Berry & Associates (United States)

BackgroundSeveral studies have demonstrated that veterinarians hold breed-specific beliefs about canine pain sensitivity. However, it remains unknown whether these beliefs impact how veterinarians recognize and treat pain in a clinical setting. Therefore, the objective of this study was to determine if there were differences in the assessment and treatment of pain across patients admitted to a veterinary emergency room (ER) from different breeds.MethodsVeterinary ER records were retrospectively analyzed to evaluate the effects of breed on the assessment and treatment of pain in canine patients admitted to a single academic ER over a two-year period. Extracted data included patient signalment and information documented in medical evaluations completed by ER clinicians.ResultsThe final sample included records from 3,744 patients across 69 breeds/breed types. Patient breed and the service the patient was transferred to from the ER were significantly explanatory for differences observed in pain scores and pain management plans assigned. The effect of breed and transfer service remained robust when accounting for covariates.Conclusions and clinical relevanceCertain breeds were assigned pain scores lower than average, while other breeds were assigned higher than average pain scores despite a lack of evidence that these breeds presented with less or more painful conditions. As breed-specific beliefs do not align with experimental measures of pain sensitivity, the present findings have implications to help refine pain education and medical decision-making and ultimately improve patient care.

Abstract BACKGROUND GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a multi-arm, international, seamless Phase 2/3 response adaptive randomization (RAR) platform trial designed to efficiently identify investigational therapies that improve overall survival and confirm efficacious therapies and biomarker signatures to support registration. GBM AGILE is a collaboration among academic investigators, patient organizations, and industry to support new drug applications for newly diagnosed and recurrent glioblastoma. METHODS The primary objective of GBM AGILE is to identify therapies that improve overall survival in patients with newly diagnosed or recurrent glioblastoma. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different companies to be evaluated simultaneously and/or over time against a common control. Investigational therapies are added as information about promising drugs is identified, while other therapies are removed as they complete evaluation. RAR is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE has screened over 2300 patients and enrollment continues to be robust. In addition to the efficient evaluation of investigational arms, a goal of GBM AGILE is to expand knowledge of glioblastoma to support advancements in treatment using the data collected within the trial (learning environment). Over 7 million data points are currently available for inclusion in the development of a longitudinal model. Such a model may be able to inform randomization by providing earlier and continuous information regarding patient and arm performance. In addition, serial magnetic resonance imaging scans and biospecimens from baseline through patient progression are being collected for further analysis. An initial 500 baseline tissue samples are being characterized by genome sequencing and transcriptome analysis. NCT number: NCT03970447.

Diaphragm dysfunction impedes weaning from mechanical ventilation. Transvenous diaphragm neurostimulation can increase diaphragm strength, but its impact on patient outcomes is uncertain. To test the safety and effectiveness of transvenous diaphragm neurostimulation to increase successful weaning in patients with difficulty weaning from mechanical ventilation in comparison with standard of care. This international, multicenter, open-label, randomized clinical trial (RESCUE-3) included adult patients requiring mechanical ventilation for ⩾96 hours who met readiness-to-wean criteria and failed two or more weaning attempts. Patients were randomized to twice-daily transvenous diaphragm neurostimulation (treatment) or standard of care (control). The primary outcome was successful weaning at Day 30. Secondary outcomes included duration of ventilation to Day 30 and mortality at Day 30. The prespecified primary analysis utilized a Bayesian approach with borrowing of prior information from a previous Phase-II randomized trial, downweighted to account for possible differences in trials. Because of slow enrollment and financial considerations, the trial was halted at the first interim analysis after 200 patients were randomized. Overall, 216 patients were randomized in the modified intent-to-treat population (treatment group, n = 102; control group n = 114). At Day 30, 71 (70%) patients in the treatment group and 69 (61%) patients in the control group were successfully weaned (adjusted hazard ratio, 1.34; 95% credible interval = 1.01-1.78; posterior probability of superiority, 97.9%). Treatment reduced the duration of ventilation (adjusted difference, -2.5 d; 95% credible interval = -5.0 to 0.1; posterior probability of superiority, 97.1%). Serious adverse events were reported in 36% of patients in the treatment group and 24% of patients in the control group; 9.8% of patients in the treatment group and 10.5% of patients in the control group died (adjusted hazard ratio, 0.74; 95% credible interval = 0.37-1.46; posterior probability of superiority, 80.6%). Although the trial was stopped early because of slow enrollment, transvenous diaphragm neurostimulation showed a high probability of potential benefit for weaning success but with a possible increase in serious adverse events.

