A hybrid approach to sample size re-estimation in cluster randomized trials with continuous outcomes.

This study presents a hybrid (Bayesian-frequentist) approach to sample size re-estimation (SSRE) for cluster randomised trials with continuous outcome data, allowing for uncertainty in the intra-cluster correlation (ICC). In the hybrid framework, pre-trial knowledge about the ICC is captured by placing a Truncated Normal prior on it, which is then updated at an interim analysis using the study data, and used in expected power control. On average, both the hybrid and frequentist approaches mitigate against the implications of misspecifying the ICC at the trial's design stage. In addition, both frameworks lead to SSRE designs with approximate control of the type I error-rate at the desired level. It is clearly demonstrated how the hybrid approach is able to reduce the high variability in the re-estimated sample size observed within the frequentist framework, based on the informativeness of the prior. However, misspecification of a highly informative prior can cause significant power loss. In conclusion, a hybrid approach could offer advantages to cluster randomised trials using SSRE. Specifically, when there is available data or expert opinion to help guide the choice of prior for the ICC, the hybrid approach can reduce the variance of the re-estimated required sample size compared to a frequentist approach. As SSRE is unlikely to be employed when there is substantial amounts of such data available (ie, when a constructed prior is highly informative), the greatest utility of a hybrid approach to SSRE likely lies when there is low-quality evidence available to guide the choice of prior.

Implementing Evidence-Based Pain Management Interventions Into an Emergency Department: Outcomes Guided by Use of the Ottawa Model of Research Use.

AIM: To implement strategies to improve the care of patients with acute pain in the emergency department (ED). DESIGN: Pre-post implementation study using a Type 2 hybrid effectiveness-implementation design. METHODS: Implementation strategies were introduced and monitored through the Ottawa Model of Research Uses' assessment, monitoring and evaluation cycles, supported by focused and sustained facilitation. RESULTS: Improvements in time-to-analgesia within 30 min (21%-27%), administration of nurse-initiated analgesia (NIA) (17%-27%) and measurement of pain (65%-75%) were achieved post-implementation. NIA was the strongest predictor of receiving analgesia within 30 min. Adoption of pain interventions into practice was not immediate yet responded to sustained facilitation of implementation strategies. CONCLUSION: Collaboration with local clinicians to introduce simple interventions that did not disrupt workflow or substantially add to workload were effective in improving analgesia administration rates, and the proportion of patients receiving analgesia within 30 min. The assessment, monitoring and evaluation cycles enabled agile and responsive facilitation of implementation activities within the dynamic ED environment. Improvements took time to embed into practice, trending upward over the course of the implementation period, supporting the sustained facilitation approach throughout the study. IMPLICATIONS: Sustained adoption of evidence-based pain interventions into the care of people presenting to the ED with acute pain can be achieved through sustained facilitation of implementation. NIA should be at the centre of acute pain management in the ED. IMPACT: This study addressed the lingering gap between evidence and practice for patients with acute pain in the ED. Implementation of locally relevant/informed implementation strategies supported by focused and sustained facilitation improved the care of patients with acute pain in the ED. This research will have an impact on people presenting to EDs with acute pain, and on clinicians treating people with acute pain in the ED. Relevant equator guidelines were followed and the StaRI reporting method used. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution in this study.

Benchmarking statistical methods for analyzing parent-child dyads in genetic association studies.

