Experimental Treatment Groups Research Articles

Estimating the Impact of Emergency Assistance on Educational Progress for Low-Income Adults: Experimental and Nonexperimental Evidence.

Methods for estimating causal impact aim to either remove or reduce bias. This study estimates the degree of bias reduction obtained from regression adjustment and propensity score methods when only a weak set of predictors are available. The study uses an experimental test of providing emergency financial assistance to participants in a job training program to estimate an experimental benchmark and compares it to nonexperimental estimates of the impact of receiving assistance. When estimating the impact of receiving assistance, those who received it constitute the treatment group. The study explores two different comparison groups: those who could have (because they were assigned to the experimental treatment group) but did not receive emergency assistance; and those who could not receive emergency assistance because they were randomly assigned to the experimental control group. It uses these groups to estimate impacts by applying three estimation strategies: unadjusted mean comparison, regression adjustment, and inverse propensity weighting. It then compares these estimates to the experimental benchmark using statistical tests recommended by the within-study comparison literature. The nonexperimental approaches to addressing selection bias suggest large positive impacts. These are statistically different from the experimental benchmark, which shows that receipt of emergency assistance does not improve educational progress. Further, over 90% of the bias from a simple comparison of means remains. Unless a stronger set of predictors are available, future evaluations of such interventions should be wary of relying on these methods for either unbiased estimation of impacts or bias reduction.

Statistical tests for two-stage adaptive seamless design using short- and long-term binary outcomes.

The adaptive seamless design combining phases II and III into a single trial has been shown growing interest for improving the efficiency of drug development, becoming the most frequent adaptive design type. It typically consists of two stages, the trial objectives being often different in each stage. The primary objectives are to select optimal experimental treatment group(s) in the first stage and compare the efficacy between the selected treatment and control groups in the second stage. In this article, we focus on a two-stage adaptive seamless design, for which treatment selection is based on the short-term binary endpoint and treatment comparison is based on the long-term binary endpoint. We thus propose an exact conditional test as a final analysis, based on the bivariate binomial distribution and given the selected treatment with the most promising short-term endpoint response rate from an interim analysis. Additionally, the mid- approach is incorporated to improve conservativeness for an exact test. Simulation studies were conducted to compare the proposed methods with a method based on the combination test. The proposed exact method controlled for type I error rate at the nominal level, regardless of the number of initial treatments or the correlation between short- and long-term endpoints. In terms of the treatment comparison power, the proposed methods are more powerful than that based on the combination test in the scenarios, with only one treatment being effective.

Replacement of fish meal with fermented plant proteins in the aquafeed industry: A systematic review and meta‐analysis

AbstractIn the aquaculture feed industry, fishmeal is widely used as a source of animal protein due to its high palatability, excellent amino acid profile and increased digestibility. However, the incorporation of fishmeal in aquaculture diets increases the costs of production due to the declining wild fish stocks hence an urgent need to search for sustainable and cheaper alternative protein sources. The use of fermented plant proteins as substitutes for fishmeal in aquaculture diets has recently gained attention due to their improved nutritional quality, easy availability and low costs. Therefore, a systematic review and meta‐analysis were conducted to quantify the effects of fermented plant proteins as substitutes for fishmeal on the growth performance, feed utilisation, survival, antioxidant, metabolic and digestive enzyme activity of several aquaculture species. Results of the meta‐analysis indicated that replacement of fishmeal with fermented plant proteins in aquaculture diets enhanced the growth performance, feed utilisation, antioxidant and digestive enzyme activities of several aquaculture species regardless of experimental duration and source of fermented plant protein. Likewise, metabolic enzyme activity (i.e., Alanine aminotransferase and Aspartate aminotransferase) was reduced in experimental dietary treatment groups relative to the fishmeal control groups. To elucidate the influence of moderators on the observed effect sizes, a mixed‐effects model was conducted and the results indicated that fishmeal substitution levels and aquaculture species influenced the observed effect sizes in both antioxidant and digestive enzyme activity. No significant differences were noted in survival between the experimental dietary treatment groups and fishmeal control diets among all aquaculture species. However, carnivorous marine species exhibited lower values for specific growth rate and protein efficiency ratio in experimental dietary treatment groups compared to the fishmeal control diets. Likewise, freshwater species exhibited poor FCR values in experimental dietary treatment groups relative to the fishmeal control diets. Overall, the replacement of fishmeal with fermented plant proteins in aquaculture diets is a safe and viable solution for increased and sustainable aquaculture production.

