papers) was 83.4 (80.1-89.0) and 76.8 (71.5-78.0), respectively. The mean range of motion among 82 patients (6 papers) was more than 100°. Two-stage primary knee replacement is a safe, effective and reliable procedure with good results in the short to medium term. Further studies are required to lay down precise indications and cost-effectiveness of this procedure, in comparison to other strategies for chronic infection. All joint registries should develop methods to identify patients undergoing two-stage procedures, to understand their long-term survival and outcomes.

Robust group strategy‐proofness

Strategy‐proofness (SP) is a sought‐after property in social choice functions because it ensures that agents have no incentive to misrepresent their private information at both the interim and ex post stages. Group strategy‐proofness (GSP), however, is a notion that is applied to the ex post stage but not to the interim stage. Thus, we propose a new notion of GSP, coined robust group strategy‐proofness (RGSP), which ensures that no group benefits by deviating from truth telling at the interim stage. We show for the provision of a public good that the Minimum Demand rule (Serizawa (1999)) satisfies RGSP when the production possibilities set satisfies a particular topological property. In the problem of allocating indivisible objects, an acyclicity condition on the priorities is both necessary and sufficient for the Deferred Acceptance rule to satisfy RGSP, but is only necessary for the Top Trading Cycles rule. For the allocation of divisible private goods among agents with single‐peaked preferences (Sprumont (1991)), only free disposal, group replacement monotonic rules within the class of sequential allotment rules satisfy RGSP.

Breast ductal Carcinoma in situ associated with microinvasion induces immunological response and predicts ipsilateral invasive recurrence.

Although microinvasion (Mi) is often thought to be an interim stage between ductal carcinoma in situ (DCIS) and established invasive ductal carcinoma, survival outcomes and biological behaviour of DCIS-Mi are still poorly understood. This study investigated the potential influence of Mi on disease-free survival (DFS) and assessed its correlations with clinicopathological parameters, prognosis, molecular, and immune markers. CD4, CD8, forkhead box P3 (FOXP3), CD68, CD163, programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression in pure DCIS and DCIS-Mi, from a cohort of 198 patients, were determined by immunohistochemistry. DFS, clinicopathological parameters, immune markers, and biomarker expression were correlated with presence of Mi. Twelve out of 198 DCIS cases were associated with Mi. DCIS-Mi was significantly linked with ipsilateral invasive recurrence (p = 0.032). Kaplan-Meier analysis revealed that DCIS-Mi had worse DFS for ipsilateral invasive recurrence (p = 0.011) and this was affirmed by multivariate Cox regression analysis (95% CI 1.181-9.010, HR = 3.262, p = 0.023). DCIS-Mi was associated with higher densities of immune infiltrates positive for CD4 (p = 0.037), FOXP3 (p = 0.037), CD163 (p = 0.01), and PD-L1 (p = 0.015). This study demonstrated that DCIS-Mi was correlated with high densities of immune infiltrates and predicted ipsilateral invasive recurrence.

Double lives: transfer of fungal endophytes from leaves to woody substrates.

Fungal endophytes are a ubiquitous feature of plants, yet for many fungi the benefits of endophytism are still unknown. The Foraging Ascomycete (FA) hypothesis proposes that saprotrophic fungi can utilize leaves both as dispersal vehicles and as resource havens during times of scarcity. The presence of saprotrophs in leaf endophyte communities has been previously observed but their ability to transfer to non-foliar saprobic substrates has not been well investigated. To assess this ability, we conducted a culture study by placing surface-sterilized leaves from a single tropical angiosperm tree (Nectandra lineatifolia) directly onto sterile wood fragments and incubating them for 6 weeks. Fungi from the wood were subsequently isolated in culture and identified to the genus level by ITS sequences or morphology. Four-hundred and seventy-seven fungal isolates comprising 24 taxa were cultured from the wood. Of these, 70.8% of taxa (82.3% of isolates) belong to saprotrophic genera according to the FUNGuild database. Furthermore, 27% of OTUs (6% of isolates) were basidiomycetes, an unusually high proportion compared to typical endophyte communities. Xylaria flabelliformis, although absent in our original isolations, formed anamorphic fruiting structures on the woody substrates. We introduce the term viaphyte (literally, “by way of plant”) to refer to fungi that undergo an interim stage as leaf endophytes and, after leaf senescence, colonize other woody substrates via hyphal growth. Our results support the FA hypothesis and suggest that viaphytism may play a significant role in fungal dispersal.