Genetic association studies of child health outcomes often employ family-based study designs. One of the most popular family-based designs is the case-parent trio design that considers the smallest possible nuclear family consisting of two parents and their affected child. This trio design is particularly advantageous for studying relatively rare disorders because it is less prone to type 1 error inflation due to population stratification compared to population-based study designs (e.g., case-control studies). However, obtaining genetic data from both parents is difficult, from a practical perspective, and many large studies predominantly measure genetic variants in mother-child dyads. While some statistical methods for analyzing parent-child dyad data (most commonly involving mother-child pairs) exist, it is not clear if they provide the same advantage as trio methods in protecting against population stratification, or if a specific dyad design (e.g., case-mother dyads vs. case-mother/control-mother dyads) is more advantageous. In this article, we review existing statistical methods for analyzing genome-wide marker data on dyads and perform extensive simulation experiments to benchmark their type I errors and statistical power under different scenarios. We extend our evaluation to existing methods for analyzing a combination of case-parent trios and dyads together. We apply these methods on genotyped and imputed data from multiethnic mother-child pairs only, case-parent trios only or combinations of both dyads and trios from the Gene, Environment Association Studies consortium (GENEVA), where each family was ascertained through a child affected by nonsyndromic cleft lip with or without cleft palate. Results from the GENEVA study corroborate the findings from our simulation experiments. Finally, we provide recommendations for using statistical genetic association methods for dyads.

BEATS: Bayesian hybrid design with flexible sample size adaptation for time-to-event endpoints.

As the roles of historical trials and real-world evidence in drug development have substantially increased, several approaches have been proposed to leverage external data and improve the design of clinical trials. While most of these approaches focus on methodology development for borrowing information during the analysis stage, there is a risk of inadequate or absent enrollment of concurrent control due to misspecification of heterogeneity from external data, which can result in unreliable estimates of treatment effect. In this study, we introduce a Bayesian hybrid design with flexible sample size adaptation (BEATS) that allows for adaptive borrowing of external data based on the level of heterogeneity to augment the control arm during both the design and interim analysis stages. Moreover, BEATS extends the Bayesian semiparametric meta-analytic predictive prior (BaSe-MAP) to incorporate time-to-event endpoints, enabling optimal borrowing performance. Initially, BEATS calibrates the expected sample size and initial randomization ratio based on heterogeneity among the external data. During the interim analysis, flexible sample size adaptation is performed to address conflicts between the concurrent and historical control, while also conducting futility analysis. At the final analysis, estimation is provided by incorporating the calibrated amount of external data. Therefore, our proposed design allows for an approximation of an ideal randomized controlled trial with an equal randomization ratio while controlling the size of the concurrent control to benefit patients and accelerate drug development. BEATS also offers optimal power and robust estimation through flexible sample size adaptation when conflicts arise between the concurrent control and external data.

The unrecognized role of fidelity in effectiveness-implementation hybrid trials: simulation study and guidance for implementation researchers.

BACKGROUND: Effectiveness-implementation hybrid designs are a relatively new approach to evaluate efficacious interventions in real-world settings while concurrently gathering information on the implementation. Intervention fidelity can significantly influence the effectiveness of an intervention during implementation. However little guidance exists for applied researchers conducting effectiveness-implementation hybrid trials regarding the impact of fidelity on intervention effects and power. METHODS: We conducted a simulation study based on parameters from a clinical example study. For the simulation, we explored parallel and stepped-wedge cluster randomized trials (CRTs) and hypothetical patterns of fidelity increase during implementation: slow, linear, and fast. Based on fixed design parameters, i.e., the number of clusters (C = 6), time points (T = 7), and patients per cluster (n = 10) we used linear mixed models to estimate the intervention effect and calculated the power for different fidelity patterns. Further, we conducted a sensitivity analysis to compare outcomes based on different assumptions for the intracluster-correlation coefficient and the cluster size. RESULTS: Ensuring high fidelity from the beginning is central to achieve accurate intervention effect estimates in stepped-wedge and parallel CRTs. The importance of high fidelity in the earlier stages is more emphasized in stepped-wedge designs than in parallel CRTs. In contrast, if the increase of fidelity is too slow despite relatively high starting levels, the study will likely be underpowered and the intervention effect estimates will also be biased. This effect is more accentuated in parallel CRTs, here reaching 100% fidelity within the next measurement points is crucial. CONCLUSIONS: This study discusses the importance of intervention fidelity for the study`s power and highlights different recommendations to deal with low fidelity in parallel and stepped-wedge CRTs from a design perspective. Applied researchers should consider the detrimental effect of low fidelity in their evaluation design. Overall, there are fewer options to adjust the trial design after the fact in parallel CRT as compared to stepped-wedge CRTs. Particular emphasis should be placed on the selection of contextually relevant implementation strategies.