Additional chemotherapy for EGFRm patients with the continued presence of plasma ctDNA EGFRm at week 3 after start of osimertinib first-line treatment (PACE).

TPS9157 Background: Epidermal growth factor receptor (EGFR) – mutated non-small cell lung cancer (NSCLC) is susceptible to EGFR targeting tyrosine kinase inhibitors (TKI), such as the third generation TKI osimertinib. However, response rate and duration vary between patients. Among others, the specific subtype of EGFR-mutation, its co-occurrence with other genetic alterations, and the detection of phosphorylated EGFR (pEGFR) in the plasma, and its clearance upon treatment were previously identified as markers that predict therapy response. A high proportion of patients with early (3-6 weeks after start) pEGFR clearance from plasma show impressive survival upon single-agent TKI. However, failure to achieve early clearance upon Osimertinib is associated with unfavorable outcome. For these patients, treatment concepts are lacking. Here, we report about the initiation of a clinical trial that evaluates the combination of EGFR-directed TKI and platinum-based chemotherapy as an early treatment escalation strategy for this high-risk patient population. Methods: PACE is a prospective multicenter single-arm investigator-initiated phase II trial. Patients with NSCLC harboring L858R or del19 EGFR mutation, who are treated with first-line Osimertinib are subjected to liquid biopsy-based early response assessment three weeks after start of therapy. Failure to clear pEGFR from plasma at this time point triggers treatment escalation with the addition of platinum-based doublet chemotherapy to the Osimertinib treatment. The primary outcome measure of the trial is progression-free survival (PFS), with the objective to assess the efficacy of biomarker-driven escalation of osimertinib therapy with a combination platinum-based regimen. Secondary outcome measures are the overall response rate (ORR), overall survival (OS), and the Quality of life (QLQ-C30, CTCAE-PROs) of the treated patients. In exploratory analyses, we will assess whether specific patterns of co-mutations are associated with early treatment failure (upon TKI) and pEGFR persistence. Fig. 1 illustrates the trial concept. A sample of 46 subjects achieves 80% power at a 0.05 significance level to detect a PFS of 14.4 months in the experimental treatment group when the PFS of the historic control group is 9.1 months; a total of 400 patients need to be screened within the national Network Genomic Medicine. Enrollment started in 12/2021. The clinical trial is supported by AstraZeneca and Guardant. EudraCT registration number: 2019-004757-88 .

Improved survival from early combined radiotherapy: A phase II clinical study and underlying mechanisms of delaying EGFR-TKI acquired resistance in patients with advanced lung cancer.

9114 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC). However, patients treated with EGFR-TKIs had a median progression-free survival (PFS) of only 8 to 18 months. The occurrence of acquired resistance greatly limits the survival benefit of TKI for NSCLC patients. Extensive efforts have been paid to find a well-tolerated drug or treatment that works before acquired resistance to EGFR-TKI with low toxicity. Focusing on clinical trials of targeted combination radiotherapy, we observed some encouraging results. Methods: Stage IV NSCLC patients with EGFR sensitive mutation (19DEL or 21L858R) have received first-line EGFR TKIs treatment and achieved stable disease or partial response have been enrolled in this prospective, multicenter, randomized controlled, phaseⅡstudy. Recruited from 4 hospitals in China, patients were divided into two groups: Stereotactic Body Radiation Therapy (SBRT) combined with TKIs group as the experimental and TKIs treatment group as an active comparator. The primary endpoint is PFS, and the secondary endpoint aims to overall survival (OS) and safety. To further confirmed these clinical observations in patients, xenograft experiments in nude mice were conducted. To examine the specific mechanism, transcriptome sequencing analysis was performed. Results: Between Mar 2015 and Mar 2018, A total of 61 patients who met the inclusion criteria were randomized to the TKI group and SBRT combined group. The median PFS of the TKI group and SBRT combined group were 9.0 vs 17.6 months (p = 0.016). Meanwhile, the median OS were 23.2 vs 33.6 months (p = 0.026). The total number of patients with T790m was 30(49.1%), and the incidence of T790M did not differ between the two groups. Toxicity data and subgroup analyses including different radiation sites will be presented at the conference. As for the xenograft experiments, data on tumor regression and time of drug resistance of early radiotherapy group was clearly superior to others. Transcriptome sequencing analysis found expression of c-Fos was the key point that led to the phenomena. Conclusions: The addition of SBRT significantly delayed the onset of EGFR TKIs acquired resistance and prolonged the PFS and OS of patients. Radiotherapy for the primary site alone might be superior to metastatic sites. Treatment-related adverse events were generally safe and controllable. The oncogenic role of c-Fos in the effect of radiotherapy on gefitinib resistance and promoting the proliferation of NSCLC cells is confirmed. Clinical trial information: NCT03595644.

