Calculating Expected Value of Sample Information Adjusting for Imperfect Implementation

Background The expected value of sample information (EVSI) calculates the value of collecting additional information through a research study with a given design. However, standard EVSI analyses do not account for the slow and often incomplete implementation of the treatment recommendations that follow research. Thus, standard EVSI analyses do not correctly capture the value of the study. Previous research has developed measures to calculate the research value while adjusting for implementation challenges, but estimating these measures is a challenge. Methods Based on a method that assumes the implementation level is related to the strength of evidence in favor of the treatment, 2 implementation-adjusted EVSI calculation methods are developed. These novel methods circumvent the need for analytical calculations, which were restricted to settings in which normality could be assumed. The first method developed in this article uses computationally demanding nested simulations, based on the definition of the implementation-adjusted EVSI. The second method is based on adapting the moment matching method, a recently developed efficient EVSI computation method, to adjust for imperfect implementation. The implementation-adjusted EVSI is then calculated with the 2 methods across 3 examples. Results The maximum difference between the 2 methods is at most 6% in all examples. The efficient computation method is between 6 and 60 times faster than the nested simulation method in this case study and could be used in practice. Conclusions This article permits the calculation of an implementation-adjusted EVSI using realistic assumptions. The efficient estimation method is accurate and can estimate the implementation-adjusted EVSI in practice. By adapting standard EVSI estimation methods, adjustments for imperfect implementation can be made with the same computational cost as a standard EVSI analysis. Highlights Standard expected value of sample information (EVSI) analyses do not account for the fact that treatment implementation following research is often slow and incomplete, meaning they incorrectly capture the value of the study. Two methods, based on nested Monte Carlo sampling and the moment matching EVSI calculation method, are developed to adjust EVSI calculations for imperfect implementation when the speed and level of the implementation of a new treatment depends on the strength of evidence in favor of the treatment. The 2 methods we develop provide similar estimates for the implementation-adjusted EVSI. Our methods extend current EVSI calculation algorithms and thus require limited additional computational complexity.

The Impact of Delayed Symptomatic Treatment Implementation in the Intensive Care Unit

We estimated the harm related to medication delivery delays across 12,474 medication administration instances in an intensive care unit using retrospective data in a large urban academic medical center between 2012 and 2015. We leveraged an instrumental variables (IV) approach that addresses unobserved confounds in this setting. We focused on nurse shift changes as disruptors of timely medication (vasodilators, antipyretics, and bronchodilators) delivery to estimate the impact of delay. The average delay around a nurse shift change was 60.8 min (p < 0.001) for antipyretics, 39.5 min (p < 0.001) for bronchodilators, and 57.1 min (p < 0.001) for vasodilators. This delay can increase the odds of developing a fever by 32.94%, tachypnea by 79.5%, and hypertension by 134%, respectively. Compared to estimates generated by a naïve regression approach, our IV estimates tend to be higher, suggesting the existence of a bias from providers prioritizing more critical patients.

How Engaged are Stakeholders in Evidence-Based Treatment Implementation Projects? Results From a Scoping Review of Children’s Mental Health Treatment Projects

Engaging stakeholders in child mental health evidence-based treatment (EBT) implementation projects may increase the likelihood of successful implementation; However, little is known about the extent of stakeholder engagement to inform the implementation of EBTs. We conducted a scoping review to characterize stakeholder engagement in child mental health EBT implementation projects. We performed data extraction and synthesis to describe key study and stakeholder characteristics, stakeholder engagement methods and rationales, reported impacts of stakeholder engagement, and quality of reporting on stakeholder engagement. We identified a total of 103 unique child mental health EBT implementation projects. The largest number of projects were in the United States and conducted in community mental health settings. Most projects engaged EBT providers during the active implementation phase and with limited depth, often gathering information from stakeholders about barriers and facilitators without sharing decision-making power. Across projects, impacts of stakeholder engagement spanned all implementation outcomes. Given that stakeholder engagement is often shallow and follows initial implementation efforts, additional effort should be made to increase engagement to preempt challenges to EBT implementation and ensure implementation success. Such efforts may ensure the just distribution of power in EBT implementation efforts and could be essential in addressing mental health disparities.