A hybrid approach to comparing parallel-group and stepped-wedge cluster-randomized trials with a continuous primary outcome when there is uncertainty in the intra-cluster correlation.

BACKGROUND/AIMS: To evaluate how uncertainty in the intra-cluster correlation impacts whether a parallel-group or stepped-wedge cluster-randomized trial design is more efficient in terms of the required sample size, in the case of cross-sectional stepped-wedge cluster-randomized trials and continuous outcome data. METHODS: We motivate our work by reviewing how the intra-cluster correlation and standard deviation were justified in 54 health technology assessment reports on cluster-randomized trials. To enable uncertainty at the design stage to be incorporated into the design specification, we then describe how sample size calculation can be performed for cluster- randomized trials in the 'hybrid' framework, which places priors on design parameters and controls the expected power in place of the conventional frequentist power. Comparison of the parallel-group and stepped-wedge cluster-randomized trial designs is conducted by placing Beta and truncated Normal priors on the intra-cluster correlation, and a Gamma prior on the standard deviation. RESULTS: Many Health Technology Assessment reports did not adhere to the Consolidated Standards of Reporting Trials guideline of indicating the uncertainty around the assumed intra-cluster correlation, while others did not justify the assumed intra-cluster correlation or standard deviation. Even for a prior intra-cluster correlation distribution with a small mode, moderate prior densities on high intra-cluster correlation values can lead to a stepped-wedge cluster-randomized trial being more efficient because of the degree to which a stepped-wedge cluster-randomized trial is more efficient for high intra-cluster correlations. With careful specification of the priors, the designs in the hybrid framework can become more robust to, for example, an unexpectedly large value of the outcome variance. CONCLUSION: When there is difficulty obtaining a reliable value for the intra-cluster correlation to assume at the design stage, the proposed methodology offers an appealing approach to sample size calculation. Often, uncertainty in the intra-cluster correlation will mean a stepped-wedge cluster-randomized trial is more efficient than a parallel-group cluster-randomized trial design.

The results of clinician-focused implementation strategies on uptake and outcomes of Measurement-Based Care (MBC) in general mental health care.

BACKGROUND: Measurement-Based Care (MBC) is the routine administration of measures, clinicians' review of the feedback and discussion of the feedback with their clients, and collaborative evaluation of the treatment plan. Although MBC is a promising way to improve outcomes in clinical practice, the implementation of MBC faces many barriers, and its uptake by clinicians is low. The purpose of this study was to investigate whether implementation strategies that were developed with clinicians and aimed at clinicians had an effect on (a) clinicians' uptake of MBC and (b) clients' outcomes of MBC. METHODS: We used an effectiveness-implementation hybrid design based on Grol and Wensing's implementation framework to assess the impact of clinician-focused implementation strategies on both clinicians' uptake of MBC and outcomes obtained with MBC for clients in general mental health care. We hereby focused on the first and second parts of MBC, i.e., the administration of measures and use of feedback. Primary outcome measures were questionnaire completion rate and discussion of the feedback with clients. Secondary outcomes were treatment outcome, treatment length, and satisfaction with treatment. RESULTS: There was a significant effect of the MBC implementation strategies on questionnaire completion rate (one part of clinicians' uptake), but no significant effect on the amount of discussion of the feedback (the other part of clinicians' uptake). Neither was there a significant effect on clients' outcomes (treatment outcome, treatment length, and satisfaction with treatment). Due to various study limitations, the results should be viewed as exploratory. CONCLUSIONS: Establishing and sustaining MBC in real-world general mental health care is complex. This study helps to disentangle the effects of MBC implementation strategies on differential clinician uptake, but the effects of MBC implementation strategies on client outcomes need further examination.

