The GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial assessed the effectiveness of four glucose-lowering medication classes in reducing hemoglobin A1c (HbA1c) in individuals with type 2 diabetes mellitus (T2DM) on metformin monotherapy but did not include sodium-glucose cotransporter-2 inhibitors (SGLT-2is). To replicate and extend GRADE findings by emulating a modified trial including SGLT-2is in a GRADE-eligible population, i.e., with low-to-moderate cardiovascular risk. A 4-arm target trial emulation-an observational design that mimics a randomized trial- comparing SGLT-2is, sulfonylureas (SUs), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in a modified GRADE trial framework, excluding insulin. Optum's de-identified Clinformatics® Data Mart, a commercial claims database in the US, from January 01, 2014-August 31, 2023 was used. GRADE-eligible patients (T2DM, age ≥ 30years, on metformin monotherapy, no recent cardiovascular events, baseline HbA1c 6-9%). Incident use of SGLT-2i, SU, GLP-1RA or DPP-4i. The primary outcome was the first occurrence of HbA1c ≥ 7.0%. Propensity score weights emulated random treatment assignment; hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression models. The weighted cohort included 2,065 SGLT-2i, 2,015 SU, 2,006 GLP-1RA, and 2,006 DPP-4i initiators. GLP-1RAs had a lower risk of HbA1c ≥ 7.0% vs. SUs (HR 0.73; 95% CI 0.68-0.78) and DPP-4is (HR 0.65; 95% CI 0.60-0.70). SGLT-2is had risk of HbA1c ≥ 7.0% comparable to DPP-4is (HR 1.04; 95% CI 0.97-1.10) but higher than GLP-1RAs (HR 1.60; 95% CI 1.48-1.72) and SUs (HR 1.17; 95% CI 1.11-1.23). Subgroups and sensitivity analyses showed consistent results. In this target trial emulation, GLP-1RAs were most effective for glycemic control, aligning with GRADE, and superior to SGLT-2is in combination with metformin for T2DM in patients with low-to-moderate cardiovascular risk.

Abstract Neurological complications of diabetes require investigation of botanical therapeutic alternatives for management. This study investigated the protective effects of methanolic extract from Brassica oleracea var . italica (broccoli) florets (MEBr) against metabolic dysfunction and neuroendocrine oxidative stress in a cafeteria diet-induced T2DM rodent model. The therapeutic efficacy of MEBr was evaluated through biochemical parameters including blood glucose, lipid profiles, malondialdehyde, and glutathione levels in hypothalamic-pituitary tissues. Male Wistar rats underwent random assignment to four experimental cohorts ( n = 12): Control, Control + MEBr, cafeteria diet (CAF), and CAF + MEBr. Groups receiving MEBr treatment were administered 200 mg/kg orally during the concluding 6 weeks of the 6-month protocol. Cafeteria feeding effectively established diabetic phenotype through elevated glycemia, abnormal lipid profiles, and glucose intolerance development. MEBr supplementation significantly attenuated cafeteria diet-induced weight gain, normalized glycemic control, and restored lipid profiles. Notably, MEBr protected the hypothalamo-hypophyseal axis by reducing lipid peroxidation and enhancing endogenous antioxidant defenses. Phytochemical analysis identified gallic acid, rutin, and syringic acid as major bioactive compounds contributing to the observed effects. These findings suggest that MEBr offers multifaceted protection against T2DM complications through modulation of oxidative stress and metabolic pathways.