NaOCl Application after Acid Etching and Retention of Cervical Restorations: A 3-Year Randomized Clinical Trial

This study evaluated the retention of composite resin restorations in noncarious cervical lesions (NCCLs) performed with or without pretreatment with 10% NaOCl solution (deproteinization). A randomized, controlled, split-mouth, double-blinded trial was carried out. Thirty patients with at least two NCCLs were included in the study. The NCCLs were randomly allocated into two treatment groups: control (acid etching with 37% phosphoric acid + placebo solution + Adper Single Bond 2/3M Oral Care + Filtek Z350/3M Oral Care) or experimental group (acid etching with 37% phosphoric acid + 10% NaOCl solution + Adper Single Bond 2 + Filtek Z350). A calibrated examiner evaluated the restorations at baseline (1 week) and recalls (6, 12, 24, and 36 months) using the FDI criteria. The primary outcome evaluated was retention of the restorations. Data were analyzed by the Kaplan-Meier method and the log-rank test (α=0.05). After 3 years, 64 restorations were evaluated in 23 patients. The annual failure rate was 9% for the control group and 17.8% for the experimental group (deproteinization technique). Considering the failures and their distribution among the characteristics of the patients and NCCLs, no statistically significant differences were observed for the control and experimental treatment groups (p=0.077) or the number of teeth in the mouth (p=0.320). Restorations in the mandible (p=0.039) and premolars (p=0.013) showed significantly lower clinical survival rates. The deproteinization pretreatment with a 10% NaOCl solution did not promote additional retention of restorations in NCCLs. (clinicaltrials. gov: NCT03086720).

Influence of hook barbs on the “through-the-gill” hook removal method for deeply hooked Smallmouth Bass

Sustainable catch-and-release fisheries are based on the assumption that most fish survive an angling event. The adoption of best practices has become important to help mitigate post-release injury, behavioral impairment and mortality. However, in any catch-and-release fishery, a proportion of fish will become inadvertently deeply hooked (e.g., in the gullet) and numerous studies have shown this to be a major driver of mortality. Although available science suggests that cutting the line tends to yield better outcomes than removing hooks in the gullet, there has been interest within the angling community with removing hooks using the “through-the-gill” method where the hook shaft is turned outwards into the gill region and then the hook is removed by pulling anteriorly by gripping the outside bend of the hook. Here, we tested the efficacy of removing barbed and barbless hooks though the gill opening from experimentally deep-hooked Smallmouth Bass (Micropterus dolomieu) relative to leaving the hooks in place. Using a control group and four experimental treatment groups (barbed and removed through the gills; barbless and removed through gills; barbed and left in; barbless and left in), we evaluated handling time, presence of bleeding, incidence of gill or esophageal injury, reflex impairment, incidence of hook shedding (for the left in treatment groups), and survival across a 24-hour monitoring period. Collectively, our results suggested that when hooks were barbed and removed through the gills, fish condition and survival were lower. In addition, barbed hooks were more likely to cause bleeding, gill damage, esophageal tearing, and impair reflexes. When hook removal was done through the gills, the chances of all sublethal outcomes across all categories were more likely to occur. While short-term mortality was not statistically linked with any treatment group, the greatest percentage of mortality (24%) occurred for fish that had barbed hooks removed using the through-the-gill method. These data suggest that when anglers use barbed hooks and encounter a deeply hooked fish, cutting the line poses the least risk to the fish.

Communication about vaccine efficacy and COVID-19 vaccine choice: Evidence from a survey experiment in the United States.