Antiproliferative Activity, Multikinase Inhibition, Apoptosis- Inducing Effects and Molecular Docking of Novel Isatin-Purine Hybrids.

The traditional single-treatment strategy for cancer is frequently unsuccessful due to the complexity of cellular signaling. However, suppression of multiple targets is vital to defeat tumor cells. In this research, new compounds for the treatment of cancer were developed successfully as novel hybrid anticancer agents. Based on a molecular hybridization strategy, we designed hybrid agents that target multiple protein kinases to fight cancer cells. The proposed hybrid agents combined purine and isatin moieties in their structures with 4-aminobenzohydrazide and hydrazine as different linkers. Having those two moieties in one molecule enabled the capability to inhibit multiple kinases, such as human epidermal receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 2 (CDK2). Anticancer activity was evaluated by performing cytotoxicity assays, kinase inhibition assays, cell cycle analysis, and BAX, Bcl-2, Caspase 3 and Caspase 9 protein level determination assays. The results showed that the designed hybrids tackled the cancer by inhibiting both cell proliferation and metastasis. A molecular docking study was performed to predict possible binding interactions in the active site of the investigated protein kinase enzymes.

A hybrid design for dose-finding oncology clinical trials.

Identifying the maximum tolerated dose (MTD) and recommending a Phase II dose for an investigational treatment is crucial in cancer drug development. A suboptimal dose often leads to a failed late-stage trial, while an overly toxic dose causes harm to patients. There is a very rich literature on trial designs for dose-finding oncology clinical trials. We propose a novel hybrid design that maximizes the merits and minimizes the limitations of the existing designs. Building on two existing dose-finding designs: a model-assisted design (the modified toxicity probability interval) and a dose-toxicity model-based design, a hybrid design of the modified toxicity probability interval design and a dose-toxicity model such as the logistic regression model is proposed, incorporating optimal properties from these existing approaches. The performance of the hybrid design was tested in a real trial example and through simulation scenarios. The hybrid design controlled the overdosing toxicity well and led to a recommended dose closer to the true MTD due to its ability to calibrate for an intermediate dose. The robust performance of the proposed hybrid design is illustrated through the real trial dataset and simulations. The simulation results demonstrated that the proposed hybrid design can achieve excellent and robust operating characteristics compared to other existing designs and can be an effective model for determining the MTD and recommended Phase II dose in oncology dose-finding trials. For practical feasibility, an R-shiny tool was developed and is freely available to guide clinicians in every step of the dose finding process.

Comparison of analysis methods and design choices for treatment-by-period interaction in unidirectional switch designs: a simulation study.

BACKGROUND: Due to identifiability problems, statistical inference about treatment-by-period interactions has not been discussed for stepped wedge designs in the literature thus far. Unidirectional switch designs (USDs) generalize the stepped wedge designs and allow for estimation and testing of treatment-by-period interaction in its many flexible design forms. METHODS: Under different forms of the USDs, we simulated binary data at both aggregated and individual levels and studied the performances of the generalized linear mixed model (GLMM) and the marginal model with generalized estimation equations (GEE) for estimating and testing treatment-by-period interactions. RESULTS: The parallel group design had the highest power for detecting the treatment-by-period interactions. While there was no substantial difference between aggregated-level and individual-level analysis, the GLMM had better point estimates than the marginal model with GEE. Furthermore, the optimal USD for estimating the average treatment effect was not efficient for treatment-by-period interaction and the marginal model with GEE required a substantial number of clusters to yield unbiased estimates of the interaction parameters when the correlation structure is autoregressive of order 1 (AR1). On the other hand, marginal model with GEE had better coverages than GLMM under the AR1 correlation structure. CONCLUSION: From the designs and methods evaluated, in general, parallel group design with a GLMM is, preferred for estimation and testing of treatment-by-period interaction in a clustered randomized controlled trial for a binary outcome.