Adjuvant immunotherapy improved patient outcomes in two trials in completely resected non-small cell lung cancer (NSCLC), but with conflicting primary end point results. The Canadian Cancer Trials Group BR.31 trial evaluated adjuvant durvalumab in completely resected early-stage NSCLC. Following resection of stage IB (≥4 cm) to IIIA NSCLC (American Joint Committee on Cancer 7th Edition) and optional adjuvant chemotherapy, patients were randomly assigned 2:1 to durvalumab 20 mg/kg or placebo 20 mg/kg once every 4 weeks for 12 cycles. Random assignment was stratified by stage, extent of nodal dissection, tumor cell (TC) PD-L1 expression, adjuvant chemotherapy use, and center. The primary end point was investigator-assessed disease-free survival (DFS). Secondary outcomes included overall survival (OS), adverse events, and quality of life. The primary analysis was in the subgroup with cancers that had a PD-L1 TC expression ≥25%, no common activating EGFR mutations (EGFR-), and no ALK gene rearrangements (ALK-). Secondary analyses in hierarchical order included DFS in the subgroup whose tumors were EGFR-/ALK- with PD-L1 TC ≥1%, followed by all patients whose tumors were EGFR-/ALK-, followed by OS in the same primary and secondary subgroups in the same hierarchical order. Of 1,415 patients randomly assigned, 1,219 (86%) had EGFR-/ALK- tumors: 815 randomly assigned to durvalumab and 404 to placebo. With a median follow-up of 60 months, there were no differences in DFS between patients assigned durvalumab (316) versus placebo (161) in the primary population (stratified hazard ratio [HR], 0.93 [95% CI, 0.71 to 1.25]; P = .64) or in the secondary populations. Grade 3 to 4 adverse events were higher in durvalumab-treated patients (D = 26% v P = 20%). Adjuvant durvalumab following complete resection was not associated with improvement in DFS compared with placebo in EGFR-/ALK- NSCLC, regardless of PD-L1 status.

To evaluate atezolizumab combined with bevacizumab and non-platinum-based chemotherapy for recurrent ovarian cancer. The double-blind randomized phase III AGO-OVAR 2.29/ENGOT-ov34 trial (ClinicalTrials.gov identifier: NCT03353831) enrolled patients with first or second relapse of ovarian cancer ≤6 months after completing platinum-based chemotherapy (or third relapse regardless of treatment-free interval). PD-L1 status was tested centrally (VENTANA SP142 assay) in recent (<3 months) biopsies before random assignment. All patients received bevacizumab and investigator-selected chemotherapy (once weekly paclitaxel or pegylated liposomal doxorubicin) until disease progression or toxicity, plus either atezolizumab 840 mg or placebo once every 2 weeks until progression (maximum 2 years), randomly assigned 1:1, and stratified by number of previous lines, planned chemotherapy, previous bevacizumab, and PD-L1 status. Primary end points were overall survival (OS) and progression-free survival (PFS) in the intention-to-treat population. Among 574 patients randomly assigned between September 2018 and July 2022, 72% were bevacizumab-pretreated, 36% had received three previous treatment lines, 26% had PD-L1-positive tumors, and 54% received paclitaxel with study therapy. After 418 patients had died, the hazard ratio for OS was 0.83 (95% CI, 0.68 to 1.01; P = .06; median 14.2 months with atezolizumab and 13.0 months with placebo) and the hazard ratio for PFS was 0.87 (95% CI, 0.73 to 1.04; P = .12; median 6.4 v 6.7 months, respectively). OS hazard ratios were similar regardless of PD-L1 status. Grade ≥3 adverse events occurred in 72% of atezolizumab-treated and 69% of placebo patients. Combining atezolizumab with bevacizumab and chemotherapy did not significantly improve OS or PFS in patients with recurrent ovarian cancer ineligible for platinum. The safety profile was as expected from previous experience with these drugs.

Coronary anatomy detects, ischemia predicts: Real-world insights from the Nancy ischemia registry

Early Intensive Behavioral Intervention (EIBI) is widely recommended for children with Autism Spectrum Disorder (ASD). However, the treatment intensity and effectiveness have been debated. We conducted a meta-analysis and examined individual participant data to evaluate the effectiveness and clinical significance of the outcomes on adaptive behavior, intellectual functioning, and autism severity. We included studies of children with ASD aged 2-6 years who received EIBI for at least 12 months. The final literature search was conducted on September 26, 2024. The GRADE tool was used to assess the risk of bias. Across the 17 identified studies, we obtained participant data from 15 studies: 341 children received EIBI and 280 were in comparison-groups. All studies had a serious risk of bias due to the lack of random assignment. Our meta-analysis yielded effect sizes of 0.66 for improvement in adaptive behavior, 0.87 for improvement in intellectual functioning and 1.36 for reductions in ASD severity. A significantly higher percentage of children in the EIBI-group met the criteria for statistically reliable change and scored in the non-clinical range post-intervention with a Number Needed to Treat between 4.1 and 6.9. We found that treatment intensity significantly contributed to changes across all outcome measures. Based on our analyses we propose benchmarks for evaluating interventions for children with ASD. Although EIBI demonstrates broad, substantial effects, some uncertainty remains due to the lack of random assignment in the reviewed studies. Nonetheless, EIBI should currently be considered as the preferred treatment for children with ASD.