Effect of Reperfusion Therapies on Incidence of Early Post-Stroke Seizures

Objective: This study aimed to determine the effect of reperfusion therapies on the occurrence of early post-stroke seizures (PSS) in patients with acute ischemic stroke (AIS).Background: Reperfusion therapies are paramount to the treatment of stroke in the acute phase. However, their effect on the incidence of early seizures after an AIS remains unclear.Design and Methods: The stroke database at Hamad Medical Corporation was used to identify all patients who received reperfusion therapies for AIS from 2016 to 2019. They were matched with patients of similar diagnosis, gender, age, and stroke severity as measured by National Institutes of Health Stroke Scale (NIHSS) who did not receive such treatment. The rates of early PSS were calculated for each group.Results: The results showed that 508 patients received reperfusion therapies (342 had IV thrombolysis only, 70 had thrombectomies only, and 96 had received both), compared with 501 matched patients receiving standard stroke unit care. Patients who received reperfusion therapies were similar to their matched controls for mean admission NIHSS score (9.87 vs. 9.79; p = 0.831), mean age (53.3 vs. 53.2 years; p = 0.849), and gender distribution (85 vs. 86% men; p = 0.655). The group receiving reperfusion therapies was found to have increased stroke cortical involvement (62 vs. 49.3%, p &lt; 0.001) and hemorrhagic transformation rates (33.5 vs. 18.6%, p &lt; 0.001) compared with the control group. The rate of early PSS was significantly lower in patients who received reperfusion therapies compared with those who did not (3.1 vs. 5.8%, respectively; p = 0.042). When we excluded seizures occurring at stroke onset prior to any potential treatment implementation, the difference in early PSS rates between the two groups was no longer significant (2.6 vs. 3.9%, respectively; p = 0.251). There was no significant difference in early PSS rate based on the type of reperfusion therapy either (3.2% with thrombolysis, 2.9% with thrombectomy, and 3.1% for the combined treatment, p = 0.309).Conclusions: Treatment of AIS with either thrombectomy, thrombolysis, or both does not increase the risk of early PSS.

A multidisciplinary approach to the comprehensive treatment of edentulous patients with perioral wrinkles of the skin

Objectives: The purpose of this study was to comparative analysis of effectiveness of isolated use of intradermal injections of modified hyaluronic acid (Hyalorepair 04) and its combination with platelet-rich autologous plasma in edentulous patients with perioral wrinkles of the skin. Materials and Methods: A total of 56 patient’s presence of perioral wrinkles of the skin participate in the study after dental implant prosthodontics rehabilitations. They were randomly divided into 2 groups in accordance with the applied therapy method (29 isolated implementation of modified hyaluronic acid bio-repairing and 27 bio-repairing combined with autologic plasmotherapy). Treatment included implant-prosthetic rehabilitation followed by hyaluronic acid injections in order to correct cheek-zygomatic sulcus, nasolabial folds and marionette wrinkles. Preparations in an amount from 1 to 4 ml were injected into the face area, depending on the zones to be corrected at the request of the patients. Results: The complex treatment restored the aesthetic profile of the face and oral cavity and increased the effectiveness of the chewing function. On M03 and M05, 2/3 of patients had significant improvement as assessed by physician and patient according to GAIS. Most of the patients also showed significant improvement at visit M12. Conclusion: A multidisciplinary approach to the treatment of edentulous patients with perioral wrinkles increases the functional and aesthetic effect of the treatment. Implementation of combined of bioreparation and autologous plasmotherapy is significantly more effective comparatively to the isolated implementation of modified hyaluronic acid. Keywords: Facial Esthetic; Implant-Prosthetic Rehabilitation; Hyaluronic Acid

The Impact of Integrated Support and Context on Treatment Implementation and Child Outcomes Following Behavioral Consultation

Assuring treatment plan implementation following consultation is critically important because implementation is strongly related to outcomes. Treatment implementation has been hypothesized to be influenced by both the nature of the follow-up support provided and contextual variables. However, studies to date have not examined both issues while directly measuring implementation. This study examined treatment implementation following consultation for 48 teachers in public schools who had referred a student for intervention services in a randomized clinical field trial. Participating teachers in the experimental group received Integrated Support (IS). IS includes social influence, planning, and performance feedback elements. IS was compared to weekly follow-up meetings alone. Treatment implementation and child outcomes were markedly superior for IS as compared to weekly follow-up. Three school climate factors were found to be correlated with treatment implementation for the IS group, but not the weekly follow-up group. Participants rated treatment implementation, treatment acceptability, and consultant effectiveness positively and similarly across conditions. The implications of these findings for future work examining school culture, consultation and intervention are discussed.