One-year outcomes of dental implants with a hybrid surface macro-design placed in patients with history of periodontitis: A randomized clinical trial.

AIM: To evaluate the radiological, clinical, and microbiological outcomes of implants with a hybrid surface macro-design in patients with a history of periodontitis. MATERIAL AND METHODS: The study was designed as a 12-month, parallel-arm, randomized controlled trial where patients with a history of treated periodontitis in need of dental implants for single-unit or short-span prosthesis were randomly allocated to a test [implants with a machined titanium surface in the coronal collar (hybrid; HS)] or a control group [conventional implants with moderately rough surface up to the implant shoulder (RS)]. Patients were followed at 3, 6, and 12 months after loading with assessment of radiological, clinical, and microbiological outcomes, as well as patient-related outcome measures (PROMs). RESULTS: Forty patients were randomly assigned to either the RS group (n = 20) or the HS (n = 20) group. At 1 year, the mean marginal bone level changes were 0.22 [standard deviation (SD) 0.36] mm for the HS group and 0.22 (SD 0.29) mm for the RS group, with no significant differences between them (p = .961). Similarly, no significant differences in clinical, microbiological, or PROMs were observed between groups. CONCLUSIONS: HS implants demonstrated radiographic, clinical, and microbiological characteristics equal to RS implants in patients with a history of periodontitis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (identifier NCT05010382).

Towards precision home visiting: results at six months postpartum from a randomized pilot implementation trial to assess the feasibility of a precision approach to Family Spirit.

BACKGROUND: Shared implementation challenges at scale in early childhood home visiting have led researchers to explore precision home visiting as a promising service delivery mechanism to better address families' unique needs and build greater program efficiencies. This randomized controlled pilot study aimed to assess the acceptability of a precision approach to one home visiting model, Family Spirit® and explore potential differences between Precision Family Spirit (PFS) and Standard Family Spirit (Standard FS) on participant-home visitor relationship and maternal outcomes. METHODS: Participants (N = 60) were at least 14 years old, pregnant or within 2 months postpartum, and enrolled in Family Spirit. Four sites in Michigan were randomized 1:1 to deliver PFS (up to 17 core lessons plus up to 13 additional lessons as needed) or Standard FS (home visiting services as usual). Primary (program acceptability, participant satisfaction, home visitor-participant relationship quality, retention, adherence) and secondary (knowledge, quality of life, difficulty with parenting problems, substance use, depression, stress) outcomes at 6 months postpartum are presented. PFS participants also self-reported on quality of life, difficulty with parenting problems, stress, substance use, and concerns with sexual and reproductive health and self and child's nutrition status at each home visit. This informed which lessons they should receive. RESULTS: Mothers in both groups reported positive program acceptability, satisfaction, and home visitor-participant relationships at 6 months postpartum. However, open-ended feedback from Standard FS participants indicates that some lesson content may not be applicable to all participants. At 6 months, retention was 82.3% for PFS and 66.7% for Standard FS, and adherence was 30.1% for PFS and 20.6% for Standard FS. CONCLUSIONS: Preliminary findings indicate that precision home visiting may be acceptable and feasible. A definitive trial is needed to build on this pilot data, assess outcomes for mothers and children participating in a precision approach to home visiting as compared to standard home visiting, and ready this approach for scale. TRIAL REGISTRATION: ClinicalTrials.gov NCT03975530 (first posted on 05/06/2019).

A Randomized Trial of Specialty Mental Health Probation: Measuring Implementation and Effectiveness Outcomes.