Safety and immunogenicity of PanChol, a single-dose live-attenuated oral cholera vaccine: results from a phase 1a, double-blind, randomised, placebo-controlled trial.

Optical system initial structure generation method based on random assignment of optical power

The purpose of this study was to see the effect of the use of SE-TG (Sport Education Model-Traditional Games) used in physical education learning at SMK 45 Lembang on Self-Eficacy. The research methodology used is Experimental Designs with Random Assignment sampling. The population in this study were 10 grade XI students of SMK 45 Lembang, totaling 300 people. The sampling technique used was Simple Random Sampling technique, so that 60 students were randomly taken and divided into two groups, where 30 students studied with SE-TG and 30 students studied with the conventional model. The results showed that in the Experimental group, the t-value -4.271, P Value 0.000 and in the control group, the t-value -0.410, P Value 0.681. This means that there was an increase in Self-Eficacy in the experimental group and there was no increase in Self-Eficacy in the control group. The results of the difference test show that for the Self-Eficacy variable, the Z value is -3.190 with P Value 0.001. This means that SE-TG learning has a better influence on Self-Eficacy than the Conventional Model of students at SMK 45 Lembang. For further research, it is very interesting if the concept of the Sport Education Model in collaboration with Traditional Games (SE-TG) can be applied to other physical education materials such as athletics, small ball games, gymnastics and games in the concept of movement (locomotor, non-locomotor and manipulative) so that the research results from this concept become more complete.

Experimental research is a primary scientific method used to elucidate cause-and-effect correlations between variables in diverse fields. Specifically, this paper outlines the essential characteristics of experimental research, encompassing variable manipulation, controlled settings, random assignment, and precise measurement procedures to enable causal inferences. Moreover, the paper clarifies many experimental designs, including randomized controlled trials, true experimental designs, quasi-experimental designs, and single-case designs, each adapted to certain research contexts. Subsequently, the paper delineates the procedural processes for doing experimental research, underscoring the significance of methodological rigor from study design to result interpretation. Furthermore, it outlines the possible challenges to internal and external validity, emphasizing the importance of addressing confounding factors to ensure strong experimental results. In addition, the paper examines the timing of pre-tests and post-tests, the complexities of experimental design, and emerging trends such as internet-based experiments and ex post facto research. Finally, this paper seeks to furnish scholars with a detailed comprehension of experimental inquiry through an extensive analysis of research procedures, designs, and applications across several academic fields.

Propensity score matching (PSM) was presented as a practical method for making fair comparisons in studies without random assignment. This paper explained PSM in accessible terms and provided a step-by-step workflow that could be followed by readers. The research was conducted to address the issue of differences between treated and untreated individuals. The key ideas behind PSM, the assumptions required for it to work, and approaches to verifying these assumptions with simple plots and summary statistics were described. Furthermore, the main steps were outlined: defining the target question, selecting baseline covariates, estimating the propensity score, performing matching or reweighting, checking balance, estimating the treatment effect, and conducting basic sensitivity analyses. To maintain a hands-on perspective, a small numerical example and a concise checklist were included to support replication in other studies. Besides, common pitfalls were discussed, such as weak overlap, overly strict calipers, and post-matching analyses that ignored the matched structure. This paper aimed to help students and applied researchers develop PSM analyses that were transparent, reproducible, and easy to communicate to non-specialists.