While mass vaccination campaigns against COVID-19 have inoculated almost 200 million Americans and billions more worldwide, significant pockets of vaccine hesitancy remain. Research has firmly established that vaccine efficacy is an important driver of public vaccine acceptance and choice. However, current vaccines offer widely varying levels of protection against different adverse health outcomes of COVID-19. This study employs an experiment embedded on a survey of 1,194 US adults in June 2021 to examine how communications about vaccine efficacy affect vaccine choice. The experiment manipulated how vaccine efficacy was defined across four treatments: (1) protection against symptomatic infection; (2) protection against severe illness; (3) protection against hospitalization/death; (4) efficacy data on all three metrics. The control group received no efficacy information. Subjects were asked to choose between a pair of vaccines—a one-dose viral vector vaccine or two-dose mRNA vaccine—whose efficacy data varied across the four experimental treatment groups. Efficacy data for each vaccine on each dimension were adapted from clinical trial data on the Johnson & Johnson/Janssen and Pfizer/BioNTech vaccines. Among all respondents, only modest preference gaps between the two vaccines emerged in the control group and when the two vaccines’ roughly equivalent efficacy data against hospitalization and death were reported. Strong preferences for a two-dose mRNA vaccine emerged in treatments where its higher efficacy against symptomatic or severe illness was reported, as well as in the treatment where data on all three efficacy criteria were reported. Unvaccinated respondents preferred a one-dose viral vector vaccine when only efficacy data against hospitalization or death was presented. Black and Latino respondents were significantly more likely to choose the one-shot viral vector vaccine in the combined efficacy treatment than were whites. Results speak to the importance of understanding how communications about vaccine efficacy affect public preferences in an era of increasing uncertainty about efficacy against variants.

EFFECT OF SUPPLEMENTATION OF PHYTO-ANTIOXIDANT (BAOBAB FRUIT PULP MEAL) ON REPRODUCTIVE PERFORMANCE OF RABBIT DOES DURING HEAT STRESS

A study was conducted to evaluate the influence of a phyto-antioxidant (baobab fruit pulp meal; BFPM) on the reproductive performance of heat-stressed rabbits does. A total of 50 New Zealand White crosses adult rabbit does of 12 months old were used in the present study. The rabbits were randomly allotted into five experimental treatment groups, with ten rabbits per treatment in a completely randomized design. The rabbits were fed diets supplemented with graded levels (0.0%, 2.5%, 3.5%, 4.5% and 5.5%) of BFPM. Parameters monitored were thyroxin and progesterone secretion, serum metabolites, reproductive traits, and physiological performance of the kitten. Initial thyroxin, progesterone, and serum metabolite levels were low in all the treatment groups, and significantly increased during and after pregnancy. BFPM significantly improved litter size and weight of litter and reduced rectal temperature of the kitten. Gestation period, kit weight at weaning, weight gain, and heart rates of kitten did not show any significant difference. It was concluded that reproductive performance of does during heat stress is enhanced by the supplementation of phyto-antioxidants and performance was higher in 5.5% inclusion level of BFPM.

The Use of Computer-Based Interactive Games in Teaching Science Con-cepts for Struggling Learners: Basis for a Compilation of Recommended Games in Teaching

Games have been used and proven effective in motivating students. Playing interactive games can enhance learning (Lieberman, 2006). This study aimed to evaluate the effectiveness of computer-based interactive games in teaching students who are struggling to learning concepts in Physical Science. It also determined to identify the students’ attitudes towards the use of computer-based interactive games. This study utilized pre-test and post-test designs. Respondents for this study were Grade 11 struggling learners and were determined based on the learners’ general average grade during the first semester. The two experimental treatment groups were randomly assigned. One group was taught using computer-based interactive games as an intervention, while the other did not have any teaching intervention. Both groups had regular class instruction in Physical Science and were taught the same content and the same amount of time. The findings reveal that upon exposure to computer-based interactive games, struggling students’ performance in science concepts as described by their pre-test and post-test scores were statistically different with the performance of the struggling students using the lecture-discussion approach. The result implies that students enhanced by the computer-based interactive games approach performed at par with those exposed to traditional learning. Hence, the use of computer-based interactive games in teaching Physical Science concepts is recommended, in addition to regular class instruction. It is suggested that science teachers, especially senior high school teachers who teach Physical Science, should integrate and use computer-based interactive games since it promotes a better understanding of the lesson.

The Use of Computer-Based Interactive Games in Teaching Science Con-cepts for Struggling Learners: Basis for a Compilation of Recommended Games in Teaching

Games have been used and proven effective in motivating students. Playing interactive games can enhance learning (Lieberman, 2006). This study aimed to evaluate the effectiveness of computer-based interactive games in teaching students who are struggling to learning concepts in Physical Science. It also determined to identify the students’ attitudes towards the use of computer-based interactive games. This study utilized pre-test and post-test designs. Respondents for this study were Grade 11 struggling learners and were determined based on the learners’ general average grade during the first semester. The two experimental treatment groups were randomly assigned. One group was taught using computer-based interactive games as an intervention, while the other did not have any teaching intervention. Both groups had regular class instruction in Physical Science and were taught the same content and the same amount of time. The findings reveal that upon exposure to computer-based interactive games, struggling students’ performance in science concepts as described by their pre-test and post-test scores were statistically different with the performance of the struggling students using the lecture-discussion approach. The result implies that students enhanced by the computer-based interactive games approach performed at par with those exposed to traditional learning. Hence, the use of computer-based interactive games in teaching Physical Science concepts is recommended, in addition to regular class instruction. It is suggested that science teachers, especially senior high school teachers who teach Physical Science, should integrate and use computer-based interactive games since it promotes a better understanding of the lesson.