Efficacy and toxicity monitoring via Bayesian predictive probabilities in phase II clinical trials

Bayesian monitoring strategies based on predictive probabilities are widely used in phase II clinical trials that involve a single efficacy binary variable. The essential idea is to control the predictive probability that the trial will show a conclusive result at the scheduled end of the study, given the information at the interim stage and the prior beliefs. In this paper, we present an extension of this approach to incorporate toxicity considerations in single-arm phase II trials. We consider two binary endpoints representing response and toxicity of the experimental treatment and define the result as successful at the conclusion of the study if the posterior probability of an high efficacy and that of a small toxicity are both sufficiently large. At any interim look, the Multinomial-Dirichlet distribution provides the predictive probability of each possible combination of future efficacy and toxicity outcomes. It is exploited to obtain the predictive probability that the trial will yield a positive outcome, if it continues to the planned end. Different possible interim situations are considered to investigate the behaviour of the proposed predictive rules and the differences with the monitoring strategies based on posterior probabilities are highlighted. Simulation studies are also performed to evaluate the frequentist operating characteristics of the proposed design and to calibrate the design parameters.

Spontaneous Color Polarization as A Modus Originis of the Dynamic Aether

We suggest the phenomenological model of emergence of the dynamic aether as a result of decay of the SU(N) symmetric field configuration containing the multiplet of vector fields. The scenario of the transition to the dynamic aether, which is characterized by one unit timelike vector field that is associated with the aether velocity, is based on the idea of spontaneous color polarization analogous to the spontaneous electric polarization in ferroelectric materials. The mechanism of spontaneous color polarization is described in the framework of anisotropic cosmological model of the Bianchi-I type; it involves consideration of the idea of critical behavior of the eigenvalues of the tensor of color polarization in the course of the Universe accelerated expansion. The interim stage of transition from the color aether to the canonic dynamic aether takes the finite period of time, the duration of which is predetermined by the phenomenologically introduced critical value of the expansion scalar.

Group sequential designs applied in psychological research

Psychological research is confronted with ever-increasing demands to save resources such as time and money while assuring high ethical standards. In medical and pharmaceutical research, group sequential designs have fundamentally changed traditional statistical testing approaches featuring only one analysis at the end of a single-stage study. They enable early stopping at an interim stage, after a group of observations, for efficacy or futility in case of an overwhelmingly large or small effect, respectively. Otherwise, the trial is continued to the next stage. On average over many studies time and money are saved and more ethical trials are facilitated by diminishing the risk of patients' exposure to inferior treatments. We provide an easy-to-use tutorial for psychological research replete with easily understandable figures highlighting the core idea of different group sequential designs, a workflow chart, an empirical real-world data set, and the annotated R code. Finally, we demonstrate the application of early stopping for efficacy.

A Practical Perspective: Application of the Generalized Approach for Adaptive Design.

Adaptive design methodology has been well studied for continuous, binary, and survival outcomes for decades. However, for complicated endpoints such as recurrent hospitalization in the joint frailty setting and composite endpoint in the win-ratio setting, adaptive design is not intuitive because of sophistication in existing methods to perform sample size re-estimation. The objective of this paper is to propose a practical generalized approach to implement the above activities at the interim stage through approximation so that sample size re-estimation becomes easily understood and readily amenable. Through simulations on representative complex situations, the proposed method can maintain the planned statistical power by sample size re-estimation while controlling the type I error. The proposed adaptive approach is easy to implement in general sample size re-estimation situations. Its validity can be verified through simulation under varying scenarios. In summary, this approach offers a transparent communication channel with regulatory agencies to facilitate clinical trial development regardless of the complexity of the underlying situations.

Reaping the Informational Surplus in Bayesian Persuasion

The Bayesian persuasion model studies communication between an informed sender and a receiver with a payoff-relevant action, emphasizing the ability of a sender to extract maximal surplus from his informational advantage. In this paper we study a setting with multiple senders, but in which the receiver interacts with only one sender of his choice: senders commit to signals and the receiver then chooses, at the interim stage, with which sender to interact. Our main result is that whenever senders are even slightly uncertain about each other's preferences, the receiver receives all the informational surplus in all equilibria of this game.