BackgroundInitiation of Glucagon-Like Peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes (T2D) treated with levothyroxine may decrease the required levothyroxine dose due to weight loss or enhance levothyroxine absorption through delayed gastric emptying. These changes may cause thyroid hormone over-replacement and increased risk of atrial fibrillation/flutter (AF/Aflutter) and stroke. Our study aims to investigate the impact of GLP-1RA initiation on risks of AF/Aflutter and stroke in patients with T2D treated with levothyroxine, compared to sodium-glucose cotransporter 2 (SGLT2) inhibitors.MethodsLeveraging the target trial emulation framework, we conducted a retrospective study using observational data to emulate a new user, active comparator trial examining the effects of initiating GLP-1RA (exposure group) versus SGLT2 inhibitors (control group), with random treatment assignment emulated by propensity score matching with 1:1 ratio. We used a 15% nationally representative sample of U.S. Medicare beneficiaries to identify participants > 65 years, continuously on stable dose of levothyroxine for ≥ 6 months before the index date (i.e., GLP-1RA or SGLT2 inhibitor initiation), with continuous Medicare enrollment, without malignant cancer or palliative care during 1 year before the index date. The primary outcome was AF/Aflutter, and secondary outcome was stroke, including ischemic stroke or transient ischemic attack. We assessed the per-protocol effects of GLP-1RA vs. SGLT2 inhibitors using inverse-probability-censoring weighted Cox proportional hazards models.ResultsAfter matching, the study cohort included 2,384 participants in both GLP-1RA and SGLT2 groups with mean age (SD): 73.3 (5.9) vs. 73.2 (5.8), and 71.5% and 71.8% of female. The median follow-up time was 1.05 years. Compared to SGLT2 inhibitors, initiation of GLP-1RA was associated with higher risk of AF/Aflutter (HR: 1.46; 95% CI: 1.28–1.67), while no statistically significant difference was observed between the two groups for stroke (HR: 1.17; 95% CI: 0.98–1.39). Sensitivity analyses showed consistent results, including restricting outcomes to inpatient visits, conducting an intention-to-treat analysis, applying a prevalent new user design, and substituting SGLT2 inhibitors with dipeptidyl peptidase-4 (DPP4) inhibitors as the active comparator.ConclusionsIn patients with T2D historically treated with stable doses of levothyroxine, GLP-1RA initiation was associated with a higher risk of AF/Aflutter. Further research is warranted to investigate the potential roles of weight loss, TSH fluctuations, and levothyroxine dose adjustment after GLP-1RA in mediating the cardiovascular risk.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12933-025-02971-7.

In this study, protection motivation theory (PMT) was used to understand the drivers of adaptation of elder individuals and individuals with chronic health conditions to heatwaves. More particularly, it examines the influence of the perception of heatwave risks and of the effectiveness of five heat protection actions commonly recommended by health authorities on the adoption of these actions. The data for this study were collected using three surveys on a sample of residents of Longueuil city - Canada. This longitudinal design allowed the use of individual and time fixed effects model to test the effects of risk perception and response efficacy on adaptation to heatwaves. In addition, the random assignment of a subset of study participants to a group that was exposed to heat warning (treatment group) and a group that was not exposed (control group) enabled the use of instrumental variable method to assess the robustness of the panel fixed effect model findings. A positive association was found between the perception of the effectiveness of heat protection actions and the likelihood of adopting these actions. However, risk perception and its interaction with the perceived effectiveness of protective actions show no significant effects. This study suggests that improving the perception of the effectiveness of heat prevention actions increases their adoption. However, it questions the relevance of raising risk awareness to achieve this objective.

BackgroundCoronary artery bypass grafting using the radial artery is performed by harvesting the graft through open or endoscopic surgery. Data from randomized trials comparing harvesting techniques are limited.MethodsWe conducted a randomized controlled trial comparing endoscopic radial artery harvest with open radial artery harvest in adults scheduled for coronary artery bypass surgery. The primary outcome was patient-reported hand function at 3 months after random assignment, assessed using the Hand Function Questionnaire (scores range from 5 to 49, with lower scores indicating more favorable outcomes; a minimal clinically important difference has not been firmly established but may be approximately 3 points). Secondary outcomes included neurologic deficits.ResultsA total of 300 patients were randomly assigned to endoscopic radial artery harvest (151 patients) or open radial artery harvest (149 patients). At 3 months, the mean score on the Hand Function Questionnaire was 7.20 points in patients assigned to endoscopic radial artery harvest and 7.74 points in patients assigned to open radial artery harvest (difference, 0.52 points; 95% confidence interval [CI], 0.06 to 0.98; P=0.03). Thirty-two of 151 (21.2%) patients in the endoscopic radial artery harvest group had neurologic deficits, compared with 82 of 149 (55.0%) patients in the open radial artery harvest group (relative risk with open radial artery harvest, 2.61; 95% CI, 1.90 to 3.63). In the endoscopic radial artery harvest group, one or more serious adverse events occurred in 9 of 151 (6.0%) patients, compared with 4 of 149 (2.7%) patients in the open radial artery harvest group (relative risk with open radial artery harvest, 0.45; 95% CI, 0.13 to 1.34).ConclusionsIn patients scheduled for coronary artery bypass surgery, endoscopic radial artery harvest, compared with open radial artery harvest, led to modestly better patient-reported hand function and was associated with reduced neurologic deficits. (ClinicalTrials.gov number, NCT01848886.)