Although the research on specialty mental health probation (SMHP) is promising, there have been no randomized controlled trials (RCT) of the prototypical model advanced in the research literature and little focus on SMHP implementation. This study assesses the adoption of SMHP in two counties and examines its impact on mental health and criminal justice outcomes. Researchers conducted a RCT within a hybrid implementation-effectiveness study to examine intervention adoption as well as mental health treatment engagement and criminal justice outcomes for 100 individuals with serious mental illnesses on probation in one rural and one urban county in a southeastern state. Randomization produced equivalent treatment (n = 47) and control (n = 53) groups with no statistically significant differences between groups on demographic or background characteristics. Compared to standard probation officers, SMHP officers addressed the mental health needs of individuals with serious mental illness (i.e., adoption) at higher rates (p < 0.001). Compared to individuals on standard caseloads, individuals on SMHP had a higher rate of mental health engagement (e.g., mental health assessment, attending treatment appointment; p < 0.050); however, more individuals on SMHP caseloads had a new crime violation during follow-up compared with individuals on standard caseloads (p < 0.01). In conclusions, results suggest successful adoption of the intervention and increased mental health engagement among those on SMHP caseloads. Results are consistent with the mixed findings on the impact of SMHP on improving criminal justice outcomes.

Outcomes of Implementing in the Real World the Women's Health CoOp Intervention in Cape Town, South Africa.

Women in South Africa living with HIV who use alcohol may not adhere to ART, affecting the country's 90-90-90 targets. The Women's Health CoOp (WHC), a woman-focused HIV intervention, has shown efficacy in numerous trials with key populations of women in South Africa who use alcohol and drugs. In a hybrid implementation effectiveness study, the WHC was implemented in usual care clinics by healthcare providers in a modified stepped-wedge design. We present the outcomes of alcohol use and ART adherence with 480 women, with a 95% 6-month follow-up rate across 4 implementation cycles. Compared with the first cycle, women in the fourth cycle were significantly less likely (OR = 0.10 [95% CI 0.04, 0.24]) to report alcohol use disorder risk and were 4 times more likely (OR = 4.16 [95% CI 1.05, 16.51]) to report ART adherence at 6-month follow-up. Overall, acceptability and satisfaction were extremely high. The WHC intervention was successful in reaching key populations of women to reduce alcohol use and increase ART adherence, which is essential for South Africa to reach the 90-90-90 goals.

Process evaluation of the implementation of a decision support system to prevent and treat disease-related malnutrition in a hospital setting.

BACKGROUND: Malnutrition is present in 30% of hospitalized patients and has adverse outcomes for the patient and the healthcare system. The current practice for nutritional care is associated with many barriers. The MyFood decision support system was developed to prevent and treat malnutrition. METHODS: This paper reports on a process evaluation that was completed within an effectiveness trial. MyFood is a digital tool with an interface consisting of an app and a website. MyFood includes functions to record and evaluate dietary intake. It also provides reports to nurses, including tailored recommendations for nutritional treatment. We used an effectiveness-implementation hybrid design in a randomized controlled trial. The RE-AIM (Reach, Efficiency, Adoption, Implementation, Maintenance) framework was used to perform a process evaluation alongside the randomized controlled trial, using a combination of quantitative and qualitative methods. An implementation plan, including implementation strategies, was developed to plan and guide the study. RESULTS: Reach: In total, 88% of eligible patients consented to participate (n = 100). Adoption: Approximately 75% of the nurses signed up to use MyFood and 50% used the reports. IMPLEMENTATION: MyFood empowered the patients in their nutritional situation and acted as a motivation to eat to reach their nutritional target. The compliance of using MyFood was higher among the patients than the nurses. A barrier for use of MyFood among the nurses was different digital systems which were not integrated and the log-in procedure to the MyFood website. Despite limited use by some nurses, the majority of the nurses claimed that MyFood was useful, better than the current practice, and should be implemented in the healthcare system. CONCLUSIONS: This study used a process evaluation to interpret the results of a randomized controlled trial more in-depth. The patients were highly compliant, however, the compliance was lower among the nurses. MyFood empowered the patients in their nutritional situation, the usability was considered as high, and the experiences and attitudes towards MyFood were primarily positive. Focus on strategies to improve the nurses' compliance may in the future improve the MyFood system's potential. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov 26/01/2018 ( NCT03412695 ).