The Effects of Flipped Learning on Learning and Motivation of Upper Secondary School Physical Education Students

New technologies are increasingly linked to the educational world. It is necessary to develop pedagogical approaches such as flipped learning so that education and technology improve the quality of teaching to contribute to quality and sustainable education. Over the years this pedagogical approach has developed quite a bit; however, the scientific literature in physical education is still limited. The objective of the present study was to quantitatively evaluate the effects of the application of flipped learning in the acquisition of the conceptual contents of sport, in the case of the present study through volleyball. A total of 265 upper secondary school students participated in the study (126 boys: 47.9% and 137 girls: 52.1%). The total sample set was divided into two treatment groups. The first experimental treatment group received lessons with the support of flipped learning, through the Edpuzzle platform. The second treatment group or control group received the same content as the first group through traditional methodology. The findings showed that upper secondary students benefited from flipped learning in their cognitive learning about volleyball in physical education, compared to the control group. Further, the findings showed the same results on motivation, although certain differences appeared according to sex, where boys seemed to develop autonomous motivation more than girls.

Individual heterogeneity influences the effects of translocation on urban dispersal of an invasive reptile

BackgroundInvasive reptiles pose a serious threat to global biodiversity, but early detection of individuals in an incipient population is often hindered by their cryptic nature, sporadic movements, and variation among individuals. Little is known about the mechanisms that affect the movement of these species, which limits our understanding of their dispersal. Our aim was to determine whether translocation or small-scale landscape features affect movement patterns of brown treesnakes (Boiga irregularis), a destructive invasive predator on the island of Guam.MethodsWe conducted a field experiment to compare the movements of resident (control) snakes to those of snakes translocated from forests and urban areas into new urban habitats. We developed a Bayesian hierarchical model to analyze snake movement mechanisms and account for attributes unique to invasive reptiles by incorporating multiple behavioral states and individual heterogeneity in movement parameters.ResultsWe did not observe strong differences in mechanistic movement parameters (turning angle or step length) among experimental treatment groups. We found some evidence that translocated snakes from both forests and urban areas made longer movements than resident snakes, but variation among individuals within treatment groups weakened this effect. Snakes translocated from forests moved more frequently from pavement than those translocated from urban areas. Snakes translocated from urban areas moved less frequently from buildings than resident snakes. Resident snakes had high individual heterogeneity in movement probability.ConclusionsOur approach to modeling movement improved our understanding of invasive reptile dispersal by allowing us to examine the mechanisms that influence their movement. We also demonstrated the importance of accounting for individual heterogeneity in population-level analyses, especially when management goals involve eradication of an invasive species.

Influence of the application methods of iron/anticoccidial products on the behaviour and associated stress factors of suckling piglets

The aim of the present study was to evaluate the effect of different treatment protocols for the control of iron-deficiency anaemia and coccidiosis, one combination injection versus injection of iron and oral application of toltrazuril, on the general behaviour of piglets. Piglets were divided into three experimental treatment groups: 24 piglets were left untreated; (control group, C); 24 piglets received an oral administration of generic anticoccidial agent (20 mg/kg BW) plus intramuscular administration of iron dextran (200 mg/ml; 1 ml/piglet) in the same handling (oral + parenteral group, O+P) and 24 piglets received an intramuscular application of the combination product (parenteral group, P). As expected, the handling time was higher in the oral + parenteral group than in the parenteral group. Regarding the behaviour of piglets, the time spent suckling after treatment was variable in the control and oral + parenteral groups, while piglets from the parenteral group spent more time suckling, and hence, their time spent resting was decreased. A statistical trend of lower concentration of cortisol was observed in P compared to O+P after processing. Regarding productivity indices, the average daily gain of piglets during lactation and, subsequently, their weaning weight were higher in P compared to O+P, and similar to the control. In conclusion, administering a combination product injection decreases the time of administration compared to individual treatments.