Objective:In a randomized, embedded, multifactorial, adaptive platform (REMAP) trial, we hypothesized that perioperative metformin would improve postoperative time alive and out of the hospital, defined by 90-day hospital-free days (HFD-90), among nondiabetic aged adults.Background:As our population ages, patients are increasingly frail requiring an emphasis on treatments to counteract their diminished resilience, especially following the stress of surgery. Growing literature supports metformin as an antiaging and anti-inflammatory therapy with beneficial effects extending into the perioperative period.Methods:At-risk adults (≥60 years) scheduled for elective surgical interventions were randomized to placebo (N = √3) or metformin (N = 1:1:1; 500 mg:1000 mg:1500 mg) for short (7–28 days), intermediate (29–90 days), or long (>90 days) preoperative durations. An adaptive sample size of (N = 1000–2500) would identify at least a 15% improvement in HFD-90 for >1 metformin doses. Using intention-to-treat analysis, Bayesian ordinal logistic regression compared HFD-90 and frequentist logistic regression compared 90-day reoperation and readmission.Results:Before trial closure, we randomized 302 (N = 106 placebo, N = 196 metformin [N = 64, 500 mg; N = 66, 1000 mg; and N = 66, 1500 mg]) patients without differences in baseline demographics (age 68 ± 6 years, 45% females, and 92% White race) or interventions (spine [29%], general [38%], colorectal [13%], and other [20%]). The odds of HFD-90 did not significantly differ between all doses and duration of metformin or placebo. There were no differences in the odds of reintervention (OR = 1.1 [95% CI, 0.6–2.0]) or readmission (OR = 1.5 [95% CI, 0.7–2.8]).Conclusions:Pretreatment with metformin did not improve postoperative outcomes in this REMAP trial, although trial enrollment was markedly limited by the COVID-19 pandemic and is underpowered.

Abstract BACKGROUND GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies efficiently against a common control (C) with a primary endpoint of overall survival (OS). VAL-083 (VAL) is a DNA targeting agent that, independent of O6-methylguanine DNA methyltransferase promoter methylation status, targets the N7 position of guanine residues and facilitates inter-strand DNA crosslinks, leading to DNA double-strand breaks and cell death. It entered the trial in January 2021, and it is the 2nd arm (of 6) to complete its evaluation. MATERIAL AND METHODS Patient subtypes considered in GBM AGILE are newly diagnosed methylated (NDM), ND unmethylated (NDU), & recurrent disease (RD). C is temozolomide (in ND) & lomustine (in RD). Arms open to all 3 subtypes are evaluated in 5 prospectively defined signatures (sig): NDU, NDM, RD, all ND and All. Randomization (rand.) to C is 20% in each subtype. Exp arms in GBM AGILE have 1 or 2 stages. Efficacy is based on OS hazard ratio (HR) of arm/C. Efficacy goal is a final Bayesian probability ≥ 98% for HR <1.00 in combined Stages 1 & 2. Arms stop accruing in Stage 1 if they reach max sample size (N) or drop for futility or safety. Exp arms in Stage 1 are adaptively rand. with allocation being proportional to an arm’s current probability of having ≥ 30% benefit in OS, P(HR <0.70). In stage 1, exp arms are evaluated monthly, and arms showing Bayesian predictive power (PP) ≥ 0.8, graduate into Stage 2 with fixed rand. in one sig. For all exp arms, follow up continues for 12 mos after accrual stops. Arms are declared futile at any monthly analysis when PP is <0.25 for all sigs. Open to all 3 subtypes, VAL entered as the 1st arm in NDM and was rand. 1:1 to C in this subtype until additional arms entered. The target max N for VAL in its Stages 1 & 2 were 150 and 50, resp. RESULTS At the interim after VAL reached max sample size in Stage 1, the PP for all sigs was <0.8 and >0.25 for at least one sig. Thus, VAL did not graduate nor drop for futility, but accrual stopped for max N in Stage 1 VAL/C sample sizes were 39/92, 28/30, 87/225, 67/122, 154/347 for sigs NDU, NDM, RD, ND, and all. Resp. PPs: 0.086, 0.286, 0.005, 0.148, and 0.014. Resp. mean HRs: 1.36, 1.07, 1.69, 1.18, 1.4. At the interim after which VAL stopped for max N, mean HRs were 1.36, 1.07, 1.69, 1.18, and 1.40 with final probabilities of benefit (HR< 1.00) equal to 0.794, 0.564, 0.345, 0.708, and 0.564. Final results will be presented at the meeting. CONCLUSION GBM AGILE is an efficient & effective model for phase 3 drug development. VAL did not increase OS compared to C in any glioblastoma subtype. GBM AGILE evaluated this agent in less time, at lower cost, & with fewer patients than typical registration trials & is currently evaluating several other arms. © 2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2024 ASCO Annual Meeting. All rights reserved.