Population-level rhythms in human skin with implications for circadian medicine.

Skin is the largest organ in the body and serves important barrier, regulatory, and sensory functions. The epidermal layer shows rhythmic physiological responses to daily environmental variation (e.g., DNA repair). We investigated the role of the circadian clock in the transcriptional regulation of epidermis using a hybrid experimental design, in which a limited set of human subjects (n = 20) were sampled throughout the 24-h cycle and a larger population (n = 219) were sampled once. We found a robust circadian oscillator in human epidermis at the population level using pairwise correlations of clock and clock-associated genes in 298 epidermis samples. We then used CYCLOPS to reconstruct the temporal order of all samples, and identified hundreds of rhythmically expressed genes at the population level in human epidermis. We compared these results with published time-series skin data from mice and found a strong concordance in circadian phase across species for both transcripts and pathways. Furthermore, like blood, epidermis is readily accessible and a potential source of biomarkers. Using ZeitZeiger, we identified a biomarker set for human epidermis that is capable of reporting circadian phase to within 3 hours from a single sample. In summary, we show rhythms in human epidermis that persist at the population scale and describe a path to develop robust single-sample circadian biomarkers.

Effects of maternal and fetal vascular endothelial growth factor a single nucleotide polymorphisms on pre-eclampsia: A hybrid design study.

Maternal and fetal gene variants play important roles in the pathology of pre-eclampsia (PE), but most studies investigating the associations between vascular endothelial growth factor A (VEGF-A) gene variates and PE focusing on maternal genetic effects. The present study firstly used a hybrid case-parent and control-mother study design investigating the both maternal and fetal effects of VEGF-A gene polymorphisms on PE among Han Chinese pregnant women. This study recruited 221 PE patients with their partners and infants and 345 normotensive women with their infants. The current study found that, in both maternal and fetal dominant model (GC + CC/GG), VEGF-A rs2010963 polymorphism was associated with an increased risk of PE (OR = 1.85, 95% CI: 1.25-2.75; OR = 1.90, 95% CI: 1.28-2.83, respectively). In the log-liner model analyses, offspring carrying the genotype of GC or CC in the rs2010963 polymorphism could increase the risk of maternal PE (OR = 1.84, 95%CI: 1.18-2.86; OR = 1.89, 95%CI: 1.02-3.49, respectively) compared to the offspring with GG. Meanwhile, the present study also found that passive smoking had a significant interaction with maternal rs2010963 polymorphism (PLRT = 0.022) on the risk of PE.

Development and evaluation of an eHealth self-management intervention for patients with chronic kidney disease in China: protocol for a mixed-method hybrid type 2 trial.

BACKGROUND: Chronic kidney disease (CKD) is a significant public health concern. In patients with CKD, interventions that support disease self-management have shown to improve health status and quality of life. At the moment, the use of electronic health (eHealth) technology in self-management interventions is becoming more and more popular. Evidence suggests that eHealth-based self-management interventions can improve health-related outcomes of patients with CKD. However, knowledge of the implementation and effectiveness of such interventions in general, and in China in specific, is still limited. This study protocol aims to develop and tailor the evidence-based Dutch 'Medical Dashboard' eHealth self-management intervention for patients suffering from CKD in China and evaluate its implementation process and effectiveness. METHODS: To develop and tailor a Medical Dashboard intervention for the Chinese context, we will use an Intervention Mapping (IM) approach. A literature review and mixed-method study will first be conducted to examine the needs, beliefs, perceptions of patients with CKD and care providers towards disease (self-management) and eHealth (self-management) interventions (IM step 1). Based on the results of step 1, we will specify outcomes, performance objectives, and determinants, select theory-based methods and practical strategies. Knowledge obtained from prior results and insights from stakeholders will be combined to tailor the core interventions components of the 'Medical Dashboard' self-management intervention to the Chinese context (IM step 2-5). Then, an intervention and implementation plan will be developed. Finally, a 9-month hybrid type 2 trial design will be employed to investigate the effectiveness of the intervention using a cluster randomized controlled trial with two parallel arms, and the implementation integrity (fidelity) and determinants of implementation (IM step 6). DISCUSSION: Our study will result in the delivery of a culturally tailored, standardized eHealth self-management intervention for patients with CKD in China, which has the potential to optimize patients' self-management skills and improve health status and quality of life. Moreover, it will inform future research on the tailoring and translation of evidence-based eHealth self-management interventions in various contexts. TRIAL REGISTRATION: Clinicaltrials.gov NCT04212923 ; Registered December 30, 2019.