Abstract We estimate the causal effects of parental incarceration on children’s short- and long-run outcomes using administrative data from Sweden. Our empirical strategy exploits exogenous variation in parental incarceration from the random assignment of criminal defendants to judges with different incarceration tendencies. We find that incarceration of a parent in childhood leads to a significant increase in teen criminal convictions, a decrease in schooling outcomes, and worse labour market outcomes in adulthood. The effects are concentrated among children from disadvantaged families, in particular families where the remaining non-convicted parent is disadvantaged. These results suggest that the incarceration of parents with young children may significantly increase the intergenerational persistence of poverty and criminal behaviour in affluent countries with extensive social safety nets and progressive criminal justice systems.

This quasi-experimental study evaluated a contextualized course learning material for Reading and Writing Skills and determined its effectiveness in remote learning. Using a matched-pair random assignment procedure, 60 Grade 11 students were paired according to pretest scores and then assigned to either a comparison group using regular course materials or an experimental group using the contextualized material as supplementary instruction. Data from pretests, formative tests, summative tests, and posttests were analyzed through paired and independent t-tests, with Cohen’s d used to measure effect size. Findings show that the experimental group consistently outperformed the comparison group in key competencies, including Techniques of Information Selection and Organization, Writing Development Patterns, and Properties of a Well-Written Text. Large effect sizes further indicate that the contextualized material produced substantial learning gains beyond those achieved through traditional resources. Participant feedback also highlighted the material's relevance and usefulness, offering insights for future revisions.

Veterans with serious mental illness (SMI) experience a higher prevalence of obesity than the general veteran population; weight loss programs are needed that are tailored to this population. To evaluate a weight loss program, CoachToFit (CTF), which includes weekly calls from a Veteran Health Administration peer specialist, a Bluetooth-enabled scale and fitness tracker, and a smartphone application that provides health education and tracks steps, goals, and weight. This randomized clinical trial was conducted within the Pittsburgh Veteran Affairs health care system and presents pre-post (6 months) analysis comparing CTF and usual care. Veterans with body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 30 or higher and diagnosis of major depressive disorder, bipolar disorder, or schizophrenia were eligible for inclusion. Exclusion criteria included history of bariatric surgery or recent psychiatric hospitalization. The study was conducted from October 1, 2020, to September 30, 2025, and data analysis was conducted from January to October 2025. Random assignment to CTF. The primary outcomes were weight (in kg), BMI, and cardiorespiratory fitness (meters walked in 6 minutes). Among the sample (n = 256), mean (SD) age was 53.5 (13.1) years, 80 participants (31.3%) were female, and 199 (77.7%) were diagnosed with major depressive disorder. Mean (SD) weight loss at 6 months was -3.2 (6.2) kg in the CTF group (n = 128) compared to -1.6 (4.9) kg in the usual care group (P = .05). After adjustment, participants in CTF experienced greater, nonsignificant weight loss compared to usual care, with an adjusted mean difference (AMD) of -1.62 kg (95% CI, -3.38 to 0.14; P = .07). For BMI, the AMD in change between groups at 6 months was -0.56 (95% CI, -1.15 to 0.03; P = .06). Change in meters walked was not statistically significant between groups, with an AMD of 3.53 m (95% CI, -12.87 to 19.92; P = .67). At 6 months, 34 participants (36.6%) from the CTF group lost 5% or more of their body weight compared to 19 (22.4%) in usual care, representing a 1.93-fold greater likelihood in adjusted analyses (95% CI, 0.96-3.91; P = .07). More participants in CTF (n = 21 [22.6%]) lost 7% or more of their body weight compared to usual care (n = 7 [8.2%]), representing a 3.9-fold greater likelihood in adjusted analyses (95% CI, 1.45-10.36; P = .007). In this randomized clinical trial, a weight loss program tailored to veterans with SMI using remote technologies and paraprofessionals demonstrated the potential to help this population lose weight. ClinicalTrials.gov Identifier: NCT04560335.