Characterization of HIV-1 Epidemic in Kyrgyzstan

Kyrgyzstan has one of the highest rates of HIV-1 spread in Central Asia. In this study, we used molecular–epidemiological approaches to examine the HIV-1 epidemic in Kyrgyzstan. Samples were obtained from HIV-positive individuals who visited HIV/AIDS clinics. Partial pol gene sequences were used to identify HIV-1 subtypes and drug resistance mutations (DRMs) and to perform phylogenetic analysis. Genetic diversity and history reconstruction of the major HIV-1 subtypes were explored using BEAST. This study includes an analysis of 555 HIV-positive individuals. The study population was equally represented by men and women aged 1–72 years. Heterosexual transmission was the most frequent, followed by nosocomial infection. Men were more likely to acquire HIV-1 during injection drug use and while getting clinical services, while women were more likely to be infected through sexual contacts (p &lt; 0.01). Heterosexual transmission was the more prevalent among individuals 25–49 years old; individuals over 49 years old were more likely to be persons who inject drugs (PWID). The major HIV-1 variants were CRF02_AG, CRF63_02A, and sub-subtype A6. Major DRMs were detected in 26.9% of the study individuals; 62.2% of those had DRMs to at least two antiretroviral (ARV) drug classes. Phylogenetic analysis revealed a well-defined structure of CRF02_AG, indicating locally evolving sub-epidemics. The lack of well-defined phylogenetic structure was observed for sub-subtype A6. The estimated origin date of CRF02_AG was January 1997; CRF63_02A, April 2004; and A6, June 1995. A rapid evolutionary dynamic of CRF02_AG and A6 among Kyrgyz population since the mid-1990s was observed. We observed the high levels of HIV-1 genetic diversity and drug resistance in the study population. Complex patterns of HIV-1 phylogenetics in Kyrgyzstan were found. This study highlights the importance of molecular–epidemiological analysis for HIV-1 surveillance and treatment implementation to reduce new HIV-1 infections.

Sustainability and clinical outcomes of routine screening for pathogenic DPYD gene variants prior to fluoropyrimidine (FP) chemotherapy for gastrointestinal (GI) cancer.

216 Background: Dihyropyrimidine dehydrogenase (DPD) deficiency is present in 3-5% of patients, and is associated with substantially increased risk of severe and/or fatal toxicity during standard-dose FP chemotherapy. Genotyping of pathogenic DPYD variants is a readily available screening test for DPD deficiency, and prospective studies show that dose-reduced FP chemotherapy can be used safely in heterozygous DPYD variant carriers. Methods: Following a sentinel toxicity event the GI medical oncology group at the Norris Cotton Cancer Center adopted a shared practice of routine screening for pathogenic DPYD gene variants prior to FP chemotherapy (5-FU or capecitabine). Screening procedures involved physicians, NP/PAs, nurses, pharmacists, and schedulers. Testing was completed at a send-out lab until late 2020, when an in-house test became available. The current test panel evaluates for 3 gene variants: c.1905+1G > A (*2A), c.1679T > G (*13), and c.2846A > T. We report on the sustainability and clinical outcomes of DPYD gene variant screening. We identified all patients starting new FP-containing intravenous chemotherapy regimens (e.g., FOLFOX, CAPOX) for treatment of GI cancer at two sites (LEB & STJ) between Jan. 2019 and May 2021. We used electronic medical records to evaluate for completion of DPYD genotyping, and we describe the prevalence and management of DPYD gene variant carriers. Results: We identified 333 patients starting FP-containing chemotherapy regimens during the study period, including 287 patients without prior history of FP chemotherapy. Screening with DPYD genotyping was completed in 228 of 287 eligible patients (79%). Screening rates increased from 34% in Q1 of 2019 to 90% in Jan-May 2021. Five GI oncology sub-specialists accounted for 89% of screen-eligible patients and 96% of completed tests, but 10 unique physicians ordered ≥1 test. Of 228 screened patients, six (2.6%) were heterozygous carriers of pathogenic DPYD gene variants (*2A [2 patients], *13 [1], and c.2846A > T [3]). Variant carriers started FP chemotherapy with a 33-50% reduction. Two of six patients required further dose reduction due to FP-related toxicity (grade 4 neutropenia, grade 3 diarrhea). All evaluable variant carriers completed planned initial treatment. Implementation challenges included variable insurance coverage of DPYD genotyping, site-specific test ordering and reporting processes, and inconsistent turn-around time for send-out testing (resolved with on-site testing). Conclusions: Routine screening for pathogenic DPYD gene variants prior to FP chemotherapy is feasible and sustainable in the U.S. DPYD genotyping coupled with chemotherapy dose reductions for DPYD variant carriers facilitates safe and timely completion of planned chemotherapy treatments.

Cholbam® and Zellweger spectrum disorders: treatment implementation and management

Background Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired peroxisomal formation, and/or defective peroxisomal functioning. In the absence of functional peroxisomes, bile acid synthesis is disrupted, and multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle, eyes, ears, and nervous system. Main body Liver disease may play an important role in morbidity and mortality, with hepatic fibrosis that can develop as early as the postnatal period and often progressing to cirrhosis within the first year of life. Because hepatic dysfunction can have numerous secondary effects on other organ systems, thereby impacting the overall disease severity, the treatment of liver disease in patients with ZSD is an important focus of disease management. Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders. This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population. Conclusions Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD. Due to the systemic impacts of hepatic damage, Cholbam should be initiated in patients without signs of advanced liver disease.