The Connectedness of Mental Health Providers Referring Patients to a Treatment Study for Post-Traumatic Stress: A Social Network Study.

We conducted a process evaluation in the context of a Hybrid Type 1 randomized controlled trial testing two treatments for post-traumatic stress, using a web-based social network survey and semi-structured interviews to illustrate the relationship between providers' influence and likelihood of referring patients to the RCT. Providers with high indegree centrality (designated by other providers as someone they seek information from) were significantly more likely to refer patients to the RCT, and serve as an influence to others' referral behavior. Interviews provided additional data to consider for future studies aimed at increasing the uptake of evidence-based practices.

Challenges and solutions in the design and execution of the PROSPECT Phase II/III neoadjuvant rectal cancer trial (NCCTG N1048/Alliance).

BACKGROUND: More than half of the 40,000 incident rectal cancer patients in the United States each year are diagnosed at clinical stage II and III (locally advanced stage). For this group, high rates of cure can be achieved with the combination of pelvic radiation and sensitizing 5-fluorouracil (chemoradiation), surgery and chemotherapy, but treatment is long, arduous and toxicities are substantial. The PROSPECT trial (N1048, NCT01515787) was designed to determine whether neoadjuvant chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX) could be used as an alternative to neoadjuvant chemoradiation without compromising treatment outcomes and to spare these patients excess toxicity. The statistical design balanced the twin co-primary goals of achieving low local and distant recurrence rates. Study design features contended with the need for stringent safeguards given limited phase II data, the need for straightforward criteria to facilitate both accrual and protocol fidelity and the importance of patients' perspectives on symptom burden and treatment toxicity. METHODS: PROSPECT is an ongoing multi-site two-group seamless phase II/III randomized trial comparing standard neoadjuvant chemoradiation versus neoadjuvant chemotherapy with selective use of chemoradiation for patients with locally advanced rectal cancer. Challenges addressed in the design and conduct of PROSPECT have included the following: (1) setting safety thresholds given limited single-center phase II data, (2) establishing workable eligibility criteria, (3) balancing competing time to local and distant recurrence as co-primary endpoints and (4) obtaining reliable and complete data for patients' symptom burden. The design and implementation challenges, choices, modifications and their implications for the design of future national cooperative group clinical trials are presented. RESULTS: PROSPECT incorporated stringent thresholds for both complete surgical resection (R0) and the time to local recurrence as early stopping rules. When predetermined stopping criteria were not met after evaluation of the first 366 participants in the randomized phase II, the study transitioned seamlessly to phase III with cumulative accrual of over 1000 participants. Eligibility criteria stipulating rectal tumor location based on distance from the anal verge were unworkable, and the protocol was amended to a more pragmatic approach that assigned surgeons with primary responsibility for determining eligibility. Central radiology review was feasible and in some cases prompted discontinuation of protocol treatment. Participation in toxicity reporting using the National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events was uniformly high and was well accepted by participants from over 200 sites in the United States, Canada and Switzerland. CONCLUSION: The strategies used to overcome these obstacles may inform the design of other studies that involve multi-modality treatment interventions, particularly trials where implementation of consistent criteria for eligibility and outcomes across hundreds of practice settings is necessary.