Association between HIV infection and outcomes of care among medicare enrollees with breast cancer

BackgroundTo assess the interaction of breast cancer, HIV infection, Medicare disability status, cancer stage and its implications for outcomes, after accounting for competing risks among female, fee-for-service Medicare enrollees. MethodsWe used data from Surveillance, Epidemiology and End Results (SEER) -Medicare (2000–2013). From primary female breast cancer cases diagnosed between 2001 and 2011, we identified those with HIV infection. We used Generalized Linear Model for phase-specific incremental cost of HIV, Cox regression for association between HIV and all-cause mortality, and Fine and Gray competing risk models to assess hazard of breast cancer-specific mortality by HIV status. We also studied this association for subgroups of cancer stage and disability status. FindingsOf 164,080 eligible cases of breast cancer, 176 had HIV infection. Compared to HIV-uninfected patients, HIV infected patients had 16% higher cost in initial phase, and 80% higher cost in interim stage of care, and at least two times higher mortality (all-cause and breast cancer-specific), after accounting for competing risk. Among disabled enrollees, HIV-infected patients had higher risk of all-cause and breast cancer-specific mortality, compared to HIV-uninfected patients. InterpretationFemale fee-for-service Medicare enrollees with breast cancer experience higher initial and interim phase cost and worse survival in the presence of HIV. This association was also significant among disabled Medicare enrollees. Medicare is the single largest source of federal financing for HIV care. Burden on Medicare will grow exponentially due to higher proportion of disabled among HIV-infected enrollees, longer survival among HIV- infected persons, increased HIV incidence in older adults, and increased age related risk of breast cancer. Future research can identify the pathways via which HIV infection affects cost and mortality, and develop integrated strategies for effective management of concomitant breast cancer and HIV and inform survivorship guidelines. FundingNational Institute on Aging, National Institutes of Health, Grant # R21AG34870-1A1

What are the most important unanswered research questions in trial retention? A James Lind Alliance Priority Setting Partnership: the PRioRiTy II (Prioritising Retention in Randomised Trials) study

BackgroundOne of the top three research priorities for the UK clinical trial community is to address the gap in evidence-based approaches to improving participant retention in randomised trials. Despite this, there is little evidence supporting methods to improve retention. This paper reports the PRioRiTy II project, a Priority Setting Partnership (PSP) that identified and prioritised unanswered questions and uncertainties around trial retention in collaboration with key stakeholders.MethodsThis PSP was conducted in collaboration with the James Lind Alliance, a non-profit making initiative, to support key stakeholders (researchers, patients, and the public) in jointly identifying and agreeing on priority research questions.There were three stages. (1) First an initial online survey was conducted consisting of six open-ended questions about retention in randomised trials. Responses were coded into thematic groups to create a longlist of questions. The longlist of questions was checked against existing evidence to ensure that they had not been answered by existing research. (2) An interim stage involved a further online survey where stakeholders were asked to select questions of key importance from the longlist. (3) A face-to-face consensus meeting was held, where key stakeholder representatives agreed on an ordered list of 21 unanswered research questions for methods of improving retention in randomised trials.ResultsA total of 456 respondents yielded 2431 answers to six open-ended questions, from which 372 questions specifically about retention were identified. Further analysis included thematically grouping all data items within answers and merging questions in consultation with the Steering Group. This produced 27 questions for further rating during the interim survey. The top 21 questions from the interim online survey were brought to a face-to-face consensus meeting in which key stakeholder representatives prioritised the order. The ‘Top 10’ of these are reported in this paper. The number one ranked question was ’What motivates a participant’s decision to complete a clinical trial?’ The entire list will be available at www.priorityresearch.ie.ConclusionThe Top 10 list can inform the direction of future research on trial methods and be used by funders to guide projects aiming to address and improve retention in randomised trials.

Amputation Versus Staged Reconstruction for Severe Fibular Hemimelia: Assessment of Psychosocial and Quality-of-Life Status and Physical Functioning in Childhood.