Statistical methods for seamless phase II/III design

The seamless phase II/III design combining phases II and III into a single trial has been shown growing interest for improving the efficiency of drug development, becoming the most frequent adaptive design type. It typically consists of two stages, the trial objectives being often different in each stage. The primary objectives are to select optimal experimental treatment group(s) in the first stage and compare the efficacy between the selected treatment and control groups in the second stage. In the final analysis, appropriate statistical methods should be applied to avoid increasing the type I error rate and selection bias. This paper reviews several statistical methods that can be applied to adaptive seamless phase II/III designs. Especially, the most representative methods such as the group sequential design approach, combination test approach, and conditional error function approach, are organized in a unified framework and the characteristics of the methods are compared. As related topics, statistical methods for the case where endpoints are different between stages 1 and 2, and the method of sample size calculation will also be discussed. Examples of actual applications are also presented.

Bacillus-based probiotics affect gut barrier integrity in different ways in chickens subjected to optimal or challenge conditions

Dietary supplementation with spore-forming Bacillus-based probiotics represents an efficient means to improve gut health while maintaining good broiler performance. This study investigated the potential of two probiotic products in chickens subjected to optimal (Experiment 1) and Clostridium perfringens-challenged (Experiment 2) conditions. The treatments in Experiment 1 were as follows: (i) CON (no probiotic additive), (ii) One-strain Pro (supplemented with Bacillus licheniformis) or (iii) Multi-strain Pro (supplemented with a multistrain Bacillus-based probiotic). The treatment groups in Experiment 2 received the same diets as those in Experiment 1 but were subjected to C. perfringens challenge. Both experiments lasted 35 days. Both products marginally affected broiler performance in the optimal or challenge conditions. In Experiment 1, Multi-strain Pro upregulated the mRNA expression level of 11 out of 15 selected genes, whereas in Experiment 2, this was less evident, and One-strain Pro was more effective. The multistrain probiotic was effective in maintaining gut morphostructure indices and increasing gut wall thickness, which was particularly evident in challenged birds. Neither additive induced bacterial activity (assessed by measuring enzymatic activity and short-chain fatty acid production) in the cecum, and Multi-strain Pro maintained the cecal butyrate concentration in challenged birds as in the challenged CON treatment, in which butyrate concentration was significantly higher than in the One-strain Pro treatment. Our findings indicated that the activity of these single- and multistrain probiotic products varies depending on rearing conditions, and the effect is highly strain- and product-specific. However, the multistrain probiotic apparently had more beneficial effects than the one-strain probiotic in the maintenance of gut functional status under optimal and challenge conditions.

Synthetizing Published Evidence on Survival by Reconstruction of Patient-Level Data and Generation of a Multi-Trial Kaplan-Meier Curve.

IntroductionIn conducting a survival meta-analysis, the typical methodological approach analyses the hazard ratios (HRs) of individual trials and then combines them into a pooled meta-analytical estimate. The length of follow-up of individual trials is not generally accounted for. Recent techniques aimed at individual patient-data reconstruction from Kaplan-Meier graphs represent an important methodological innovation. These techniques permit the combination of the survival curves published in a single clinical trial but are also applicable to more than one trial. In the case of multiple trials, a meta-analysis can be conducted without using any statistical model of meta-analysis.MethodsAs an example of this new approach, we applied a technique of individual patient data reconstruction to the Kaplan-Meier graphs of overall survival reported in two phase-III trials, which were conducted on patients with locally advanced/advanced non-small cell lung cancer selected according to their PD-L1 expression status, not previously treated for their metastatic disease. Only subjects with PD-L1 ≥50% were considered for our analysis. The experimental arms received pembrolizumab monotherapy while the control arms were given platinum-based chemotherapy. The survival graphs were obtained for both trials. For each Kaplan-Meier curve, the graph was firstly digitalized. Then, the Shiny package was used to reconstruct patient-level data. Finally, the pooled survival curves were generated from the reconstructed patient-level data along with the relevant Cox statistics; for this purpose, we used three packages (“coxph”, “survfit”, and “ggsurvplot”) under the R-platform.ResultsIn our pooled analysis based on this procedure, we compared 453 patients given pembrolizumab vs. 451 controls given chemotherapy. The HR estimated from reconstructed patient-level data was 0.670 (95% confidence interval [CI], 0.566 to 0.793).ConclusionThe analysis described herein demonstrates the easy applicability of the Shiny technique. This technique was successful in generating a pooled survival graph for the experimental treatment groups vs. controls and efficiently estimated the pooled HR in which the results of the two trials were combined.