2005 Background: GBM AGILE (NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies efficiently against a common control (C) with a primary endpoint of overall survival (OS). VAL-083 (VAL) is a DNA targeting agent that, independent of O6-methylguanine DNA methyltransferase promoter methylation status, targets the N7 position of guanine residues and facilitates inter-strand DNA crosslinks, leading to DNA double-strand breaks and cell death. It entered the trial in January 2021, and it is the 2nd arm (of 6) to complete its evaluation. Methods: Patient subtypes considered in GBM AGILE are newly diagnosed methylated (NDM), ND unmethylated (NDU), & recurrent disease (RD). C is temozolomide (in ND) & lomustine (in RD). Arms open to all 3 subtypes are evaluated in 5 prospectively defined signatures (sig): NDU, NDM, RD, all ND and All. Randomization to C is 20% in each subtype. Exp arms in GBM AGILE have 1 or 2 stages. Efficacy is based on OS hazard ratio (HR) of arm/C. Efficacy goal is a final Bayesian probability ≥ 98% for HR <1.00 in combined Stages 1 & 2. Arms stop accruing in Stage 1 if they reach max sample size (N) or drop for futility or safety. Exp arms in Stage 1 are adaptively randomized with allocation being proportional to an arm’s current probability of having ≥ 30% benefit in OS, P(HR <0.70). In stage 1, exp arms are evaluated monthly, and arms showing Bayesian predictive power (PP) ≥ 0.8, graduate into Stage 2 with fixed randomization in one sig. For all exp arms, follow up continues for 12 mos after accrual stops (clinical cutoff). Arms are declared futile at any monthly analysis when PP is <0.25 for all sigs. Open to all 3 subtypes, VAL entered as the 1st arm in NDM and was randomized 1:1 to C in this subtype until additional arms entered. The target max N for VAL in its Stages 1 & 2 were 150 and 50, resp. Results: At the interim after VAL reached max sample size in Stage 1, the PP for all signatures was <0.8 and >0.25 for at least one sig. Thus, VAL did not graduate nor drop for futility, but accrual stopped for maximum N in Stage 1 (see table). Final results will be presented at the meeting. Columns 2-5 show results at the interim after which VAL stopped for max N. Columns 6-8 show near final results. Conclusions: GBM AGILE is an efficient & effective model for phase 3 drug development. VAL did not increase OS compared to C in any glioblastoma subtype. GBM AGILE evaluated this agent in less time, at lower cost, & with fewer patients than typical registration trials & is currently evaluating several other arms. Clinical trial information: NCT03970447 . [Table: see text]

BackgroundThe use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and it is recommended in many guidelines, but this is based on limited evidence. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leukocidins (eg, Panton-Valentine leukocidin, toxic shock syndrome toxin 1, exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question.Methods and AnalysisThe Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multicenter adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality rates. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either 5 days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard-of-care antibiotics. Most participants with SAB (within 72 hours of index blood culture and with no contraindications) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol, and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and Panton-Valentine leukocidin–positive isolate.

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This study seeks to determine whether giving an explicit incentive to students in an upper-division first-semester electromagnetism course (EM1), in the form of partial credit for reworking unit exam problems, will improve their problem-solving skills as measured by performance on identical problems on the final exam. Three problems–a primarily algorithmic problem, a primarily conceptual problem, and a problem that blended conceptual with algorithmic–were selected and analyzed over the course of three consecutive sections of EM1, for which each student could freely choose whether or not to rework mistakes on each one of the given problems in exchange for the aforementioned partial credit. Regression models were chosen for quantitative analysis, with the covariate being unit exam performance and whether the student reworked the problem. Results indicate that overall, students who choose to rework problems perform better on the final exam attempt, at a level that often does not correlate strongly with unit exam performance, whereas students who decline to rework problems have a stronger correlation between unit exam and final exam performances. The results show a clear difference between the two stages of problem-solving, namely, invoking the correct principles and applying the principles, where the latter showed a more significant effect with a much larger effect size. Qualitative analysis of a sample of students interviewed about their exam solutions showed that reworking an exam problem for some students did result in more expertlike problem-solving trends; that being said, there were instances of persistent novicelike trends regardless of reworking, as well as instances of students independently reviewing unit exam problems in preparation for the final even though the partial credit incentive was declined at the time of the unit exam. Thus, while the intervention showed overall benefits insofar as exam performance is concerned, the usage of more well-defined scaffolding, e.g., tutorials, may prove a more thorough and definite benefit for improving problem-solving skills.