Background:Fibular hemimelia, a congenital disorder characterized by the partial or complete absence of the fibula, tibial growth inhibition, and foot and ankle deformity and deficiency, is the most common deficiency of long bones. The purpose of the present study of children with congenital fibular hemimelia was to examine the functional and psychosocial outcomes at a minimum of 2 years after treatment either with amputation and a prosthesis or with reconstruction and lengthening.Methods:Twenty children who were managed with primary amputation were compared with 22 children who were managed with staged limb reconstruction. The average age of the patients at the time of evaluation was 9 years (range, 5 to 15 years). Patients and parents completed psychosocial, quality-of-life, and satisfaction surveys. Patients underwent instrumented gait analysis and a timed 25 or 50-yard dash. The number and nature of surgical procedures were recorded from a retrospective chart review.Results:Families of children managed with amputation had lower economic and educational levels and were more ethnically diverse compared with the families of children managed with limb reconstruction. Scores on psychosocial and quality-of-life surveys were comparable with those from healthy patient populations. Parents of males treated with amputation perceived a lower school-related quality of life for their child; socioeconomic and ethnic differences between groups might account for this finding. Statistically but not clinically significant differences were measured during instrumented gait analysis at a self-selected walking speed and during a timed 25 or 50-yard dash. The majority of patients and parents reported satisfaction with the treatment method selected and would select the same treatment method again.Conclusions:At this interim stage of growth, there were no significant functional or psychological differences between groups. Both groups were satisfied with the outcome in mid-childhood, irrespective of the selection of amputation or limb reconstruction.Level of Evidence:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A Practical Perspective: Application of the Generalized Approach for Adaptive Design

Adaptive design methodology has been well studied for continuous, binary, and survival outcomes for decades. However, for complicated endpoints such as recurrent hospitalization in the joint frailty setting and composite endpoint in the win-ratio setting, adaptive design is not intuitive because of sophistication in existing methods to perform sample size re-estimation. The objective of this paper is to propose a practical generalized approach to implement the above activities at the interim stage through approximation so that sample size re-estimation becomes easily understood and readily amenable. Through simulations on representative complex situations, the proposed method can maintain the planned statistical power by sample size re-estimation while controlling the type I error. The proposed adaptive approach is easy to implement in general sample size re-estimation situations. Its validity can be verified through simulation under varying scenarios. In summary, this approach offers a transparent communication channel with regulatory agencies to facilitate clinical trial development regardless of the complexity of the underlying situations.

Molecular characterization of GTP binding protein overexpressed in skeletal muscle (GEM) and its role in promoting adipogenesis in goat intramuscular preadipocytes

GTP binding protein overexpressed in skeletal muscle (GEM) is an important gene with many functions, such as regulating the rearrangement of cytoskeleton and the activity of voltage-dependent calcium channel, and GEM was regarded as a candidate gene for obesity. However, little investigation has been carried out to explore whether GEM affected the intramuscular fat (IMF) deposition of goat. To explore the role of GEM gene in goat, this gene was cloned and its tissue and temporal expression profile were detected. Effect of GEM on adipogenesis was examined by losing function of GEM in vitro. Thereafter, several lipid metabolism-related genes were examined, including CCAAT/enhancing-binding protein α (C/EBPα), CCAAT/enhancing-binding protein β (C/EBPβ), lipoprotein lipase (LPL), preadipocyte factor 1 (Pref-1), peroxisome proliferator activated receptor γ (PPARγ) and sterol regulatory element binding protein 1 (SREBP1). We found that the goat GEM gene consisted of 936 bp, which encoded a protein of 311 amino acids. The expression of GEM was higher in spleen, lung and large intestine and it appeared sharp in the interim stage of differentiation. Furthermore, GEM knockdown blocked adipogenesis and the expression of C/EBPα, C/EBPβ, LPL, PPARγ and SREBP1. These results indicated that GEM might promote lipid accumulation and adipogenesis.

An approach to use of an adaptive procedure to clinical trials for molecularly heterogenous subject selection at interim

For clinical trials, molecular heterogeneity has played a more important role recently. Many novel clinical trial designs prospectively incorporate molecular information to evaluation of treatment effects. In this paper, an adaptive procedure incorporating a non-pre-specified genomic biomarker is employed in the interim of a conventional trial. A non-pre-specified binary genomic biomarker, which is predictive of treatment effect, is used to classify study patients into two mutually exclusive subgroups at the interim review. According to the observations at the interim stage, adaptations such as adjusting sample size or shifting eligibility of study patients are then made in case of different scenarios.

Expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67 in ductal carcinoma in situ (DCIS) and DCIS with microinvasion.