In Situ Vaccination with Combination of Class B and Class C Toll-like Receptor 9 Agonist CpG Immune Adjuvant Nanoparticles to Induce a Systemic Anti-Lymphoma Response

Introduction: Treatment of relapsed and refractory aggressive B cell lymphomas is challenging, especially after autologous stem cell transplant or chimeric antigen receptor T cell therapy. CpG oligodeoxynucleotides (CpGs) mimic bacterial DNA and bind to toll-like receptor 9 (TLR9). TLR9 is expressed in the endosomes of innate immune cells and B lymphocytes as well as B cell lymphomas. CpG binding to TLR9 in these cells leads to a pro-inflammatory response and induces apoptosis of lymphoma cells by altering NF-kB activation. However, clinical utility of CpGs is limited due to difficulties delivering the DNA directly to the innate immune cells and lymphoma cells, and these DNA strands are easily degraded in biological fluids. Therefore, we designed a nano-carrier to deliver two classes of CpGs to improve clinical efficacy of CpGs in treating lymphoma. Class B CpGs (B-CpGs) mainly stimulate B cells while class C CpGs (C-CpGs) act on both B cells and plasmacytoid dendritic cells. Though C-CpGs are the focus of current clinical trials, B-CpGs may have a special a role in the treatment of lymphoma due to their more potent, direct cytotoxic effect on the malignant lymphoma cells. Here, we evaluated the anti-lymphoma effect of the combination of B-CpG nanoparticles (BNP) and C-CpG nanoparticles (CNP) by optimizing lymphoma cell death and immune stimulation.Methods: BNP and CNP were synthesized by surface-functionalizing gold nanoparticles with modified B-CpGs and C-CpGs, followed by purification via centrifugation. We used a dual flank tumor murine lymphoma model to evaluate the local and systemic anti-lymphoma efficacy of the CpG NPs and screen for the most effective formulation. A20 lymphoma tumors were implanted on both flanks of Balb/c mice. When the tumors were 5-7mm in diameter, various treatments were injected intratumorally on days 1, 4, and 8 on the side with the larger tumor. Treatment groups include PBS, B-CpG, C-CpG, B+C-CpG, BNP, CNP, BNP+CNP. Free CpGs were injected at 50ug/ml in 50ul (2.5ug CpG per injection) and nanoparticles at 100nM (equivalent to 50ug/ml CpGs) in 50ul. Tumor growth were measured every other day. Event is defined as tumor volume > 3cm 3. Second, we used an advanced disease lymphoma model to evaluate intravenous delivery of combination NPs. We implanted A20 lymphoma cells on a flank tumor (on day -14), then we injected A20 cells intravenously to mimic advanced disease (on day -7). We treated the mice with intravenous (tail vein) injections of PBS, B+C-CpG, or BNP+CNP on days 1, 4, and 8.Results: We found that the combination of BNP and CNPs had the most significant reduction in total tumor volume (TTV) (treated + untreated tumor size) (393mm 3 on day 22). The PBS group demonstrated rapid tumor growth (TTV 3516mm 3). The experimental treatment groups, B-CpG (TTV 949mm 3), C-CpG (TTV 2230mm 3), B+C-CpGs (TTV 1680mm 3), BNP (TTV 1224mm 3), and CNP (1894mm 3) had similar TTV growth curves. Separating the treated tumor and untreated tumor growth curves, we found that B-CpG and BNP along with combination of BNP+CNP had the best tumor suppression on the treated side. This is not surprising as B-CpG sequences are more directly cytotoxic to lymphoma cells versus C-CpGs. Interestingly, combination nanoparticle treatment (BNP+CNP) was the only group that had significantly reduced tumor growth of the untreated tumor compared with all other conditions (p<0.03) where no statistical difference was measured when the PBS treatment group with the other groups. The BNP+CNP treatment group also had significantly prolonged event free survival compared with all other treatment groups. Furthermore, in the advanced disease model, when BNP and CNP were both injected intravenously, the flank tumor was notably smaller (149mm 3) compared with the other two groups (B+C-CpG 1310mm 3 or PBS 1555mm 3). Importantly, there were no visible lymphoma nodules on liver in the nanoparticle treatment group while there are obvious nodules for both the PBS and the free CpG groups.Conclusions: Overall, the combination of class B and class C CpG nanoparticles can generate a strong in situ anti-lymphoma vaccination response, presumably through the combination of by combining the superior cytotoxicity of BNPs with the enhanced immune stimulation effect of the CNPs. Further evaluation of the combined mechanism of action of this dual CpG nanoparticle approach and toxicity studies are in progress. DisclosuresThaxton: Zylem biosciences: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding.