Observational studies in kidney transplantation often face confounding bias due to the absence of randomization, which can compromise validity and limit generalizability. Propensity score matching (PSM) helps mitigate this bias by mimicking random assignment. This guide outlines the implementation of PSM in kidney transplant research, focusing on methodology, practical considerations, common pitfalls, and reporting standards. We summarize key steps, including selecting covariates related to both treatment and the probability of receiving a transplant, estimating propensity scores, applying appropriate matching techniques, assessing balance, and conducting sensitivity analyses to test robustness. Practical considerations include ensuring sufficient overlap in propensity scores and balancing sample size with matching quality. Common challenges involve omitting relevant covariates, inadequate overlap, suboptimal matching, and loss of statistical power due to reduced sample size. By adhering to rigorous methodological practices and transparent reporting, researchers can improve the credibility and impact of their findings. When carefully implemented, PSM can substantially reduce confounding bias, enhance causal inference, and ultimately support better decision-making in kidney transplantation research. The example provided is illustrative only and does not replace a formal time-to-event analysis accounting for competing risks.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-31596-9.

Introduction: Hamstring injuries are common in soccer and are associated with eccentric strength deficits and inter-limb functional asymmetries. The Nordic Hamstring Curl (NHC) is effective for prevention; however, the influence of execution velocity on functional adaptations in young athletes remains unclear. Objective: To determine the effects of two execution velocities of the Nordic Hamstring Curl on eccentric knee flexor strength and functional asymmetry in young soccer players. Methods: A quasi-experimental study with random assignment was conducted in male U-17 soccer players (n=20), divided into a fast-velocity group (FG) and a slow-velocity group (SG). The intervention lasted 4 weeks (3 sessions per week) with progressive volume. Bilateral eccentric strength was recorded in real time during the Nordic Hamstring Curl using a validated load-cell device; inter-limb asymmetry was calculated. Results: Improvements in eccentric strength were observed in both groups. Statistical significance was reached only in the non-dominant limb of the FG (p=0.0157). No between-group differences were found bilaterally. Functional asymmetry was significantly reduced in the FG (p=0.0119), while it remained stable in the SG. Discussion: A short Nordic Curl training cycle improved eccentric strength and reduced inter-limb asymmetry, especially with a fast tempo as a key modulator, showing both agreements and discrepancies with previous studies. Conclusions: The execution velocity of the Nordic Curl emerges as a key factor in short-term adaptations: both tempos improve eccentric strength, and the fast, braking-emphasized variant additionally promotes the correction of asymmetries.

Randomized rollout trial designs, including stepped wedge designs, are commonly used to examine how well an evidence-based intervention or package is being implemented in community or healthcare settings. The multitude of implementation research questions and specific hypotheses suggest the need for diverse randomized rollout implementation trial designs, assignment principles and procedureds, and statistical modeling. We separate key research questions and identify mixed effect models for randomized implementation rollout trials involving 1) a single implementation strategy that tests how this strategy varies over time and/or resources that are allocated, 2) comparison of two distinct implementation strategies, and 3) three distinct strategies or components tested in a single trial. Appropriate rollout designs, optimal assignment methods, and other design and analysis considerations are discussed for trials of up to three distinct implementation strategies. To examine improvement in implementation outcomes we present a Fixed-Length Staggered Rollout Trial Design to examine how well a sustainment period continues to produce outcomes, The Rollout Implementation Optimization (ROIO) methodology illustrates testing for quality improvement. For comparing an existing to new strategy, we focus on a Stepped Wedge design, and for comparing two new strategies we describe a Head-to-Head Rollout trial design. To test for synergy between two components, we introduce a Head-to-Head Rollout trial design, and for testing an existing strategy to a new one followed by a sustainment period, we recommend using a Three-Phase Sequential Rollout Implementation trial design. Modeling choices are described, including options for specifying random effects that capture variations in site and clustering. We discuss comparisons of superiority versus non-inferiority testing and multiple contrasts. To support uses of these six designs and analyses, we provide computational code. The large class of randomized rollout implementation trial designs provides rich opportunities to address research questions posed by implementation scientists. Balance in assigning sites to cohorts is important before random assignment to time of transition to a new implementation occurs. Specific hypotheses are tested with mixed effects models where fixed effects include comparisons of implementation conditions and random effects that account for variation in sites and clustering.