Ductal carcinoma in situ (DCIS) represents a heterogeneous disease in its histologic appearance and biological potential. Some women treated for DCIS subsequently develop invasive breast cancer. DCIS with microinvasion is considered as the interim stage in the progression from DCIS to invasive breast cancer. Analysis of the differences between DCIS and DCIS with microinvasion may aid in understanding the characteristic of DCIS with microinvasion and identifying biological factors determining progression of DCIS to invasive disease.Retrospective analysis of 219 cases between 2012 and 2018 was performed in our institution. The pathological results and axillary lymph nodes status were collected. Analysis of the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 in pure DCIS (164 cases), and DCIS with microinvasion (55 cases) using immunohistochemistry.DCIS with microinvasion had a higher nuclear grade (P < .001) and was more likely to have sentinel lymph node biopsy (SLNB) positivity (P = .039) than DCIS. Expression of ER, PR were significantly higher in DCIS compared with DCIS with microinvasion (P < .001, P < .001). While the expression of HER-2 in DCIS with microinvasion (56.4%) was significantly higher than in DCIS (36.6%, P = .01). Furthermore, DCIS with microinvasion was significantly more likely to have aggressive subtype (Triple-negative and HER2-enriched tumors, P = .005).Our results indicated that DCIS with microinvasion was different from pure DCIS in clinicopathologic characteristics and molecular alterations. It displayed a more aggressive biological nature than pure DCIS. It may be a distinct entity.

A hierarchical Dempster-Shafer evidence combination framework for urban area land cover classification

This paper presents a novel evidence combination framework for urban area land cover classification by using Light Detection And Ranging (LIDAR) data fused with co-registered near infrared and color images. The newly developed combination framework is built with a hierarchical structure involving an improved Dempster-Shafer (DS) theory of evidence for decision making. In the framework, a fuzzy basic probability assignment (BPA) function with fuzzy classes is firstly established based on the DS theory of evidence, and a probability is then assigned to each data source, that is derived from the original airborne LIDAR and the co-registered images. Secondly, an interesting approach is to introduce noise removal in an interim stage at the output of the probability distribution, and then the probability assigned to each data source is redistributed with a designated rule. Finally, a decision is made based on a “maximum normal support” rule, leading to the classification results. The proposed framework has been tested on two datasets. The testing results have shown that it can dramatically reduce the computational time in the classification process, and significantly improve the classification accuracy, i.e. 8.22% on Test 1 and 5.76% on Test 2 compared to the basic DS method. Due to its non-iterative and unsupervised nature, the proposed method is fast in computation, does not require training samples, and has achieved high classification accuracy.

Econometric assessment of customers’ personality biases and communication preferences correlation

The tendency of bias identification and quantification with the goal of better estimation and prediction, grows. The purpose of this paper is to question how deep analysis is necessary to increase prediction of communication preferences given the customer’s personality traits/biases. Examined communication preferences regard to the communication approach, language use and information sharing. This paper offers a psychometric assessment of the personality estimates and traits, as well as econometric examination of correlation to consumer first-choice communication preferences using linear logit model with binomial dependent variable. The results point out that the more detail analysis provides more accurate predictions, to the point where estimators as regressors for communication choices provide more accurate prediction than the use of the personality traits as independent variables. Paper delivers empirical assessment of consumers’ communication preferences using primary data set. Practical implications relate to the use of the findings in communication with consumers in online and/ or digital marketing communication. One of the possible practical use of the results can be as an input for the recommendation agents. Theoretical implications of the findings request questioning the use of the personality traits as an interim stage in decision-making predictions. In addition, these findings fill the gap in the field of communication preference based on personality traits and personality estimators. The data set has been previously used for the doctoral thesis research. For the purpose of this research, data was re-coded and analyzed using different approach, namely binomial logistic regression.

Bayesian predictive monitoring with bivariate binary outcomes in phase II clinical trials

Traditionally, phase II single-arm trials are based on a binary response variable that represents the efficacy of the experimental treatment. However, the introduction of an additional binary endpoint to assess whether the new therapy is also sufficiently safe for a further evaluation in larger phase III studies is often suggested. A Bayesian predictive strategy for interim monitoring in phase II trials focused on bivariate binary outcomes is proposed. At any interim analysis, the stopping rules are based on the evaluation of the predictive probability that the trial will show a conclusive result at the planned end of the study, given the observed data. The proposed procedure is applied using hypothetical scenarios that represent different situations which may occur at the interim stage. A real data application is also illustrated with the use of both non-informative and informative prior distributions. Finally, simulation studies to evaluate the operating characteristics of the design have been performed.