Myofascial points treatment with focused extracorporeal shock wave therapy (f-ESWT) for plantar fasciitis: an open label randomized clinical trial.

Plantar fasciitis (PF) is a common cause of heel pain. Among the several conservative treatment options, extracorporeal shock wave therapy (ESWT) is considered the standard treatment. However, recent studies suggest that PF may be sustained by a myofascial impairment proximal to the pain area with a biomechanical disequilibrium of the entire limb and pelvis. By combining the concepts of fascial manipulation and ESWT, the purpose of this study was to evaluate the effectiveness of the ESWT on myofascial points in a sample of subjects with PF. Open label randomized controlled clinical trial. Outpatient clinic. Patients with PF were randomly assigned to an experimental treatment group (EG), treated with focused ESWT on myofascial points, and a control group (CG), treated with the focused ESWT traditional approach on the medial calcaneal tubercle. Every patient underwent a 3-session program and follow-up after 1 and 4 months. Outcome measures included the Foot and Ankle Outcome Score (FAOS) and the Italian Foot Functional Index (17-iFFI). Thirty patients were enrolled in the study. Four patients of the CG dropped out the study, therefore twenty-six patients were included in the final analysis. Improvement in 17-iFFI and FAOS scores was observed in both groups starting from the third treatment and confirmed at the 1-month and 4-month follow-ups, with earlier improvement in the score values observed in the EG. Treatment of the myofascial points with ESWT in subjects suffering from plantar fasciitis could be an effective treatment option. It fosters the hypothesis that a global biomechanical re-equilibrium of the body would be necessary to completely solve the pathology. ESWT on myofascial points could provide an interesting alternative with better outcomes in terms of time needed for recovery compared to traditional ESWT for the conservative management of PF.

Efficacy and safety of early aspirin withdrawal and continuation of ticagrelor monotherapy post PCI for STEMI. A post hoc analysis of the randomized global leaders trial

Abstract Background Clinical presentation with STEMI is considered as a highly prothrombotic condition often associated with recurrent ischemic events. The role of aspirin as part of antiplatelet regimens in STEMI patients needs to be clarified especially in the context of new potent P2Y12 inhibitors Aim To assess the benefit and risk of 23-month ticagrelor monotherapy after one month of DAPT against the conventional 12-month DAPT with aspirin and ticagrelor followed by aspirin monotherapy among STEMI patients in the GLOBAL LEADERS trial. Methods We did a post hoc analysis of STEMI patients in the GLOBAL LEADERS trial (2092 patients). We compared the experimental ticagrelor monotherapy group (1062 patients) with the standard 12-month DAPT group (1030 patients) in rates of GLOBAL LEADERS predefined primary (composite of all-cause mortality or non-fatal, new Q-wave myocardial infarction (MI) and secondary end points (BARC 3 or 5 bleeding). NACE (Net Adverse Clinical Events) and POCE (Patient- Oriented Composite End points). We also compared GLOBAL LEADERS predefined end points in STEMI, UA, NSTEMI and CCS in both treatment arms. Results At two years, there were no significant differences in rates of GLOBAL LEADERS primary end points in patients who had or did not have STEMI. BARC bleeding in either treatment group didn't vary significantly among STEMI, NSTEMI and UA. Nevertheless, the experimental strategy had led to significant increase in BARC bleeding in CCS compared with STEMI at 1 and 2 years. There were similar rates of NACE and POCE in both the experimental and reference treatment groups at 1 and 2 years post PCI. Conclusions and relevance The incidence of GLOBAL LEADRER defined end points has not been impacted by STEMI presentation. Our findings suggest that an earlier cessation of DAPT at 1 month post primary PCI, with continuation of a potent P2Y12 antagonist monotherapy, could be safe and avoids additional bleeding risk in the STEMI setting. Given the post-hoc nature of the analysis, our findings should not necessitate changes in recommendations for practice by professional associations and regulatory agencies. However, all reported findings should rather be considered only as hypothesis-generating and need be replicated in dedicated large-scale randomized trials to further assess the role of Aspirin free antithrombotic strategies post PCI in STEMI. Funding Acknowledgement Type of funding sources: None.